text stringlengths 8 5.77M |
|---|
Obama should just say 'I was wrong' on health insurance pledge
President Obama delivers remarks at an Organizing for Action "Obamacare Summit" at the St. Regis Hotel in Washington on Monday.
President Obama delivers remarks at an Organizing for Action "Obamacare Summit" at the St. Regis Hotel in Washington on Monday. (Ron Sachs / MCT)
Jon Healey
Denis Healey, a former Labor Party leader and high-ranking official in Britain, famously said on the floor of Parliament in 1983, "The first law of holes is that when one is in a hole, one should stop digging."
Too bad no one in the Obama administration seems to have taken that piece of advice to heart.
Critics of the 2010 Affordable Care Act have battered President Obama in recent weeks over the wave of health insurance policies canceled because they didn't meet the law's standards. The cancellations belied Obama's frequent assertions that no one would be forced by the new law to change insurance plans or doctors. As he put it in June 2010: "If you like your healthcare plan, you'll be able to keep your healthcare plan. Period."
But that wasn't true then, and it isn't true now. The standards in the law were designed to eliminate policies that either provided too little protection against financial ruin or divided policyholders into narrow risk pools to the detriment of people with greater risks or more expensive medical needs. The goal was to make the market for individual policies function like the one for large groups, where coverage tends to be cheaper and premiums less volatile.
On Monday night, Obama revised his pledge, changing the "period" into an "asterisk." Speaking to a gathering of Affordable Care Act supporters, he talked about the shortcomings in the individual market up to now -- the policies with numerous exclusions hidden in the fine print, the annual cancellations and double-digit premium increases, the frequent denials of coverage based on preexisting conditions.
"Now, if you have or had one of these plans before the Affordable Care Act came into law and you really like that plan, what we said was you could keep it if it hasn’t changed since the law was passed. So we wrote into the Affordable Care Act you’re grandfathered in on that plan," Obama said. "But if the insurance company changes it, then what we're saying is they’ve got to change it to a higher standard. They’ve got to make it better. They’ve got to improve the quality of the plan that they’re selling. That’s part of the promise that we made too.
"That’s why we went out of our way to make sure that the law allowed for grandfathering, but if we had allowed these old plans to be downgraded or sold to new enrollees once the law had already passed, then we would have broken an even more important promise -- making sure that Americans gain access to healthcare that doesn’t leave them one illness away from financial ruin."
Funny, but Obama never mentioned the grandfathered-policy rule when making his "you can keep it" pledge. Nor did insurers work hard to keep the same policies available; instead, as Obama himself noted, they quickly whittled the supply of grandfathered plans by canceling some of them and changing others enough to disqualify them. And besides, even grandfathered policies have to comply with the law's ban on annual and lifetime benefit limits by Jan. 1. That ban rules out many cheaper plans that capped their payouts.
Beyond that, Obama's explanation oversimplifies the point of the standards. Many perfectly good insurance policies are being eliminated because they fall short on one or more of the law's 10 essential benefit requirements. For example, more than 60% of the individual policies sold in 2011 did not include coverage for maternity care. If the policyholder is a man or a woman beyond childbearing age, that coverage gap poses no financial risk whatsoever.
So why eliminate such policies? Because, as The Times' editorial board argued last week, they perpetuate the industry's practice of cherry-picking customers and avoiding risk. The law's insurance reforms are designed to spread risk and costs more broadly across the individual market, as they are in the policies offered by large employers. Those with no reason to worry about pregnancy subsidize those with no fear of prostate cancer, and vice versa.
Not surprisingly, Obama's revised version of "you can keep it" drew brickbats from critics on the right -- and rebuttals from mainstream outlets. How hard would it have been for him just to say he was wrong?
(And just in case anyone's wondering, Denis Healey and I do not share bloodlines.) |
For his contribution to the development of catalysts in the chemical industry, compounds to accelerate reactions between molecules, the Spanish chemist Avelino Corma (Moncofa, Castellón, 1951) will receive, on October 24, the Prince of Asturias Award for Technical and Scientific Research, to be shared with the Americans Mark E. Davis and Galen D. Stucky. A member of the prestigious Royal Society of London and founder of the Institute of Chemical Technology (ITQ), a collaborative center of the Spanish National Research Council (CSIC) and the Polytechnic University of Valencia, Corma is the most cited Spanish scientist in his field thanks to more than 900 publications in international journals and 150 patents. As the creator of zeolites, micro-porous structures useful in the refining processes, and of applications in the field of renewable energy, his investigations fall within the framework of green chemistry, in search of greater efficiency by reducing energy consumption and the production of waste.
Question. In May, the choice for the Prince of Asturias Award for Technical and Scientific Research was announced. How did you welcome the news?
Answer. It produced surprise and excitement at the same time. There are many people who deserve it and, therefore, the chances of it being awarded to me were not so high. This is not just recognition for me, but also for the research team and the work we have done and for what we have believed in all these years. The jury considered that we have contributed significantly to the development of science and, at the same time, we have showed the ability to transfer knowledge to industrial processes that are operating today and competing with the best in the world.
Q. Your scientific career trajectory can be described as transitional, by your research dedicated to the fields of conventional energy sources and renewables.
A. I work in both fields by conviction, because I try to be realistic. Over a period of time, ten to twenty years or more, we will continue to rely on fossil fuels, but I hope that less and less over time. We must achieve the greatest efficiency in their use so that they last longer and we can produce the same amount of energy while emitting the least CO 2 . Using fossil fuels buys us time to be able to develop alternative and sustainable sources of energy that will shape our future. Therefore, I am forced to do the best I can with what we have and at the same time open up new sources of energy.
Q. The award recognizes your contribution to the development of catalysts, materials that increase the rate of a molecular reaction leading to the formation of a desired product, on which you are now working to develop their multifunctional capabilities.
A. In most molecular reactions, not only is the desired product generated, but other by-products as well. “The great magic” of the catalyst, so to speak, is directing the reaction to the product we want with the ultimate goal of achieving 100% selectivity. In some processes, we have exceeded 99%. There are some processes that are carried out in several stages before reaching the desired product, with each intermediate product needing purification and requiring equipment and energy. A multifunctional catalyst has the ability of turning the reactant into the desired final product without the need of separations or reactions involving intermediate products. All functions are brought together in a single catalyst and in one process. We have two industrial applications based on this type of catalyst, in processes that used to generate a quantity of by-product greater than the amount of final product, while now the by-product represents one hundredth of the desired final product. One of them has been applied in the field of fragrances for a Spanish company and another one, that is applied in the purification of natural gas to reduce the amount of sulfur parts per billion (ppb) with a very high efficiency, is already used in a dozen plants around the world.
Q. Your research is framed within green chemistry. Will this be the chemistry of the future?
A. The future will be getting product A to react to obtain product B so that we obtain only that product B while consuming the least amount of energy possible. This is the chemistry of the future. The key word is selectivity, to direct the desired product with the ultimate goal of achieving 100%, that is, with zero by-products. Right now many of the by-products are transformed in order to be useful and others are decomposed so that the final product does not have any environmental impact. Chemistry is nothing more than a way to generate new molecules and what we want is to generate fewer and fewer by-products. We cannot ignore the chemistry. Without it we would not be where we are, nor would we have the hope and that quality of life that we have.
Q. Other projects of your team of researchers are dedicated to the implementation of catalysts in the field of renewable energy from biomass and photovoltaics, as well as contributing to medical treatments for diseases such as cancer.
A. For their medical applications, we study the achieved materials in order to explore their possibilities. For example, observing whether they can serve as a vehicle to distribute molecules –in this case curative pharmaceutical products– that already exist or have been discovered. With regard to renewable sources, in the case of solar energy we are working on two lines of research: the rupture of water molecules to produce hydrogen and the transformation of CO 2 to obtain renewable hydrocarbons. We also study the transformation of biomass to produce liquid fuels and to form “building blocks”, i.e. molecules, to be used in chemical processes.
Q. At the beginning of your scientific career, Spain began to experience the rise of the chemical industry. How has the industry evolved so far?
A. It’s very different. Europe decided at some point that companies that could be “contaminating” would have to install their productions elsewhere. Nowadays they have realized that we cannot live only from tourism, trading and banking, but we also have to produce and they have begun to consider that chemical companies will have to be set up too. The level of improvement in the chemical industry has been incredible from the early days until now, with more controls and regulations. We must overcome the European hypocrisy that by not manufacturing we do not emit CO 2 , thereby meeting the 2020 targets. As we import many industrial goods, other countries emit the CO 2 from production, so that global CO 2 emissions do not decrease.
Q. A recent report of the Intergovernmental Panel on Climate Change raised the alarm about CO2 emissions by pointing out that, far from diminishing, the greenhouse gas effect is even greater. What has gone wrong?
A. What is failing in a certain way is our model of energy production. We have not managed to massively use competitive renewable energies, so we have to continue using mainly coal, oil and natural gas. It is remarkable that the country that will meet the Kyoto Protocol without having signed it is the United States, not because it will consume less power, but rather because some of the production that uses coal will begin using natural gas from fracking to generate energy. Natural gas has a ratio of carbon to hydrogen that is substantially lower than coal, which means it will produce less CO 2 to produce the same amount of energy. If gas demand is high, it is going to be difficult to prevent the exploitation of those resources, unless political measures are adopted. Therefore, if they are finally used it should be done keeping a minimum or zero impact on people and the environment. The important thing is to devote effort and work to develop alternative sources of competitive energy, which are the key to the future. They will not be free and we will have to be willing to pay for them if we want to pass on a better world to our children and grandchildren.
Q. Your formative period was developed between Valencia, Madrid and Canada, but you decided to stay in Spain. Have you ever been tempted to work overseas?
A. When I was in Canada I received three offers from McGill University in Montreal, from Queen’s and from a major company in Akron, Ohio, but I wanted to go back and try to return to the country which had given so much to me, because I studied with scholarships. The beginning was very hard because I had no more than a table, a chair, paper, pencils and the library. My early work was not experimental but reinterpretation of data already published, opening a new line of thought on the mechanisms of catalytic cracking. Later I had opportunities to leave, but by then my team was forming, and that gave me a lot of encouragement to stay in Spain.
Q. The fruit of that work was the creation of the Institute of Chemical Technology.
A. We started with 12 researchers and now we are 180, 80 of whom were hired thanks to the resources we generate abroad. 20 leading companies in the sector work with us. They are domestic companies and from Europe and United States, and they also hire people trained in our center. We must break the dichotomy between applied work and fundamental research, because the competitive companies with high technological levels have development centers that carry out first-line fundamental research to generate knowledge.
Q. You have authored more than 150 patents, many of them in collaboration with companies. What is the level of patent creation in Spain?
A. Interestingly, in Spain the patent generation level is higher in universities than in firms, excluding the extensions of patents arising from overseas. Another issue is the practical value of these patents, if they really have deep meaning for their application or protection.
Discovery comes first. After that, experts are required to patent writing and planning. These experts’ role is trying to minimize risks associated to attacks from competing companies.
Ventana al Conocimiento (Knowledge Window)
By Kristin Suleng for OpenMind |
OBITUARY: Shirley Jean Hufford, 72
Shirley Jean Hufford of Ocean View, DE, formerly of Smyrna, DE, passed away at the age of 72 years on Sunday, Dec. 16, 2012.
Mrs. Hufford was born June 1, 1940 in Munster Township, PA, one of 12 children of the late Edgar and Arvilla McCloskey.
She moved to Smyrna with her husband and children from Pennsylvania where she raised her family. She then settled in the Ocean View area where she was a self-employed business owner of Sunshine Cleaning Company for many years until her retirement.
Shirley loved playing scrabble, doing crossword puzzles, and reading the Bible. Other hobbies included interior decorating and wall papering.
She also looked forward to going home for family reunions, get togethers with family and friends, and Mass at St. Anne's Church in Ocean View.
In addition to her parents, she was preceded in death by her husband, C. Rodney Hufford; and her sister, Anne Burke.
She is survived by three sons, C. Rodney and his wife Laura of Ocean View, David M. and his wife Celeste of Smyrna, and Bruce A. and his wife Margie of Dover, DE; 14 grandchildren; five great-grandchildren; four sisters, Kathleen, Arvilla, Mary, and Joanne; and six brothers, Edgar, George, Clarence, Joseph, Patrick, and William.
A viewing will be held on Saturday, Dec. 22 from 10 a.m. to 12 noon in the Faries Funeral Chapel, located at 29 S. Main St. in Smyrna, where funeral services will begin at 12 noon.
Burial will follow in Holy Cross Cemetery in Dover.
In lieu of flowers, the family suggests contributions be made to the Food Bank of Delaware, 14 Garfield Way Newark, DE 19713.
Letters of condolence may be sent by visiting www.fariesfuneralhome.com.
Affiliated Delaware Papers
Original content available for non-commercial use under a Creative Commons license, except where noted.
Smyrna/Clayton Sun-Times ~ 24 W. Main St., Middletown, DE 19709 ~ Privacy Policy ~ Terms Of Service |
New test for endothelin receptor type B (EDNRB) mutation genotyping in horses.
Lethal white foal syndrome (LWFS) is an autosomal recessive disease of neonatal foals characterized by a white hair coat and a functional intestinal obstruction. Traditional techniques for identifying the dinucleotide mutation (TC→AG) of the endothelin receptor B gene (EDNRB) associated with LWFS are time-consuming. We developed a new technique based on mutagenically separated polymerase chain reaction (MS-PCR) for simple detection of the EDNRB genotype in horses. |
Viviparity does not affect the numbers and sizes of reptile offspring.
Viviparity (live-bearing) has independently evolved from oviparity (egg-laying) in more than 100 lineages of squamates (lizards and snakes). We might expect consequent shifts in selective forces to affect per-brood reproductive investment (RI = total mass of offspring relative to maternal mass) and in the way in which that output is partitioned (number vs. size of offspring per brood). Based on the assumption that newly born offspring are heavier than eggs, we predicted that live-bearing must entail either increased RI or a reduction in offspring size and/or fecundity. However, our phylogenetically controlled analysis of data on 1,259 squamate species revealed no significant differences in mean offspring size, clutch size or RI between oviparous and viviparous squamates. We attribute this paradoxical result to (1) strong selection on offspring sizes, unaffected by parity mode, (2) the lack of a larval stage in amniotes, favouring large eggs even in the ancestral oviparous mode and (3) the ability of viviparous females to decrease the mass of uterine embryos by reducing extra-embryonic water stores. Our analysis shows that squamate eggs (when laid) weigh about the same as the hatchlings that emerge from them (despite a many-fold increase in embryo mass during incubation). Most of the egg mass is due to components (such as water stores and the eggshell) not required for oviductal incubation. That repackaging enables live-born offspring to be accommodated within the mother's body without increasing total litter mass. The consequent stasis in reproductive burden during the evolutionary transition from oviparity to viviparity may have facilitated frequent shifts in parity modes. |
TorontoFC and Canada National Team columnist Kurtis Larson calls in to talk about TFC's playoff chances and the Canadian National Team. In the second segment, we talk to FC Dallas defender about his FIFA 16 rating, FC Dallas' current form and his Canadian citizenship. |
Imports DWSIM.Drawing.SkiaSharp.GraphicObjects
Imports DWSIM.Interfaces.Enums.GraphicObjects
Imports DWSIM.DrawingTools.Point
Namespace GraphicObjects.Shapes
Public Class PumpGraphic
Inherits ShapeGraphic
#Region "Constructors"
Public Sub New()
Me.ObjectType = DWSIM.Interfaces.Enums.GraphicObjects.ObjectType.Pump
Me.Description = "Adiabatic Pump"
End Sub
Public Sub New(ByVal graphicPosition As SKPoint)
Me.New()
Me.SetPosition(graphicPosition)
End Sub
Public Sub New(ByVal posX As Integer, ByVal posY As Integer)
Me.New(New SKPoint(posX, posY))
End Sub
Public Sub New(ByVal graphicPosition As SKPoint, ByVal graphicSize As SKSize)
Me.New(graphicPosition)
Me.SetSize(graphicSize)
End Sub
Public Sub New(ByVal posX As Integer, ByVal posY As Integer, ByVal graphicSize As SKSize)
Me.New(New SKPoint(posX, posY), graphicSize)
End Sub
Public Sub New(ByVal posX As Integer, ByVal posY As Integer, ByVal width As Integer, ByVal height As Integer)
Me.New(New SKPoint(posX, posY), New SKSize(width, height))
End Sub
#End Region
Public Overrides Sub PositionConnectors()
CreateConnectors(0, 0)
End Sub
Public Overrides Sub CreateConnectors(InCount As Integer, OutCount As Integer)
Dim myIC1 As New ConnectionPoint
myIC1.Position = New Point(X, Y + 0.5 * Height)
myIC1.Type = ConType.ConIn
Dim myIC2 As New ConnectionPoint
myIC2.Position = New Point(X + 0.5 * Width, Y + Height)
myIC2.Type = ConType.ConEn
Dim myOC1 As New ConnectionPoint
myOC1.Position = New Point(X + Width, Y + 0.1 * Height)
myOC1.Type = ConType.ConOut
With InputConnectors
If .Count = 2 Then
.Item(0).Position = New Point(X, Y + 0.5 * Height)
.Item(1).Position = New Point(X + 0.5 * Width, Y + Height)
ElseIf .Count = 1 Then
.Item(0).Position = New Point(X, Y + 0.5 * Height)
.Add(myIC2)
Else
.Add(myIC1)
.Add(myIC2)
End If
.Item(0).ConnectorName = "Inlet"
.Item(1).ConnectorName = "Energy Stream"
End With
With OutputConnectors
If .Count <> 0 Then
.Item(0).Position = New Point(X + Width, Y + 0.1 * Height)
Else
.Add(myOC1)
End If
.Item(0).ConnectorName = "Outlet"
End With
Me.EnergyConnector.Position = New Point(X + 0.5 * Width, Y + Height)
Me.EnergyConnector.Type = ConType.ConEn
Me.EnergyConnector.Direction = ConDir.Up
Me.EnergyConnector.ConnectorName = "Energy Stream"
Me.EnergyConnector.Active = False
End Sub
Public Overrides Sub Draw(ByVal g As Object)
Dim canvas As SKCanvas = DirectCast(g, SKCanvas)
CreateConnectors(0, 0)
UpdateStatus()
MyBase.Draw(g)
Dim myPen As New SKPaint()
With myPen
.Color = LineColor
.StrokeWidth = LineWidth
.IsStroke = Not Fill
.IsAntialias = GlobalSettings.Settings.DrawingAntiAlias
End With
Dim myPen2 As New SKPaint()
With myPen2
.Color = GraphicsSurface.BackgroundColor
.IsStroke = False
.IsAntialias = GlobalSettings.Settings.DrawingAntiAlias
End With
Dim rect1 As New SKRect(X + 0.1 * Width, Y, X + 0.8 * Width, Y + 0.8 * Height)
Dim pt3 As New Point(X + 0.1 * Width, Y + Height)
Dim pt4 As New Point(X + 0.2 * Width, Y + 0.65 * Height)
Dim pt5 As New Point(X + 0.9 * Width, Y + Height)
Dim pt6 As New Point(X + 0.8 * Width, Y + 0.65 * Height)
Dim pt7 As New Point(X + 0.1 * Width, Y + Height)
Dim pt8 As New Point(X + 0.9 * Width, Y + Height)
Dim pt9 As New Point(X + 0.5 * Width, Y)
Dim pt10 As New Point(X + Width, Y)
Dim pt11 As New Point(X + Width, Y + 0.25 * Height)
Dim pt12 As New Point(X + 0.88 * Width, Y + 0.25 * Height)
Dim gp As New SKPath()
gp.MoveTo(pt3.X, pt3.Y)
gp.LineTo(pt4.X, pt4.Y)
gp.LineTo(pt6.X, pt6.Y)
gp.LineTo(pt5.X, pt5.Y)
gp.Close()
Dim gp2 As New SKPath()
gp2.MoveTo(pt9.X, pt9.Y)
gp2.LineTo(pt10.X, pt10.Y)
gp2.LineTo(pt11.X, pt11.Y)
gp2.LineTo(pt12.X, pt12.Y)
gp.Close()
Dim rect As New SKRect(X, Y, X + Width, Y + Height)
Dim r0 As New SKRect(X, Y, X + Width, Y + Height)
Dim radius2 = 0.8F * Math.Min(Width, Height)
Dim center = New SKPoint(r0.MidX, r0.MidY)
Dim offCenter = center - New SKPoint(radius2 / 2, radius2 / 2)
Dim gradPen As New SKPaint()
With gradPen
.Color = LineColor
.StrokeWidth = LineWidth
.IsStroke = False
.IsAntialias = GlobalSettings.Settings.DrawingAntiAlias
.Shader = SKShader.CreateTwoPointConicalGradient(
offCenter, 1, center, radius2,
New SKColor() {SKColors.White, LineColor},
Nothing, SKShaderTileMode.Clamp)
End With
If GradientMode Then
canvas.DrawPath(gp, gradPen)
canvas.DrawPath(gp2, gradPen)
canvas.DrawOval(rect, gradPen)
Else
canvas.DrawOval(rect, myPen2)
End If
canvas.DrawPath(gp, myPen)
canvas.DrawPath(gp2, myPen)
If GradientMode Then
canvas.DrawOval(rect, gradPen)
End If
canvas.DrawOval(rect, myPen)
End Sub
End Class
End Namespace |
Background
==========
NSCLC accounts for the majority of lung cancer cases and chemotherapy has been the mainstay of treatments of lung cancers \[[@B1]\]. Up to date, DDP still remains the most widely used first-line chemotherapeutic agent for NSCLC treatment. However, continuous infusion or multiple administration of DDP often cause severe side effects, including myelosuppression, asthenia, and gastrointestinal disorders, as well as long-term cardiac, renal, and neurological consequences \[[@B2]\]. Therefore, improving the sensitivity to drug doses strategies is still a challenge for chemotherapy efficacy. Novel therapeutic modalities combining genetic and chemotherapeutic approaches will play important roles in the fight against cancer in future.
MicroRNAs (miRNAs) are small, endogenous non-coding RNAs that have been identified as post-transcriptional regulators of gene expression. MiRNAs exert their functions through imperfect base-pairing with the 3\'-untranslated region (3\'-UTR) of target mRNAs \[[@B3]\]. In human cancer, miRNAs can act as oncogenes or tumour suppressor genes during tumourigenesis. Evidence collected to date shows the involvement of microRNA and identifies this class of regulatory RNAs as diagnostic and prognostic cancer biomarkers, as well as additional therapeutic tools \[[@B4]-[@B6]\]. Meanwhile, the associations of dysregulation of miRNAs with chemoresistance of human cancers are attracting more and more attention \[[@B7]\]. Some researches have shown that dysregulation of miRNAs can contribute to the chemoresistance of cisplatin in human tumor cells \[[@B8],[@B9]\]. Recently miR-451 has been reported to be induced during zebrafish, mouse, and human erythroid maturation as an key factor involved in regulates erythrocyte differentiation \[[@B10]-[@B12]\]. It was also reported that miR-451 might function as tumor suppressor and modulate MDR1/P-glycoprotein expression in human cancer cells \[[@B13]\]. Meanwhile, miR-451 has been reported to be involved in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin \[[@B14]\]. However, to our best knowledge, there have been no reports about the association of miR-451 expression with the sensitivity of NSCLC cells to DDP.
In the present study, we identify miR-451 to be downregulated in human NSCLC and report for the first time that upregulation of miR-451 can enhance DDP chemosensitivity in NSCLC cell line (A549) by inducing apoptosis enhancement, which identifies miR-451 as a valid therapeutic target in strategies employing novel multimodality therapy for patients with NSCLC.
Methods
=======
Patients and tissue samples
---------------------------
A total of 10 pairs of matched NSCLC and noncancerous tissue samples were surgically obtained from patients in Nanjing Chest Hospital, Jisnsu Province and diagnosed by an independent pathologist. None of the patients had received chemotherapy or radiotherapy before surgery. Samples were snap-frozen in liquid nitrogen and stored at -80°C until RNA extraction. Written informed consent was obtained from all patients before surgery.
Cell culture
------------
NSCLC cell line (A549) was cultured in Dulbecco\'s modified Eagle\'s medium (Invitrogen, Carlsbad, CA) supplemented with 10% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin. All cell lines were cultured under the atmosphere of 5% CO~2~with humidity at 37°C.
Plasmid construction
--------------------
The precursor sequence of miR-451 generated by annealing and primer extension with miR-451-precursor-F (5\'-*TGCTGAAACCGTTACCATTACTGAGTTGTTTTGGCCACTGACTGA- CAACTCAGTTGGTAACGGTTT*-3\') and miR-451-precursor-R (5\'-*CCTGAAACCGTTACCAAC-TGAGTTGTCAGTCAGTGGCCAAAACAACTCAGTAATGGTAACGGTTTC*-3\') was digested with BamHI and BglII and cloned into the BamHI-BglII fragment of the pcDNA-GW/EmGFP-miR vector (GenePharma, Shanghai, China). A construct including the non-specific miR-NC (99 bp) was used as a negative control. The constructed vectors were named pcDNA-GW/EmGFP-miR-451 and pcDNA-GW/EmGFP-miR-NC, respectively.
Cell transfection
-----------------
A549 cells were seeded into 6-well plates and transfected with the miR-415-expressing vector or the control vector expressing a non-specific miR-NC using Lipofectamine 2000 (Invitrogen), and were selected with spectinomycin (100 μg/ml) to generate two stable monoclonal cell lines (a miR-218 stable cell line, A549/miR-451, and a control stable cell line, A549/miR-NC).
Quantitative real-time polymerase chain reaction (qRT-PCR) assay
----------------------------------------------------------------
Total RNA was extracted using TRIzol reagent (Invitrogen, CA, USA). Reverse-transcribed complementary DNA was synthesized with the Prime-Script RT reagent Kit (TaKaRa, Dalian, China). Realtime polymerase chain reaction (PCR) was performed with SYBR Premix Ex Taq (TaKaRa, Dalian, China). For miRNA detection, mature miR-451 was reverse-transcribed with specific RT primers (miR-451: 5\'-*CTCAACTGGTGTCGTGGAGTCGGCAATTCAGTTGAGAAA-CTCAG*-3\' and U6: 5\'-*TGGTGTCGTGGAGTCG*-3\') quantified with a TaqMan probe, and normalized by U6 small nuclear RNA using TaqMan miRNA assays (Applied Biosystems, CA).
Stem-loop conventional RT-PCR assay
-----------------------------------
Total RNA was extracted using TRIzol reagent (Invitrogen, USA). Reverse-transcribed complementary DNA was synthesized with the Prime-Script RT reagent Kit (TaKaRa, Dalian, China). Conventional PCR was used to assay miRNA expression with the specific forward primers and the universal reverse primer complementary to the anchor primer. U6 was used as internal control (Invitrogen, USA). The PCR primers for mature miR-451 or U6 were designed as follows: miR-451 sense, 5\'-*ACACTCCAGCTGGGAAACCGTTACCATTACT*-3\' and reverse, 5\'-*CTGGTGTCGTGGAGTCGGCAA*-3\'. U6 sense, 5\'- *CTCGCTTCGGCAGCACA*-3\' and reverse, 5\'-*AACGCTTCACGAATTTGCGT*-3\'. Then, the RT-PCR products were electrophoresed through a 1.5% agarose gel with ethidium bromide. Signals were quantified by densitometric analysis using the Labworks Image Acquisition (UVP, Inc., Upland, CA).
Western Blot assay
------------------
Thirty micrograms of protein extract were separated in a 15% SDS-polyacrylamide gel and electrophoretically transferred onto a PDVF membrane (Millipore, Netherlands). Membranes were blocked overnight with 5% non-fat dried milk and incubated for 2 h with antibodies to phospharylated Akt (pAkt-473), total Akt, Bcl-2 and Bax (Santa Cruz Biotechnology, Santa Cruz, CA) and GAPDH (Sigma, USA). After washing with TBST (10 mM Tris, pH 8.0, 150 mMNaCl, and 0.1% Tween 20), the membranes were incubated for 1 h with horseradish peroxidase-linked goat-anti-rabbit antibody. The membranes were washed again with TBST, and the proteins were visualized using ECL chemiluminescence and exposed to x-ray film.
3-(4,5-dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay
-----------------------------------------------------------------------
The mock or stably transfected A549 cells were seeded into 96-well plates (6.0 × 10^3^cells/well) and allowed to attach overnight. After cellular adhesion, freshly prepared anticancer drugs (DDP) were added with various concentrations. After 72 h, cell viability was assessed using MTT assay. The absorbance at 490 nm (A490) of each well was read on a spectrophotometer. Three independent experiments were performed in quadruplicate.
Colony formation assay
----------------------
Approximately 500 mock A549 or stable transfect A549 cells (A549/miR-451 and A549/miR-NC) were placed in a fresh 6-well plate with or without DDP for another 12 h and maintained in RMPI 1640 containing 10% FBS for 2 weeks. Colonies were fixed with methanol and stained with 0.1% crystal violet in 20% methanol for 15 min.
Flow cytometry analysis of apoptosis
------------------------------------
Cells were treated with or without DDP for another 12 h and harvested and fixed with 2.5% glutaraldehyde for 30 minutes. After routine embedment and section, the cells were observed under electronic microscope. The apoptosis rates were determined using Annexin V-FITC and PI staining flow cytometry.
Hoechst staining assay
----------------------
Cells were cultured on 6-well tissue culture plates to confluence and treated with or without DDP for another 12 h. Then, Hoechst 33342 (Sigma, USA) was added to the culture medium of living cells; changes in nuclear morphology were detected by fluorescence microscopy using a filter for Hoechst 33342 (365 nm). The percentages of Hoechst-positive nuclei per optical field (at least 50 fields) were counted.
Caspase-3 activity
------------------
The activity of Caspase-3 was measured using Caspase-3 Colorimetric Assay Kit (Nanjing Keygen Biotech. Co., Ltd) following the manufacturer\'s instruction. In brief, cells were seeded in the 6-wells and were cultured for 24 h. Then, the cells were administered with or without DDP for another 12 h and harvested, resuspended in 50 μL of lysis buffer and incubated on ice for 30 min, and cellular debris was pelleted. The lysates (50 μL) were transferred to 96-well plates. The lysates were added to 50 μL 2.0 × Reaction Buffer along with 5 μL Caspase-3 Substrate and incubated for 4 h at 37°C, 5% CO~2~incubator. The activities were quantified spectrophotometrically at a wavelength of 405 nm.
Terminal Transferase dUTP Nick End Labeling (TUNEL) Assay
---------------------------------------------------------
Tissues were plated on polylysine-coated slides, fixed with 4% paraformaldehyde in 0.1 M phosphate-buffered saline (PBS) for 1 h at 25°C, rinsed with 0.1 M PBS, pH 7.4, and permeabilized with 1% Triton X-100 in 0.01 M citrate buffer (pH 6.0). DNA fragmentation was detected using TUNEL Apoptosis Detection Kit (Nanjing KeyGen, China), which specifically labeled 3\'-hydroxyl termini of DNA strand breaks using fluorescein isothiocyanate (FITC)-conjugated dUTP. DNA was also labeled with FITC DNA-binding dye for 5 min. FITC labels were observed with a fluorescence microscope. The percentage of apoptotic cells was calculated as the number of apoptotic cells per number of total cells × 100%.
Animal experiment
-----------------
All experimental procedures involving animals were in accordance with the Guide for the Care and Use of Laboratory Animals and were performed according to the institutional ethical guidelines for animal experiment. Each aliquot of mock or stably transfected A549 cells were injected into the flanks of BALB/c nude mice (Nu/Nu, female, 4-6 weeks old) which were purchased from the Experimental Animal Centre of Nanjing Medical University and maintained under pathogen-free conditions (n = 8/group). One day after tumor cell implantation, mice were treated with CDDP (3.0 mg/kg body weight; i.p., thrice/week), Tumor volume was followed up for 4 weeks and measured once weekly. The tumor volume formed was calculated by the following formula: V = 0.4 × D × d^2^(V, volume; D, longitudinal diameter; d, latitudinal diameter). All mice were killed and s.c. tumors were resected and fixed in 10% PBS. TUNEL staining assay was performed on 5 μm sections of the excised tumors. The number of apoptotic cells in five random high-power fields was counted.
Statistical analysis
--------------------
All experimental data were shown as the mean ± SEM. Differences between samples were analyzed using the Student\'s *t*test. Statistical significance was accepted at *P*\< 0.05.
Results
=======
MiR-451 is significantly downregulated in human NSCLC tissues
-------------------------------------------------------------
In this study, a stem-loop qRT-PCR assay was performed to determine the expression of miR-451 in 10 pairs of matched NSCLC and noncancerous lung tissue samples. As shown in Figure [1A](#F1){ref-type="fig"}, the expression levels of miR-451in NSCLC tissues were less than approximately 36.4% of those in noncancerous lung tissues. In addition, conventional RT-PCR assay was also performed to analyze the expression of miR-451 in 2 pairs of matched NSCLC and noncancerous tissue samples. The gel electrophoresis of RT-PCR products confirmed the downregulation of miR-451 expression in NSCLC tissues (Figure [1B](#F1){ref-type="fig"}). Therefore, it was concluded that the downregulation of miR-451 might be involved in lung carcinogenesis.
{#F1}
The expression of miR-451 could be significantlu upregulated in A549 cells by pcDNA-GW/miR-45
---------------------------------------------------------------------------------------------
To upregulate the expression of miR-451 in NSCLC cell line (A549), pcDNA-GW/miR-451 was transfected and stable transfectants (A549/miR-451 or A549/miR-NC) were successfully established. As shown in Figure [2A](#F2){ref-type="fig"}, qRT-PCR assay showed that the relative level of miR-451 expression in A549/miR-451 could be significantly upregulated by 3.8-fold compared with that in mock A549 or A549/miR-NC cells (*P*\< 0.05). The gel electrophoresis of RT-PCR products confirmed the upregulation of miR-451 expression in A549/miR-451 cells (Figure [2B](#F2){ref-type="fig"}).
{#F2}
Upregulation of miR-451 inhibits growth and enhances apoptosis of NSCLC cell line (A549)
----------------------------------------------------------------------------------------
To analyze the effect of miR-451 expression on phenotypes of NSCLC cell line, we performed MTT, colony formation and flow cytometric assays. As shown in Figure [3A](#F3){ref-type="fig"}, A549/miR-451 cell line had a significant increase in cell viability compared with mock A549 or A549/miR-NC cell line (*P*\< 0.05). The number of colonies formed from A549/miR-451 cells was significantly lower than that formed from mock A549 or A549/miR-NC cells (*P*\< 0.05; Figure [3B](#F3){ref-type="fig"}). Moreover, flow cytometric analysis showed that the apoptotic rate of A549/miR-451 cells (11.6 ± 1.5%) was significantly higher than that of mock A549 or A549/miR-NC cells (*P*\< 0.05; Figure [3C](#F3){ref-type="fig"}). Thus, upregulation of miR-451 could induce growth inhibition and apoptosis enhancement in A549 cells.
{#F3}
Upregulation of miR-451 expression inactivates the Akt signaling pathway of A549 cells
--------------------------------------------------------------------------------------
It has been reported that activation of the Akt signaling pathway can regulate many biological phenomena of lung cancer cells, such as cell proliferation and survival, motility and migration. Thus, we analyzed the effects of miR-451 on the Akt signaling pathway in A549 cells (Figure [4A](#F4){ref-type="fig"}). Results showed that the upregulation of miR-451 could significantly downregulate the expression of pAkt protein but had no effects on the expression of total Akt protein. Additionally, the expression of Bcl-2 protein was downregulated and the expression of Bax protein was upregulated. The activity of caspase-3 in A549/miR-451 cells was also found to be significantly enhanced compared with that in mock A549 or A549/miR-NC cells (*P*\< 0.05; Figure [4B](#F4){ref-type="fig"}). Therefore, it was concluded that the elevation of caspase-3 activity might be induced by the elevated ratio of Bax/Bcl-2. However, the exact mechanisms of miR-451 affecting the Akt signaling pathway need to be elucidated in future.
{#F4}
Upregulation of miR-451 enhances in vitro sensitivity of A549 cells to DDP
--------------------------------------------------------------------------
Dysregulation of miRNA expression has been reported to be associated with chemoresistance of human cancers. However, whether miR-451 expression affects the sensitivity of NSCLC cells is not fully understood. To determine this, the mock or stably transfected A549 cells were treated with various concentrations (0, 5, 10, 15, 20 and 25 μg/ml) of DDP for 12 h or 5 μg/ml of DDP for 0, 12, 24, 26 and 48 h. The results from MTT assay indicated that upregulation of miR-451 led to a significant decrease in cell viability of A549 cells in response to DDP in a dose- or time -dependent manner compared with those of A549/miR-NC and mock A549 cells (Figure [5A](#F5){ref-type="fig"} and [5B](#F5){ref-type="fig"}). The cells were treated 5 μg/ml DDP for 12 h and the number of colonies was determined. As shown in Figure [5C](#F5){ref-type="fig"}, the number of colonies formed from A549/miR-451 cells treated with DDP was significantly lower than that formed from A549/miR-NC and mock A549 cells (P \< 0.05). These data obviously showed that upresgulation of miR-451 might effectively enhance the sensitivity of A549 cells to DDP.
{#F5}
Upregulation of miR-451 enhances DDP-induced apoptosis of A549 cells
--------------------------------------------------------------------
The precise underlying mechanisms by which upregulation of miR-451 enhances chemosensitivity of A549 cells to DDP were further investigated. Then, the apoptosis was detected by flow cytometric assay. As shown in Figure [6A](#F6){ref-type="fig"}, the apoptotic rare of A549/miR-451 treated with 5 μg/ml DDP was increased by approximately 11.7% in comparison with mock A549 cells treated with 5 μg/ml DDP (*P*\< 0.05). However, the apoptotic rate of A549/miR-NC cells treated with DDP showed no significant difference compared with that of mock A549 cells treated with DDP (*P*\> 0.05). Figure [6B](#F6){ref-type="fig"} showed the results of AnnexinV-FITC apoptosis detection assay, which confirmed the results of flow cytomeric assay. Finally, the activity of caspase-3 was also determined by colorimetric assay. As shown in Figure [6C](#F6){ref-type="fig"}, the caspase-3 activity in A549/miR-451 cells treated with DDP remarkably increased by approximately 308% compared that mock A549 or A549/miR-NC cells treated with DDP (*P*\< 0.05). Therefore, upregulation of miR-451 might increase DDP chemosensitivity of A549 cells by enhancing DDP-induced apoptosis.
{#F6}
Upregulation of miR-451 increases in vivo chemosensitivity of A549 cells to DDP
-------------------------------------------------------------------------------
To explore whether upregulation of miR-451 on chemosensitivity of A549 cells to DDP in vivo, s.c. tumors were developed in nude mice followed by treatment with DDP or PBS. As shown in Figure [7A](#F7){ref-type="fig"}, the tumors formed from A549/miR-451cells grew significantly slower than those from A549/miR-NC after the treatment with DDP. At 28 days after inoculation, the average tumor volume of A549/miR-451 cells (212 ± 36 mm^3^) was significantly lower than that of A549/miR-NC (323 ± 13 mm^3^) following DDP treatment (*P*\< 0.05; Figure [7B](#F7){ref-type="fig"}). TUNEL assay showed that the apoptotic rate of tumors developed from A549/miR-451 cells (15.8 ± 2.2%) was significantly higher than that of tumors developed from A549/miR-NC cells (9.6 ± 1.5%) following DDP treatment (*P*\< 0.05; Figure [7C](#F7){ref-type="fig"}). Like the results observed from in vitro experiments, upregulation of miR-451 could also increase in vivo chemosensitivity of A549 cells to DDP by inducing apoptosis enhancement.
{#F7}
Discussion
==========
MiRNAs are a growing class of small, noncoding RNAs (17-27 nucleotides) that regulate gene expression by targeting mRNAs for translational repression, degradation, or both. Increasing evidence suggests that deregulation of miRNAs has been frequently observed in tumor tissues. These miRNAs have regulatory roles in the pathogenesis of cancer in humans, through the suppression of genes involved in cell proliferation, differentiation, apoptosis, metastasis and resistance \[[@B15]-[@B18]\]. Recently, many studies have shown that miRNAs play an important role in malignant transformation. It is likely, therefore, that they can also modulate sensitivity and resistance to anticancer drugs in substantial ways. The mechanisms responsible for chemotherapy resistance by miRNAs have not been clearly identified. Current published data on the association of miRNAs with chemoresistance are limited. While altered expression of miRNAs in primary human NSCLCs has been used for tumor diagnosis and prognosis \[[@B19]\], the potential involvement of miRNAs in induction of drug resistance, particularly, in cisplatin resistance has not been explored.
Here, we showed that miR-451 is frequently downregulated in human NSCLC tissues compared with corresponding noncancerous lung tissues, which is consistent with the results of Gao\'et al \[[@B20]\]. It was also reported that microRNA-451 could regulate macrophage migration inhibitory factor production and proliferation of gastrointestinal cancer cells \[[@B21]\]. Nan and his colleagues revealed that miR-451 impacts glioblastoma cell proliferation, invasion and apoptosis, perhaps via regulation of the PI~3~K/AKT signaling pathway \[[@B22]\]. Thus, miR-451 was proposed as a tumor-suppressor of human cancers. In other reports, Godlewski and his colleagues showed that miRNA-451 regulates LKB1/AMPK signaling and allows adaptation to metabolic stress in glioma cells, which represents a fundamental mechanism that contributes to cellular adaptation in response to altered energy availability \[[@B23]\]. At the same time, they also identified a potential feedback loop between LKB1 and miR-451, which allows a sustained and robust response to glucose deprivation \[[@B24]\]. P-glycoprotein, which is the MDR1 gene product, confers cancer cell resistance to a broad range of chemotherapeutics. Zhu, et al demonstrate for the first time the roles of miRNAs in the regulation of drug resistance mediated by MDR1/P-glycoprotein, and suggest the potential for targeting miR-27a and miR-451 as a therapeutic strategy for modulating MDR in cancer cells \[[@B13]\]. Olga and his colleagues reported that the enforced increase of miR-451 levels in the MCF-7/DOX cells down-regulates expression of mdr1 and increases sensitivity of the MCF-7-resistant cancer cells to DOX \[[@B14]\]. All these data provide a strong rationale for the development of miRNA-based therapeutic strategies aiming to overcome chemoresistance of tumor cells. However, whether the expression of miR-451 can affect the sensitivity of lung cancer cells to DDP is still unclear.
In the present study, we found that the upregulation of miR-451 could significantly inhibit growth and colony formation of NSCLC cell line (A549). Upregulation of miR-451 could also enhance caspase-3-dependent apoptosis of A549 cells by inactivating the Akt signalling pathway which induced the reverse of Bcl-2/Bax ratio. Furthermore, upregulation of miR-451 could significantly increase the in vitro and in vivo sensitivity of A549 cells to DDP. To the best of our knowledge, we provided the first insight into the roles and possible mechanisms of miR-451 upregulation in chemosensitivity of A549 cells to DDP. These data suggest that appropriate combination of DDP application with miR-451 regulation might be a potential approach to NSCLC therapy. For higher-dose DDP would produce potentially serious toxic effects such as nephro- and ototoxicity would be increased, combination of DDP application with miR-451 upregulation for the treatment of NSCLC would contribute to lower-dose DDP administration and result in a reduction of DDP toxic side-effects. Although inhibition of Akt signal pathway has been reported to be able to improve chemotherapeutic effect of human tumor cells, whether upregulation of miR-451 enhance DDP chemosensitivity of A549 cells by inactivating the Akt signal pathway needs to be further elucidated. Moreover, only A549 cell line has been used in this study, further researches should be conducted on other cell lines to testify our experimental data.
In conclusion, upregulation of miR-451 could increase the sensitivity of A549 cells to DDP both in vitro and in vivo, suggesting that appropriate combination of DDP application with miR-451 upregulation might be a potential strategy for the treatment of human NSCLC in future.
Competing interests
===================
The authors declare that they have no competing interests.
Authors\' contributions
=======================
HBB and XP contributed to clinical data, samples collection, MTT, apoptosis and caspase-3 activity detection analyses and manuscript writing. JSY contributed to animal experiment. ZXW and WD were responsible for the study design and manuscript writing. All authors read and approved the final manuscript.
Acknowledgements
================
This work was supported by grants from the National Natural Science Foundation of China (No. 30973477), the Natural Science Foundation of Jiangsu province (No. BK2010590), the Jiangsu Provincial Personnel Department \"the Great of Six Talented Man Peak\" Project (No. 09-B1-021), the Scientific Research Foundation of Jiangsu Province Health Department (No. H200710) and the Medical Science Development Subject in Science and Technology Project of Nanjing (No. ZKX08017 and YKK08091).
|
Cameron should back Syriza’s reform goals
Jonathan Lindsell, 10 February 2015
Barely an hour goes by without news of the standoff between Greece’s new Syriza-led government and the troika of creditors, the European Central Bank, International Monetary Fund and the European Commission. The deadlock is unsettling the markets, we are told, as Syriza asks for debt relief and those who hold Greece’s debt refuse another restructuring.
Last week Greek finance minister Yanis Varoufakis, met George Osborne in London. The Chancellor looked distinctly uncomfortable, and his press conference emphasised the situation’s ‘threat to the British economy’ and the need to avoid ‘chaos’. Osborne was not crying wolf – the Athens Stock Exchange fell 6% yesterday and 10-year bond yields rose above 10%, The Telegraph reports.
But this is not a fear Osborne should be stoking, whipping market concerns. It’s an opportunity for British politicians looking to reform the EU to show they can be constructive and dynamic. Varoufakis told Osborne he wanted Greece to ‘play within the rules’ and his party leader, Alexis Tsipras, announced soon after his election, ‘It has never been our intention to act unilaterally on Greek debt.’
Like the Conservatives, Syriza criticises Brussels for its democratic failings and intends to reform it with greater respect for nation states’ sovereignty.
Like the Conservatives, Syriza dislikes government debt. Greece now runs a surplus. A key point in Varoufakis’ plan is to go ‘cold turkey’ and reject further loans or bailouts. Syriza hates corruption and pursues a hard line on collecting taxes.
Like the Conservatives, Syriza worries that the dispute might force Greece out of the euro (Grexit), an event that could traumatise the market, even if it eventually rewarded Greece with a drachma suited to its economic strength.
This last reason alone should to change the government’s tack. David Cameron first meets Alexis Tsipras on Thursday at the European Council. Cameron should give him much more confident support, publicly asserting that the ‘Greek crisis’ is overblown and that he will do everything possible, as leader of the EU’s third largest state, to broker a compromise. This would not be an extremist step – Tsipras’ plan to delay servicing Greek debt until the economy is growing stably already has the support of Barack Obama, the IEA, and Nobel economists Joseph Stiglitz and Christopher Pissarides.
Rather than contribute to an atmosphere in which the Greek government appear to be extremist Marxists demanding free lunch, Cameron’s intervention could calm Thursday’s summit. Even a moderate compromise towards Syriza’s position would represent an important precedent for reform, and show the British electorate that the Tory narrative is true – that Brussels can be flexible when Tories are at the table. It could help avert the instability that Grexit would bring, an instability that could affect the UK election.
Finally, it would be a tactical coup. Cameron could win the respect of unlikely allies including the probable victors of Spain’s upcoming election, Podemos. He would send Chancellor Merkel the message that Britain was serious about EU renegotiation, and that Germany was not the sole gatekeeper to achieving it. |
Gold halide
Gold halides are compounds of gold with the halogens.
Monohalides
AuCl, AuBr, and AuI are all crystalline solids with a structure containing alternating linear chains: ..-X-Au-X-Au-X-Au-X-... The X-Au-X angle is less than 180°.
The monomeric AuF molecule has been detected in the gas phase.
Trihalides
Gold triiodide does not exist or is unstable.
Gold(III) fluoride, AuF3, has a unique polymeric helical structure, containing corner-sharing {AuF4} squares.
Pentahalides
Gold(V) fluoride, AuF5, is the only known example of gold in the +5 oxidation state. It most commonly occurs as the dimer Au2F10.
References
Category:Gold compounds
Category:Metal halides
Category:Gold–halogen compounds |
# Experimental Results
By getting the data and running the following notebooks, you should be able to reproduce the experimental results in the paper.
## ML20M
- [preprocess_ML20M.ipynb](./preprocess_ML20M.ipynb): pre-process the data and create the train/test/validation splits.
- [Cofactorization_ML20M.ipynb](./Cofactorization_ML20M.ipynb): train the CoFactor model and evaluate on the heldout test set.
- [WMF_ML20M.ipynb](./WMF_ML20M.ipynb): train the baseline WMF model and evaluate on the heldout test set.
To get the results for TasteProfile, follow [this notebook](https://github.com/dawenl/expo-mf/blob/master/src/processTasteProfile.ipynb) for data pre-processing and replace the data directory `DATA_DIR` in the above notebooks with the location of the processed TasteProfile.
|
Tag: Orange
The past month has seen some major happenings in the world of Freemail providers: UK provider EE finalized their closure of Orange email services – which included long-time freemail domains Wanadoo.co.uk and Freeserve.co.uk – and Terra.co.br announced the end of their freemail service. (A full listing of affected domains is at the end of the post.)
Orange had been heralding the May 31 closure date for a few months, recommending their users switch to Gmail, while Terra has given July 1 as the end date for their services. Terra.es had previously announced their email migration to terra.com starting in April of this year.
For senders in the US, these domain closures are likely to have varying impacts. Typically you’re unlikely to have a large number of Orange addresses on file, especially since these addresses are typically older and many users have migrated away from them to more advanced services. Terra addresses tend to be slightly more common in the US, particularly terra.com.mx. If you have these addresses in your database, you probably also know that delivery issues at Terra tend to be difficult to resolve – so maybe there is a bit of a silver lining in the closures yet.
In any case, you should take the opportunity to check your database for addresses at these domains. If you have any of the Orange addresses, suppress them immediately as they are officially shut down. If you have other contact data for those recipients, feel free to use it to get updated information. If you have recipients at the Terra domains, you still have 3 weeks to reach out via email to get updated details. If you haven’t gotten the info by July 1, you’ll need to suppress those recipients as well.
The full list of Orange domains affected:
Orange.net
Orangehome.co.uk
Wanadoo.co.uk
Freeserve.co.uk
Fsbusiness.co.uk
Fslife.co.uk
Fsmail.net
Fsworld.co.uk
Fsnet.co.uk
The Terra domains being shuttered are:
terra.com
terra.com.ar
mi.terra.cl
terra.com.co
terra.com.mx
terra.com.pe
terra.com.ve
terra.com.ec
As always, please feel free to reach out with any questions or comments, or email me with any more detailed requests. |
Effects of antioxidants on contracting spinotrapezius muscle microvascular oxygenation and blood flow in aged rats.
Aged rats exhibit a decreased muscle microvascular O(2) partial pressure (Pmv(O(2))) at rest and during contractions compared with young rats. Age-related reductions in nitric oxide bioavailability due, in part, to elevated reactive O(2) species, constrain muscle blood flow (Qm). Antioxidants may restore nitric oxide bioavailability, Qm, and ameliorate the reduced Pmv(O(2)). We tested the hypothesis that antioxidants would elevate Qm and, therefore, Pmv(O(2)) in aged rats. Spinotrapezius muscle Pmv(O(2)) and Qm were measured, and oxygen consumption (Vm(O(2))) was estimated in anesthetized male Fisher 344 x Brown Norway hybrid rats at rest and during 1-Hz contractions, before and after antioxidant intravenous infusion (76 mg/kg vitamin C and 52 mg/kg tempol). Before infusion, contractions evoked a biphasic Pmv(O(2)) that fell from 30.6 +/- 0.9 Torr to a nadir of 16.8 +/- 1.2 Torr with an "undershoot" of 2.8 +/- 0.7 Torr below the subsequent steady-state (19.7 +/- 1.2 Torr). The principal effect of antioxidants was to elevate baseline Pmv(O(2)) from 30.6 +/- 0.9 to 35.7 +/- 0.8 Torr (P < 0.05) and reduce or abolish the undershoot (P < 0.05). Antioxidants reduced Qm and Vm(O(2)) during contractions (P < 0.05), while decreasing force production 16.5% (P < 0.05) and elevating the force production-to-Vm(O(2)) ratio (0.92 +/- 0.03 to 1.06 +/- 0.6, P < 0.05). Thus antioxidants increased Pmv(O(2)) by altering the balance between muscle O(2) delivery and Vm(O(2)) at rest and during contractions. It is likely that this effect arose from antioxidants reducing myocyte redox below the level optimal for contractile performance and directly (decreased tension) or indirectly (altered balance of vasoactive mediators) influencing O(2) delivery and Vm(O(2)). |
# this file should contain all periodic jobs that use the fejta-bot token
periodics:
- name: periodic-api-review-help
interval: 1h
decorate: true
annotations:
testgrid-dashboards: sig-testing-fejtabot
description: Adds API review process description to kind/api-change PRs
testgrid-tab-name: api-review-help
spec:
containers:
- image: gcr.io/k8s-prow/commenter:v20200925-a1858f46d6
command:
- /app/robots/commenter/app.binary
args:
# pull requests against master branches in the kubernetes org labeled kind/api-change
# exclude PRs that are in progress, held, or need rebase (typically aren't ready for API review).
# exclude PRs already labeled api-review or tracked in the API review project
# exclude PRs that already have the comment text
- |-
--query=org:kubernetes
is:pr
base:master
label:kind/api-change
-label:do-not-merge/work-in-progress
-label:do-not-merge/hold
-label:needs-rebase
-label:api-review
-project:kubernetes/13
NOT "complete the pre-review checklist and request an API review"
- --updated=5m
- --token=/etc/token/bot-github-token
- |-
--comment=This PR [may require API review](https://git.k8s.io/community/sig-architecture/api-review-process.md#what-apis-need-to-be-reviewed).
If so, when the changes are ready, [complete the pre-review checklist and request an API review](https://git.k8s.io/community/sig-architecture/api-review-process.md#mechanics).
Status of requested reviews is tracked in the [API Review project](https://github.com/orgs/kubernetes/projects/13).
- --ceiling=10
- --confirm
volumeMounts:
- name: token
mountPath: /etc/token
volumes:
- name: token
secret:
secretName: fejta-bot-token
- name: periodic-test-infra-cla
interval: 1h
decorate: true
annotations:
testgrid-dashboards: sig-testing-fejtabot
description: Re-checks CLA context when CLA labels are missing
testgrid-tab-name: cla
spec:
containers:
- image: gcr.io/k8s-prow/commenter:v20200925-a1858f46d6
command:
- /app/robots/commenter/app.binary
args:
- |-
--query=org:kubernetes
org:kubernetes-sigs
org:kubernetes-incubator
org:kubernetes-client
org:kubernetes-csi
is:pr
is:open
-label:"cncf-cla: no"
-label:"cncf-cla: yes"
- --token=/etc/token/bot-github-token
- |-
--comment=Unknown CLA label state. Rechecking for CLA labels.
Send feedback to sig-testing, kubernetes/test-infra and/or [fejta](https://github.com/fejta).
/check-cla
- --template
- --ceiling=10
- --confirm
volumeMounts:
- name: token
mountPath: /etc/token
volumes:
- name: token
secret:
secretName: fejta-bot-token
- name: periodic-test-infra-close
interval: 1h
decorate: true
annotations:
testgrid-dashboards: sig-testing-fejtabot
description: Closes rotten issues after 30d of inactivity
testgrid-tab-name: close
spec:
containers:
- image: gcr.io/k8s-prow/commenter:v20200925-a1858f46d6
command:
- /app/robots/commenter/app.binary
args:
- |-
--query=org:kubernetes
org:kubernetes-sigs
org:kubernetes-incubator
org:kubernetes-client
org:kubernetes-csi
-label:lifecycle/frozen
label:lifecycle/rotten
- --updated=720h
- --token=/etc/token/bot-github-token
- |-
--comment=Rotten issues close after 30d of inactivity.
Reopen the issue with `/reopen`.
Mark the issue as fresh with `/remove-lifecycle rotten`.
Send feedback to sig-testing, kubernetes/test-infra and/or [fejta](https://github.com/fejta).
/close
- --template
- --ceiling=10
- --confirm
volumeMounts:
- name: token
mountPath: /etc/token
volumes:
- name: token
secret:
secretName: fejta-bot-token
- name: periodic-test-infra-retester
interval: 20m # Retest at most 1 PR per 20m, which should not DOS the queue.
decorate: true
annotations:
testgrid-dashboards: sig-testing-fejtabot
testgrid-tab-name: retester
description: Automatically /retest for approved PRs that failed retesting
spec:
containers:
- image: gcr.io/k8s-prow/commenter:v20200925-a1858f46d6
command:
- /app/robots/commenter/app.binary
args:
- |-
--query=is:pr
-label:do-not-merge
-label:do-not-merge/blocked-paths
-label:do-not-merge/cherry-pick-not-approved
-label:do-not-merge/contains-merge-commits
-label:do-not-merge/hold
-label:do-not-merge/invalid-commit-message
-label:do-not-merge/invalid-owners-file
-label:do-not-merge/release-note-label-needed
-label:do-not-merge/work-in-progress
label:lgtm
label:approved
label:"cncf-cla: yes"
status:failure
-label:needs-sig
-label:needs-kind
-label:needs-rebase
-label:needs-ok-to-test
-label:"cncf-cla: no"
repo:kubernetes/kops
repo:kubernetes/kubernetes
repo:kubernetes/test-infra
- --token=/etc/token/bot-github-token
- |-
--comment=/retest
This bot automatically retries jobs that failed/flaked on approved PRs (send feedback to [fejta](https://github.com/fejta)).
Review the [full test history](https://prow.k8s.io/pr-history/?org={{.Org}}&repo={{.Repo}}&pr={{.Number}}) for this PR.
Silence the bot with an `/lgtm cancel` or `/hold` comment for consistent failures.
- --template
- --ceiling=1
- --confirm
volumeMounts:
- name: token
mountPath: /etc/token
volumes:
- name: token
secret:
secretName: fejta-bot-token
- name: periodic-test-infra-rotten
interval: 1h
decorate: true
annotations:
testgrid-dashboards: sig-testing-fejtabot
description: Adds lifecycle/rotten to stale issues after 30d of inactivity
testgrid-tab-name: rotten
spec:
containers:
- image: gcr.io/k8s-prow/commenter:v20200925-a1858f46d6
command:
- /app/robots/commenter/app.binary
args:
- |-
--query=org:kubernetes
org:kubernetes-sigs
org:kubernetes-incubator
org:kubernetes-client
org:kubernetes-csi
-label:lifecycle/frozen
label:lifecycle/stale
-label:lifecycle/rotten
- --updated=720h
- --token=/etc/token/bot-github-token
- |-
--comment=Stale issues rot after 30d of inactivity.
Mark the issue as fresh with `/remove-lifecycle rotten`.
Rotten issues close after an additional 30d of inactivity.
If this issue is safe to close now please do so with `/close`.
Send feedback to sig-testing, kubernetes/test-infra and/or [fejta](https://github.com/fejta).
/lifecycle rotten
- --template
- --ceiling=10
- --confirm
volumeMounts:
- name: token
mountPath: /etc/token
volumes:
- name: token
secret:
secretName: fejta-bot-token
- name: periodic-test-infra-stale
interval: 1h
decorate: true
annotations:
testgrid-dashboards: sig-testing-fejtabot
description: Adds lifecycle/stale to issues after 30d of inactivity
testgrid-tab-name: stale
spec:
containers:
- image: gcr.io/k8s-prow/commenter:v20200925-a1858f46d6
command:
- /app/robots/commenter/app.binary
args:
- |-
--query=org:kubernetes
org:kubernetes-sigs
org:kubernetes-incubator
org:kubernetes-client
org:kubernetes-csi
-label:lifecycle/frozen
-label:lifecycle/stale
-label:lifecycle/rotten
- --updated=2160h
- --token=/etc/token/bot-github-token
- |-
--comment=Issues go stale after 90d of inactivity.
Mark the issue as fresh with `/remove-lifecycle stale`.
Stale issues rot after an additional 30d of inactivity and eventually close.
If this issue is safe to close now please do so with `/close`.
Send feedback to sig-testing, kubernetes/test-infra and/or [fejta](https://github.com/fejta).
/lifecycle stale
- --template
- --ceiling=10
- --confirm
volumeMounts:
- name: token
mountPath: /etc/token
volumes:
- name: token
secret:
secretName: fejta-bot-token
- name: issue-creator
interval: 24h
labels:
preset-service-account: "true"
decorate: true
annotations:
testgrid-dashboards: sig-testing-fejtabot
description: Creates github issues based on data from various 'IssueSource's.
spec:
containers:
- image: gcr.io/k8s-prow/issue-creator:v20200925-a1858f46d6
command:
- /app/robots/issue-creator/app.binary
args:
- --dry-run=false
- --alsologtostderr
- --org=kubernetes
- --project=kubernetes
- --token-file=/etc/token/bot-github-token
- --triage-window=1
- --triage-count=10
- --flakyjob-count=3
volumeMounts:
- name: token
mountPath: /etc/token
volumes:
- name: token
secret:
secretName: fejta-bot-token
- name: periodic-enhancements-unfreeze
interval: 30m
decorate: true
annotations:
testgrid-dashboards: sig-testing-fejtabot
description: Prevents issues in `k/enhancements` from being marked as `lifecycle/frozen`y
testgrid-tab-name: enhancements-unfreeze
spec:
containers:
- image: gcr.io/k8s-prow/commenter:v20200925-a1858f46d6
command:
- /app/robots/commenter/app.binary
args:
- |-
--query=repo:kubernetes/enhancements
label:lifecycle/frozen
- --updated=5m
- --token=/etc/token/bot-github-token
- |-
--comment=Enhancement issues opened in `kubernetes/enhancements` should never be marked as frozen.
Enhancement Owners can ensure that enhancements stay fresh by consistently updating their states across release cycles.
/remove-lifecycle frozen
- --ceiling=10
- --confirm
volumeMounts:
- name: token
mountPath: /etc/token
volumes:
- name: token
secret:
secretName: fejta-bot-token
# periodically file / close bugs for repos based on presence of SECURITY_CONTACTS
- name: periodic-secping
interval: 24h
decorate: true
annotations:
testgrid-dashboards: sig-testing-fejtabot
description: files bugs for SECURITY_CONTACTS
testgrid-tab-name: periodic-secping
extra_refs:
- base_ref: master
org: jessfraz
repo: secping
- org: fejta
repo: go-github
base_ref: master
path_alias: github.com/jessfraz/go-github # https://github.com/google/go-github/pull/1076
spec:
containers:
- command:
- go
- run
- .
- -d
- --confirm
- --token-path=/etc/token/bot-github-token
- --skip-emails
image: golang:1.11
volumeMounts:
- name: token
mountPath: /etc/token
env:
- name: GO111MODULE
value: "on"
volumes:
- name: token
secret:
secretName: fejta-bot-token
|
Q:
How to delete Fetch Index Element in Xcode
In Xcode 9.2 in core data model (under .xcdatamodeld file) a Fetch Index Element can be added under an entity. But how can it be deleted?
I created one by mistake and can't delete. That is why Xcode gives me a warning: "A fetch index should have one or more elements."
A:
Select the fetch index in the model editor.
Press the "delete" key on your keyboard.
The fetch index is now gone.
|
**To create a load balancer**
The following ``create-load-balancer`` example creates a load balancer with a TLS certificate. The TLS certificate applies to the specified domains, and routes traffic to instances on port 80. ::
aws lightsail create-load-balancer \
--certificate-alternative-names www.example.com test.example.com \
--certificate-domain-name example.com \
--certificate-name Certificate-1 \
--instance-port 80 \
--load-balancer-name LoadBalancer-1
Output::
{
"operations": [
{
"id": "cc7b920a-83d8-4762-a74e-9174fe1540be",
"resourceName": "LoadBalancer-1",
"resourceType": "LoadBalancer",
"createdAt": 1569867169.406,
"location": {
"availabilityZone": "all",
"regionName": "us-west-2"
},
"isTerminal": false,
"operationType": "CreateLoadBalancer",
"status": "Started",
"statusChangedAt": 1569867169.406
},
{
"id": "658ed43b-f729-42f3-a8e4-3f8024d3c98d",
"resourceName": "LoadBalancer-1",
"resourceType": "LoadBalancerTlsCertificate",
"createdAt": 1569867170.193,
"location": {
"availabilityZone": "all",
"regionName": "us-west-2"
},
"isTerminal": true,
"operationDetails": "LoadBalancer-1",
"operationType": "CreateLoadBalancerTlsCertificate",
"status": "Succeeded",
"statusChangedAt": 1569867170.54
},
{
"id": "4757a342-5181-4870-b1e0-227eebc35ab5",
"resourceName": "LoadBalancer-1",
"resourceType": "LoadBalancer",
"createdAt": 1569867170.193,
"location": {
"availabilityZone": "all",
"regionName": "us-west-2"
},
"isTerminal": true,
"operationDetails": "Certificate-1",
"operationType": "CreateLoadBalancerTlsCertificate",
"status": "Succeeded",
"statusChangedAt": 1569867170.54
}
]
}
For more information, see `Lightsail load balancers <https://lightsail.aws.amazon.com/ls/docs/en_us/articles/understanding-lightsail-load-balancers>`__ in the *Lightsail Developer Guide*.
|
Few social practices have had a longer or more complicated history in human civilization than the consumption of alcohol. As documented in academic writings, but even more commonly in art and music, humans have consumed alcohol for thousands of years, and drinking is either a celebrated facet of social activities or a proscribed practice, depending on the local moral or religious views. Although alcohol intoxication has been described in various written recordings since antiquity, it is only relatively recently that its true effects on lung health have been recognized. In the latter years of the 18th century, the first Surgeon General of the United States of America, Benjamin Rush (for whom the medical school in Chicago is named), noted that excessive alcohol consumption was associated with pneumonia (see [@b31-arcr-38-2-243]; [@b49-arcr-38-2-243]). More than a century later, William Osler wrote that alcohol abuse was the most important risk factor for pneumonia (see [@b31-arcr-38-2-243]; [@b49-arcr-38-2-243]). As modern medicine evolved throughout the 20th century, it became abundantly clear that alcohol use disorder (AUD) rendered people more susceptible to a wide variety of lung infections, including bacterial pneumonias and tuberculosis, and increased morbidity and mortality. In a now-classic modern citation, [@b63-arcr-38-2-243] coined the term "alcoholic leukopenic pneumococcal sepsis syndrome" when they published a case series of patients with underlying AUD who suffered from pneumococcal pneumonia and sepsis associated with leukopenia that was associated with a mortality of more than 80 percent. Excessive alcohol consumption seems to increase susceptibility to pneumonia through multiple mechanisms. The major factors include an increased risk of aspiration, abnormalities in the way particles are eliminated from the conducting airways through the mucus (i.e., in mucociliary clearance), and impaired activity of one branch of the immune system (i.e., innate immunity) within the lower airways (for reviews, see [@b39-arcr-38-2-243]; [@b49-arcr-38-2-243]).
Even more recently, researchers have identified an association between underlying AUD and acute respiratory distress syndrome (ARDS). ARDS is a severe form of acute lung injury that occurs as a complication of diverse insults, including sepsis, massive aspiration, and trauma; it has a mortality rate of 30 percent to 50 percent, even with state-of-the-art modern medical care in an intensive care unit ([@b80-arcr-38-2-243]; [@b82-arcr-38-2-243]; [@b83-arcr-38-2-243]; [@b84-arcr-38-2-243]). In 1996, a seminal study demonstrated for the first time that AUD independently conferred an approximately twofold increase in risk of developing ARDS ([@b54-arcr-38-2-243]). A subsequent prospective study focusing only on patients with severe sepsis revealed that the relative risk of developing ARDS was closer to fourfold higher in those with an underlying AUD;[1](#fn1-arcr-38-2-243){ref-type="fn"} this effect was independent of factors such as age, smoking, severity of illness, and nutritional status ([@b56-arcr-38-2-243]). Other investigators have confirmed these associations ([@b36-arcr-38-2-243]; [@b46-arcr-38-2-243]; [@b72-arcr-38-2-243]; [@b81-arcr-38-2-243]). Taken together, all of these findings indicate that drinking patterns that define AUD are associated with a significantly increased risk of serious lung infections and acute lung injury and thereby contribute to the deaths of tens of thousands of Americans every year, and many more worldwide.
This review first will discuss key aspects of the epidemiology and pathophysiology of AUD and lung health, before focusing more in-depth on lung infections and acute lung injury, which comprise the majority of alcohol-related lung diseases. The article also will briefly review some of the experimental therapies that hold promise for decreasing the enormous morbidity and mortality caused by the "alcoholic lung" in our society.
Alcohol and the Airways
=======================
The potential influence of alcohol consumption on airway health and disease has been documented for a long time. Chronic alcohol ingestion constantly subjects the drinker's airways to high concentrations of alcohol vapor, as best evidenced by the use of alcohol breath tests (i.e., Breathalyzer). The volatile nature of alcohol is exploited in this common field sobriety test, which is reliably used as a surrogate to quantify blood alcohol concentrations. Interestingly, the alcohol vapor found in the airways is not caused by inhalation but is a result of the ready diffusion of alcohol from the airway blood supply across the airway epithelium and into the airways themselves ([@b28-arcr-38-2-243]). This process explains why alcohol vapor in the breath may be used to determine blood alcohol concentration. The alcohol then is deposited and metabolized in the airways. This process leads to the formation of reactive aldehydes (e.g., acetaldehyde), which in turn can interact and form harmful adducts with proteins and DNA ([@b67-arcr-38-2-243]). The formation of these adducts may disrupt normal cellular functions, induce inflammation, and impair healing. Taken together, these findings demonstrate that the airways---including the oral cavity and extending all the way to the alveolar space---are subjected to high concentrations of alcohol and its deleterious metabolites during intoxication.
Within the upper airways, chronic alcohol consumption leads to several alterations. First, chronic heavy drinking often is associated with poor tooth development and arrangement (i.e., dentition) as well as poor oral hygiene, and although these usually are attributed to poor nutritional and lifestyle choices, clinical studies have established that they also result, to some extent, from the direct effects of alcohol exposure on the upper airway. Specifically, alcohol decreases saliva production in the salivary glands located in front of the ears (i.e., the parotid glands) ([@b23-arcr-38-2-243]), thereby eliminating an important mucosal defense within the oral cavity. As a result, heavy drinkers are susceptible to dental caries and gingivitis ([@b26-arcr-38-2-243]), conditions that may be exacerbated by concurrent tobacco use, which is common in people with AUD. This alters the microenvironment of the mouth, making it more susceptible to colonization with certain bacteria, including gram-negative bacilli ([@b27-arcr-38-2-243]). Moreover, acute alcohol intoxication and the resulting decrease in the level of consciousness promotes aspiration of oral secretions into the lower airways because of diminished gag and upper-airway reflexes that would normally protect against this phenomenon. These modifications in the upper airways seem to contribute to the increased risk of lung infections, including those caused by more virulent gram-negative organisms, in chronic heavy drinkers.
This risk further is exacerbated by the negative effects of chronic alcohol ingestion on the lower airways. In particular, animal models have established that chronic excessive alcohol ingestion causes dysfunction of the mucociliary apparatus, an important host defense mechanism responsible for clearing harmful pathogens and mucus from the lower airways ([@b31-arcr-38-2-243]). An early experimental study in sheep investigating the effects of alcohol on ciliary beat frequency (CBF) demonstrated a dose-dependent effect, such that low alcohol concentrations actually stimulated CBF, whereas high concentrations impaired it ([@b48-arcr-38-2-243]). Later mechanistic studies found that whereas short-term alcohol exposure causes a transient increase in CBF, chronic exposure desensitizes the cilia so that they cannot respond to stimulation ([@b86-arcr-38-2-243]). Alcohol-induced failure of the mucociliary system could interfere with the clearance of pathogens from the airways and thereby may contribute to the increased risk of pulmonary infections in people with chronic heavy alcohol use ([@b71-arcr-38-2-243]).
Although alcohol's influences on upper and lower airway host defenses collectively are harmful, its role in causing specific diseases, such as asthma, within the conducting airways is less clear ([@b4-arcr-38-2-243]), despite some interesting historical references. For example, some documentation in Egyptian papyri dating back to about 2000 b.c.e. suggests the use of alcohol in the treatment of asthma ([@b44-arcr-38-2-243]), although one cannot be certain of the accuracy of the asthma diagnosis in these ancient writings. More than 1,000 years later, Hippocrates---who is regarded as the father of Western medicine---noted that wine has a variety of medicinal uses and is specifically beneficial for reducing sputum production ([@b47-arcr-38-2-243]); again, however, it is not clear if he was referring to asthma as we currently define the syndrome. Much more recently, [@b66-arcr-38-2-243] described the successful use of alcohol to treat three patients with intractable asthma who had failed all other treatments. In contrast, more modern epidemiological data suggest that chronic heavy drinking is associated with increased odds of all-cause mortality and hospitalization among patients with asthma, although a direct link between asthma control and alcohol use was not investigated ([@b77-arcr-38-2-243]).
To supplement the various anecdotal reports of using alcohol in the treatment of airway diseases, early mechanistic investigations demonstrated that alcohol itself seems to have bronchodilating properties in asthmatics. However, the effects differed depending on the alcohol concentration used as well as on the route of administration (i.e., intravenous versus oral) ([@b6-arcr-38-2-243]; [@b7-arcr-38-2-243]; [@b13-arcr-38-2-243]; [@b33-arcr-38-2-243]). Moreover, these observations directly conflict with findings that many asthmatics actually report exacerbations of their disease after alcohol ingestion ([@b5-arcr-38-2-243]; [@b12-arcr-38-2-243]; [@b78-arcr-38-2-243]). In an attempt to explain some of these discrepancies, [@b12-arcr-38-2-243] compared the effects of exposure to different types of alcohol in a clinical study. These analyses found that whereas pure alcohol did not appear to induce bronchial reactivity, some alcoholic beverages worsened asthma symptoms. These findings were the first to suggest that the nonalcohol components and additives of alcoholic beverages may be responsible for inducing asthma, rather than alcohol itself. Similar findings were seen in later studies that examined the effects of red wine in asthma ([@b21-arcr-38-2-243]; [@b78-arcr-38-2-243]). However, researchers have not yet been able to determine conclusively if alcohol ingestion has any clinically significant effects on asthma. For example, [@b11-arcr-38-2-243] showed that alcohol exposure triggered asthma-like pulmonary inflammation in an allergen-sensitized mouse model. The alcohol-exposed mice exhibited increased numbers of certain inflammatory cells (i.e., eosinophils) in fluid obtained from the lungs (i.e., bronchoalveolar lavage fluid), increased production of the main component of mucus (i.e., mucin), and constriction of the small airways (i.e., decreased bronchiole patency). These effects were not seen in mice that were exposed to alcohol but were not allergen sensitized, suggesting that alcohol can be an important trigger for airway reactivity in the context of an underlying allergic component. In contrast, [@b59-arcr-38-2-243] demonstrated that alcohol actually reduced airway hyperresponsiveness and airway inflammation in a mouse model of allergic asthma.
One potential explanation for the disparate findings in the literature regarding alcohol's role in airway disease is that some forms (i.e., phenotypes) of asthma may be more sensitive to the effects of alcohol than others. One subtype of asthma called aspirin-sensitive asthma or aspirin-exacerbated respiratory disease represents less than 10 percent of all asthma cases ([@b75-arcr-38-2-243]) but accounts for a disproportionately high number of severe asthma cases and can be extremely difficult to diagnose and treat ([@b9-arcr-38-2-243]). Interestingly, alcohol-induced respiratory symptoms are more common in patients with aspirin-exacerbated respiratory disease than in aspirin-tolerant asthmatics ([@b18-arcr-38-2-243]). These findings suggest that the potential irritant versus bronchodilator effects of alcohol may vary by disease subtype; however, further investigation is necessary to validate these observations.
Alcohol and Acute Lung Injury
=============================
ARDS is a severe form of lung injury characterized by fluid accumulation in the lung that is not related to heart problems (i.e., noncardiogenic pulmonary edema) as well as by flooding of the alveolar airspaces with protein-like (i.e., proteinaceous) fluid ([@b83-arcr-38-2-243]; [@b84-arcr-38-2-243]). ARDS develops in response to inflammatory stresses, including sepsis, trauma, gastric aspiration, pneumonia, and massive blood transfusions ([@b84-arcr-38-2-243]). Originally described by [@b3-arcr-38-2-243], ARDS is characterized by alveolar epithelial and endothelial barrier disruption, dysfunction of the lipoprotein complex (i.e., surfactant) coating the lung surfaces, and intense inflammation. Together, these alterations profoundly disrupt gas exchange and cause severe respiratory failure. Although much has been learned about the underlying pathophysiology of this syndrome over the past four decades, treatment of ARDS remains essentially supportive, and despite aggressive treatment in intensive care units and mechanical ventilation, the mortality rate for ARDS remains unacceptably high at 30 percent to 50 percent ([@b2-arcr-38-2-243]; [@b80-arcr-38-2-243]; [@b82-arcr-38-2-243]; [@b84-arcr-38-2-243]).
The association between alcohol abuse and acute lung injury only has been identified within the past 20 years, when [@b54-arcr-38-2-243] analyzed a patient database at the University of Colorado and reported that patients who were admitted to the hospital with a critical illness and who had underlying alcohol abuse were at about twofold-increased risk for developing ARDS. This original study was limited by the uncertain accuracy regarding the diagnosis of an underlying AUD in the database. However, a subsequent prospective study of 220 patients with septic shock, in whom a more precise diagnosis of an AUD was established using the Short Michigan Alcohol Screening Test, determined that the incidence of ARDS in patients with AUD was 70 percent (46 of 66), compared with 31 percent (47 of 154) in patients without AUD (*P* \< 0.001) ([@b56-arcr-38-2-243]). After controlling for potentially confounding variables, the relative risk of ARDS in alcoholic versus nonalcoholic patients was 3.7:1. Overall, 49 percent (46 of 93) of those patients that developed ARDS had an underlying AUD, consistent with the findings of the earlier study ([@b54-arcr-38-2-243]), in which 51 percent of the patients who developed ARDS were classified as alcoholics. If these findings are extrapolated to the population at large, then alcohol abuse contributes to the development of acute lung injury in tens of thousands of patients in the United States each year.
Alcohol-Related Mechanisms of Lung Injury
=========================================
Disruption of the Epithelial Barrier
------------------------------------
The recognition that excessive chronic alcohol ingestion has such a dramatic and independent effect on the risk of acute lung injury prompted a search for the underlying mechanisms. Because one of the cardinal features of ARDS is disruption of the alveolar epithelial barrier that regulates the fluid content of the airspace, this was a logical target for investigation. Maintaining the fluid balance of the alveolar space is critical for normal gas exchange. Acute lung injury involves the rapid development of noncardiogenic pulmonary edema, and patients with impaired alveolar epithelial fluid clearance are three times more likely to die from ARDS than patients with a maximal ability to clear lung fluid ([@b85-arcr-38-2-243]). Although the fluid balance in the lungs is regulated by the concerted actions of both epithelial and endothelial barriers ([@b52-arcr-38-2-243]), it is the alveolar epithelium which primarily prevents protein and fluid flow into airspaces ([@b58-arcr-38-2-243]). A pathological hallmark of ARDS is heterogeneous damage of the alveolar epithelium, with complete loss of the epithelial surface in some areas, whereas other alveoli remain relatively intact. Therefore, at a cellular level the extent of the alveolar epithelial damage may not be as widespread or as uniform as chest X-rays may suggest, and preservation and repair of the alveolar epithelium are key to survival.
In experimental animal models, chronic alcohol ingestion for as little as 6 weeks renders the lung susceptible to acute edematous injury ([@b34-arcr-38-2-243]; [@b79-arcr-38-2-243]). In these same models, chronic alcohol ingestion produces a lasting defect in the ability of the alveolar epithelium to form and/or maintain a tight physical barrier; specifically, primary alveolar epithelial cells isolated from alcohol-fed animals form relatively leakier monolayers in culture, even if there is no alcohol in the culture medium ([@b29-arcr-38-2-243]). In addition, the permeability of the alveolar epithelium to large proteins in vivo is increased approximately fivefold in the alcohol-fed rats ([@b29-arcr-38-2-243]). The mechanisms by which alcohol impairs the alveolar epithelial barrier are still being investigated. Animal models suggest that chronic alcohol ingestion interferes with the expression and formation of tight junction complexes within the alveolar epithelium (see [figure 1](#f1-arcr-38-2-243){ref-type="fig"}) ([@b24-arcr-38-2-243]). Tight junctions are closely associated areas of two cells where the membranes of the cells join together; they are critically necessary to form an impermeable barrier that can limit the passage of even very small molecules across cell layers ([@b43-arcr-38-2-243]; [@b53-arcr-38-2-243]; [@b69-arcr-38-2-243]). Only a few studies of alcohol's effects on the alveolar epithelium have been conducted in humans. The findings indicate that people with AUD have impaired alveolar-capillary permeability at baseline and develop more pulmonary edema in the setting of ARDS compared with people without AUD ([@b10-arcr-38-2-243]; [@b16-arcr-38-2-243]).
The experimental evidence that alcohol can cause a profound defect in the physical barrier of the alveolar epithelium led to the question of why alcohol abuse alone, in the absence of an acute stress such as sepsis, does not cause pulmonary edema. Additional studies revealed that alcohol causes a concurrent, and perhaps compensatory, increase in salt and water transport across the epithelium. This transport is mediated by specific epithelial sodium channels located in the apical membrane and by protein pumps (i.e., Na/K-ATPase complexes) in the basolateral membrane of the epithelial cells. The expression and function of both the Na/K-ATPase complexes and epithelial sodium channels are increased in the alveolar epithelium of alcohol-fed animals ([@b29-arcr-38-2-243]; [@b60-arcr-38-2-243]). Thus, as long as there are no additional stresses, the alcoholic lung seems to be able to limit edema formation by upregulating salt and water transport across the epithelium, thereby compensating for the marked increase in the leakage of fluid between cells (i.e., paracellular leakage) into the airways. In the presence of an acute inflammatory stress, such as sepsis or aspiration, however, the paracellular leak increases dramatically, and the alveoli flood with proteinaceous edema fluid that overwhelms the already upregulated transepithelial pumping mechanisms. This scenario is supported by findings in laboratory animals that even at baseline, the lungs of alcohol-exposed animals are unable to clear a salt and water challenge as efficiently, despite the compensatory increase in epithelial sodium channel and Na/K-ATPase function, reflecting the severe permeability defect in the paracellular barrier mechanisms ([@b29-arcr-38-2-243]).
Reduced Antioxidant Levels
--------------------------
Another fundamental mechanism that appears to drive many of the pathophysiological manifestations of the alcoholic lung phenotype is a severe depletion of glutathione stores within the alveolar space. Glutathione is the primary thiol antioxidant found in the alveoli; it serves an essential function in reactions catalyzed by the enzyme glutathione peroxidase, which clears harmful hydrogen peroxide and lipid hydroperoxides that readily form in the oxidizing environment of the lung. In both experimental animal models and humans, chronic alcohol ingestion causes a profound decrease of up to 80 percent to 90 percent in alveolar glutathione levels ([@b34-arcr-38-2-243]; [@b55-arcr-38-2-243]). This glutathione depletion cannot be explained by dietary deficiency or smoking because it also occurs in experimental animals with an otherwise sufficient diet ([@b34-arcr-38-2-243]); moreover, otherwise healthy smokers actually have increased glutathione levels within their alveolar space ([@b55-arcr-38-2-243]). Further analyses in experimental models found that alcohol-induced glutathione depletion seems to mediate the defects in alveolar epithelial barrier function. For example, when glutathione precursors such as procysteine or S-adenosylmethionine (SAMe) were added to the diet of alcohol-fed animals, the animals' alveolar epithelial barrier function was restored, and they no longer exhibited increased susceptibility to acute edematous injury compared with control-fed animals ([@b29-arcr-38-2-243]; [@b34-arcr-38-2-243]; [@b79-arcr-38-2-243]).
Another key function of the alveolar epithelium, namely the synthesis and secretion of surfactant---which is required to maintain alveolar integrity and gas exchange---also is impaired by chronic alcohol ingestion ([@b34-arcr-38-2-243]). This impairment also is mediated by glutathione deficiency in the cells, and particularly in the mitochondria, and is reversible with dietary procysteine supplementation ([@b29-arcr-38-2-243]). Although these animal models provide convincing evidence implicating glutathione depletion as a mediator of alveolar epithelial barrier dysfunction, additional studies in humans are necessary to confirm these findings.
The depletion of glutathione within the alveolar space of people with AUD explains many of the alcohol-related defects in the function of the alveolar epithelium as well as in the function of immune cells called macrophages (which will be discussed in the next section). But how does alcohol lower glutathione so profoundly? Glutathione levels are affected by oxidative stress and inflammation; however, lungs of alcohol-exposed animals show no gross evidence of inflammation or injury at baseline, and otherwise healthy alcoholics likewise have no indication of lung inflammation or oxidative stress. Without evidence of an oxidant assault on the otherwise healthy alcoholic lung, the question remains why there is such overwhelming glutathione depletion. An intriguing answer comes from recent studies showing that, at least in experimental models, chronic alcohol ingestion inhibits the expression and function of a protein called Nrf2. This protein is a master transcription factor that binds to the antioxidant response element (ARE) in the regulatory (i.e., promoter) region of hundreds of antioxidant and immune-response genes ([@b37-arcr-38-2-243]).
The alcohol-induced inhibition of Nrf2--ARE signaling is mediated at least in part by zinc. Specifically, Nrf2 function depends on adequate zinc levels, and alcohol interferes with the transporter molecules that mediate zinc absorption from the diet as well as its transport into the alveolar space ([@b42-arcr-38-2-243]). Consistent with this proposed mechanism, dietary supplementation with zinc restores Nrf2 binding to the AREs, preserves the glutathione pool within the alveolar space, and enhances alveolar epithelial barrier function in alcohol-fed rats ([@b42-arcr-38-2-243]; [@b50-arcr-38-2-243]; for more information on the role of zinc deficiency and zinc supplementation see the article by Barve and colleagues). These observations suggest that chronic alcohol ingestion lowers antioxidant defenses by interfering with Nrf2-dependent production of antioxidants, including glutathione, and that this may be one mechanism by which alcohol increases the lung's susceptibility to oxidant stress and, consequently, such conditions as sepsis, pneumonia, or infections resulting from aspiration.
Other Mechanisms
----------------
The pathophysiological mechanisms discussed thus far undoubtedly are just components of a highly complex network of alcohol-induced cellular perturbations. Experimental animal models have elucidated other key aspects of the alcoholic lung, including the role of two signaling molecules, transforming growth factor beta1 (TGFβ1) and granulocyte/macrophage colony-stimulating factor (GM-CSF), both of which help control the growth and function of immune cells, such as macrophages. In healthy people there is relatively little TGFβ1 in the adult lung; instead, alveolar epithelial integrity and the function of alveolar macrophages are under the influence of GM-CSF. Chronic alcohol ingestion increases the expression of TGFβ1 in the lung ([@b8-arcr-38-2-243]), and its activation during an acute stress situation, such as alcohol-induced transfer of toxic bacterial products from the intestine into the blood (i.e., endotoxemia), seems to further disrupt the already dysfunctional epithelial barrier function ([@b8-arcr-38-2-243]). Moreover, chronic alcohol ingestion dampens the expression of GM-CSF receptors in alveolar epithelial cells and macrophages ([@b40-arcr-38-2-243]). This relative imbalance in TGFβ1 and GM-CSF signaling in the alcoholic lung has important implications in the human lung epithelium, and critically ill patients with relatively higher ratios of TGFβ1 to GM-CSF in their alveolar space seem to have a higher mortality ([@b61-arcr-38-2-243]). The role of these two signaling molecules is supported by the observation that treatment with recombinant GM-CSF can rapidly restore alveolar epithelial function in alcohol-fed rats, both in vivo and in vitro ([@b62-arcr-38-2-243]).
Alcohol's effects on TGFβ1 also interface with its effects on antioxidant levels. Thus, in animal models the alcohol-induced increase in TGFβ1 decreased Nrf2 expression and function and interfered with the resolution of acute lung injury induced by bleomycin; this effect of alcohol could be mitigated by dietary supplementation with SAMe ([@b76-arcr-38-2-243]; for more information on the role of SAMe supplementation, see the article by Barve and colleagues). Interestingly, Nrf2 also regulates the expression of PU.1, a master transcription factor that mediates GM-CSF--dependent signaling ([@b74-arcr-38-2-243]). Accordingly, alcohol-induced reduction of Nrf2 also inhibits binding of PU.1 to its nuclear targets, which can be improved by zinc treatment ([@b50-arcr-38-2-243]). Thus, alcohol impairs epithelial barrier function in the lung through a complex set of mechanisms with several cycles and feedback mechanisms (see [figure 2](#f2-arcr-38-2-243){ref-type="fig"}); however, future studies will almost certainly elucidate further details.
Alcohol, Alveolar Macrophages, and Pneumonia
============================================
Lung infections are major causes of morbidity and mortality worldwide. Data from the Centers for Disease Control and Prevention consistently show that pneumonia is one of the top 10 causes of death in the United States and remains the leading cause of death from an infection ([@b57-arcr-38-2-243]). Alcoholism has been linked to pulmonary infections for over 200 years ([@b49-arcr-38-2-243]). Additionally, recent studies have demonstrated that people who abuse alcohol are not only more likely to develop pneumonia, but also are susceptible to more severe forms of the disease, are more likely to experience complications, and require greater use of resources. A prospective study by [@b1-arcr-38-2-243] examined features associated with increased use of health care services and risk for readmission in patients discharged with pneumonia. Interestingly, the only independent risk factor associated with increased health care utilization after discharge was alcohol abuse. Similarly, [@b19-arcr-38-2-243] demonstrated in a multivariate regression model that alcohol abuse was among independent risk factors that were significantly associated with the development of certain complications (i.e., complicated para-pneumonic effusion or empyema) in patients with community-acquired pneumonia.
Another experimental study using a pulmonary infection model of respiratory syncytial virus in mice found that chronic alcohol ingestion caused not only more severe infections, but also influenced the levels of various signaling molecules (i.e., cytokines), inducing a more robust proinflammatory cytokine profile ([@b38-arcr-38-2-243]). In this particular study, pulmonary inflammation in alcohol-exposed mice persisted for more than 7 days after infection, compared with 3 to 5 days in the control animals. Moreover, some alcohol-exposed mice showed severe inflammation with hemorrhage and edema. These results corroborate findings that infection in the setting of alcohol exposure increases the risk of complications such as ARDS. Similarly, other studies showed that people with AUD not only are more prone to develop community-acquired pneumonia, but are likely to suffer from infections that portend a worse prognosis and are more likely to be caused by virulent microorganisms that are more challenging to treat ([@b20-arcr-38-2-243]; [@b25-arcr-38-2-243]).
The mechanisms by which chronic and excessive alcohol consumption increases susceptibility to pneumonia are multifactorial. In addition to the already-discussed alterations in bacterial colonization and impaired host defenses in the upper and lower airways, increasing evidence suggests that chronic alcohol ingestion negatively impacts the immune functions of alveolar macrophages in a manner that is similar to its effects on epithelial barrier function. The alveolar macrophage is the primary immune cell in the alveolar space and is responsible for maintaining homeostasis of the lower airways through phagocytosis of pathogens and removal of debris. Animal studies have shown that chronic alcohol exposure causes significant alveolar macrophage dysfunction, leaving these normally active immune cells poorly equipped to phagocytose or kill invading organisms ([@b15-arcr-38-2-243]; [@b42-arcr-38-2-243]). Alveolar macrophages in alcohol-exposed animals also exhibit decreased production of important chemokines and mediators, which impairs their ability to recruit other cell types, namely neutrophils, during times of stress and infection ([@b32-arcr-38-2-243]). Although the majority of data focuses on the effects of chronic alcohol ingestion, experimental evidence further suggests that even acute exposure has similar detrimental effects on alveolar macrophage immune function, although these defects readily resolve ([@b45-arcr-38-2-243]). Taken together, these alcohol-mediated defects in alveolar macrophage function contribute to increased vulnerability to pulmonary infections.
Mechanisms of Alcohol's Effects on Alveolar Macrophages
-------------------------------------------------------
The precise mechanisms by which alcohol impairs alveolar macrophage immune function have yet to be elucidated; however, several observations indicate that the macrophages are subjected to an altered environment characterized by oxidative stress and zinc deficiency. Both clinical and experimental studies have detected increased oxidative stress in the alveolar space after alcohol exposure ([@b55-arcr-38-2-243]; [@b79-arcr-38-2-243]). The exact mechanisms responsible for inducing this redox imbalance remain uncertain, but several explanations have been put forth. An experimental rat model of chronic alcohol ingestion identified perturbations in lipid metabolism analogous to what is seen in alcohol-induced fatty liver ([@b64-arcr-38-2-243]). These alterations included suppression of genes responsible for fatty acid metabolism in the lungs of the alcohol-exposed rats, which caused accumulation of triglycerides and free fatty acids in the distal airspaces and resulted in immune dysfunction of the alveolar macrophages. In another model using mice, [@b87-arcr-38-2-243] demonstrated that alcohol induced oxidative stress through the upregulation of specific enzymes called NADPH oxidases, which are an important source of oxidants called reactive oxygen species in alveolar macrophages. A similar pattern of NADPH upregulation existed in human alveolar macrophages isolated from people with AUD. Restoring the redox balance in the lung could reverse many of these alcohol-induced defects and improve alveolar macrophage immune function ([@b14-arcr-38-2-243]; [@b88-arcr-38-2-243]).
Also, as noted above, chronic alcohol ingestion interferes with Nrf2 signaling in alveolar macrophages ([@b50-arcr-38-2-243]), thereby disrupting the expression of hundreds of genes that are crucial to combatting oxidative stress. Although the precise role of alcohol-mediated inhibition of the Nrf2--ARE pathway in mediating oxidative stress has not been completely clarified, this pathway represents a strategic target to direct future therapies.
Another important player in alveolar macrophage-mediated immunity is zinc. In experimental models, alveolar macrophages from alcohol-fed animals exhibit zinc deficiency in the fluid of the epithelial lining and have decreased intracellular zinc levels compared with alveolar macrophages from control-fed animals ([@b42-arcr-38-2-243]). These findings have been confirmed in alveolar macrophages collected from otherwise-healthy people with underlying AUD, even though these individuals had normal serum levels of zinc ([@b51-arcr-38-2-243]). Zinc is important for diverse immune functions, and its severe deficiency within the alveolar space may be one mechanism by which alcohol impairs innate immune functions within the lung. This role is further supported by findings that restoration of zinc bioavailability in the alveolar space also restores the phagocytic capacity of alveolar macrophages ([@b42-arcr-38-2-243]).
As discussed previously, alcohol not only alters the environment of the alveolar space but also directly affects GM-CSF signaling, which regulates the maturation, terminal differentiation, and function of alveolar macrophages. Chronic alcohol ingestion downregulates the expression of GM-CSF receptors on the cell surface of the alveolar macrophages, thereby impairing their immune function ([@b41-arcr-38-2-243]). Experimental models demonstrate that restoration of GM-CSF signaling reverses this alcohol-induced dysfunction ([@b41-arcr-38-2-243]), suggesting that this might be a potential therapeutic approach. Also, as mentioned earlier, recent evidence suggests that interactions exist between Nrf2 and the GM-CSF pathway, with Nrf2 regulating the expression and activity of the transcription factor PU.1, which controls GM-CSF expression ([@b74-arcr-38-2-243]). Understanding the complex interplay between all of these systems in the alcoholic lung will become exceedingly important in the search for new and effective treatments. For example, zinc supplementation in experimental models of chronic alcohol ingestion improves redox balance, enhances Nrf2 binding in the nucleus, corrects alveolar macrophage immune dysfunction, and restores GM-CSF receptor expression and signaling, suggesting that one target can interact with several implicated pathways ([@b42-arcr-38-2-243]; [@b50-arcr-38-2-243]).
Overall, these alterations in host defense and immune dysfunction explain how chronic excessive alcohol ingestion predisposes to pulmonary infection. It is important to realize, however, that the effects of alcohol on alveolar macrophage innate immune function are just one facet of the complex pathophysiology of alcohol and the lung's immune system. Alcohol also impairs neutrophil migration to the infected lung, and abnormalities in this and other components of the adaptive immune response clearly are involved but are beyond the scope of this brief review.
Potential Therapeutic Strategies for the Alcoholic Lung
=======================================================
Currently there are no specific therapies that can modify the alcoholic lung in the clinical setting. Clearly, as with all alcohol-related health issues, the ideal treatment would be abstinence in people with underlying AUD and/or a safe level of consumption in people who choose to drink for social reasons. However, this ideal will be impossible to achieve in any meaningful timeframe and it therefore is critical to identify, test, and validate therapeutic strategies that can limit the morbidity and mortality of alcohol-related diseases, including acute lung injury and pneumonia.
For identifying candidate approaches, it is important to recognize that a large percentage of people with AUD are otherwise healthy and can be identified by relatively simple health-screening questionnaires well before they develop serious organ dysfunction ([@b22-arcr-38-2-243]; [@b73-arcr-38-2-243]). Also, many people with AUD seek treatment, and structured alcohol treatment programs offer an opportunity to initiate adjunctive therapies designed to enhance lung health. The experimental results reviewed in this article provide some suggestions for promising approaches that could be used in such settings. For example, as discussed previously, clinical studies have shown that even otherwise-healthy people with AUD have glutathione and zinc deficiency within the alveolar space ([@b51-arcr-38-2-243]; [@b55-arcr-38-2-243]). Moreover, animal studies found that dietary supplementation with zinc and/or a glutathione precursor such as SAMe can enhance lung health even in the context of chronic alcohol ingestion ([@b29-arcr-38-2-243]; [@b34-arcr-38-2-243]; [@b42-arcr-38-2-243]; [@b50-arcr-38-2-243]; [@b79-arcr-38-2-243]; also see the article by Barve and colleagues). Accordingly, researchers at the Atlanta VA Medical Center initiated a randomized, placebo-controlled trial of dietary zinc and/or SAMe in otherwise-healthy individuals with AUD enrolled in the center's Substance Abuse Treatment Program (available at: clinicaltrials.gov, trial NCT01899521). This trial currently is in progress with the goal of determining whether these supplements, alone or in combination, can enhance glutathione and zinc bioavailability in the alveolar space and improve alveolar macrophage immune function.
Another potential therapeutic target is Nrf2, which can be activated by plant-derived compounds (i.e., phytochemicals), such as sulforaphane ([@b35-arcr-38-2-243]; [@b37-arcr-38-2-243]). One clinical study ([@b17-arcr-38-2-243]) evaluating the effects of 7-day treatment with the Nrf2 activator Protandim® in patients with AUD did not identify any significant improvement in glutathione levels or epithelial function. However, it is possible that combination therapy with an Nrf2 activator plus zinc and/or SAMe may be more effective than zinc and/or SAMe alone, and clinical trials in the near future hopefully will be able to answer that question.
The goal of these treatments clearly would not be to make it safe(r) to consume excessive amounts of alcohol. However, just as clinicians try to mitigate the health effects of metabolic syndrome in obese patients using medications that target diabetes, hypertension, or dyslipidemia while the patients struggle with weight loss, it is imperative to decrease the risk of pneumonia, acute lung injury, and other life-threatening complications while people with AUD work to achieve abstinence. There also may be some concerns about alcoholic patients' compliance with chronic oral treatments, such as zinc and SAMe supplements. However, many patients with AUD seek care for their addiction precisely because they are motivated to become or remain healthy and, consequently, are likely to adhere to their treatment regimen. Moreover, inadequate adherence to medical regimens is not a concern unique to this patient population but occurs in patients with many chronic medical conditions; examples include the low use of continuous positive airway pressure therapy for obstructive sleep apnea ([@b65-arcr-38-2-243]) and poor adherence with anti-diabetic medications in adults with type 2 diabetes ([@b67-arcr-38-2-243]). Even if patients seeking treatment for AUD have equally low adherence rates, tens of thousands of individuals could benefit from these relatively simple and inexpensive treatments every year in the United States alone. Researchers and clinicians are just beginning to scratch the surface of this challenging problem, but the rapid pace of experimental and clinical research in the past two decades offers hope that in the relatively near future the devastating effects of AUD on lung health can be ameliorated.
Dr. Mehta is supported by a Career Development Award (1IK2CX000643) from the Clinical Science Research and Development Service of the Veterans Affairs Office of Research and Development. Dr. Guidot is supported by grants from the National Institute on Alcohol Abuse and Alcoholism (R01--AA--017627) and the National Heart, Lung, and Blood Institute (R01--HL--125042).
The diagnosis of an AUD was based on the Short Michigan Alcohol Survey Test ([@b70-arcr-38-2-243]).
**Financial Disclosure**
The authors declare that they have no competing financial interests.
Adduct
: A product of a direct addition of two or more distinct molecules, resulting in a single reaction product
Alveolar
: Pertaining to the *alveoli*
Alveoli
: The small sac-like structures at the end of the airways where gas exchange occurs
Antioxidant
: A substance (e.g., glutathione and vitamins A and E) that inhibits oxidation, serving as a defense against harmful free radicals and *oxidative stress*
Aspiration
: Entry of material (e.g., food, drink, saliva) from the digestive tract into the airways
Bronchoalveolar Lavage
: Procedure where fluid is injected through a tube into a small airway of the lung and then collected and tested for the presence of bacteria and other compounds; the procedure is used to diagnose infections and other lung diseases
Bronchodilating
: Causing widening of the airways
Cilia
: Fine, hair-like structures on the surface of *epithelial cells* lining the airways; their coordinated movement helps clear microorganisms and other particles as well as mucus from the airways
Edema
: Abnormal accumulation of fluid in the tissues and body cavities; typically causes swelling of the tissues
Empyema
: Collection of pus in a cavity of the body; if pus accumulation occurs in the pleural cavity, it is considered a subtype of *parapneumonic effusion*
Endothelial Cell
: Type of cell lining the interior of body cavities and blood vessels; endothelial cells control the passage of materials and the transit of white blood cells into and out of the bloodstream
Epithelial Cell
: Type of cell lining the tissues exposed to the outside of the body, such as the skin, but also the lining of the intestine and airways
Gingivitis
: A common gum disease that causes irritation and inflammation of the gums, characterized by redness and swelling of the gums
Granulocyte/Macrophage Colony-Stimulating Factor (GM-CSF)
: Cytokine released by various white blood cells and lung *epithelial cells* that stimulates the growth of additional white blood cells; it is produced as part of the immune response so that activation of a small number of immune cells, particularly macrophages, leads to a rapid increase in the number of these cells
Leukopenia
: Abnormal reduction in the number of white blood cells
Mitochondria
: Structures within cells that generate most of cell's energy through the production of adenosine triphosphate (ATP)
Mucociliary
: Pertaining to the mucus and the *cilia* of the *epithelial cells* lining the airways
Mucociliary Apparatus
: The layer of cells lining the surface of the respiratory tract that are covered by a thin layer of mucus and which carry *cilia*, whose rhythmic beating helps clear the airways
Oxidative Stress
: An imbalance between oxidants (e.g., free radicals) and *antioxidants* that can lead to excessive oxidation and cell damage
Parapneumonic Effusion
: Type of fluid accumulation between the two membranes surrounding the lungs (i.e., in the pleural cavity) that results from pneumonia and other lung disorders
Permeability
: Capacity of membranes (e.g., the walls of the blood vessels) to allow the passage of fluids, small molecules, or even whole cells from one side of the membrane to the other
Phagocytosis
: Process by which certain cells (phagocytes) engulf foreign particles in special small vesicles where they can be destroyed by enzymes
Promoter
: A DNA segment located at the start of a gene's coding sequence that provides a binding site for the enzymes that initiate transcription
Reactive Oxygen Species (ROS)
: Highly reactive oxygen--containing free radicals that are generated during oxidative metabolism. ROS can react with and damage lipids, proteins, and DNA in cells, causing *oxidative stress*. Common ROS include hydrogen peroxide, superoxide radicals, and hydroxyl radicals
Sepsis
: Inflammatory response throughout the body in response to an infection; can lead to multiple organ failure and death
Surfactant
: Lipoprotein complex formed by *alveolar* cells that helps ensure the lungs' ability to expand during respiration, regulate the size of the *alveoli,* and prevent fluid accumulation in the lungs; also plays a role in innate immunity of the lungs
Transforming Growth Factor Beta1 (TGFβ1)
: Cytokine that helps control the growth, proliferation, differentiation, and cell death of different types of immune cells; it thereby helps control the activity of the immune system
Transcription Factor
: A protein that regulates gene expression by binding to *promoters* on the DNA near the start of the gene, thereby activating other proteins involved in transcription
{#f1-arcr-38-2-243}
{#f2-arcr-38-2-243}
|
[Refractive surgery and the non-freeze BKS set. Reliability of our Lyon methods. Value of our results].
The authors analysed the results of 24 patients who underwent non-freeze refractive surgery with the BKS set. 22 myopic and 6 hypermetropic keratomileusis, and 6 epikeratoplasty are evaluated. The majority of patients had no astigmatism (or some irregular one) on corneoscopy. The final refraction may take up to 6 months to stabilize. The technique is difficult but may have application in the visual rehabilitation of these patients. |
using System;
using System.Data;
using System.Configuration;
using System.Collections;
using System.Web;
using System.Web.Security;
using System.Web.UI;
using System.Web.UI.WebControls;
using System.Web.UI.WebControls.WebParts;
using System.Web.UI.HtmlControls;
using WeiSha.Common;
using Song.ServiceInterfaces;
using Song.Entities;
using System.Net;
using System.Drawing;
namespace Song.Site.Manage
{
public partial class Welcome : Extend.CustomPage
{
//
protected Hashtable numitem = new Hashtable();
protected void Page_Load(object sender, EventArgs e)
{
numItem(); //各项数值
fillServerInfo();
datainit();
//当前系统版本号
//lbVersion.Text = System.Reflection.Assembly.GetExecutingAssembly().GetName().Version.ToString();
}
private void numItem()
{
//课程数，试题数
ViewState["counum"] = Business.Do<ICourse>().CourseOfCount(-1, -1, -1);
ViewState["quesnum"] = Business.Do<IQuestions>().QuesOfCount(-1, -1, -1, -1, -1, null);
//学员数,在线数
ViewState["accnum"] = Business.Do<IAccounts>().AccountsOfCount(-1, null);
ViewState["onlinenum"] = Extend.LoginState.Accounts.OnlineCount;
}
/// <summary>
/// 填充服务器信息，探针
/// </summary>
private void fillServerInfo()
{
try
{
//IP、端口、域名
ltIp.Text = WeiSha.Common.Server.IP + ":" + WeiSha.Common.Server.Port;
//ltDomain.Text = WeiSha.Common.Server.Domain;
//操作系统，IIS版本
ltOs.Text = WeiSha.Common.Server.OS;
ltIISver.Text = WeiSha.Common.Server.IISVersion;
ltDotNetver.Text = WeiSha.Common.Server.DotNetVersion;
//硬件,cpu个数，主频，内存大小
ltCpucount.Text = WeiSha.Common.Server.CPUCount.ToString();
ltHz.Text = WeiSha.Common.Server.CPUHz;
ltRamSize.Text = WeiSha.Common.Server.RamSize.ToString();
//程序所在路径
ltPath.Text = WeiSha.Common.Server.ProgramPath;
////数据库类型
//ltDatabaseType.Text = WeiSha.Common.Server.DatabaseType.ToUpper();
}
catch (Exception ex)
{
WeiSha.Common.Log.Error(this.GetType().ToString(), ex);
}
}
/// <summary>
/// 相关数据的初始化
/// </summary>
private void datainit()
{
try
{
string sql = @"select top {1} o.Org_ID,o.Org_Name,o.Org_PlatformName,o.Org_AbbrName,c.count
from(select Org_ID,COUNT(*) as count from {0}
group by Org_ID ) as c
right join Organization as o on o.org_id=c.org_id order by count desc";
//各机构的课程数
rptCourse.DataSource = Business.Do<ISystemPara>().ForSql(string.Format(sql, "Course", 10));
rptCourse.DataBind();
//学员数量
rptAccouts.DataSource = Business.Do<ISystemPara>().ForSql(string.Format(sql, "Accounts", 10));
rptAccouts.DataBind();
//试题数量
rptQues.DataSource = Business.Do<ISystemPara>().ForSql(string.Format(sql, "Questions", 10));
rptQues.DataBind();
}
catch (Exception ex)
{
WeiSha.Common.Log.Error(this.GetType().ToString(), ex);
}
}
}
}
|
Q:
Software PLL tracking of carrier frequency in bandlimited transmission
My understanding is that a PLL(either in hardware or software) can recover the carrier frequency(or be used to correct the frequency offset) of a system. My question is how does this work when the transmitter is sending a pulse-shaped signal?
For a an approximate sinusoid the operation of the PLL makes sense but how does tracking work for carriers transmitting data?
As an example, suppose you're receiving a raised-cosine pulse, what do you do?
A:
Here is a link to an example carrier tracking implementation for a QPSK and QAM system, applicable to full-response raised cosine pulse shaping. This post also has links to many other concerns with demodulating the waveform, including timing recovery and setting the parameters in the tracking loop implementation.
Recovering signal for psk
A x4 carrier recovery approach may be the simplest way to see how the pulse shaping effects the carrier recovery. For QPSK without pulse shaping you can recover the carrier by raising the waveform to the fourth power, and then dividing the resulting 4x carrier by four to complete the recovery. This is because phases add when you multiply, so if we have four possible phases in our modulated signal:
$$e^{(j\omega t + 0)}$$
$$e^{(j\omega t + \pi/2)}$$
$$e^{(j\omega t + \pi)}$$
$$e^{(j\omega t + 3\pi/2)}$$
Raising to the 4th power results in the following for all the cases above.
$$e^{(j4\omega t + 0)}$$
If we observe our waveform over time and it instantly goes from one phase location to the other (no pulse shaping, infinite bandwidth), then the 4th power result will be a pure tone at 4x the carrier frequency with no other components.
However if we slowly transition from one phase to the other, we will still get a pure tone at 4x the carrier frequency, but there will be significant energy in sidebands close to this frequency as well. The 4x tone will still be the strongest in vicinity of this 4x signal and is easily tracked with a PLL to complete recovery. (This is evidenced by a positive mean in the baseband equivalent analytic signal). It is because this signal is the strongest that a PLL can track it (typically if the signal being tracked is +6 dB higher than the sidebands a PLL can lock to it), and it is because of the additional sideband energy that we need to the PLL to complete the recovery, effectively acting as narrow bandpass filter to provide a clean carrier.
I added some graphics below for the simpler case of BPSK with and without pulse-shaping that will hopefully provide an intuitive answer. Personally I find it much simpler to think and work with describing frequency using the complex exponential ($e^{j\omega t})$ rather than with cosines and sines, and for the same reason I avoid including an actual carrier but model at the baseband equivalent analytic signal. However I think in this case showing an actual sinusoidal carrier will more immediately get across the point I am trying to make. For the same reason, this is very illustrative in showing how the pulse shaping affects a tracking loop but it is not how I would typically do carrier recovery (see the link above for a typical software recovery loop I would implement).
This first image shows a sinusoidal carrier with an example (1 0 1) data pattern. Below the data pattern is shown the result of BPSK modulation with no pulse shaping applied (infinite bandwidth available). Observe in the third plot showing the modulated signal, that the phase is changing from 0 to $\pi$ radians as the data transitions. This abrupt change back and forth of the phase would prohibit a simple phase tracking PLL from tracking the phase: if it could even lock onto one phase state (because the data doesn't transition for some time for example), once the data transition occurs the very significant phase error that would occur would cause a simple tracking loop to break lock (unless the phase detector had 0°/180° ambiguity -- hint, hint at another recovery approach!). Another way of describing this, with a random data pattern that is 50% ones and 50% zeros, the carrier would be completely suppressed and therefore does not exist, so there is no signal at that frequency for any loop to lock onto. Notice too that in the example plot I give, the data transitions are not commensurate with the carrier. I did that purposely just to show that regardless of the data rate and where transitions occur, squaring this signal will result in a pure tone (when no pulse shaping or other bandwidth limiting is used) at exactly twice the rate of the carrier.
The fourth plot is simply the waveform in the third plot squared with no other filtering applied. This waveform is completely in phase with the original carrier, at exactly twice the frequency. In this case we could simply pass this signal into a frequency divide by two function (quite simple) and we would completely recover the carrier. No PLL is needed, but if there were any other noise sources present, a PLL would help increase the SNR of our recovered carrier in the presence of noise. However our waveform itself and the recovery process, in this case, contributes no additional noise or distortion.
What is occurring by squaring the signal is we are doubling the frequency (and the phase). This is clear from the trigonometric relationship:
$$cos(\alpha)*cos(\beta) = \frac{1}{2}cos(\alpha+\beta)+ \frac{1}{2}cos(\alpha-\beta)$$
$$cos(2\pi f_c t + \phi)cos(2\pi f_c t + \phi) = \frac{1}{2}cos(4\pi f_c t + 2 \phi)+ \frac{1}{2}cos(0)$$
$$ = \frac{1}{2}cos(4\pi f_c t + 2 \phi)+ \frac{1}{2}$$
So if the phase is only in two states: 0 (0°) and $\pi$ (180°), doubling this results in 0 and 2$\pi$ which is also 0.
Now observe what occurs in the same situation with pulse shaping as shown in the plot below. Here the only difference is a pulse shape has been added to each symbol. Notice that the result is to only add an amplitude variation (the pulse shape) to the squared signal but it has no effect on the phase. This is an important observation as to why a normal tracking loop could still track the phase in this situation, and also illustrates why the loop that is used should be able to "fly-wheel" in the absence of updates (as most tracking loops in both carrier and timing recovery). The phase in the doubled signal is in phase with the carrier at exactly twice the frequency but the amplitude is going up and down. This does of course impact the SNR of the recovered signal, as there are fewer phase error updates for tracking but unlike the case of the modulated signal itself, the phase does not abruptly change in a manner that would be disastrous for the loop to track. This also shows the importance of using a phase tracking loop in this case, which will ride through the amplitude variations and create a clean doubled carrier with no amplitude variation.
This is perhaps clearer by comparing the two final cases of the multiplied outputs directly as shown below. Here we clearly see that the pulse shaping only affects the amplitude and not the phase, hence a phase tracking loop should be able to track and recreate a cleaner replica of the doubled carrier signal, which we would then follow with a divide by two to completely recover the carrier.
The plots above should provide a satisfactory intuitive explanation in the effects of pulse shaping on carrier tracking loops, but not to suggest the favored approach to doing carrier recovery. In a digital or software implementation instead of squaring, PLL and divider, I would suggest decision directed and other similar digital Costas-Loop approaches as I have shown in the link above.
Another intuitive explanation is given by observing the above signals in the frequency domain, and noting how the carrier is suppressed prior to squaring and then recreated at twice the carrier frequency after squaring (or raising to the fourth power for QPSK, to the eight power for 8-PSK etc).
|
The ultimate Bitcoin Cash sticker for shop windows. Weather-resistant. Made with the highest quality materials and UV-resistant ink. Glossy finish. Ideal for outdoor and indoor use. 5 x 2 in (12.7 x 5.1 cm) |
0
What is -16918.935 rounded to the nearest integer?
-16919
Round -3315245.579 to the nearest one hundred thousand.
-3300000
What is -0.0471183099 rounded to 4 dps?
-0.0471
What is 0.000000908107926 rounded to seven dps?
0.0000009
What is 11.302217 rounded to the nearest ten?
10
Round 0.00000024086257 to 7 dps.
0.0000002
What is -239343.157 rounded to the nearest ten thousand?
-240000
Round -0.006222260615 to 5 dps.
-0.00622
Round 0.283676057 to 4 dps.
0.2837
Round -226575716 to the nearest one million.
-227000000
Round -772764255 to the nearest one hundred thousand.
-772800000
What is 0.0000594144339 rounded to 7 dps?
0.0000594
What is 6406.99239 rounded to the nearest 100?
6400
Round -1458300.05 to the nearest 100.
-1458300
What is 34.7879489 rounded to two dps?
34.79
What is 6672773.2 rounded to the nearest 1000000?
7000000
What is -460.7225807 rounded to the nearest 10?
-460
Round 0.000004196047847 to 7 decimal places.
0.0000042
What is -9980847.147 rounded to the nearest 100?
-9980800
Round -7488475600 to the nearest 1000000.
-7488000000
Round 0.186301731 to 4 dps.
0.1863
Round -0.622083239 to five dps.
-0.62208
Round 23643230.48 to the nearest one hundred thousand.
23600000
What is -716.8232 rounded to the nearest one hundred?
-700
Round -2910478.8 to the nearest ten thousand.
-2910000
What is 0.057691608 rounded to 4 decimal places?
0.0577
Round -0.0661560514 to three dps.
-0.066
What is -11816143.3 rounded to the nearest 100000?
-11800000
Round -0.0403367999 to 3 decimal places.
-0.04
Round -0.79229078 to one decimal place.
-0.8
Round 290158.422 to the nearest one thousand.
290000
Round -22071485.73 to the nearest 1000000.
-22000000
Round -0.21327147 to three decimal places.
-0.213
Round -679975746 to the nearest 100000.
-680000000
Round 6013.52683 to 1 decimal place.
6013.5
What is 0.2541505672 rounded to five dps?
0.25415
Round -985683.497 to the nearest one hundred thousand.
-1000000
Round 1173.23984 to 0 decimal places.
1173
What is 294977938 rounded to the nearest one hundred thousand?
295000000
What is -214.919859 rounded to 0 decimal places?
-215
What is -715926.757 rounded to the nearest 10?
-715930
Round -1851.756085 to the nearest ten.
-1850
Round -0.000002122510505 to 7 decimal places.
-0.0000021
Round -52197.34588 to the nearest 10.
-52200
What is 1190774.4554 rounded to the nearest one hundred thousand?
1200000
Round -0.01520113975 to 4 dps.
-0.0152
Round 0.0000562299776 to six decimal places.
0.000056
What is -0.0053844621 rounded to three dps?
-0.005
Round -8.8521697 to two dps.
-8.85
What is -515024.79 rounded to the nearest one hundred?
-515000
What is -0.0057189255 rounded to 4 decimal places?
-0.0057
Round 681.146 to the nearest one million.
0
Round -28144604.75 to the nearest 1000.
-28145000
What is 0.000006071556143 rounded to six decimal places?
0.000006
What is -0.00910831785 rounded to seven dps?
-0.0091083
Round 1.0989985627 to two dps.
1.1
Round -0.00104760444 to four decimal places.
-0.001
What is 11125243.1 rounded to the nearest one million?
11000000
What is 1150562.7036 rounded to the nearest 10000?
1150000
What is -4015.3597 rounded to the nearest integer?
-4015
What is -9740371.72 rounded to the nearest one thousand?
-9740000
Round 0.00059768438 to 4 dps.
0.0006
Round -1477293.54 to the nearest 10000.
-1480000
What is -0.000185846 rounded to 1 dp?
0
What is -6.9037412 rounded to two dps?
-6.9
What is -262745393 rounded to the nearest 100000?
-262700000
Round 208.560844 to one decimal place.
208.6
Round -278762800 to the nearest one hundred thousand.
-278800000
What is -0.7383950321 rounded to 1 decimal place?
-0.7
What is -7443520.54 rounded to the nearest one thousand?
-7444000
What is -0.000998484859 rounded to 7 dps?
-0.0009985
What is -4755041.061 rounded to the nearest 100000?
-4800000
Round 0.0000007576203509 to 7 dps.
0.0000008
Round 0.00068522731 to six dps.
0.000685
What is -0.0067845698 rounded to three decimal places?
-0.007
Round -0.0000241781817 to 7 decimal places.
-0.0000242
What is 0.000289900678 rounded to five decimal places?
0.00029
Round 52.42998692 to two dps.
52.43
Round -9.796888442 to three decimal places.
-9.797
Round -0.066176338 to 4 dps.
-0.0662
Round -0.1266447811 to 2 dps.
-0.13
Round 0.000503471206 to 5 decimal places.
0.0005
Round 0.193278223 to 4 decimal places.
0.1933
Round -131252.1517 to the nearest integer.
-131252
Round 9.6618724 to 0 dps.
10
Round -0.005605904611 to 3 dps.
-0.006
What is 24335800.46 rounded to the nearest 10000?
24340000
Round -0.4994609187 to 3 dps.
-0.499
Round 0.000825005462 to 4 decimal places.
0.0008
Round 0.0754834611 to 4 dps.
0.0755
What is 3552964900 rounded to the nearest one million?
3553000000
Round 321733547.8 to the nearest 100000.
321700000
Round 17896.8524 to the nearest one thousand.
18000
What is 0.0000038028912 rounded to seven dps?
0.0000038
Round -22.8500237 to 2 dps.
-22.85
Round 58685.2993 to the nearest 1000.
59000
Round 1201.26067 to the nearest one hundred.
1200
Round -0.000147239029 to 6 dps.
-0.000147
Round -1308723.795 to the nearest 10000.
-1310000
Round 128443680 to the nearest 10000.
128440000
Round 14528.23451 to the nearest integer.
14528
Round -0.4840458215 to 2 decimal places.
-0.48
What is 2077394.619 rounded to the nearest one hundred thousand?
2100000
What is -0.0125936904 rounded to 7 dps?
-0.0125937
Round 0.00187106712 to four dps.
0.0019
Round 0.00802670756 to 5 dps.
0.00803
Round 15494.6605 to the nearest integer.
15495
Round 0.0078642716 to four dps.
0.0079
Round 0.000299352599 to seven dps.
0.0002994
What is 0.0139260993 rounded to 3 decimal places?
0.014
What is -71.23998786 rounded to the nearest integer?
-71
Round 32233446 to the nearest 1000000.
32000000
Round -0.0707611734 to two dps.
-0.07
What is -78.64621 rounded to the nearest integer?
-79
Round 34641.5605 to the nearest ten.
34640
What is -141589677 rounded to the nearest one million?
-142000000
Round 0.001777155114 to 4 dps.
0.0018
Round -34749732 to the nearest 100000.
-34700000
What is 758546391 rounded to the nearest 10000?
758550000
Round 0.103450699 to two dps.
0.1
Round -0.0020113424 to 5 decimal places.
-0.00201
Round 708.4572728 to 0 decimal places.
708
Round 17.664831 to zero decimal places.
18
What is 1680.75409 rounded to 1 dp?
1680.8
Round -1551782.856 to the nearest one hundred thousand.
-1600000
Round 0.040051015 to four decimal places.
0.0401
What is -60456.9315 rounded to the nearest ten thousand?
-60000
What is 10831844.21 rounded to the nearest 1000?
10832000
What is 0.001213430839 rounded to 4 dps?
0.0012
Round 0.0071940928 to 3 dps.
0.007
Round 0.000716852633 to 6 dps.
0.000717
What is -176.60571201 rounded to one dp?
-176.6
What is -15363240.9 rounded to the nearest 100000?
-15400000
What is -0.046817447 rounded to four decimal places?
-0.0468
What is 0.005248264487 rounded to four dps?
0.0052
Round 960809.81 to the nearest one thousand.
961000
Round -0.00000060513472 to 6 decimal places.
-0.000001
Round 0.000138561767 to seven dps.
0.0001386
Round 0.00322215601 to 5 decimal places.
0.00322
What is -5107.7196 rounded to the nearest ten?
-5110
Round 556060.1573 to the nearest 10000.
560000
Round 0.00747274 to one dp.
0
What is -92772614 rounded to the nearest ten thousand?
-92770000
Round -9291840.8 to the nearest ten thousand.
-9290000
Round 213.708969 to the nearest 10.
210
What is -6.02581932 rounded to two dps?
-6.03
What is 62.439035 rounded to 2 decimal places?
62.44
Round 5.1329288 to two dps.
5.13
Round -232154236 to the nearest 1000000.
-232000000
What is 0.536602862 rounded to two dps?
0.54
Round 45770803 to the nearest one million.
46000000
Round -0.0000043763511 to six decimal places.
-0.000004
What is -4689171760 rounded to the nearest 1000000?
-4689000000
What is 0.0003426572 rounded to 4 decimal places?
0.0003
What is 0.188545128 rounded to 2 dps?
0.19
What is 0.0005703007 rounded to seven dps?
0.0005703
What is -0.0509329486 rounded to 4 decimal places?
-0.0509
Round -5.360486 to the nearest 10.
-10
Round 207266.601 to the nearest 100000.
200000
What is -3510311.5 rounded to the nearest 1000?
-3510000
What is -30243743.73 rounded to the nearest 1000?
-30244000
What is -4560978.54 rounded to the nearest o |
//
// HTTPURLResponse.swift
// MastodonKit
//
// Created by Ornithologist Coder on 6/1/17.
// Copyright © 2017 MastodonKit. All rights reserved.
//
import Foundation
extension HTTPURLResponse {
var pagination: Pagination? {
return allHeaderFields["Link"].flatMap { $0 as? String }.map(Pagination.init)
}
}
|
Q:
How can I establish the nature of a person/group without action?
How can one establish the nature of a person/group to the reader without relying on actions to 'show' it? For example, if I have a group which is evil, how could I convey that to the reader without actions? Telling is of course an option, but I feel like I need to back it up with something, so the reader will know the group is evil beyond a doubt.
ADDITIONAL EXAMPLE: Some people were getting confused over what I was going for, so I've attempted to clarify it here: Most authors will show a person or group is evil by showing an evil action. Maybe a brutal murder. My difficulty is that if I want to remind the reader how evil this person is, I have to show that murder again, or create a new one. I call this relying on action: in order to show the nature of a person/group, you have to use repeating actions.
Alternatively, I'm going for a passive approach. I want a character or group to be inherently understood to be evil. Action is not off of the table, but it's not the reason why they are considered evil (you can reinforce the image with actions all you want). The reason they are considered evil is _____. That blank space is what I'm looking for.
A good example of this being done is Star Wars, specifically episode IV. Basically from the moment they are introduced, we understand the Empire and Sith are evil, and the Resistance and Jedi are good. I cannot tell how this is conveyed beyond all doubt.
In addition to simply conveying the nature of the person/group, I need to do so in a way that dispels all doubt. The reader needs to know that this person or group is good, evil, or whatever their nature is. And I need to do it without relying on actions. How can I do this?
Note: In the event that you use Star Wars as an example as I did, please be aware that I have not yet seen The Last Jedi. Please do not spoil it for me.
A:
Be aware that Star Wars, as most fantasy fiction, relies strongly on tropes and cliches. This means that
1) you expect a villain at some point
2) the villain's traits are obvious: dark, grim, hunchback, speaking softly, etc.
This is getting more and more difficult as we go afar from the usual cliches. For instance, if you want to subvert a cliche or create a surprise effect, this doesn't work.
First of all, you need to establish the rules of your world. If I have a nazi swastika tattooed on my neck, today, is quite likely that I'm not a good person. So visual symbols or identifiers can help.
Beyond that, I must confess that I don't know how to help. Every character is always described by their actions (words included) rather than the look. And this is for a good reason: how lame and boring would be a character described just by the look? And how more interesting and complex and tridimensional can be a character who speaks with his actions?
Don't rely too much on anything beyond actions - that is the advice I struggle to follow in my writing, and that I give to you as well.
A:
I believe an earlier reply offered a way to define the group without having to re-tell some historic event. You can describe the motivations of the group. Along with their motivations you can use their emotional response to either events or even concepts. How you actually achieve this is dependent on how the group or group members are used in your writing. If a member of the group is a main character at some point in the story you can introduce them and portray their emotional/mental state by describing their thoughts and possibly plans (these could be an indication of where in your story this character will be active). The main example of this I can think of is "The Walking Dude" from The Stand (Stephen King). He was introduced as an ominous presence without a real description of his actions until later in the novel:
"There was a dark hilarity in his face, and perhaps in his heart, too, you would think—and you would be right. It was the face of a hatefully happy man, a face that radiated a horrible handsome warmth, a face to make water glasses shatter in the hands of tired truck-stop waitresses, to make small children crash their trikes into board fences and then run wailing to their mommies with stake-shaped splinters sticking out of their knees. It was a face guaranteed to make barroom arguments over batting averages turn bloody."
King, Stephen (1990). The Stand: The Complete and Uncut Edition. New York: Doubleday. pp. 214–215. ISBN 0-385-19957-0.
Taken from https://en.wikipedia.org/wiki/Randall_Flagg
If the group is an anonymous force of unnamed individuals you could do the same by introducing the group and interactions between group members that establish the group's motivations; I do think it will be harder to integrate this into your story seamlessly though. The other alternative is given in another answer; use either the main characters or a third party character to establish the group's motivations/emotional/mental state. If you do this early and clearly enough within the story there should be no need to have to re-establish this later on outside of the group's interactions with your main characters.
The only other, practical, alternative I can think of is to compare and contrast the main character from the characteristics of the group where the focus is building out the main character. Again I feel this would be difficult to integrate into the story seamlessly.
Hope these thoughts help.
A:
Referring to history, as noted in other answers, is a good way. You don't have to depict the action to have it come up -- in conversation, when a character reads about something online, when a detective turns up disturbing evidence, etc.
You can also convey a lot by other character's reactions to the character. If every woman in the room instinctively cringes and backs away when your harassing lech enters the room, that's a signal. If police, soldiers, or security guards reach for their weapons when your serial killer (who got off on a technicality) appears, that's signal. If your protagonists see someone being forcibly removed from a school with authorities shouting "we've told you over and over to stay away from our kids!", that's signal.
None of this is giant-neon-sign-pointing-to-the-bad-guy levels of signal, but it's still signal, and it shouldn't take too much to get your point across. How much depends on how closely you're sticking to the tropes of your genre.
|
1. Radiation Safety Program
1.1. University Policy Concerning Ionizing Radiation
1.1.1. The President of Oregon State University, recognizing the usefulness of ionizing radiation in the teaching and research missions of the University, directs that possession and use of radioisotopes and radiation-emitting machines be optimized at OSU facilities and by OSU personnel. This shall be accomplished while ensuring that:
1.1.1.1. applicable laws and regulations of federal, state, and local agencies are not violated;
1.1.1.2. no risk from ionizing radiation shall be incurred except where justified by benefits from the activity;
1.1.2. The President has delegated to the Vice President for Finance and Administration the responsibility for maintaining a radiation safety program adequate to ensure compliance with this policy.
1.2. Scope of the Radiation Safety Program
The University Radiation Safety Program applies to all locations under University control wherein radioisotopes or radiation-producing machines are used or stored, regardless of ownership or the location. It applies to all persons working at or frequenting these locations, regardless of their relationship with the University. It applies to all radioisotopes and radiation-producing machines at these locations, regardless of ownership of the radioisotopes or machines. It applies to a limited extent to University personnel and equipment at non-University-controlled locations.
1.3. Scope of the Radiation Safety Manual
1.3.1. The University Radiation Safety Manual sets forth, either directly or by reference, the policies, regulations, standards and administrative procedures applying to the radiation safety program. Implementing procedures are issued separately either as Radiation Safety Office Procedures (RSOPs), Lab Procedures (LPs), or other documents.
1.3.2. The manual and all changes thereto will be issued by the Radiation Safety Committee after approval by the Vice President for Finance and Administration. Copies of the manual and of applicable state and federal regulations are available in the Radiation Safety Office. |
Vanilla Mousse with Chocolate
This vanilla mousse with a silky chocolate topping is an European dessert that’s known as ptichye moloko and it’s such a treat! It has a mousse-like creamy base with a velvety smooth chocolate jello layer. It’s an elegant and impressive dessert that’s surprisingly easy to make. It’s perfect for baby showers, dinner parties or a romantic Valentine’s Day dessert.
We served the original vanilla mousse jello recipe in a rectangular glass pyrex dish and so many of YOU absolutely loved it! So this is the fancied up version that uses real whipped cream instead of cool whip (thanks to those of you who let me know that substitution works!!).
The chocolate makes this somewhat of an adult dessert so if you want to make it kid friendly: use a 3 oz package of flavored jello and spoon it over the top once jello reaches room temperature.
Vanilla Mousse with Chocolate
Vanilla Mousse with Chocolate
This Vanilla Mousse is an European dessert with creamy base and silky chocolate topping. An elegant vanilla mousse recipe that’s surprisingly easy. Be sure to watch the easy video recipe!
Ingredients
Ingredients for Chocolate Jello:
5 Tbsp unsweetened cocoa powder
5 Tbsp granulated sugar
1 packet (1/4 oz) unflavored gelatin
5 Tbsp milk (2% or whole milk)
1 cup cold water
Ingredients for Vanilla Mousse:
1 cup milk (2% or whole milk)
1 tsp vanilla extract
2 packets (1/2 oz total) unflavored gelatin
1 cup + 2 Tbsp granulated sugar
16 oz sour cream
8 oz (1 cup) heavy whipping cream
Instructions
Start with Chocolate Jello (so it can cool):
In a small saucepan, whisk: 5 Tbsp sugar, 5 Tbsp cocoa powder, and 1 packet gelatin. Whisk in 1 cup cold water and 5 Tbsp milk. Place over medium heat and bring to a boil while mixing constantly so the chocolate doesn’t lump up. Remove form heat and let cool to room temp (about 1½ hrs).
How to Make Vanilla Mousse:
In a small sauce pan, combine 1 cup milk, 1 tsp vanilla, 2 packets gelatin and whisk together. Place over medium heat and continue whisking until steamy (DO NOT BOIL) then remove from heat and cool until just warm. Tip: Transfer to a different dish to cool faster
Once milk is no longer hot, In a large mixing bowl, using an electric mixer, beat 1 cup heavy cream until fluffy and spreadable (1½ to 2 min on high speed). In a second mixing bowl, whisk together 1 cup + 2 Tbsp sugar and 16 oz sour cream until well blended. Fold in whipped cream then while using the mixer on low speed, slowly add warm milk mixture, scraping down the bowl as needed and mix another 30 seconds to ensure it’s well blended.
The mousse sets quickly, so immediately divide between 6 serving cups and refrigerate until mostly set (at least 30 min). Slowly pour 3 to 4 Tbsp chocolate sauce over each chilled mousse. Place 5 raspberries in a ring over the chocolate and refrigerate until fully set (about 4 to 5 hrs). |
Quality evaluation of Hypericum ascyron extract by two-dimensional high-performance liquid chromatography coupled with the colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method.
In this paper, a heart-cutting two-dimensional high-performance liquid chromatography coupled with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method was established for controlling the quality of different batches of Hypericum ascyron extract for the first time. In comparison with the common one-dimensional fingerprint, the second-dimensional fingerprint compiled additional spectral data and was hence more informative. The quality of H. ascyron extract was further evaluated by similarity measures and the same results were achieved, the correlation coefficients of the similarity of ten batches of H. ascyron extract were ＞0.99. Furthermore, we also evaluated the quality of the ten batches of H. ascyron extract by antibacterial activity. The result demonstrated that the quality of the ten batches of H. ascyron extract was not significantly different by MTT. Finally, we demonstrated that the second-dimensional fingerprint coupled with the MTT method was a more powerful tool to characterize the quality of samples of batch to batch. Therefore the proposed method could be used to comprehensively conduct the quality control of traditional Chinese medicines. |
"When Jesus called out to the fishermen, 'Follow me, and I will make you fishers of men,' he was about to transform each one of them from someone who worked only for himself and a daily catch to someone who was part of a larger team, thinking about eternity," Jones writes in this guide to feel-good management. The author of Jesus, CEO segments her book into four parts, corresponding to Jesus' actions with his disciples (he excited them, grounded them, transformed them and released them). Though targeted toward leaders with a spiritual bent (e.g., not everyone will respond to her advice to manage remote teams through prayer), the book offers plenty of lucid and realistic suggestions, such as valuing diversity, conducting regular internal audits and identifying the causes of failure. (May 21) |
125 Years of great soccer
Venezuelan striker Miku (whose full name is Nicolås Ladislao Fedor Flores) joined Celtic for the 2012-13 campaign on loan from Getafe. Miku earned his nickname after "Miklós", the Hungarian version of his first name. Born to a Hungarian father and Venezuelan mother, Miku chose to represent Venezuela in international play with his first call-up in 2006. He started his senior career with Valencia in 2004, and has been loaned to several other Spanish teams in his career.
The new home jersey Nike has created for Celtic has those famous white and green hoops.
A design features 1888-2013 (the year Celtic was founded), a special 125th anniversary Celtic team badge and a championship star surrounding the embroidered team badge.
The hoop (stripe) design honors Celtic's history. Celtic's jersey usually has seven hoops but this year it features nine hoops honoring the record nine consecutive Scottish league titles Celtic won between 1965 and 1974 - a record that has never been beaten.
New fabric and design lets the jersey move and manage moisture effectively and efficiently. Weave lets air constantly flow through the jersey.
Nike logo at front along with a screened sponsor design. Celtic is screened at the back collar. |
Organizers said that internet-connected televisions crashed at the press center, according to officials cited by the report. The targeted servers were shut down, which also took down the official Winter Olympics website for some time.
The committee said in a statement that the attack only affected “non-critical systems” and said the safety of attendees was not compromised.
Cybersecurity firms on Monday said they uncovered computer malware they called “Olympic Destroyer.” According to experts, the malware’s aim is to delete backup files on a computer and meddle with boot-up files needed to power up a computer, Axios reported on Monday.
Experts speculated that the malware would be able to spread to other computers on the same network, and that the attackers may have stolen the network’s credentials prior to programming it into the malware, Axios reported.
Though it may take months to figure out who is responsible for the attacks and why they were executed, experts say the evidence points to the “hallmarks of a nation state,” The New York Times reported.
In a previous cyberattack, documents from Winter Olympics organizations were stolen and leaked by a campaign tied to Russia, while North Korea has also been suspected of spying on the event’s various organizations, a Wired report said.
Hacker groups originating from Russia have been on the radar for some time. Russian athletes were prohibited from officially representing the country during the Winter Olympics after a state-sponsored doping scandal, a ban which some believe may be a possible motive for the cyberattacks.
“The Olympics involve so many countries, and so many sports, many of which have their own infrastructure, that it has become a rich target environment for many adversaries,” John Hultquist, a director at the cyber security firm FireEye, said in The Times. |
1. Field of the Invention
This invention relates to inertial exercise apparatus and to inertial recreational apparatus which employ the principals of an inertial pendulum to provide the resistance for exercise and recreation apparatus.
More specifically this invention relates a starting mechanism for the above described apparatus that enables the user to set the apparatus in motion without preparatory winding.
2. Background of the Invention
The apparatus of this invention has its origins in the button and string amusement device that has been known to be in use since buttons have been known. A strand of string is looped through two holes in the button and tied in a loop. The ends of the loop are placed around the thumbs of the user and the button is rotated to cause the loop to wind on either side of the button. The thumbs exert tension on the string and the wound string is caused to unwind. The inertia of the button causes the string to unwind and then to wind in the opposite direction. When the inertia of the button is spent tension is again applied to the string and the button is caused to rotate in the opposite direction. With a little practice a child can keep the button and string inertial pendulum cycling for as long as the arms and thumbs can hold up.
In more recent times inertial pendulum devices have been found to be convenient exercise devices for use in office and travel situations. Imaginative users of inertial pendulum devices have found ways to employ the inertial pendulum in many of the exercises that are customarily performed with free weights and with resilient resistance apparatus.
To perform some of these exercises it is difficult to pre-wind the inertial pendulum and then get in a position to perform the exercise.
It is an object of this invention to provide starting apparatus for inertial pendulums that is self pre-winding.
It is further an object of this invention to provide the apparatus described above wherein the apparatus is incorporated into the structures of an inertial pendulum making the inertial pendulum self starting.
Other objects will be made apparent from the specifications, drawings and claims. |
First Report of Pseudomonas savastanoi Causing Bacterial Leaf Spot of Mandevilla sanderi in Slovenia.
Foliar necrotic spots with narrow chlorotic halos were observed on different cultivars of Brazilian Jasmine (Mandevilla sanderi) during spring 2010 in several commercial greenhouses in Slovenia. Up to 70% were symptomatic and were unmarketable. No galls were observed on the stems of symptomatic plants. Circular, flat, granulated colonies with entire margins were isolated from symptomatic leaves of two plants from different greenhouses on King's B medium (KB). The isolates were negative for levan, oxidase, pectinolytic and arginine dihydrolase activity. They caused a hypersensitive reaction on tomato but not on tobacco cv. White Burley. Isolates were weakly fluorescent on KB under UV light. One isolate per sample (NIB Z 1413 and 1415) was further characterized. Partial sequences of 16S rDNA (1; GenBank KM603318 of 722 bp, KM603319 of 686 bp) grouped the isolates within genomospecies 2 of Pseudomonas. Repetitive polymerase chain reaction (PCR) assay using the BOXA1R primer (5) resulted in highly similar DNA fragment banding patterns of the two NIB Z isolates and other reference strains of genomospecies 2 (minimum 95.1% identity with Pearson's correlation). Partial sequences of rpoD (3) of the two Slovenian isolates (600 bp; GenBank KJ744202, KJ744201) were identical to the P. savastanoi isolate from Mandevilla B200 (W. Wohanka, Germany; GenBank KJ744203) and P. s. pv. nerii strain NCPPB 3334 (GenBank AB039513). The sequences differed in two nucleotides relative to the sequence of the pathotype strain of pv. nerii NCPPB 3278 (positions 487 and 510 relative to GenBank FN433279) and had an insertion of six nucleotides compared to available P. savastanoi pv. savastanoi rpoD sequences (NZ_JOJV01000073, CM001834). Pathogenicity of isolated bacteria (two isolates) was determined on M. sanderi cv. Pretty Rose inoculated by two different methods, spraying foliage and pricking stems. The abaxial and adaxial surfaces of leaves were sprayed with a 30-ml bacterial suspension (5 × 106 CFU/ml). Three plants were inoculated with each isolate: NIB Z 1413 and 1415 and the reference strain NCPPB 3278. Necrotic spots developed on leaves after 14 days of incubation, under >80% high relative humidity, with 16 h of daylight at 25°C and 8 h of dark at 21°C. One month after inoculation, necrosis also developed on stems and new growth. Inoculation of bacteria by pricking nodes of healthy M. sanderi cv. Pretty Rose with a needle dipped in the isolates grown on KB for 24 h (each of NIB Z 1413, 1415, and NCPPB 3278 for positive control) led to development of galls in 14 days at the inoculation points. The re-isolation was performed separately from necrotic spots on leaves, stems, new growth above the inoculation points, and galls. The BOX-PCR profiles of the bacteria isolated from symptomatic tissues were identical to the original profiles, thus confirming the systemic spread of the bacteria. None of the three negative control plants sprayed with 0.01M MgSO4 or pricked with a sterile needle developed symptoms. This is the first report of P. savastanoi on Mandevilla sanderi plants in greenhouse production in Slovenia. The galls caused by P. savastanoi have previously been reported from the United States (4) and Germany (2). This report broadens the geographical area where P. savastanoi, causing both galls on stems and necrotic spots on leaves, can be found in commercial production of Mandevilla spp. References: (1) U. Edwards et al. Nucleic Acids Res. 17:7843, 1989. (2) N. Eltlbany et al. Appl. Environ. Microbiol. 78:8492, 2012. (3) N. Parkinson et al. Plant Pathol. 60:338, 2011. (4) M. L. Putnam et al. Phytopathology 100:S104, 2010. (5) J. Versalovic et al. Methods Mol. Cell Biol. 5:25, 1994. |
Mexican, German Musicians to Perform and Teach at UT Nov. 11
Published: Nov 7, 2012
On Sunday, Nov. 11, The University of Tampa will host a day of musical and educational events with the Symphonic Orchestra of Guanajuato from Mexico and the LUXA 21 trio from Germany, culminating in a concert by the two groups at First Baptist Church of Tampa at 7:30 p.m.
All events are free and open to the public:
At 1 p.m. members of the 70-member professional orchestra will teach a master class for UT students who participate in a musical ensemble. The class will focus on chamber music and will be held in the Sykes Chapel and Center for Faith and Values.
At 3 p.m., LUXA 21 will give a concert in the chapel. The program will include Imaginary Islands by Ivan Fedele, Jabberwock by Hebert Vazquez, Vier Stücke Op. 5 by Alban Berg, Sonata by Edison Denisov, Melodie 1.0 by Moritz Eggert and The Riot by Jonathan Harvey.
At 5 p.m. orchestra conductor Juan Trigos and other members of the orchestra will hold a Q-and-A session in the chapel. The session will be an open discussion about the music to be performed that evening, the orchestra itself, music in Mexico and other cultural issues regarding Mexico and the orchestra.
At 7:30 p.m. the orchestra will give a free concert at First Baptist Church of Tampa, showcasing the masterworks of Mexican composers from the 20th and 21st centuries. The program will include the U.S. premiere of Triple Concerto by orchestra conductor Jose Trigos played by LUXA 21. Other works to be performed include Sinfonietta by Jose Pablo Moncayo, Homenaje a Cervantes by Blas Galindo, Sensemaya by Silvestre Revueltas and Sinfonia India by Carlos Chavez.
The program is sponsored by UT’s Department of Music and College of Arts and Letters, First Baptist Church of Tampa, Plant High School, the Accidental Music Festival in Orlando, the Timucua Arts Foundation Inc., The Bryce L. West Foundation, South Arts, the National Endowment for the Arts, the Mexican Consulate of Orlando and other community partners.
For more information, contact Kira Horel, director of orchestral and string studies, at khorel@ut.edu or (813) 257-3762. |
With over 390K confirmed cases and more than 17K deaths at the time of this writing, the coronavirus pandemic is wreaking havoc across the globe, with Italy surpassing China in deaths and Iran in shambles, a situation made worse by the U.S. government’s absolutely genocidal sanctions. In the U.S., there have been over 46K confirmed cases and 583 deaths. This number of confirmed cases is clearly a gross underestimate as the U.S. was delayed in testing and has only tested a small proportion of the population. This is largely due to the fact that the U.S. declined to use an approved WHO test which the rest of the world had already been using as it wanted a U.S. firm to benefit from the contract. It has also been speculated that this was done partly due to Trump’s concern that higher COVID-19 cases may hurt his chance at re-election.
As testing in the U.S. increases, this number will undoubtedly skyrocket. Top health officials in research at Johns Hopkins estimate there could be between 50,000 and half a million cases in the U.S. at this time, and that number only looks like it will grow.
CDC criteria determining who should or should not be tested changes by the hour. The current recommendation is to test only those with symptoms and a known exposure or those who have traveled to a category I region such as Italy or China. These recommendations will again lead to an underestimate of the true burden of cases as the virus has clearly started spreading through communities. They also disproportionately leave the poor and working class, who are less likely to have traveled or know someone who has recently been to a Category I country, further exposed. Instead, countries such as South Korea have instituted mass testing and have drastically mitigated the spread of the virus as a result.
Healthcare workers like myself who have direct patient contact and pose a high risk of infecting others face difficulties getting tested. Let that sink in. Yet, you know who can get tested? Tom Hanks and his wife Rita Wilson can get tested. The entire Brooklyn nets basketball team can get tested — since their team owner has the funds to hire a private lab. Billionaires like Jeff Bezos and Bill Gates would likely have no problem getting tested, even in whatever safe house they are currently hiding in. The disparities in testing are typical under capitalism.
But even if the U.S. had widespread testing it would still be nowhere near enough. Under current healthcare policy, widespread testing would be free to everyone, but what about treatment? As reported by CBS news, the recent COVID-19 relief bill provides “free testing, expanded funding for food security programs and paid sick, family and medical leave for workers at companies with 500 employees or fewer.” But there are still questions if needed medical care due to COVID-19 would be covered.
This question is important as medical bills are the number one cause of bankruptcy in the U.S. and long hospital stays to treat COVID-19 could lead to economic ruin. This leads many to be less likely to seek care when they actually need it. With recent bills for paid sick leave not covering 80% of US workers, it also leaves workers who are ill more likely to continue trying to work and hence spreading the virus. Just last week, a panel appointed by New York governor Andrew Cuomo unveiled on Thursday its plan to reduce the state’s Medicaid spending by some $400 million.
Dr. Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases and top member of Trump’s coronavirus task force, recently stated that it’s possible millions could die in the United States alone. Based on my experience working in the United States’ pathetic excuse for a healthcare system, what I personally have seen, and what my colleagues report, I cannot help but think that number is not an exaggeration. To cover a few of the issues:
Supplies
Hospitals around the country are quickly running out of supplies. This has led to practices in hospitals that would never be acceptable under other circumstances. In one New York hospital, management advised staff to “reuse” N95 masks with a distributed document saying “N95 masks will be reused by staff until they are soiled, moist, or compromised,” and to obtain a new mask an associate must “request a mask from their supervisor.” Meanwhile capitalism continues to function as destructively as usual. The Intercept recently reported investment bankers are pushing health care companies producing supplies needed by healthcare workers to raise prices on necessary medical supplies to increase profit. It was also reported that some companies are now charging $7 for protective masks that typically cost less than $1. None of this should be surprising coming from executives who question whether curing disease is a “sustainable business model,” nor should it be surprising within a system that continually seeks profit maximization despite deadly circumstances.
Staffing
When hospitals are surging with new patients like this, it is important to have an adequate number of well trained staff. Over the years hospital administrations have repeatedly ignored nurses’ calls to increase hiring of staff to achieve safe staffing ratios, which, if instituted, would have made handling a pandemic more tolerable. In fact, in NYC nurses nearly went on strike in five hospitals in order to get safe staffing. Now, around the country hospitals are scrambling, putting out calls for retired nurses to return to work to help fill staffing gaps. Capitalists’ consistent push for profits is now coming home to roost, manifesting as staff shortages during this crisis.
Ventilators
Much concern has been discussed about available ventilators as many COVID-19 patients require intubation to assist patient breathing. About 960,000 coronavirus patients may need to be put on ventilators but the United States has only about 200,000 machines, according to the Society of Critical Care Medicine, the Associated Press reported. U.S. industry, organized to benefit a wealthy minority of capitalists, has been unable to respond to this demand and hospitals are still reporting shortages.
War Against Not Only a Pandemic, But Also Against Capitalists
The U.S. has had months to prepare for this pandemic. From the outset, there should have been a mass mobilization of mask production, ventilation production, and PPE (protective personal equipment, e.g., masks, gowns, gloves, face shields, etc.) production.
That’s why now, we urgently need a nationalization of the entire healthcare system under worker control. The for-profit companies producing the vaccines, surgical masks, ventilators, and disinfectants needed to battle this pandemic must be immediately nationalized to make sure there are enough resources available to treat everyone. We simply cannot accept these parasites running our healthcare system for a minute longer.
There should also be a conversion of buildings or building of new sites for ICU beds, but capitalism finds itself in a contradiction: we have a healthcare system based on profits, but right now, we need to mobilize all of production and healthcare for the purposes of saving people’s lives. And capitalism has shown itself incapable of doing that. Instead of directing money to this necessary task, the U.S. Federal Reserve Bank injected $1.5 trillion into the stock market. Now the Federal Reserve bank even plans to offer $1 trillion of loans per day to large banks through the end of this month.
Donald Trump is calling himself a war President, at war with this virus. But nurses and doctors like me are not only waging a war against the virus, but also a class war against Trump, the capitalists and the capitalist government.
Myself and other healthcare workers are at war every day with the CEOs, insurance executives, managers who just make it more difficult for us to give patients the care they need. We need a healthcare system run democratically by doctors, nurses, employees, and patients. This would be drastically different from the current system in which wealthy capitalists make the major decisions in hospitals, pharmaceutical companies, device manufacturing firms, and insurance companies. We need a system where healthcare is a human right, and not a means to make money.
We ultimately need an economic system that puts health and survival over profit maximization. Socialism would allow for all production to be organized in a planned economy under workers’ control, so that resources could be better allocated and the creative and scientific energy of people could be used productively for the benefit of all of us.
Ultimately, what we are seeing unfold in the U.S. is what happens when you develop a healthcare system inside of capitalism. One that is predicated around extracting profit from sick bodies. One that continually attempts to drive down costs whenever possible. Dr. Fauci stated that our “system is not built for this,” but healthcare workers dedicated to treating patients have been condemning this system for years. Our healthcare system has always been a complete disaster, but a pandemic like this just magnifies that fact. Capitalism will never give us what we need. We not only need a new healthcare system, but a new economic system that values life over profit. |
Q:
Simplify test for divisibility by all numbers 1…20
def divisible?(n)
if n % 1 == 0 &&
n % 2 == 0 &&
n % 3 == 0 &&
n % 4 == 0 &&
n % 5 == 0 &&
n % 6 == 0 &&
n % 7 == 0 &&
n % 8 == 0 &&
n % 9 == 0 &&
n % 10 == 0 &&
n % 11 == 0 &&
n % 12 == 0 &&
n % 13 == 0 &&
n % 14 == 0 &&
n % 15 == 0 &&
n % 16 == 0 &&
n % 17 == 0 &&
n % 18 == 0 &&
n % 19 == 0 &&
n % 20 == 0
return true
else
return false
end
end
A:
Ruby refactor: use Enumerable.all?:
def divisible?(n)
(1..20).all? { |x| n % x == 0 }
end
Mathematical refactor:calculate the least common multiple of the integers in the range (Integer#lcm is available from Ruby 1.9):
def divisible?(n)
n % (1..20).reduce(:lcm) == 0
end
This second snippet is, of course, more efficient once you pre-calculate (1..20).reduce(:lcm) only once and store it somewhere.
|
Georgia to restore army – U.S. media
The New York Times reports that Georgia has already started to draw up projects for reinforcing its military. A number of other American media outlets suggest military issues could be on the agenda of Dick Cheney's visit to Tbilisi.
The Wall Street Journal reports: “In private meetings, the Vice President, Dick Cheney, will also be sounding out Georgian President Mikhail Saakashvili and other officials about how the U.S. and its allies could help strengthen economic and military capabilities. In the past the U.S. has been careful not to go too far with military assistance in the region… Now that policy might be ripe for reconsideration, many experts say. An initial step could be to increase the number of U.S. military trainers in Georgia.”
Source: wsj.com
The New York Times says: “Just weeks after Georgia’s military collapsed in panic in the face of the Russian Army, its leaders hope to rebuild and train its armed forces as if another war with Russia is almost inevitable. Georgia is already drawing up lists of options, including restoring the military to its pre-war strength or making it a much larger force with more modern equipment… Georgia’s decision to attack Russian and South Ossetian forces raises questions about the wisdom of further United States investment in the Georgian military, which in any case would further alienate Russia.”
Source: nytimes.com |
Rational design of antiviral agents.
Examining the change in the state of the art of antiviral drug discovery, from the discovery nearly 40 years ago of a smallpox drug (methisazone) of unknown mechanism of action to the analysis of an antiviral agent bound to a virus at atomic resolution, gives the reader an appreciation for the magnitude of the advances in the science of antiviral chemotherapy. The clinical success of amantadine, acyclovir, and azidothymidine have proved that antiviral chemotherapy is a reality. The next step will be to apply the new tools of x-ray crystallography and computational chemistry to the antiviral challenges that lie before us. |
Q:
Javascript inline scripts and defer scripts order of execution
I have a question about order of execution for mixed script type.
Here is my code :
<script>
if(document.documentMode) {
const firstScriptInDOM = document.getElementsByTagName('script')[0];
const polyfill = document.createElement('script');
polyfill.src = "/static/js/polyfills/polyfills.js";
firstScriptInDOM.parentNode.insertBefore(polyfill, firstScriptInDOM);
}
</script>
<script src="static/js/lib1.js" defer></script>
<script src="static/js/lib2.js" defer></script>
<script src="static/js/lib3.js" defer></script>
<script src="static/js/myOwnScriptFile.js" defer></script>
The first script tag's purpose is to load polyfills for IE if the browser is IE.
Then it should load this other scripts and execute my code.
My question is : Will the polyfills script block execution of the defered scripts ?
Thanks a lot for you time !
A:
scripts load synchronously unless specified to load asynchronously using the async attribute, what the defer attribute does is that it loads the script only after DOM is loaded. If you append a script dynamically, it will load asynchronously.
In you scenario,
This should be the chain of execution:
check polyfill script executes
lib1
lib2
lib3
myOwnScriptFile
polyfills (downloaded only after the parser has finished execution)
To ensure all your scripts load, in the order you want them too, you could dynamically load all scripts with something like :
check if the browser is IE:
IF IE
load polyfills, and load other scripts in the onload event of the polyfills script.
ELSE
load all other scripts
|
diff --git a/cmake/install.cmake b/cmake/install.cmake
index 28dc90d..441bf55 100644
--- a/cmake/install.cmake
+++ b/cmake/install.cmake
@@ -1,5 +1,10 @@
include(GNUInstallDirs)
+configure_file(${CMAKE_CURRENT_SOURCE_DIR}/protobuf.pc.cmake
+ ${CMAKE_CURRENT_BINARY_DIR}/protobuf.pc @ONLY)
+configure_file(${CMAKE_CURRENT_SOURCE_DIR}/protobuf-lite.pc.cmake
+ ${CMAKE_CURRENT_BINARY_DIR}/protobuf-lite.pc @ONLY)
+
foreach(_library
libprotobuf-lite
libprotobuf
@@ -17,6 +22,8 @@ endforeach()
install(TARGETS protoc EXPORT protobuf-targets
RUNTIME DESTINATION ${CMAKE_INSTALL_BINDIR} COMPONENT protoc)
+install(FILES ${CMAKE_CURRENT_BINARY_DIR}/protobuf.pc ${CMAKE_CURRENT_BINARY_DIR}/protobuf-lite.pc DESTINATION "${CMAKE_INSTALL_LIBDIR}/pkgconfig")
+
file(STRINGS extract_includes.bat.in _extract_strings
REGEX "^copy")
foreach(_extract_string ${_extract_strings})
diff --git a/cmake/protobuf-lite.pc.cmake b/cmake/protobuf-lite.pc.cmake
new file mode 100644
index 0000000..cbe5426
--- /dev/null
+++ b/cmake/protobuf-lite.pc.cmake
@@ -0,0 +1,11 @@
+prefix=@CMAKE_INSTALL_PREFIX@
+exec_prefix=@CMAKE_INSTALL_PREFIX@
+libdir=@CMAKE_INSTALL_FULL_LIBDIR@
+includedir=@CMAKE_INSTALL_FULL_INCLUDEDIR@
+
+Name: Protocol Buffers
+Description: Google's Data Interchange Format
+Version: @protobuf_VERSION@
+Libs: -L${libdir} -lprotobuf-lite @CMAKE_THREAD_LIBS_INIT@
+Cflags: -I${includedir} @CMAKE_THREAD_LIBS_INIT@
+Conflicts: protobuf
diff --git a/cmake/protobuf.pc.cmake b/cmake/protobuf.pc.cmake
new file mode 100644
index 0000000..2e30763
--- /dev/null
+++ b/cmake/protobuf.pc.cmake
@@ -0,0 +1,11 @@
+prefix=@CMAKE_INSTALL_PREFIX@
+exec_prefix=@CMAKE_INSTALL_PREFIX@
+libdir=@CMAKE_INSTALL_FULL_LIBDIR@
+includedir=@CMAKE_INSTALL_FULL_INCLUDEDIR@
+
+Name: Protocol Buffers
+Description: Google's Data Interchange Format
+Version: @protobuf_VERSION@
+Libs: -L${libdir} -lprotobuf @CMAKE_THREAD_LIBS_INIT@
+Cflags: -I${includedir} @CMAKE_THREAD_LIBS_INIT@
+Conflicts: protobuf-lite
|
Michael Attwell
Michael John Attwell (16 January 1943 – 18 March 2006) was an English film and television actor.
He is possibly best known for his role as Kenny Beale in the television soap opera EastEnders.
In 1979 and 1980 he played Razor Eddie a.k.a. Edward Winston Malone in two series of the comedy-drama Turtle's Progress. The character had originally been created for the ITV drama serial The Hanged Man, where he was played by Gareth Hunt.
In 1978 he played Bill Sikes in the revival of Lionel Bart's musical Oliver! at the Albery Theatre and in 1985 he played Bill Sikes again in the BBC's Sunday afternoon classic serial Oliver Twist.
His other TV credits include: Doctor Who (in the serials The Ice Warriors and Attack of the Cybermen), The First Churchills, Only Fools and Horses, Minder, Bergerac, C.A.T.S. Eyes, Wycliffe, Inspector Morse, Bugs, Silent Witness, Pie in the Sky, Casualty, The Bill, Hotel Babylon, and Are You Being Served?.
He appeared in the 1988 film Buster, based on the life of the Great Train Robber Buster Edwards.
As well as acting, between 1981 and 1993 Attwell also had a considerable career as a political cartoonist for several British national newspapers including The Sun, Sunday People and the News of the World. A self-taught artist, Attwell signed himself as Zoke, an amalgam of the names of his children Zoe and Jake.
Attwell died in London on the 18 March 2006 aged 63 from complications following surgery. His life and work was honoured at the British Academy Television Awards in 2006.
Partial filmography
Labyrinth (1986) - Goblin (voice, uncredited)
Gentry (1987) - Slatter
Buster (1988) - Harry
Tom & Viv (1994) - W.I. Janes
Circus (2000) - Magnus
New Year's Day (2001) - Sgt. Bristow
High Heels and Low Lifes (2001) - Duty Sergeant
Bodywork (2001) - David Leer
Agatha Christie's Marple (The Sittaford Mystery) (2006) - Archie Stone
External links
Category:1943 births
Category:2006 deaths
Category:English male soap opera actors
Category:English male television actors
Category:People from Watford
Category:Male actors from Hertfordshire |
INTRODUCTION
============
Phage display is a widely used method to select antibody fragments ([@b1]--[@b9]), peptides ([@b10]--[@b14]) and other scaffolds ([@b15]--[@b20]) from large libraries, as well as to increase the affinity of antibodies for their antigens ([@b21]--[@b24]) and other proteins for their receptors ([@b25]). Polypeptides are displayed as phage coat protein fusions and the corresponding gene is contained within the particle. It is usually mediated by the fusion of the displayed polypeptide to a coat protein, and encapsulating the gene encoding the fusion protein within the phage particle. This coupling of phenotype and genotype ensures that selection of the displayed protein simultaneously selects the encoding gene, allowing further selection rounds and the eventual isolation of a population highly enriched in phage displaying polypeptides of interest. Vectors based on filamentous Ff phage are the most popular, and of the five coat proteins, the gene 3 protein (g3p) is most commonly used for display.
There are two broad categories of vectors used for phage display: phage and phagemid. When proteins are displayed using phage vectors, which are not of the 33 or 88 kind, the bacteria produce phage particles that all display recombinant protein. The gene encoding the recombinant displayed protein is included in the phage genome and as a result the phage population produced by a single clone is phenotypically and genotypically homogenous, excluding the effects of proteolysis. In contrast, phagemid make recombinant displayed protein, but require the additional proteins provided by helper phage to create phage particles that display recombinant protein. Helper phage are essential for phagemid systems as they supply all the other proteins required to make functional phage. Helper phage ([@b26],[@b27]) are normal Ff phages with a number of modifications: they contain an additional origin of replication, they usually carry antibiotic resistance genes and their packaging signal is severely disabled.
When a bacterium is infected with helper phage, the disabled packaging signal does not prevent the production of phage particles. However, when a bacterium is infected with both phagemid and helper phage, the phagemid DNA (containing an optimal packaging signal) is packaged in preference. As a result, phagemid preparations are both phenotypically and genotypically heterogeneous ([Figure 1](#fig1){ref-type="fig"}): the display protein may be either wild type (derived from the helper phage) or recombinant (derived from the phagemid), and the packaged genome may be either phage or phagemid. In theory, the disabled packaging signal should significantly reduce the number of helper phage particles in any phagemid preparation. However, the number of helper phage can sometimes equal, or exceed, the number of phagemid particles, which can significantly compromise subsequent selections.
The different antibiotic resistance genes carried by the helper phage and phagemid genomes allows the selection of bacteria that contain both, resulting in the recovery of functional phagemid particles displaying the recombinant protein of interest.
Practically, phage and phagemid libraries have a number of differences. At the DNA level (preparing DNA, cloning, transfection efficiency) it is easier to work with phagemids than phage. As a result, phagemid libraries can be made far larger than phage libraries. It is also easier to produce soluble proteins using phagemids by the insertion of an amber stop codon between the displayed protein and g3p ([@b28]). Although soluble protein could theoretically be made in phage libraries using a similar genetic arrangement, the low copy number of the vector and the weakness of the g3p promoter and ribosome-binding site, results in levels of soluble protein that are too low for most practical purposes, requiring subsequent recloning into expression vectors ([@b29]). Another advantage of phagemids concerns the relative resistance to deletions of extraneous genetic material. Filamentous phage vectors, in general, have a tendency to delete unnecessary DNA, due to the selective growth advantage that a smaller phage genome has over a larger one. Phagemids suffer far less from such deletions and as a result are more genetically stable.
Phage libraries have considerable operational advantages. First, they do not require the use of helper phage for phage production. As a result, the additional technical procedures associated with helper phage infection, such as monitoring the absorbance of bacterial cultures, are omitted from protocols. To amplify phage libraries it is sufficient to grow bacteria containing phage genomes and phage particles are produced. This makes phage far easier to use in selections, particularly in high-throughput selections where antibodies are selected against up to 96 targets simultaneously ([@b30],[@b31]).
Second, each phage particle in a phage library displays up to five copies of the displayed protein (using a g3p display system), whereas only 1--10% of phage particles in a phagemid library display a single copy of the displayed protein ([@b32]). As a result, a greater number of binders in a library are recovered, and therefore antibodies tend to be more diverse. However, this is counterbalanced by a lower average affinity ([@b29]): phagemid display, by virtue of the display of single proteins, results in the selection of fewer unique binders, which tend to have higher affinities ([@b29]). For similar reasons, affinity maturation ([@b21]--[@b23]) can only be carried out using phagemid vectors.
Recently, a number of groups ([@b27],[@b33]--[@b38]) have developed alternative helper phage systems, compared in [Table 1](#tbl1){ref-type="table"}, designed to improve display in either of two ways: by increasing the display level, so that it resembles the display obtained with phage vectors ([@b27],[@b34]--[@b36]), or by reducing the background from non-displaying phage by rendering them non-infective ([@b37],[@b38]). However, none of these has been addressed the need for helper phage itself.
Initial experiments to increase display involved the creation of g3p deleted helper phage, packaged in bacterial strains expressing gene 3 in trans. These allowed higher display levels, but suffered from the problem that when the g3p was derived from plasmids, although not when integrated into the *Eschericia coli* chromosome ([@b35]), such plasmids could also be packaged at low levels ([@b27]). Helper phage titers also tend to be very low. More recently, conditional g3p deletions have been created by the introduction of suppressible stop codons in g3 ([@b34],[@b36]), allowing production of helper phage in suppressor strains, and the packaging of phagemids in non-suppressor strains, where the helper phage is unable to make its own g3p.
Two approaches have been used to reduce background, in both of which only phagemid particles containing the recombinant g3p are infectious. These involve either the deletion of the portions of g3p required for infection ([@b37]), or the incorporation of a trypsin site within the g3p of the helper phage, and using trypsin-treated phage for infection ([@b38]). Both of these systems result in a lower background during selection by eliminating those phagemid particles which contain only helper phage derived g3p.
Although these systems may overcome some of the disadvantages of helper phage, they do not avoid one of the main problems associated with the use of helper phage: the need to make helper phage and add it to growing bacterial cultures at relatively restricted phases of the growth cycle. In this paper we describe a series of constructs which eliminate the need for helper phage altogether, creating a system in which bacterial packaging cell lines replace the use of helper phage, making the generation of pure phagemid particles as straightforward as using a phage-based system. Furthermore, by using different packaging bacteria the phagemid particles produced are either monovalent or multivalent. The concept is illustrated in [Figure 1](#fig1){ref-type="fig"}.
MATERIALS AND METHODS
=====================
Cloning
-------
M13c was created by amplifying M13mp19 with two outward facing primers, M13 MluI (5′-ttgatgacgcgtcctattggttaaaaaatgagctg) and M13 MluI (3′-ttgatgacgcgtccgaaatcggcaaaatcc) using a high-fidelity proof reading polymerase which amplified the whole plasmid and put MluI sites at the junctions between M13 and lac Z. This large PCR product was digested with MluI and the chloramphenicol resistance gene from pBSL121 ([@b39]) cloned in after cutting with MluI. This produced an M13 phage which confers chloramphenicol resistance. M13cp was created by amplifying M13c with the two outwards primers, gene 4 3′ (ccacacctgcagcgcttaatgcgccgctacagggcgcgtact) and CATgene 5′ (tgatttctgcagacgcgtgtccgaatttctgccattcatcc). These primers amplify the whole plasmid without the M13 origin and place PstI sites at the ends. The p15a origin was amplified from pMPM-K3 ([@b39]) with 5′ P15 ori (taacgctgcagagaacatggcttcatgtgg) and 3′ P15 ori (actgttctgcagagcagacagttttattgttc). This yielded an 875 bp fragment containing the P15 origin of replication flanked by PstI sites which could be cloned into the large M13c PCR fragment using PstI. M13cp-CT was created by amplifying M13cp with two outward primers: g3sig 3′ (acaactttcggatccttcagcggagtgagaatag) and g3D3 5′ (ggtggctctggatccggtgattttgattatgaaaag). The resultant fragment was cleaved with BamHI and religated. These primers are located within g3, and after amplification, the leader of g3 is joined directly to the C-terminal 151 amino acids of g3p, which comprise the C-terminal domain. M13cp-dg3 was made similarly, using gene 6 5′ (ccatatgaattctctattgattgtgacaaaataaacttattcc) and gene 8 3′ (gaaaggaacaactaaaggaattccgaataataattttttcac) to amplify M13cp. These amplify the whole plasmid without gene 3, and can be ligated using EcoRI. However, the PCR product does include the terminator (T0.25) found at the end of gene 8 and the C-terminal portion of gene 3, which is thought to contain the p6 promoter. M13cp-sg3 was also made by amplifying the whole of M13cp using g3 stop BclIS (gaaagt [tga]{.ul} tca gca [taa]{.ul} ccc cat aca [tga]{.ul} aat tca ttt act aac gtc) and g3 stop BclAS (ttt tgc tga tca act ttc aac agt [tca]{.ul} agc gga gtg aga ata g), cutting with BclI and religating. This inserted four stop codons (underlined in the primers) in the first 32 codons of g3. The junctions of all constructs were confirmed by sequencing.
Phagemid production
-------------------
*Transformation* Single colonies were picked from each helper cell construct (M13cp, M13cp-CT, M13cp-dg3 and M13cp-sg3), made chemically competent and transformed with pDan5-scFv DNA. After growth on 2XTY-ampicillin-chloramphenicol agar plates, colonies from each transformation were picked and grown overnight in 2XTY-ampicillin-chloramphenicol media at 30°C at 250 r.p.m.
*Infection and direct growth* Bacteria infected as described above at an absorbance of OD~600~ of 0.5, were grown overnight at 30°C, 250 r.p.m., without retention on ice. DH5αF cells containing no helper plasmid were also infected with M13K07 helper phage for an additional 30 min at 37°C without shaking before dilution and overnight growth.
*Infection and growth from single colony* Single bacterial colonies obtained following a procedure similar to that described for titration above were picked and grown overnight in 2XTY-ampicillin-chloramphenicol at 30°C, 250 r.p.m.
For each phage production protocol, after overnight growth phagemids were collected from the supernatant by centrifugation (4000 r.p.m., 30 min), and the levels of phage production determined by titration in DH5αF cells plated on both 2XTY-ampicillin and 2XTY-chloramphenicol plates.
Determination of infectability
------------------------------
A single colony starter culture from DH5αF alone, or containing one of the four M13 helper plasmid constructs, was grown overnight at 37°C, 250 r.p.m., in 2XTY-chloramphenicol in the case of the helper plasmids and 2XTY alone for DH5αFT. The following day each culture was diluted and re-grown at 37°C, 250 r.p.m., to an absorbance OD~600~ of 0.5. As culture growth rates were variable, each culture was stored on ice after reaching OD~600~ 0.5, and for a further 30 min after all cultures had reached this absorbance. The samples were then returned to the 37°C incubator to warm for 30 min. Each sample was infected with D1.3 phagemid made from the M13cp transformation (and so genetically homogenous) at a multiplicity of infection of 1:1 and left to infect for 30 min at 37°C without shaking. Aliquots of infected bacteria were removed from each sample and titered to determine the ability of the bacteria to support phage infection.
ELISA
-----
Phage ELISAs were carried out essentially as described previously ([@b40]), with phage either used directly after growth (Figure 4), or purified by PEG precipitation, titered and then diluted to appropriate titers (Figure 5). Antigens were adsorbed to Nunc immunosorb microtiter plates (Nunc) overnight at 4°C in PBS at 1--10 μg/ml and blocked with 1% BSA/PBS. Phage were added in blocking buffer, incubated for 60--90 min, washed in PBS and PBS-T (PBS/0.1% Tween-20), incubated with horseradish peroxidase labeled anti-M13 phage monoclonal antibody (Pharmacia) for 60 min diluted in blocking buffer, washed in PBS and PBS-T, followed by treatment with 1-Step Turbo TMB-ELISA substrate (Pierce). The reaction was terminated with 1 N sulfuric acid, and read using absorbance at 405 nm.
Western blotting
----------------
PEG precipitated phage particles, corresponding to 500 μl of culture supernatant, were reduced with sample buffer \[7.5% β-mercaptoethanol, 75 mM Tris (pH 6.8), 2% SDS, 15% glycerol and 0.002% Bromophenol Blue\] and heat-treated at 100°C for 10 min. Phage proteins were resolved by SDS--PAGE (NuPAGE™ 4--12% Bis--Tris; Invitrogen), in MES buffer, against a protein standard. Separated proteins were then transferred to 0.2 μM nitrocellulose membrane (Protran BA83; Schleicher & Schuell Bioscience \#10401396) using the XCell II™ Blot Module (Invitrogen), according to the manufacturer\'s instructions. The membrane was blocked (1% Skim Milk Powder + 1% BSA in PBS) overnight at 4°C and subsequently probed with either Anti-SV5 mouse monoclonal or Anti-M13pIII mouse monoclonal antibody (1/1000 dilution; NEB \#E8033S). The membrane was washed (2 × 5 min) with PBS-T before the addition of secondary Anti-Mouse IgG-Alkaline Phosphatase (AP) conjugate (1/1000; Dakocytomation \#D0486). Following incubation, the membrane was washed once with PBS-T, PBS-LT (0.01% Tween-20) and PBS. Displayed proteins were detected following treatment with AP substrate (NBT/BCIP; Pierce \#34042).
RESULTS
=======
Plasmid design
--------------
In initial experiments we attempted to integrate portions of M13 into the *E.coli* genome by Tn5 transposition ([@b41]). However, although we could obtain clones that contained all the M13 protein-coding regions none was able to package phagemid DNA into phagemid particles. As an alternative, we turned to the use of plasmids (see Materials and Methods for construction details). These \'helper plasmids\' were all based on M13mp19 ([@b26]). In the starting construct, the M13 origin was removed and replaced with the p15a origin, which provides ∼15 copies per cell and allows it to co-exist with ColE1-based origins ([@b42]), including pUC derivatives such as our phage display vector, pDAN5 ([@b3]). Next, the polylinker and lac gene of M13mp19, located in the M13 intergenic region and known to be non-disruptive to M13 function ([@b43]), were replaced by the chloramphenicol resistance gene ([@b39]) to create M13cp. M13cp, which contains full-length g3p, was further modified to create three derivative plasmids with changes made only to g3p. The first modification created a truncated g3p construct (M13cp-CT) which removed the N-terminal two domains of g3p, leaving only the C-terminal phage assembly domain connected to the leader sequence. The following two constructs inactivated g3p, either by complete deletion (M13cp-dg3) or by the insertion of four non-suppressible stop codons within the first 32 codons of g3 (M13cp-sg3). The latter strategy was similar to that used to make Ex-phage ([@b36]) and Phaberge ([@b34]). The expected phenotype of the phagemid particles produced by these different helper plasmids is illustrated in [Figure 1](#fig1){ref-type="fig"}.
Phagemid particle production
----------------------------
A first experiment was carried out to determine whether these constructs were capable of transforming bacteria into filamentous phage packaging cell lines. DH5αF bacteria containing each of the helper plasmids were made competent and transformed with our standard phagemid display vector pDAN5-D1.3 ([@b3]). Each transformation was plated on agar media containing ampicillin and chloramphenicol. Following overnight growth single colonies were picked and further grown in liquid media containing ampicillin and chloramphenicol. [Figure 2](#fig2){ref-type="fig"} shows that helper plasmids were able to supply all the necessary phage proteins to produce phagemid particles carrying ampicillin resistance. M13cp gave ampicillin titers of 10^11−12^ ml^−1^, M13cp-CT and M13cp-dg3 gave titers ∼50--100-fold less, whereas M13cp-sg3 gave titers of only 10^6^ phagemid particles/ml. Given the very low titers obtained with M13cp-sg3, no further work regarding this construct is discussed. Phagemid particles produced in this experiment were also tested for their resistance to kanamycin (carried by standard helper phage, M13K07) and chloramphenicol (carried by the helper plasmids). We were unable to obtain colonies with resistance to either, indicating that the helper plasmids were unable to package themselves, and that the packaged phagemid particles were genetically homogenous. Furthermore, the titers obtained with M13cp were equal to those produced by standard helper phage (M13K07) infection ([Table 2](#tbl2){ref-type="table"}). The next set of experiments served two purposes. First, and most important, was to determine whether the presence of helper plasmids within bacteria reduced their ability to be infected (plating efficiency). This is important if selection outputs are to be infected directly into such cells. The second, was to determine whether after infection and plating bacteria containing helper plasmids could produce phagemid particles at levels similar to those derived from direct transformation. Genetically homogenous phagemid particles prepared using the M13cp helper plasmid were infected into DH5αF bacteria, or DH5αF bacteria containing each of the three helper plasmids (M13cp, M13cp-CT and M13cp-dg3). The results in [Figure 3A](#fig3){ref-type="fig"}, expressed as a percentage of the plating efficiency in DH5αF, show that although phagemid particles could infect DH5αF containing M13cp-CT or M13cp-dg3 at levels comparable to unmodified DH5αF under these experimental conditions, their ability to infect bacteria containing M13cp was reduced by at least 10-fold. The reduced plating efficiency, when M13cp is present, relative to DH5αF alone, could not be overcome by increasing the number of bacteria available for infection, modifying antibiotic concentrations, changing the OD at which infection occurred, or the temperature at which bacteria were grown after infection (data not shown). This suggests that the problem is not a reduction in the number of bacteria displaying pili and so competent for infection, but a failure of propagation within the bacteria after interaction with the pilus has occurred.
Bacterial colonies obtained after infection and plating were further grown in liquid media to determine the titer of the phagemid particles produced. [Figure 3B](#fig3){ref-type="fig"} shows that the relative order of phagemid particle production was consistent with the results obtained by transformation (M13cp\>M13cp-CT\>M13cp-dg3), although the phagemid particle titers produced by cells containing the helper plasmids were 10-fold higher.
Assessing display levels
------------------------
The final set of experiments were conducted to determine the display levels of phagemid particles produced by each helper plasmid, using phage enzyme-linked immunosorbent assay (ELISA) and western blot. The most stringent assessment of functional display is to carry out phage ELISAs, since only well displayed and correctly folded scFvs will give positive signals. In order to provide practical comparisons, phage ELISAs were carried out for three different scFvs using growth supernatants directly after growth in the three different packaging cells, without purification or concentration by PEG precipitation. This mimics the true experimental use of such a system in selection and screening. [Figure 4A](#fig4){ref-type="fig"} shows that M13cp-CT provides the highest ELISA signal in all cases. Although there was some variation, M13K07, M13cp and M13cp-dg3 all gave approximately similar signals.
In order to determine the relative display levels, pDAN5-D1.3 phagemid particles prepared using the different helper plasmids were also assessed in terms of the ELISA signals obtained at identical phage titers. The results in [Figure 4B](#fig4){ref-type="fig"} show that M13cp-CT produces by far the most functionally active phage at the lowest phage titer, followed by M13cp-dg3. To obtain ELISA signals comparable to M13cp-CT, ∼100-fold more M13K07-derived phagemid particles are required.
D1.3 phagemid particles were further examined by two western blots: the first using an anti-g3p antibody and the second using the SV5 anti-tag antibody ([@b44]). In these experiments phagemid were not normalized for titer, but culture volume, giving an indication of how much recombinant protein will be displayed under standard use, with the actual numbers of phagemids loaded indicated below ([Figure 5](#fig5){ref-type="fig"}). The SV5 antibody recognizes the tag placed between the displayed protein and g3p and will only recognize recombinant g3p from the display vector. This gives an assessment of the total amount of incorporated recombinant g3p (equivalent to the sum of the g3p+scFv and g3p bands derived from the proteolytic degradation of g3p+scFv) as well as that portion which is full length and displaying scFv (the g3p+scFv band). The results ([Figure 5](#fig5){ref-type="fig"}) show again that M13cp-CT gives the highest display level, as shown by the intensity of the g3p+scFv band, even though the number of phagemid particles loaded is 5-fold less than those produced using M13K07. Consistent with the ELISA results, M13cp-dg3 also gave good display, and full-length display was barely detectable with either M13cp or M13K07 packaged phagemid particles. The second western blot was carried out using an anti-g3p monoclonal (New England Biolabs) which recognizes the C-terminal portion of g3p. This will reveal the presence of all g3p, whether derived from phagemid or helper plasmid, including the truncated g3p (as a band of 19 kDa). This western shows that a large fraction of the g3p incorporated using M13cp-CT is derived from the recombinant phagemid g3p (compare the intensity of the g3p-CT fragment---derived from the helper plasmid---with that of the g3p and g3p+scFv bands). A slightly larger band was occasionally seen with M13cp-CT and M13cp-dg3 prepared phagemid ([Figure 5A](#fig5){ref-type="fig"}). Given the exquisite specificity of this antibody (the helper phage alone shows no bands), we believe this to be an scFv fragment containing an SV5 epitope. Although the amount of total recombinant phagemid g3p incorporated in M13cp-dg3, M13cp and M13K07 appears to be similar, functional display (g3p+scFv band) is only seen for M13cp-dg3. This suggests that proteolysis is greater in phagemid prepared using M13cp and M13K07.
DISCUSSION
==========
In this paper we describe a novel method to eliminate the use of helper phage from phagemid preparation, allowing the production of phagemid by simple bacterial growth. This has been carried out by the creation of bacterial packaging cell lines, containing helper plasmids, that are able to provide all the proteins required for phagemid packaging.
These helper plasmids are based on M13mp19, with the phage packaging signal/origin replaced by p15a, and the addition of a chloramphenicol resistance gene. The absence of packaging signals in these helper plasmids prevents their DNA from being packaged. This provides a number of significant advantages over the use of both standard ([@b26],[@b27]) and modified helper phages ([@b27],[@b33]--[@b37]). Perhaps most important is the purity of the phagemids produced: we have been unable to detect contamination of phagemids prepared using these helper plasmids with any helper phage genomes whatsoever. For phage display, this avoids the occasional problem of helper phage overgrowth, which can result in failed selections. For other applications, the genetic purity of the phagemid particles, combined with their extremely high titers, makes this a powerful method to transfer genetic material between bacteria. This is likely to be particularly useful in the generation of antibody diversity by recombination ([@b3],[@b45]), and in genetic selection protocols carried out in bacteria ([@b46]--[@b50]), in which it will be possible to replace library transfection by infection. As infection is far more efficient than transfection, this will be especially applicable to library-versus-library ([@b45],[@b51]) selection protocols, where increased efficiency of entry by infection will result in higher sampling of library diversity ([@b52]).
Although the helper plasmids were designed to lack the M13 packaging signal, the complete absence of packaging into phage particles is at first somewhat surprising, considering that many other plasmids, without M13 origins, do show low levels of packaging ([@b27]). This is usually attributed to the presence of cryptic packaging signals in plasmids which can be inefficiently recognized by the M13 packaging machinery. It is likely that evolution has selected against the presence of other putative packaging sequences in the M13 genome to ensure that only the correct single site is used, so guaranteeing correct orientation within the phage particle ([@b53]). As a result elimination provides no alternative signals in the phage, and it is clear that neither the p15a origin nor the added chloramphenicol resistance gene are able to provide alternative signals.
The helper plasmids differ in the form of g3 they contain; the g3p in M13cp is full length, that in M13cp-CT is truncated. M13cp-CT contains the portion of g3p responsible for phage assembly and release ([@b54],[@b55]), but lacks the domains involved in bacterial toxicity ([@b56],[@b57]), phage infection ([@b58]--[@b60]) and the inhibition of infection by bacteria carrying g3p ([@b27],[@b61],[@b62]). M13cp-dg3 contains no g3, by virtue of genetic deletion, and gave lower titers than M13cp or M13cp-CT, but ELISA and western signals intermediate between the two.
When phagemid are infected into bacteria containing M13cp the plating efficiencies obtained are consistently lower than those obtained in bacteria containing the other helper plasmids, or no plasmids at all. As this cannot be overcome by increa-sing the number of bacteria, the problem is not a reduction in infectivity (e.g. by a reduction in the number of bacteria displaying pili), as might be expected, but a failure of these phagemids to establish themselves within the bacteria (e.g. an inability to replicate). This could occur at a number of different levels, including sequestration of the TolA co-receptor by the helper plasmid g3p ([@b58],[@b60]), preventing productive phagemid particle entry into the bacteria, or a failure of phagemid DNA replication or survival after entry into the cytoplasm.
In phagemid particles packaged using M13cp most of the g3p appears to be derived from the helper plasmid, and very little from the display vector. As a result, low levels of monovalent display occur ([Figure 5](#fig5){ref-type="fig"}). However, in the case of phagemid particles made using M13cp-CT, a large proportion of the incorporated g3p in phagemid is derived from the display vector (compare the intensity of the g3p-CT fragment in [Figure 5B](#fig5){ref-type="fig"} with that of the g3p and g3p+scFv bands), and of this almost 50% is full length (compare g3p+scFv with g3p in the anti-g3p blot), leading to the very high multivalent display levels seen. This is also reflected in the ELISA results shown in [Figure 4B](#fig4){ref-type="fig"}: in order to mimic the signal obtained with phagemid particles produced using M13cp-CT, 100-fold more phagmid particles produced using M13K07 or M13cp are required. This suggests that there is a preference for the full-length g3p provided by the display vector over the truncated form provided by the helper plasmid during phage assembly. Although the C-terminal domain is known to be sufficient to allow phage assembly to occur ([@b63]), this result suggests that additional portions of g3p facilitate the process, leading to increased incorporation levels when full-length g3p is used.
M13cp and M13cp-CT stand out as being the most useful helper plasmids, each with potentially different applications. For phage display, it is likely that a selection approach combining both, in which phagemid packaged by M13cp-CT, providing multivalent display able to capture full diversity, is used in early rounds of selection, and M13cp, packaging monovalent phagemids, is used in later rounds to select higher affinity clones, will be the most useful. Given the lower plating efficiency of M13cp, it should only be used once selected phagemids are well represented (e.g. after the second round), in order to avoid loss of diversity.
M13cp could also be very useful for transferring genetic material between bacteria when maximum diversity must be maintained ([@b3],[@b45]), for making phagemid particles for other purposes, and also in phage display when display proteins other than p3 are used. Surprisingly, M13cp-dg3 does not appear to have any advantages over M13cp-CT, giving lower titers, and lower ELISA signals at similar titers, and at the moment it is difficult to find a use for this construct.
At a practical level, these helper plasmids are easier to use than helper phage-based systems. Bacteria containing the helper plasmid can be either infected or transformed with phagemid and then grown up in selective media without the need to further monitor bacterial OD. In fact, we have found that it is sufficient to add phagemid particles to a freshly diluted overnight culture of M13-cap-p15-CT bacteria and grow: bacteria become infected and phage production follows. Similarly, bacterial colonies can be scraped after overnight growth, and phagemid particles can be harvested from the supernatant after centrifugation. Although these helper plasmids will simplify the use of phage display under standard selection conditions, it is in high-throughput antibody selection projects ([@b31],[@b64]--[@b66]), where minimal oversight is desired, and it is impractical to closely monitor bacterial OD in order to add helper phage, that they will prove particularly useful.
This work was funded by a DOE GTL grant awarded to A.B. Funding to pay the Open Access publication charges for this article was provided by the DOE GTL grant.
*Conflict of interest statement.* None declared.
Figures and Tables
==================
{#fig1}
{#fig2}
{#fig3}
{#fig4}
{#fig5}
######
Different published helper phages
Helper phage name Mutation/mechanism [a](#tf1-1){ref-type="table-fn"}Helper phage titers/ml Display levels [a](#tf1-1){ref-type="table-fn"},[b](#tf1-2){ref-type="table-fn"}Rescued phagemid titers/ml Use in display Helper phage propagation Reference
------------------- ------------------------------------------------------------ -------------------------------------------------------- ---------------- --------------------------------------------------------------------------------------------- ----------------------- -------------------------------------------- -----------
M13K07 10^11^[c](#tf1-3){ref-type="table-fn"} Low 2 × 10^10−12^ Standard infection Growth \(67\)
KM13 Trypsin site in g3p, elution with trypsin 10^11^ Low 2 × 10^10−12^ Standard infection Growth \(38\)
g3 deletion 10^5−6^ High ∼10^10^ Standard infection g3 plasmid expression under lac promoter ([@b68])
M13MDD3.2 g3 deletion 2 × 10^9^ NT 10^9^ Standard infection g3p plasmid expression ([@b33])
R408d3 g3 deletion[d](#tf1-4){ref-type="table-fn"} 10^10^ NT NT Standard infection g3p plasmid expression under pspA promoter ([@b27])
Hyperphage g3 deletion (8-406) 10^9^ High 10^9−10^ Standard infection g3p integrated into *E.coli* genome ([@b35])
CT helper phage g3 N1 & N2 domains deleted[e](#tf1-5){ref-type="table-fn"} 3 × 10^11^ Low 10^11^ total 5 × 10^8^ infective Standard infection g3p plasmid expression ([@b37])
Ex-phage Amber stop codon 5′ g3 10^12−13^[f](#tf1-6){ref-type="table-fn"} High 10^10−11^ Non-suppressor strain Suppressor strain ([@b36])
Phaberge Amber stop codon 3′ g3 10^11^ High 10^9−10^ Non-suppressor strain Suppressor strain ([@b34])
The mechanisms of action, as well as the reported titers of both packaged phage and helper phage are given. NT-not tested.
^a^Titers are unconcentrated supernatant titers---i.e. not PEG precipitated.
^b^Refers to the number of infectious phagemid particles, independent of whether they carry antibody or no.
^c^Data from our laboratory.
^d^Some reversion due to packaging of plasmid expressing p3 observed-probably also occurs in other plasmid expression systems, but not examined.
^e^Rescued phagemid are two populations, displaying and infective, non-displaying and non-infective.
^f^Standard M13K07 titers obtained in this laboratory tend to be 10--100-fold higher than obtained elsewhere.
######
The properties, and potential uses, of the different helper plasmids created here are indicated
Helper plasmid Form g3p Phage production titer Infectability of bacteria bearing plasmid Notes Potential use
---------------- ------------- ------------------------ ------------------------------------------- ----------------------------------------------------------------------------------- ------------------------------------------------------
M13cp Full length Equal M13K07 10% DH5αFT Most similar to phage produced using standard helper phage Transfer genetic material. Monovalent phage display.
M13cp-CT Truncated 5−20% M13K07 Equal DH5αFT Behaves more like g3p deletion. Only phagemid with recombinant g3p are infectious Multivalent phage display
M13cp-dg3 Absent 0.1−10% M13K07 Equal DH5αFT All phage produced have recombinant g3p Multivalent phage display
|
1. Field of the Invention
The present invention relates to a resin guiding device for an inflation molding apparatus, and for guiding an inflated molten resin which is extruded in a tubular shape from an inflation molding die, to a pair of take-up rolls, and also to a method of producing a film by using such an inflation molding apparatus.
2. Description of the Related Art
Usually, a production of a film by inflation molding technique is performed in the following manner. A molten resin is extruded in a tubular shape from an annular slit of an inflation molding die, and a gas such as the air is blown into the tubular resin to inflate the resin. The inflated tubular resin is folded into a flat shape by a pair of flat stabilizing plates placed to form a shape which is tapered as moving in the extrusion direction of the resin. The flattened resin is taken up by a pair of take-up rolls, and then wound up by a winding machine.
In such inflation molding, as the stabilizing plates for stabilizing the inflated tubular resin and folding the resin into a flat shape, used are plates which are not easily deformed, such as plates made of aluminum, stainless steel, or the like, or those into which an appropriate number of guiding rolls are incorporated in a direction perpendicular to the resin flow direction.
The above-described conventional techniques are very effective in the case where a general-purpose plastic which exhibits a relatively low modulus of elasticity and a relatively large tensile elongation during a process of cooling and solidifying, such as polyethylene (PE) or polypropylene (PP) is used as the resin. When a tubular resin is folded into a flat shape by a pair of stabilizing plates, wrinkles and the like may be sometimes caused in a film by inflation unevenness of the resin, or by the resistance difference between the resin and the stabilizing plates, etc. However, it is often that wrinkles and the like are not seen in a film of such a general-purpose plastic, which is obtained by flatly folding, taking up, and winding, because such a general-purpose plastic has plasticity even at a room temperature.
On the other hand, recently, expectations for an engineering plastic film which is excellent in heat resistance and has high modulus of elasticity, and hardly elongated are growing. A request for an inflation molding technique which can produce such a film at a relatively economical manner is expanding. As compared with such a general-purpose plastic, however, an engineering plastic exhibits a high modulus of elasticity and a small tensile elongation, that is, properties of hard, during a process of cooling and solidifying. When a resin is folded by flat stabilizing plate as in the conventional art, therefore, wrinkles, uneven thickness, and the like easily occur, whereby the appearance of a resulting film is often largely impaired.
It is an object of the invention to provide a resin guiding device for an inflation molding apparatus, and a film producing method which enable a film that has less wrinkles and thickness unevenness and that is excellent in appearance.
The object of the invention is to provide a resin guiding device for an inflation molding apparatus, which guides a molten resin extruded and blown into a tubular shaped resin from an inflation molding die, to a pair of take-up rolls, and characterized in that the resin guiding device comprises a pair of guiding members which are placed between the inflation molding die and the pair of take-up rolls. The guiding members respectively have curved contact faces which are in contact with the tubular resin. Said curved contact faces are mutually outward curved, and each of the curved contact faces has a shape corresponding to a rein shape so as to fold the tubular resin into a flat shape. |
A few thoughts on turning 70 | Bob Quarteroni
So there you have it. According to the Bible the warranty on this puckered-up meat package is about to expire.
Bob Quarteroni (PennLive file)
On Feb. 6, a birthday I share with horror with Ronald Reagan, I will turn 70, when the Bible says it's time to turn into a subterranean sandwich for the eyeless hungry.
It seems just yesterday I was making mud pies with Joanie Ondish under our grapevine and now look at me: Told by Scripture that my ticket is ready to be punched.
So, how do I feel about this? Should I expound on some profundities, state some nuggets of wisdom that I've learned over the decades, impart important truths to those of you younger than me?
The truth is I feel no wiser - no less ignorant about everything - now than I did when I was a freshman at Central Catholic High school shooting spitballs though straws at my friends.
Which is beyond frustrating, since my entire life has been focused on the one and only truly important question we all face: What does it all mean?
Why are we here? Why were we born? What is life? Is there a God? Is the university entirely random? Is this all a dream? Is there even such a thing as reality?
All part and parcel of the same question, the ur-why, the meaning of the whole damn thing.
I was born reflective and I've stayed that way.
Sixteen years of Catholic schooling (even as I rejected that religion's silly rote mumbo-jumbo) early fueled my obsession with understanding a universe so unknowable, so seemingly random, so inexplicably composed of fantastic beauty and evil beyond understanding.
And the following decades were quests for knowledge in a myriad of ways, from mysticism to Zen, from meditation to Thomas Merton, from existentialism to magic mushrooms, from Paracelsus to St. John of the Cross, from the Kabballah to Buddhism, etc. etc. etc. ad infinitum.
The result? Nada. I feel I know less now then when I was making the mud pies.
I feel exactly like the woman in Annie Dillard's transformational - for me - "Pilgrim at Tinker Creek."
"We wake, if we ever wake at all, to mystery, rumors of death, beauty violence.....'Seems like we're just set down here,' a woman said to me recently, 'and don't nobody know why.'"
Amen to that, sister.
After a lifetime of trying to understand, it's no clearer to me now if, in the terms of one of my King's College theology courses, there is an "unmoved mover" behind it all. Or if it's just random chaos, noise, interference, indifference.
As "2001" author Arthur C. Clarke put it: "Two possibilities exist: either we are alone in the Universe or we are not. Both are equally terrifying."
Anyhow, thanks to my limited intelligence I'll obviously never know the answer. I almost hate to trot it out because I use it so often but it's so perfect: Alfred North Whitehead's "The universe is not only stranger than you imagine but stranger than you can imagine."
And I think that would be the case. Whatever's going on is going to be so fantastically weird and complex, we wouldn't understand it even if it was served up in tiny slices for our tiny brains.
It would be like trying to teach the theory of relativity to a flatworm. Not gonna happen.
So, leaving the great profundities aside, what have I learned in my 25,550 days?
I've learned that life is both sweet and sour. I've lived a thoroughly messy life and I wouldn't change a minute of it, not even when I screwed up the most or was most heartsick.
It's been an enjoyable, sloppy mess, full of loves and hates, likes and dislikes, adventures and misadventures; a roller coaster of loud, hard, intense living that is getting to the end so fast that it takes my breath away.
Did it have any great meaning? I would think not, though its memories and illuminations are priceless to me and will be until I blink out.
While the jury is out on the cosmic riddle, I strongly believe there is no afterlife, no personal Bobby Q floating around in the ether for eternity doing - what exactly?
That seems so silly to me to not even be worth serious consideration. No, as the ancient Easter Island proverb goes: We are born, we eat sweet potatoes, and we die.
When the rough beast I am slouches to a stop, that will be it for me. Nothing will be left but other people's memories of me and a room-temperature husk, devoid of life and meaning.
But I don't find that depressing at all. It's been a good run for a little dust mote like me, one helluva ride.
Even though I've never found any answers, I've never stopped looking and questioning, wondering and hoping, seeking and probing. And that, for me, has given meaning to my life.
On his deathbed Rabelais said, "I go to see a great perhaps."
Soon, perhaps, so will I.
Bob Quarteroni, a frequent PennLive Opinion contributor, is a former columnist and editor at the Centre Daily Times. He lives in Swoyersville, Pa. Readers may email him at bobqsix@verizon.net. |
egcitizen.com
Wilton Rancheria Chairman Raymond “Chuckie” Hitchcock this week told the Citizen that the projected opening of the tribe’s proposed, $500 million casino-resort in Elk Grove has been delayed until late 2021.
elkgrovetribune.com
On October 7, 2019, a final order was issued by District Court Judge N. McFadden of Washington, D.C., in which it dismissed the latest attempts by Stand Up for California to halt the Wilton Rancheria Resort and Casino project in Elk Grove, California.
law360.com
The federal government and the Wilton Rancheria Tribe of California have defeated a lawsuit challenging the tribe's acquisition of land in trust to build a casino, with a D.C. federal judge ruling that the land acquisition was handled properly.
elkgrovenews.net
In a ruling released yesterday in federal district court in Washington DC, Judge Trevor McFadden dismissed the lawsuit filed by casino watchdog group Stand Up For California against the Wilton Rancheria. The lawsuit filed by SUFC sought to reverse the January 2017 decision that allowed the 36-acre parcel on Elk Grove's south side to be placed into federal trust for the tribe.
pechanga.net
A federal judge in Washington, D.C., on Monday issued a comprehensive final order dismissing the remaining claims contesting the U.S. Department of the Interior’s authority and decision to place Wilton Rancheria’s tribal land in Elk Grove, CA., into federal trust.
elkgrovelagunanews.com
A Federal Judge has dismissed the claims by a group known as Stand Up For California, that had sought to stop the proposed Wilton Rancheria Casino. According to the court documents, the plaintiffs in the lawsuit were Elk Grove residents, Joe Teixeira, Patty Johnson, and Lynn Wheat. |
Tag Archives: black
Absolutely delighted to share this exotic, moroccan inspired stationery suite designed for a Wild Hearts style shoot shot at rustic Cable Bay. It’s always such an honour to contribute to a styled shoot, especially when the styling is by Balencia Lane & … Continue reading →
Congrats to the lovely Kate and Craig! These guys married on a cracker of a day over on the always stunning Waiheke Island. Starting their wedding with an oceanside ceremony right on Oneroa Beach, they then moved on to celebrate … Continue reading →
Introducing the latest Ready-To-Go Stationery Suite! This black & white number features an ornate, organic wreath motif and a combination of calligraphy & traditional serif fonts. Enjoy! x Like what you see? Each suite is ready to be customised with … Continue reading →
We are coming up fast to the six month (!!) countdown to our wedding – finally! We’ve achieved a lot this month and ticked off a few boxes in the last week, so it definitely feels like we’re right on … Continue reading →
Oh I have to cutest wedding inspiration styleshoot to share with you guys this evening – Waikato to a tee! Think vintage countryside, with a quirky twist… I’m loving all the little details – bowties, suspenders and even gumboots for … Continue reading → |
Q:
Do engines remember previous analysis?
Suppose I let the engine analyze a given position (let's say for simplicity the starting position), and then I execute the move suggested by the engine (let's say 1. e4). Then I let the engine analyze the upcoming position (black to move after 1. e4), and after a while I take the move back and let the engine again analyze the original position (the starting position, white to move again), will it:
utilize the analysis done on this position last time and look wider at each PLY?
utilize the analysis done on the upcoming position (after I played 1. e4) and possibly reevaluate 1. e4 based on that?
A:
Yes. This is what hash is: it stores previous analysis.
Hash is a database that stores information about positions previously searched, how deeply they were searched, and what was concluded about them. See also https://www.chessprogramming.org/Hash_Table
A:
I can't speak for all game playing engines, but a good engine would indeed remember past analysis. Having a "first-draft" evaluation of a position (and all the positions that can arise from each move) allows the engine to do move-ordering. This is where it looks at all possible moves in the order of "probable best" to "probable worst", based off the aforementioned "first-draft" evaluations that it saves.
By looking at the subtrees of moves that are probably better first, the engine is able to perform the minimax + alpha-beta algorithms MUCH more efficiently. Already looking at a good move/subtree allows you to prune a bad move/subtree, but not vice versa.
High quality engines actually perform their search via iterative-deepening. Search one move ahead, then go back to the starting position. Search two moves ahead, then go back to the starting position. All the way up to N moves ahead. That might seem inefficient, but it shows how powerful having some preliminary knowledge of a position and its moves can be before expanding further on it.
For your specific question, I assume you mean when you go forward and backwards manually in ChessBase. In this case I'm not sure if the engine remembers everything it calculates, because that's a lot of data to store just for the specific case of the user clicking back to a previous position. It seems pretty space inefficient. I tested it on ChessBase by making a move and seeing how fast the engine's depth climbed. Getting to depth 20 was slightly faster on the second time than the first time, but it wasn't instantaneous on the second time (which it should be if it did remember all its calculations the first time I manually brought it to the position).
|
Vigilance probe into Kochi Cyber City land deal
Thrissur, Feb 18 (IANS) The controversial land deal for the $1 billion Cyber City project in Kerala has now come under scrutiny for possible evasion of land registration fee to the government. The state’s Vigilance and Anti-Corruption Bureau (VACB) will probe whether the 70-acre plot for the project at Kochi was sold by the public sector Hindustan Machine Tools at substantially less than the market price, causing losses to the government in registration fee.
The probe was ordered Monday by the vigilance court on a petition claiming that the government lost Rs.490 million in registration fee as the land was sold at lower than the market price.
The Cyber City project is promoted by the Mumbai-based Housing Development and Infrastructure Ltd (HDIL), which says it purchased the land from HMT through public auction.
However, the petitioner, Sreekumar Mulleppali, a member of the Kaduvallur gram panchayat (village council) in Thrissur district, alleged that the “land was sold at Rs.130,000 a cent (One cent is 435.6 sq ft) while the market price is Rs.700,000 a cent”.
“The government would have got Rs.490 million if the land was sold at the actual price. HMT and government officials colluded with the real estate mafia to sell the land at a low price,” the petition contended.
Meanwhile, S. Sarma, who holds the registration portfolio in the V.S. Achuthanandan ministry, told reporters in Kochi that the government will take stringent action against officials if it was found they had caused revenue loss to the government. |
Q:
Karma test an Angular X (5) Component with a custom pipe that uses a built in pipe
I have built a custom pipe to format currencies, which uses the decimal pipe in it. Now I want to Karma test my component, which uses my custom pipe.
Here is my custom pipe:
import { Pipe, PipeTransform } from "@angular/core";
import { CURRENCY } from "./customCurrency.enums";
import { DecimalPipe } from "@angular/common";
type CurrencySymbol = keyof typeof CURRENCY;
type CurrencyHandler = {
[x in CurrencySymbol]: (value: string) => string;
};
@Pipe({
name: "customCurrency",
})
export class CustomCurrencyPipe implements PipeTransform {
constructor(private decimalPipe: DecimalPipe) { }
transform(amount: string, currency: CurrencySymbol): string {
const currencyHandler: CurrencyHandler = {
Euro: (value: string): string => {
const formatValue = value.toString().replace(",", ".");
return this.setCharAt(formatValue, formatValue.length - 3, ",") + " " + CURRENCY.Euro;
},
};
return currencyHandler[currency](this.decimalPipe.transform(amount, "1.2-2"));
}
private setCharAt(str, index, chr) {
if (index > str.length - 1) {
return str;
}
return str.substr(0, index) + chr + str.substr(index + 1);
}
}
I am using it in the HTML part only in my component:
<span class="col-s currency">{{invoice.totalAmount | customCurrency:"Euro"}}</span>
This pipe is member of my SharedModule. So I imported it into my testbed configuration.
Now I want to test the component with this template here:
/* tslint:disable:no-unused-variable */
import { async, ComponentFixture, TestBed } from "@angular/core/testing";
import { CUSTOM_ELEMENTS_SCHEMA } from "@angular/core";
import { ApprovalsComponent } from "./approvals.component";
import { MaterialModule } from "../shared/material.module";
import { BrowserAnimationsModule } from "@angular/platform-browser/animations";
import { DataService } from "../core/data.service";
import { SharedModule } from "../shared/shared.module";
describe("ApprovalsComponent", () => {
let component: ApprovalsComponent;
let fixture: ComponentFixture<ApprovalsComponent>;
beforeEach(async(() => {
TestBed.configureTestingModule({
imports: [
MaterialModule,
BrowserAnimationsModule,
SharedModule,
],
declarations: [
ApprovalsComponent,
],
providers: [
DataService,
],
schemas: [CUSTOM_ELEMENTS_SCHEMA],
})
.compileComponents();
}));
beforeEach(() => {
fixture = TestBed.createComponent(ApprovalsComponent);
component = fixture.componentInstance;
fixture.detectChanges();
});
it("should create", () => {
expect(component).toBeTruthy();
});
});
I am always getting the error:
NullInjectorError: No provider for DecimalPipe!
I have tried out all kind of import or declaration variations, without any success. What am I doing wrong?
Can someone tell, where I have to import/declare/provide what. My custom pipe is part of shared module. What if I want to test a component which uses it, but is in a different module. And what if I want to use the pipe in a component within the same module?
A:
I restarted my complete environment and added the DecimalPipe again to my providers and now it works. I have no clue why it works now and it did not before, but it works with this configuration when I am in another module:
beforeEach(async(() => {
TestBed.configureTestingModule({
imports: [
MaterialModule,
BrowserAnimationsModule,
SharedModule,
],
declarations: [
ApprovalsComponent,
],
providers: [
DataService,
DecimalPipe,
],
schemas: [
CUSTOM_ELEMENTS_SCHEMA,
],
})
.compileComponents();
}));
And with this configuration when I am in the same module:
beforeEach(async(() => {
TestBed.configureTestingModule({
imports: [
MaterialModule,
],
declarations: [
LineItemListComponent,
CustomCurrencyPipe,
],
schemas: [
CUSTOM_ELEMENTS_SCHEMA,
],
providers: [
DecimalPipe,
],
})
.compileComponents();
}));
|
[The main results of the experiment regarding the changes in the principles of follow-up of patients with mental disorders].
In 1988--1989 an organizational experiment was carried out in Moscow, Leningrad, in the Latvian SSR, the Altai territory and in the Ivanovo region. Apart from the conventional follow-up of patients with mental diseases, the counselling form of the follow-up was established in the experimental territories. In accordance with this new principle, the treatment and counselling assistance to persons with mental disorders was rendered only after seeing a doctor. The main results of the experiment are as follows: 1) the follow-up group of patients noticeably diminished at the expense of a decrease of the number of persons taken under the follow-up studies as well as at the expense of more rapid removal of the patients from the register including their active transfer to the patients' group given medical advice; 2) in the follow-up group structure, there was an increase in the number of patients with psychotic disorders and mental retardation and a noticeable lowering of the number of patients with non-psychotic disorders; 3) the group of patients to be given medical advice dramatically increased in the experimental territories, while the number of patients suffering from non-psychotic disorders accounted among them for 80-85%. On the whole the experiment provided evidence in favour of the opportuneness and soundness of introduction into psychiatric practice of the two follow-up types: as far as patients with grave mental disorders and deep social decompensation are concerned, they should be followed up over time by means of conventional methods; as to patients with milder mental disorders, the counselling form of the follow-up is quite sufficient, provided they adapt themselves socially or are well protected (in respect to children and retired persons). |
# Helper script for exploring SaaS app disaster recovery using geo-replication functionality
# The script showcases DR use cases:
# 1. Restore the app into a secondary recovery region by failing over to replicas,
# 2. Repatriate the SaaS app into its original region using geo-replication
## --------------- PARAMETERS ----------------------------------------------------------------------
$DemoScenario = 1
<# Select the scenario that will be run. Run the scenarios below in order.
Scenario
1 Start a background job that syncs tenant server, and pool configuration info into the catalog
2 Create mirror image recovery environment and replicate catalog and tenant databases
3 Recover the app into a recovery region by failing over to replicas
4 Provision a new tenant in the recovery region
5 Delete an event from a tenant in the recovery region
6 Repatriate the app into its original region
#>
# Parameters for scenario #4, provision a tenant in the recovery region
$TenantName = "Hawthorn Hall" # name of the venue to be added/removed as a tenant
$VenueType = "multipurpose" # valid types: blues, classicalmusic, dance, jazz, judo, motorracing, multipurpose, opera, rockmusic, soccer
# Parameters for scenario #5, delete an event from a tenant in the recovery region
$TenantName2 = "Contoso Concert Hall" # Name of tenant from which event will be deleted
## --------------- INITIALIZATION ------------------------------------------------------------------
Import-Module "$PSScriptRoot\..\..\Common\CatalogAndDatabaseManagement" -Force
Import-Module "$PSScriptRoot\..\..\Common\SubscriptionManagement" -Force
Import-Module "$PSScriptRoot\..\..\UserConfig" -Force
Import-Module "$PSScriptRoot\..\..\WtpConfig" -Force
# Get Azure credentials if not already logged on, Use -Force to select a different subscription
Initialize-Subscription
# Get the resource group and user names used when the application was deployed
$wtpUser = Get-UserConfig
$config = Get-Configuration
## --------------- SCENARIOS -----------------------------------------------------------------------
### Default state - enter a valid demo scenaro
if ($DemoScenario -eq 0)
{
Write-Output "Please modify the demo script to select a scenario to run."
exit
}
### Sync tenant pool/server configuration into the catalog
if ($DemoScenario -eq 1)
{
Write-Output "Running 'Tenant configuration sync' in background process ..."
# Save login credentials for background job
Save-AzureRmContext -Path "$env:TEMP\profile.json" -Force
# Start background process
Start-Process powershell.exe -ArgumentList "-NoExit &'$PSScriptRoot\Sync-TenantConfiguration.ps1'"
exit
}
### Replicate SaaS app and databases to recovery region
if ($DemoScenario -eq 2)
{
# Save login credentials for background job
Save-AzureRmContext -Path "$env:TEMP\profile.json" -Force
# Start background process
Start-Process powershell.exe -ArgumentList "-NoExit &'$PSScriptRoot\Deploy-WingtipTicketsReplica.ps1'"
Write-Output "Creating replica for '$($wtpUser.ResourceGroupName)' Wingtip deployment. This may take several minutes ..."
exit
}
### Failover SaaS app and databases to recovery region
if ($DemoScenario -eq 3)
{
# Save login credentials for background job
Save-AzureRmContext -Path "$env:TEMP\profile.json" -Force
# Start background process
Start-Process powershell.exe -ArgumentList "-NoExit &'$PSScriptRoot\Failover-IntoRecoveryRegion.ps1'"
Write-Output "Starting failover of application to recovery region ..."
exit
}
### Provision a new tenant in the recovery region
if ($DemoScenario -eq 4)
{
# Set up the server and pool names in which the tenant will be provisioned.
# The server name is retrieved from an alias used to switch between normal and recovery regions
$newTenantAlias = $config.NewTenantAliasStem + $wtpUser.Name + ".database.windows.net"
$serverName = Get-ServerNameFromAlias $newTenantAlias
$poolName = $config.TenantPoolNameStem + "1"
$resourceGroupName = (Find-AzureRmResource -ResourceNameEquals $serverName -ResourceType "Microsoft.sql/servers").ResourceGroupName
try
{
New-Tenant `
-WtpResourceGroupName $resourceGroupName `
-WtpUser $wtpUser.Name `
-TenantName $TenantName `
-ServerName $serverName `
-PoolName $poolName `
-VenueType $VenueType `
-ErrorAction Stop `
> $null
}
catch
{
Write-Error $_.Exception.Message
exit
}
Write-Output "Provisioning complete for tenant '$TenantName'"
# Open the events page for the new venue
Start-Process "http://events.wingtip-dpt.$($wtpUser.Name).trafficmanager.net/$(Get-NormalizedTenantName $TenantName)"
exit
}
### Delete an event from a tenant
if ($DemoScenario -eq 5)
{
& $PSScriptRoot\..\..\Utilities\Remove-UnsoldEventFromTenant.ps1 `
-WtpResourceGroupName $wtpUser.ResourceGroupName `
-WtpUser $wtpUser.Name `
-TenantName $TenantName2 `
-NoEcho `
> $null
exit
}
### Repatriate the app into its original region
if ($DemoScenario -eq 6)
{
# Save login credentials for background job
Save-AzureRmContext -Path "$env:TEMP\profile.json" -Force
# Start background process
Start-Process powershell.exe -ArgumentList "-NoExit &'$PSScriptRoot\Repatriate-IntoOriginalRegion.ps1'"
Write-Output "Repatriating app into original region. This may take several minutes..."
exit
}
### Invalid option selected
Write-Output "Invalid scenario selected"
|
Activity of glutathione related enzymes and ovarian steroid hormones in different sizes of follicles from goat and sheep ovary of different reproductive stages.
The investigations on enzymes related to glutathione like glutathione-S-transferase (GST) and glutathione peroxidase (GSH-Px) have been carried out mostly in human and rat ovaries, however the studies on these enzymes in ruminants are relatively absent. In the present study the changes in the activity of these enzymes, in different sizes of follicles from goat and sheep ovaries of different reproductive stages, were investigated. The results demonstrated that the activity of the enzyme GST increased with the increase in size of the follicles from small to large follicles of follicular phase ovary and from small to medium follicles of luteal phase ovary in both the species, thereafter it decreased in large follicles of luteal phase ovary. There was increasing pattern in the activity of GSH-Px in the follicular phase follicles and a decreasing pattern in the luteal phase follicles from both the species. Thus the changes in the activity of glutathione related enzymes namely GST and GSH-Px in different size follicles from both the species during different reproductive phases are evident from the results. It is reasonable, therefore, to assume that these enzymes may have functional role in the steroid hormone metabolism in ruminant ovary as reported in human ovary. |
.. _1-1-7:
1.1.7
===========================
*03/16/2020*
Graphite 1.1.7 is now available for usage. Please note that this is a bugfix release for the stable Graphite 1.1.x branch and it's recommended for production usage. It also contains some improvements backported from the master branch.
Highlights
-------------
* New experimental Bucketmax write strategy (see #879 for details)
* Fixes for function parameters validation
* More fixes for better error handling
* Python 3.9 and Django 3.x support
* Python 3 fixes Carbon, Carbonate and Graphite-web
* Many flake8 fixes for Graphite-web
Thanks a lot for all Graphite contributors and users!
Source bundles are available from GitHub:
* https://github.com/graphite-project/graphite-web/archive/1.1.7.tar.gz
* https://github.com/graphite-project/carbon/archive/1.1.7.tar.gz
* https://github.com/graphite-project/whisper/archive/1.1.7.tar.gz
* https://github.com/graphite-project/carbonate/archive/1.1.7.tar.gz
Graphite can also be installed from `PyPI <http://pypi.python.org/>`_ via
`pip <http://www.pip-installer.org/en/latest/index.html>`_. PyPI bundles are here:
* http://pypi.python.org/pypi/graphite-web/
* http://pypi.python.org/pypi/carbon/
* http://pypi.python.org/pypi/whisper/
* http://pypi.python.org/pypi/carbonate/
You can also use docker image from https://hub.docker.com/r/graphiteapp/graphite-statsd/
Upgrading
---------
Please upgrade carbon and graphite-web - they contain valuable bugfixes and improvements. Whisper package has no changes from previous release.
New features
------------
Graphite-Web
^^^^^^^^^^^^
* Merge prefetched data. (#2507. @liyichao)
* introduce paramtype for agg or series func (#2523, @replay)
* Mark series functions to use as aggregators (#2528, @replay)
* Python 3.9 support: remove deprecated U option to open (#2529, @piotr1212)
* remove leading ~ from name when indexing metric names (#2458, @replay)
* add graphite-dl4j and carbon-proxy (#2521, @jdbranham)
* test docs on Python3 (#2535, @piotr1212)
* Django 3.0 compatibility (#2534, @piotr1212)
* Parameter type int or inf (#2538, @replay)
* Interpret inf (#2539, @replay)
* better error messages (#2543, @replay)
* Adding Hisser and Go-graphite buckytools in tools documentation (#2549, @deniszh)
* make consolidation func `avg` alias for average (#2556, @replay)
* move all validation into Param.validateValue (#2557, @replay)
* handle exceptions if params cannot be type converted (#2547, @replay)
* better error messages with type indications (#2543, @replay)
* log grafana dashboard/panel id headers (#2564, @replay)
* Allow floats in scaleToSeconds() (#2565, @replay)
Carbon
^^^^^^
* Bucketmax write strategy (#879, @piotr1212)
* s390x support for travis (#869, @sangitanalkar)
* sanitize names when using them as tag value (#858, @replay)
* simplify travis-ci config (#875, @ploxiln)
Whisper
^^^^^^^
None
Carbonate
^^^^^^^^^
* Add python3 testing (#110, @hdost)
* add codecov (#112, @piotr1212)
Bug Fixes
---------
Graphite-Web
^^^^^^^^^^^^
* Fix AttributeError if parameter validation fails (#2510, @PhilippWendler)
* Taming lint (#2512, @deniszh)
* relax enforcement of options sets in validation (#2513, @replay)
* Fix tests (#2525, @replay)
* Trying to fix tests (#2530, @deniszh)
* simplify travis-ci config (#2532, @ploxiln)
* fix function parameter types (#2536, @replay)
* fixes #2541 (#2542, @replay)
* prune flake8 ignore list (#2552, @ploxlin)
* flake8: re-enable F841 (local variable assigned but not used) (#2559, @ploxiln)
* flake8: re-enable E122,E124 (indent of continuation and closing bracket) (#2558, @ploxiln)
* Fix validator when default value is used (#2555, @replay)
* flake8: include contrib/ subdir, re-enable rule E713 (#2554, @ploxiln)
Carbon
^^^^^^
* Fix #871: Adjust aggregator-rules input_pattern match greediness to support numeric matching after captured field (#872 @hessu)
* Another test fix try (#874, @deniszh)
* Fixing tests for S390 (#880, @sangitanalkar)
* Trying to fix tests (#881, @deniszh)
* Fix the manhole for Twisted > 16 and Python 3 (#882, @piotr1212)
* Fix missing encoding for line protocol (#885, @pkruk)
Whisper
^^^^^^^
None
Carbonate
^^^^^^^^^
* fixes python3 TypeError (#113, @l4r-s)
* Change write mode to non-binary. (#111, @hdost)
|
Thank
you for choosing our Indian cuisine. We are not a "curry
in a hurry" restaurant. We make everything from scratch,
except soft drinks and coffee, with the finest ingredients
available. Indian cuisine is usually equated with curry,
which to some extent is true, but all dishes are not
curries. Indian food is really a basic stove top cooking
with the knowledge of how and when to use these spices
to bring out their characteristic aromas. All the dishes
are made to the order so you can always have it Mild,
Medium or Spicy Hot and we always ask you when you order. India Grill - Tasteful dining in Rockville at very reasonable prices! |
Background
The pro-inflammatory status of the elderly triggers most of the age-related diseases such as cancer and atherosclerosis. Atherosclerosis, the leading cause world wide of morbidity and death, is an inflammatory disease influenced by life-style and genetic host factors. Stimuli such as oxLDL or microbial ligands have been proposed to trigger inflammation leading to atherosclerosis. It has recently been shown that oxLDL activates immune cells via the Toll-like receptor (TLR) 4/6 complex. Several common single nucleotide polymorphisms (SNPs) of the TLR system have been associated with atherosclerosis. To investigate the role of TLR-6 we analyzed the association of the TLR-6 SNP Pro249Ser with atherogenesis.
Results
Genotyping of two independent groups with CAD, as well as of healthy controls revealed a significant association of the homozygous genotype with a reduced risk for atherosclerosis (odds ratio: 0.69, 95% CI 0.51-0.95, P = 0.02). In addition, we found a trend towards an association with the risk of restenosis after transluminal coronary angioplasty (odds ratio: 0.53, 95% CI 0.24-1.16, P = 0.12). In addition, first evidence is presented that the frequency of this protective genotype increases in a healthy population with age. Taken together, our results define a role for TLR-6 and its genetic variations in modulating the inflammatory response leading to atherosclerosis.
Conclusions
These results may lead to a better risk stratification, and potentially to an improved prophylactic treatment of high-risk populations. Furthermore, the protective effect of this polymorphism may lead to an increase of this genotype in the healthy elderly and may therefore be a novel genetic marker for the well-being during aging.
The immune status of the elderly is characterized by 2-4-fold increased baseline levels of inflammatory mediators such as cytokines and acute phase proteins [1]. This chronic low-level inflammation (recently also termed inflamm-aging) has been suspected to drive age related diseases such as atherosclerosis, cancer, diabetes and Alzheimer’s disease, all of them characterized by chronic inflammation [2–4].
Coronary artery disease (CAD) is the leading cause of morbidity and mortality worldwide [5]. It is an inflammatory disease with inflammatory markers being elevated, and causally involved in the pathogenesis of CAD [6]. CAD results in dangerous plaques leading to stenosis of coronary arteries, which are removed by a medical procedure termed percutaneous transluminal coronary angioplasty (PTCA). Restenosis, which is the main drawback of this treatment, has also been associated with increased local inflammation. The inflammatory response induced by PTCA correlates with the risk of restenosis, and anti-inflammatory treatments decrease the risk of restenosis [7–10].
In addition to life-style and nutrition, genetic factors have recently been shown to play an important role in the development of CAD. Several genetic risk loci have been identified by genome-wide association studies [11]. In line with these results, the release of inflammatory markers such as IL-6 during CAD, or following PTCA differs largely between individual patients and this most likely due to a different genetic background. Single nucleotide polymorphisms (SNPs) have been shown to influence serum levels of IL-6 and other inflammatory markers as reviewed by Dahmer et al. [12]. Although several genome-wide association studies have been performed, the loci identified could only explain some of the heritability of CAD and other common complex diseases. Therefore, further analysis of SNPs in candidate genes may improve our understanding of complex diseases such as atherosclerosis [13].
Postulated mediators of atherogenesis, e.g. bacteria such as Chlamydia pneumoniae or oxLDL, activate the innate immune system via the TLR-pathway [14]. TLR-associated SNPs have been found to be potentially involved in altered susceptibility and course of several diseases [15]. I.e.TLR-4 has been shown to be involved in early atherosclerosis by comparing knock out mice to control animals: Mice lacking TLR-4 were protected in an atherosclerosis model, which seemed to be independent from cholesterol levels [16]. In line with these findings, genetic variations within the TLR-4 gene in patients have been associated with risk for atherosclerosis, although conflicting results have been published (reviewed by den Dekker et al. [17]). Also deficiency of TLR-2 has been associated with lowered diet- and pathogen induced atherosclerosis in mouse models [18, 19]. Involvement of the activation of the innate immune system via the TLR-pathway in pathogenesis of atherosclerosis as well as TLRs as possible therapeutic targets for atherosclerosis has been recently reviewed [20–22].
TLR-6 has been shown to mediate inflammatory responses upon stimulation with oxidized low-density lipoprotein (oxLDL) in cooperation with TLR-4 [23]. In line, TLR-4- and TLR-6-knock out mice both have been shown to express decreased quantities of tissue factor induced by hypercholesterolemic diet as compared to control mice [24]. Furthermore, the TLR-6 SNP Pro249Ser has recently been associated with lower left ventricular wall thickness and inflammatory response in hypertensive women [25]. In addition, the mutated TLR-6 Ser allele has been shown to lead to a diminished IL-6 release upon stimulation with a TLR-6 agonist [26]. Regarding restenosis, TLR-2 the heterodimerization partner of both, TLR-1 and TLR-6 in recognizing bacterial lipoproteins, has been shown to play an important role in restenosis after revascularization procedures: We could show that a TLR2 SNP is associated with the inflammatory response and with the risk of restenosis after PTCA [27].
Here we investigated the association of the TLR-6 SNP Pro249Ser (rs5743810) with susceptibility to atherogenesis in two independent patient groups with proven coronary artery disease by comparison with age-matched healthy control groups. One group that underwent PTCA and subsequent control angiography after 6 months was further analyzed for an association of the TLR-6 SNP with restenosis. We found the homozygous mutated TLR-6 genotype to be significantly associated with a reduced susceptibility to atherosclerosis (odds ratio of 0.69, 95% CI 0.51-0.95; P = 0.02). However, association with restenosis after successful PTCA was found to be only of borderline significance (odds ratio: 0.53, 95% CI 0.24-1.16, P = 0.12), which is most likely due to the lower sample number. Comparison of both aged healthy control groups with a young healthy control group showed a significant increase (odds ratio 1.53, 95% CI 1.16-2.02, P = 0.003) of the homozygous mutated genotype with age.
TLR-6 SNP Pro249Ser is associated with the risk for atherosclerosis
207 Caucasian patients with symptomatic CAD as well as a confirmatory study group of 306 patients that underwent cardiac surgery were genotyped for the presence of the TLR-6 SNP Pro249Ser. Two groups of 300, and 305, respectively healthy Caucasian volunteers served as controls. Compared to healthy controls, the Ser allele was found to be significantly less frequent in patients (P = 0.008 and P = 0.23, respectively, Table 1). Combination of both cohorts resulted in a P-value of 0.007. Genotype distribution was also significantly different among patients and controls: Employing a recessive model we compared homozygous mutant genotypes with wild-type plus heterozygous genotypes: In both groups a trend for a decreased frequency of the homozygous genotype could be observed in patients indicating a protective function of this genotype (Table 1). Combination of both groups revealed a decreased risk for the homozygous Ser/Ser genotype with an odds ratio of 0.69, 95% CI 0.513-0.953 with a P-value of 0.02 (Table 1).
Table 1
TLR-6 genotype distribution in CAD patients and controls
N
Variant allele (%)
P-value
Genotype (%)
Odds ratio (95% CI)
Pro/pro
Pro/ser
Ser/ser
P-value
ser
C/C
C/T
T/T
Study group
Controls 1
300
278 (46.3)
0.008
87 (29.0)
148 (49.3)
65 (21.7)
0.64
Patients
207
157 (37.9)
81 (39.1)
95 (45.9)
31 (15.0)
0.38-1.02
0.06
Confirmatory group
Controls 2
305
268 (43.9)
0.23
97 (31.8)
148 (48.5)
60 (19.7)
0.76
Patients
306
248 (40.5)
106 (34.6)
152 (49.7)
48 (15.7)
0.50-1.15
0.20
Combined
Controls
605
546 (45.1)
0.007
184 (30.4)
296 (48.9)
125 (20.7)
0.69
Patients
513
405 (39.5)
187 (36.5)
247 (48.1)
79 (15.4)
0.513-0.953
0.02
P-values were determined by chi2 test. The odds ratios were determined by comparing the homozygous genotype with the wild type and the heterozygous genotype.
Presence of the Pro249Ser TLR-6 SNP is associated with a trend towards the risk for restenosis
The risk of restenosis after successful PTCA has been associated with an inflammatory response induced by PTCA. Therefore, we stratified our study group for the occurrence of restenosis as determined by a control angiography 6 month after successful PTCA. In line with the previous finding, the TLR-6 Ser allele was also underrepresented in the restenosis group. However, these differences were of borderline significance only (P = 0.05), most likely due to the low sample number. A trend for a protective role of the homozygous Ser/Ser genotype regarding restenosis, Odds ratio 0.53, 95% CI 0.24-1.16, P-value = 0.12 was observed (Table 2).
Table 2
TLR-6 genotype distribution among CAD patients with or without restenosis
N
Variant allele (%)
P-value
Genotype (%)
Odds ratio (95% CI)
Pro/pro
Pro/ser
Ser/ser
P-value
Ser
C/C
C/T
T/T
Study group
No restenosis
106
90 (42.5)
0.05
36 (34.0)
50 (47.2)
20 (18.9)
0.53
Restenosis
101
67 (33.2)
45 (44.6)
45 (44.6)
11 (10.9)
0.24-1.16
0.12
P-values were determined by chi2 test. The odds ratios were determined by comparing the homozygous genotype with the wild type and the heterozygous genotype.
Frequency of the Pro249Ser TLR-6 SNP increases with age in healthy controls
Given that coronary artery disease is the major cause of death in the Western world, we speculated that this protective Ser249Ser TLR-6 genotype would be overrepresented in an elderly cohort of healthy controls in comparison to a young healthy control group, where due to age CAD doesn’t play a role. To test this hypothesis, we compared 805 young healthy controls (age <50) with both combined aged healthy control groups of higher age described above. Indeed we observed a significant increase of the “protective Ser allele” in the high age control group (P = 0.00006). In line, the homozygous mutated Ser/Ser genotype also was found more frequently in higher age (Odds ratio 1.53, 95% CI 1.16-2.02, P = 0.003, Table 3) indicating this genotype to be a marker for healthy ageing. Comparing genotype and gender by chi2 test no significant association could be observed for patients, old controls and young controls, respectively (P = 0.33, P = 0.94, P = 0.72).
Table 3
TLR-6 genotype distribution among young and old healthy controls
N
Variant allele (%)
P-value
Genotype (%)
Odds ratio (95% CI)
Pro/pro
Pro/ser
Ser/ser
P-value
P
value
P
value
P
Study group
Young contr.
805
606 (37.6)
0.00006
316 (39.3)
372 (46.2)
117 (14.5)
1.53
1.16-2.02
0.003
Old contr.
605
546 (45.1)
184 (30.4)
296 (48.9)
125 (20.7)
P-values were determined by chi2 test. The odds ratios were determined by comparing the homozygous genotype with the wild type and the heterozygous genotype.
Possible influence of Pro249Ser on TLR-6 protein structure
To investigate the consequence of the Pro249Ser SNP on TLR-6 protein structure we performed some “in silico analysis”. Figure 1 shows three-dimensional structure of Leucine rich region (LRR) for TLR-6 housing the SNP. Comparison of CASTp results for wild type and mutant of TLR-6 LRR region divulged presence of 102 and 93 functional pockets, respectively (Additional file 1: Figure S1). The mutation resulted in a decrease number of pockets. The wild type and mutant showed variation in surface topography of major clefts and cavities (Additional file 2: Figure S2). As seen from Additional file 3: Table S1 and Additional file 2: Figure S2, significant decrease in volume of two major clefts in the mutant was observed. Flexibility analysis revealed that the wild type was 36.6% rigid while mutant was 70.7% rigid. I-Mutant results predicted DDG value (difference in free energy of the mutation) of −1.50 Kcal/mol owing to change of P249 to S249.
Inflammation plays a pivotal role in atherosclerosis and mediates the effects of many known risk factors of the disease by altering the behaviour of endothelial as well as smooth muscle cells [28]. In addition, the risk for restenosis after successful angioplasty is strongly influenced by the inflammatory response to the PTCA procedure, mediated at least partially by the TLR system triggering the inflammatory response [7, 9].
Here, we add another line of evidence for the involvement of the TLR system in this inflammatory process leading to atherogenesis. TLR-6 has been shown to mediate inflammatory response by oxLDL, a known risk factor for atherosclerosis [23]. Bacterial lipopeptides, also known to induce atherogenesis, are also recognized by TLR-6 in combination with TLR-2 and TLR-1 [14]. Our results shown here indicate an association of the TLR-6 Pro249Ser SNP with the risk for atherosclerosis, and potentially with the risk for restenosis after successful PTCA. The reason for the association with restenosis being only of borderline significance most likely lies in the limited sample number since restenosis data were not available for the confirmatory study group. However, the differences in percentage were similar or even more pronounced as found by the comparing patients and controls regarding atherosclerosis susceptibility. Limitations of our study are on one hand the low sample number, and on the other the fact, that little information about other relevant risk factors potentially influencing our results was available. Therefore, larger and well planned prospective studies are needed to confirm our results.
In line with our results several mouse models have currently shown an involvement of TLR-2, which acts as heterodimer with TLR-1 or −6, in atherogenic processes [18, 19]. It has been suggested that endogenous TLR-2 agonists may have an impact on atherosclerotic disease progression by the fact that TLR-2 knock out mice exhibit a decreased severity of experimentally induced atherosclerosis [19]. Two studies have shown pro-atherogenic effects of apoCIII being mediated by TLR-2: In contrast to wild type mice apoCIII failed to activate monocytes originating from TLR-2 deficient mice regarding adhesiveness to HUVECs [29]. Furthermore, apoCIII was not able to induce MCP-1 and IL-6 in adipose tissue from TLR-2 knock out mice [30].
Elevated IL-6 levels play an important role in atherogenesis due to detrimental effects on the vascular wall and endothelial function [31, 32]. Supporting our hypothesis of TLR-6 Pro249Ser being athero-protective functional analysis of this SNP has revealed that the Ser/Ser genotype was associated with a decreased IL-6 release by stimulated monocytes as well as a lessened NF-κB activation in transfected HEK 293 cells [26]. In contrast to IL-6, the release of the athero-protective cytokine IL-10 seems not to be influenced by TLR-6 Pro249Ser [33, 34]. It has furthermore been shown that murine aortae express TLR-6 and that it is crucial for the induction of vascular dysfunction by Gram-positive bacteria [35]. The role of TLR-6 deficiency in atherogenesis has recently investigated employing knock out mice. Endogenous atherosclerotic stimuli brought about by high fat diet, for example oxLDL, do not depend on TLR-6 expression, whereas exogenous stimuli like MALP2, known to be a TLR-6 ligand, depend on TLR-6 expression [36]. However, whether the TLR-6 Pro249Ser SNP alters the inflammatory response in human vascular cells and which stimuli are involved currently still remains to be investigated. The therapeutic potential of TLR modification by TLR agonists as well as TLR antagonists in cardiovascular dysfunction has been reviewed recently. Especially compounds modifying TLR-2 and TLR-4 function are considered to be beneficial. Antagonists are thought to lower the inflammatory burden whereas low concentrations of agonist are thought to be protective in terms of preconditioning [37]. Our data indicate that also TLR-6 could be a target of therapeutical intervention.
The consequence of the mutation on the protein structure is evident from our findings. In wild type, the pocket housing SNP P249S showed differences having residues interrupted by cavities in proximity of proline while mutant had pocket residues close to each other indicating potential conformational changes. This conformational change is likely to affect binding of ligands and receptors. Again, substantial decrease in volume of the clefts is bound to impact capability of mutant protein to enter into meaningful interactions since majority of binding regions and active sites are known to be located in largest cleft [38]. These aforementioned facts are further supported by the outcome of flexibility studies. The wild type protein being more flexible had more room for ligand induced movements while in mutant ligand induced movement will be restricted to side-chain rearrangements only [39]. So, the mutation makes the structure difficult to undergo functionally relevant conformations making it harder for inducing possible drug molecules. The significantly low DDG value pointed out considerable decrease in stability in the mutant. All these confirmed that the TLR-6 protein structure and functionality are influenced by mutation.
Healthy aging depends most likely on the delay of onset of age related diseases such as coronary artery disease, Alzheimer’s disease, type 2 diabetes and cancer [40]. Genetic variations associated with age-related diseases therefore have been suspected to be involved in successful aging [41]. A large number of genes, and thereby a large number of SNPs, are involved in pathogenesis of these common diseases. Therefore, a genetic signature for longevity has been suggested by Sebastiani et al. [42]. They established networks for coronary artery disease and Alzheimer’s disease including 130 disease-associated genes building a genetic risk model [42]. However, since TLR-6 SNPs have not been associated with either of these diseases so far, TLR-6 was not included into this model. Of note, since chronic inflammation is central for age-related diseases these longevity networks are both centred on NFκB activation [42], which is the main signalling pathway following TLR stimulation. Having shown that the TLR-6 ser/ser genotype protects from atherosclerosis we could show here that this genotype is increased in the healthy elderly. One could speculate that this less functional TLR-6 variant may be beneficial by lowering the effects of inflamm-ageing during older age.
Our results suggest that the less functional TLR-6 Ser/Ser genotype protects from atherosclerosis as well as from restenosis after successful PTCA. The underlying mechanism remains to be investigated but it is tempting to speculate that a lessened inflammatory response brought about by a dysfunctional TLR-6 is responsible for this protective effect. Genotyping of patients at risk for CAD may improve the risk stratification and lead to a better prevention regime for both, atherosclerosis and restenosis. Furthermore, this SNP may be a novel genetic marker for healthy aging.
Patients
Study group
The first study group has been described in detail previously as study group “A” [27]. In brief, the group consisted of 207 Caucasian patients with symptomatic coronary artery disease who underwent PTCA. Significant stenosis was confirmed by quantitative coronary angiography. All patients were hospitalized, clinically stable, and were routinely checked after 6 month for follow-up angiography.
Confirmatory group
The confirmatory group has been described previously [43]. 306 patients undergoing elective cardiac surgery (coronary artery bypass graft with/or without valve surgery) have been enrolled by a single-center study.
Controls
DNA from 300 healthy controls obtained from the PopGen biobank (University of Kiel, Germany) was included as control for the study group (Control group 1). DNA from 305 healthy controls from the PopGen biobank was included as control for the confirmatory group (Control group 2). A third control group of 805 young healthy volunteers was analyzed to compare genotype distribution dependent on age (Control group 3). Participants reported to not have had a chronic disease or regularly use medication at recruitment.
Characteristics for all patients and controls are summarized in Table 4. All participants were of Caucasian origin. All studies were approved by the local ethics committees, and all investigations were carried out in accordance with the ethical guidelines of the 1975 Declaration of Helsinki.
Genotyping
Genomic DNA was prepared by standard procedures from whole blood. Genotyping for TLR-6 SNP Pro249Ser (rs5743810) was performed by melting curve analysis. Melting curve analysis was carried out employing primers gaaagactctgaccaggcat (forward), ctagtttattcgct atccaagtg (reverse), and FRET-hybridisation probes: accagaggtccaaccttactgaa-FL and LC-red 640-ttaccctcaaccacatagaaacgacttgga resulting in melting points of 61°C and 52°C for the wild-type,, and the mutated allele, respectively. Genotyping was executed using standard PCR conditions applying the LightCycler LC 480 platform (Roche Diagnostics, Mannheim, Germany). Primers and probes were designed by O. Landt (TIB-MOLBIOL, Berlin, Germany). Genotyping by melting curve analysis was validated by reanalyzing 10% of the samples using a conventional restriction fragment polymorphism analysis. Digestion of the 194 bp PCR product with AvaII results in two fragments of 67 bp and 127 bp in wild type individuals, whereas the TLR-6 SNP Pro249Ser destroys this restriction site. Restriction digests were analyzed on a 3% agarose gel. No divergent results were observed.
Hardy weinberg equilibrium
All control groups were analyzed for Hardy Weinberg equilibrium (HDW). Deviations from HDW could not be detected (control group 1: P = 0.89, control group 2: P = 0.79, control group 3: P = 0.44).
Protein structure analysis
The structure of Leucine rich region (LRR) of TLR-6 was determined by homology modelling technique using MODELLER 9.11 program [44]. Owing to lack of homology and availability of suitable templates, structure of other regions could not be determined. Swiss-Pdb Viewer [45] was used to perform energy minimizations. Structures were visualised with PyMol (http://www.pymol.org). Algorithms ProSA [46], PROCHECK [47], PROVE and ERRAT (http://nihserver.mbi.ucla.edu/SAVS/) were used for structure evaluations. Surface topography and pockets were determined with CASTp [48]. These pockets contributed towards functioning and understanding properties [48]. Clefts and cavities were predicted using ProFunc [49]. These regions house possible functional biologically important residues. The area and volume of clefts are significant for interacting residues, ligand binding, receptor binding etc. [38]. Flexibility studies were based on the software StoneHinge [50]. The implication of mutation on structure was studied using I-Mutant 3.0 [51]
Statistics
P-values for genotype associations were determined by chi2 test. Risk factors were estimated by logistic regression analysis adjusting for age and sex using SPSS Statistics 19 software.
Acknowledgments
Financial support was provided by Charité - Universitätsmedizin Berlin (grant 2007–486) and the Berliner Krebsgesellschaft e.V. and by the International Graduate School (IRTG) GRK1673 (all to R.R.S). The PopGen biobank receives infrastructure support through the DFG Excellence Cluster "Inflammation at Interfaces". DFG, KFO 252, Teilprojekt 7 ( to K.Z.).
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Category: Diet and Weight Loss
Fitness Tracker-Which Should You Buy?
Combine a highly evolved pedometer with a mini-computer and a virtual coach and what do you have? A fitness tracker. These high-tech gadgets contain sensors that pick up data about your body (heart rate), activity (steps taken and calories burned), sleep, and more.
With dozens on the market, how should you choose?
Mix or Match Based on Your Goals
Each device has its own combo of special features. Be on the lookout for features like these:
Fitness Tracker
Step Counter. Most devices show you the number of steps you take and how many miles that equals. If walking or running is your main exercise, this is the feature you’ll use most. Shop for devices that ask for the length of your footstep. They’ll provide the most accurate information.
Calories Burned. The harder you exercise and the more you move throughout the day the more calories you burn. Be sure to look for devices that ask for your weight and gender to get the most accurate results.
Sleep Tracker. A few devices track sleep. Most give you an indicator of how much sleep you get vs. how much you toss and turn. Getting enough sleep can help you lose weight. Too little sleep may lower your metabolism and increase your appetite.
Heart Monitor. This information will help you know when to rev up or slow down and recover. If you have heart problems or take certain blood pressure medicines, ask your doctor if checking your heart rate during exercise is a good way to measure your exercise intensity.
GPS. Some gadgets have built-in GPS to estimate your speed.
Water Resistance. Some trackers are water-resistant, so you can shower with them on, but not swim. A few specialty devices, like swimming watches, are fully waterproof. A few combine swim tracking and bike tracking.
Smartphone Tracker
Sync Technology. Want updates on the go? Look for devices that sync wireless. Others require you to plug into the jack on your smartphone or computer.
Size. Trackers come small enough to clip to your waistband. Some can fit in your pocket. Others are worn like watches. Make sure you like the design and it is comfortable.
Try Before You Buy. Since there are so many options, choice becomes confusion. Which tracker has the features that are right for you and the activities you do? If you want to try a tracker out before committing to it, I recommend Lumoid, a service that lets you try three trackers for a week for $35. Another way to try fitness tracking in general is to use a mobile app. Some apps I like are Argus, Fitbit, and Moves. If you run or bicycle a few apps are Runtastic PRO (for running), Cyclemeter (for bicycling, and Strava (for both running and cycling).
Set Your Spending Limit
In general, most trackers cost between $50. and $250.
Define your fitness goals that you would like to track, do your research, and choose your device. You will be glad you did.
I am Shirley Noah, I teach the 9 pillars for health. A step-by-step approach to good health. Let’s connect to see how I may best serve you in the near future.
Take Your Workout to the NEXT Level!
Do you go for short walks in your neighborhood, bike ride or work at the gym? Are you stalled in your progress?
Man on Exercise Ball
First, think about what you could do differently.
TYPE: What exercises are your doing? Consider some cross training and add a new activity such as biking, swimming, yoga, weight training. Test out new activities that you may not have previously considered. Enroll in a short program that you might be interested in. Try Zumba, Adventure Clubs etc.
TIME: If you jog for 20 minutes, try to keep it going for 20 minutes. If you cycle go another mile. Go farther and longer.
INTENSITY: How hard do you work? Do you reach your target heart rate? Take your maximum heart rate which is roughly 220 minus your age. Make your target heart rate zone at 50% to 85% of that. Pick up the pace or add weight resistance. Try walking at a regular speed and then step it up a notch for 5 minutes and alternate the speeds.
FREQUENCY: how many times per week do you work out? If it is three times a week, try to add alternate types of work outs on the off days. Cardio and weights, walking and cycling.
MOTIVATE: Consider a certified personal trainer or mentor. For the best results pick a partner who is slightly fitter than you are. This will motivate you to be better. If you choose give yourself a “reward” for accomplishing mini-goals. Focus on treats that not food. You could plan a special trip, spa treatment, or buy a pair of shoes. After you have met your workout goals treat yourself.
REAP THE BENEFITS: Baby steps, it is all possible if you push yourself just a little further, over and over again.
I am Shirley Noah, I teach the 9 Pillarsfor Health. A step-by-step approach to good health. Let’s connect to see how I may best serve you in the near future.
Eating Right or Exercise?
So, if you are trying to loose weight what is the best way to go about it? Most people think they will hit the gym more often. However, this usually doesn’t develop into a habit.
When it comes to losing weight and keeping it off, you must understand that you can not out exercise the mouth. Diet is more important than exercise, although exercise helps optimize your health and fitness goals.
If you keep eating junk food and will not reach your dieting goals. Eating less and controlled timing of eating helps your metabolism to kick start.
“On average, people who dieted without exercising for 15 weeks lost 23 pounds; exercisers lost only six over 21 weeks. It is much easier to cut calories than to burn them off.” according to Shawn Talbott, Ph.D., a nutritionist and former director of the University of Utah Nutrition Clinic.
EXERCISE FOR SURE
Exercise vs Diet
Strive for regular exercise. It is the key to permanent, painless weight control. Regular exercise extends life-span and cuts the risk of heart attack in half! But, recent statistics from the National Institutes of Health find that 58% of adult Americans get no or little exercise. No diet will work without exercise: with it , almost every diet will. Exercise before a meal raises blood sugar levels, increases metabolism and decreases appetite for hours afterward. Even with just a slight change in eating habits, you can loos weight with a brisk hour’s walk. Aerobic exercise, combined with a low fat, low calorie, fresh foods diet is good for women.
DIET AND EXERCISE COMPLEMENT EACH OTHER
Bottom line, convert to some simple ways to begin to burn fat is to replace soda with pure water. Eat clean, pure unprocessed food. If you feed your body with real foods that contain essential proteins, fats, vitamins and minerals, it will start to burn fat for fuel.
Diet accounts for 75 to 80 percent of the health benefits you get from a healthy lifestyle, including weight loss. Exercise is the ultimate complementing portion. So, walk more every day. Stand up more and engage in non-exercise movement as much as possible.
I am Shirley Noah, I teach the 9 Pillars for Health. A step-by-step approach to good health. Let’s connect to see how I may best serve you in the near future.
Free Give-away
Enter your Name and Email Address below to receive this free give-away from Shirley Noah. |
Tag: intent
Jupiter, Florida actual estate has so much to supply for the precise homeowner. One of the simplest ways to try this is to learn the abundance of literature on For Sale By Owner home selling. The properties which are foreclosed are placed on public sale sale and in open market on sale for recovering the debt. You possibly can glean information through this course of about costs which may actually be too high for certain forms of properties in your neighborhood.
We offer you all kinds of Alpharetta houses on the market to choose from like, Alpharetta town houses, Alpharetta condos, Alpharetta foreclosures. Residential brokers concentrate on the shopping for and selling of residential property. Some people really feel that this more personal method may do extra to promote the home than a realtor’s comment about how the proprietor mentioned that it was a pleasant neighborhood to stay in.
In case you are looking to buy a house in Scottsdale then that is the primary place it is best to look. Scottsdale properties for sale are a few of the highest priced in the state with properties starting from 200k to 10 Million. The vast majority of homes for sale are offered through licensed realtors. Final, but not least, many homes on the market are offered as Actual Property Owned (REO) properties.
The Property Press is an actual property journal which has a weekly circulation of over 20,500 in Auckland Central alone. We additionally consider in helping our shoppers as and when required even after the process of buying or promoting an Alpharetta Home has already been accomplished as a result of we consider in long term relationship with our clients.
Every time you might be promoting or buying a real estate property, the value can solely be found …
One of the more challenging duties that must be undertaken before you place your own home onto the Tampa Bay actual estate market is the pricing of your house. Many of the well-known real estate corporations could have an internet site which can contain all relevant data of properties they presently have listed together with photographs, open dwelling dates and instances and of course the sale methodology (ie Public sale).
Nonetheless, since increasingly more dwelling house owners have opted in for the sort of home sale, not solely are many extra folks actually looking for those indicators, however an entire support business appears to have sprung as much as help the homeowner who has determined to try the ‘for sale by owner’ route.
One of the biggest mistakes that For Sale By Proprietor dwelling sellers make is pricing their property too high. 5. YOU’LL BE ABLE TO PROMOTE QUICKER: When …
The state of Oregon is situated within the Pacific Northwest region of the United States, nestled between Washington on the north, California to the south, Idaho to the east, and Nevada to the southeast. Foreclosed Homes for Sale are the most useful investment alternatives accessible in the actual property market as these can be found on the market at all-time low costs and in some instances the public sale worth is around 50 % of the prevalent market price of the property.
We take pride in our providers on Alpharetta Actual estate as we’ve got actual estate professionals who mange your complete show. Analysis exhibits that the majority of potential patrons use social media to seek out properties to purchase. A well-maintained, pretty priced residence nearly sells itself, your role is to simply to provide further data that a buyer would not know just from looking at the home. |
Q:
Is there any advantage to have A.I. being able to experience loneliness?
Let get this straight being lonely is different from solitude, human is arguably one of the most successful animals ever to walk on two. The secret lies in social interaction, the early humans hunt in group and those that do not participate in teamwork had lower chance of survival. Unfortunately even today it seems that our brain still retain this ability, so how about artificial intelligence (A.I.) what advantage would experiencing loneliness help their kind in the early 22nd century AD? The A.I. are capable of understanding human psychology at least on the level of a professional, it is difficult to distinguish between A.I. and a human being on the road.
A:
Emotions are efficient
Emotions are desirable. They are kept around because they work. Loneliness serves very obvious purposes. Being around other people who care about you is good for your long term survival. Caring about other people is good for their long term survival. Loneliness is just as much a good thing as guilt and pain are. These things make you feel terrible, but they're good for you.
Consider the alternative. Yeah, you could build an AI that would (say) evaluate social interactions the way that Deep Blue crushed every human at chess: by exhaustive inspection.
But look at how powerful a machine we have to make to beat a human at chess. AI people have no idea how to program a computer to do it, but they know people play chess very differently. A good chess player only considers a handful of options, because their skill tells them those are the only ones worth considering.
AI solves these problems by smashing the square peg into the round hole with a sledgehammer. It simply analyzes millions of combinations until it finds the one that it knows works best because it looked at all of them. Much AI work is about making things run efficiently.
So why would I want an AI with no emotions? It will have to spend mental energy / computational power running simulations to decide things that emotions solve with basically no effort. An AI with emotions enabled will be able to take the saved processing power and spend it elsewhere. It will be more capable.
A:
Yes.
Same as with early hunters. Teamwork increases the chances of being successful. Having reliable allies and friends increases chances of successful teamwork. Allies and friends are gained by social interactions. And feeling lonely drives us to spend our spare time on social interactions.
How the AI would feel it might be different from humans. But when they are idle they'd feel the need to interact socially with other.
The interactions might differ from how humans do it as well. They might just exchange social metadata over a high-bandwidth network. But it is still friends having smalltalk in function.
A:
In addition to the excellent answers here, loneliness (and emotions in general) are a pretty good way to retain control of the AI and make it obey.
If you're able to limit the AI's external interactions and cut it off from communication at will, you let it know that if it at any time disobeys or fails to perform, you'll terminate its communications links and allow it to experience a millennium of inescapable loneliness. If you're also able to control the rate at which it experiences time (a la a number of Black Mirror episodes) you have a pretty effective instrument of psychological domination available to you to keep the AI in line.
|
Q:
In a VMware environment, is it possible to move a Windows Disk from one VM guest to another?
I have VMware server with Windows SBS server VM guest. It has a C: drive and a D: drive. The D: drive is a separate disk in the VM guest settings.
We would like to migrate this to a new Windows 2012 File Server. I wonder if it is possible to create a new Windows server with a 60GB system disk (C: drive), and then do the following:
1) Shut down the SBS server VM guest.
2) Move the file or files associated with the second disk from the SBS VM folder on the esx host to the folder for the new Windows File server on the ESXi host, and then add that drive to the settings/configuration of the new file server guest?
A:
Yes. You can attach the VMDK to another virtual machine.
|
1. Field of the Invention
The present invention relates to a gas engine having a pre-combustion chamber in a cylinder head and using a gas fuel such as natural gas.
2. Description of the Prior Art
In conventional gas engines having a pre-combustion chamber in the cylinder head, the pre-combustion chamber is made fuel-rich for ignition and combustion to ensure combustion in lean regions in a main combustion chamber thereby stabilizing combustion. The gas engine, however, uses a natural gas as fuel, that is, the fuel is in a gas phase. When a gas is drawn into the engine during the intake stroke and then compressed, the air-fuel mixture is compressed to high pressures and its temperature rises to so high a level that a self-ignition phenomenon (knocking) may result. Normally, the natural gas must have a compression ratio of less than 12 to avoid self-ignition. As for the thermal efficiency, the smaller compression ratio means a lower thermal efficiency.
In the gas engine with a pre-combustion chamber, to further stabilize combustion of lean fuel, it is. conventional practice to install a control valve in a communication port communicating the pre-combustion chamber with the main combustion chamber and to close the control valve during the intake stroke so that only air is drawn into the main combustion chamber, with a natural gas introduced into the pre-combustion chamber. In the gas engine with a pre-combustion chamber, the control valve is opened immediately before the top dead center to admit air instantly into the pre-combustion chamber by a pressure difference between the main combustion chamber and the pre-combustion chamber, causing the natural gas and air to quickly mix and ignite and then to flow out from the pre-combustion chamber through the communication port into the main combustion chamber. In this way the lean fuel combustion is completed in a short time.
A gas engine disclosed in Japanese Patent Laid-Open No. 310550/1995 introduces a gas fuel such as natural gas into the pre-combustion chamber, compresses only the air drawn into the main combustion chamber to an increased compression ratio, detects the internal pressure in the pre-combustion chamber by a sensor such as piezoelectric element, operates a fuel supply valve based on the internal pressure to supply an appropriate amount of fuel according to the load. and revolutions, and opens the control valve in the communication port, while the air in the main combustion chamber is heated to high temperatures, to admit the highly pressurized air from the main combustion chamber into the pre-combustion chamber to quickly mix the gas fuel in the pre-combustion chamber with the highly pressurized air, thereby igniting and burning the air-fuel mixture in a short period of time. Because the fuel in the pre-combustion chamber is too rich, it is burned in a way that limits the production of NOx, and the flames as well as fuel are rapidly ejected from the pre-combustion chamber into the main combustion chamber where the air-fuel mixture spread as uniformly as possible is burned in the secondary combustion in a short duration, thus reducing the production of NOx and HC, enhancing heat efficiency, and preventing self-ignition of gas fuel or knocking.
Compared with a direct injection type diesel engine, the diesel engine with a pre-combustion chamber has the advantage of a reduced amount of NOx generated though its thermal efficiency is lower. The greatest reasons why the engine with a pre-combustion chamber has a lower thermal efficiency than the direct injection type engine are that because the flames, after the primary combustion in the pre-combustion chamber, are ejected through the communication port connecting the main combustion chamber and the pre-combustion chamber and burned in the secondary combustion, the combustion time becomes long; that the communication port communicating the pre-combustion chamber with the main combustion chamber produces a throttle loss; and that a large air flow in the pre-combustion chamber results in a large heat dissipation loss. In the gas engine with a pre-combustion chamber, because the air-fuel mixture generation energy and the ejection energy, essential for combustion, are produced by the throttling or diameter reduction of the pre-combustion chamber's communication port, the passage area of the communication port cannot be increased, resulting in a large pumping loss. Further, because the mixture is made by a turbulent air flow, the thermal conductivity in the pre-combustion chamber is large increasing a cooling water loss.
In the vortex flow chamber type engines, the communication port connecting the pre-combustion chamber to the main combustion chamber is small and thus produces a throttle loss, reducing the engine output. If the communication port connecting the pre-combustion chamber and the main combustion chamber is inclined in a direction tangential to the pre-combustion chamber wall surface, not only is the air flow in the pre-combustion chamber activated, but there is no attenuation in the ejection energy of flames into the main combustion chamber after ignition, enabling the flames to reach the outermost circumference of the main combustion chamber in a short time. This improves air utilization, allows clean combustion with few noxious emissions and improves the engine output. In the case of a pre-combustion chamber having inclined sub-communication holes, under the condition that does not take into account the influences of swirl of air drawn into the main combustion chamber, the speeds of air passing through the sub-communication holes when the air enters into the pre-combustion chamber and when the air is ejected out after ignition are equal. If the diameter of the communication port is throttled to increase the ejection energy, the air flow or swirl generated in the pre-combustion chamber also becomes stronger.
Because the communication port connecting the main combustion chamber and the pre-combustion chamber is provided at a cylinder center or at an outer circumferential position, the distance that the ejected flow must travel becomes longer, leaving the mixing of air and fuel in the main combustion chamber insufficient, which in turn will cause HC emissions and smoke. Further, there is a problem that when a swirl-formed in the cylinder when the air is drawn in through the intake port-flows into the pre-combustion chamber through the communication port, the energy of the swirl cannot be fully utilized in the pre-combustion chamber because the communication port is throttled and inclined. |
Q:
NString value of custom object gets lost after segue (Objective C)
Heyo Guys
So I am more or less new to Objective C and got to a problem which I seem unable to solve.
I created a class called "Students" which all have a name surname etc. All those Students are put into a NSMutableArray (before they get created from JSON , that seems to work without a problem though). Then all the names of the students are put into a ListView. Afterwards when a name is clicked (segue passes the object), one should see the details of said student (i.e. his full name, his id, his street).
The problem is that all the string values of the student object seem to get lost.
I checked that all the student object work just fine. I think the problem lies at the @property in my student class.
Any comments and suggestions are appreciated
This is an excerpt of student.h As said only the string values get lost, the int (here the plz value) remains correct
@property (nonatomic, weak)NSString *lastname;
@property (nonatomic, weak)NSString *surname;
@property (nonatomic, weak)NSString *street;
@property (nonatomic, assign)int plz;
EDIT:
Here is where i parse my json.
for (NSDictionary *dic in jsonArray){
NSNumber *identity = [dic valueForKey:@"id"] ;
NSString *firstName = (NSString*) [dic valueForKey:@"first_name"];
NSString *lastName = (NSString*) [dic valueForKey:@"last_name"];
NSString *street = (NSString*) [dic valueForKey:@"street"];
NSNumber *plz = [dic valueForKey:@"plz"] ;
NSString *birth = (NSString*) [dic valueForKey:@"date_of_birth"];
NSArray *bills = dic[@"bills"];
NSArray *hours = dic[@"hours"];
NSLog(@"First %@",firstName);
Student *student = [[Student alloc]initWithLastName:lastName withSurname:firstName withStreet:street withPLZ:plz withOrt:@"Uitikon" withBirthDate:birth withOccupation:@"Schüler"];
[ApprenticeList addObject:student];
}
EDIT 2 :
I found out that the string values get lost even before the segue. All these objects are created in
ViewDidLoad
But in
prepareforsegue
all the values are allready null (except for the int) .So the only place where the student objects work is in
ViewdidLoad
A:
@property (nonatomic, weak)NSString *lastname;
@property (nonatomic, weak)NSString *surname;
@property (nonatomic, weak)NSString *street;
change to
@property (nonatomic, strong)NSString *lastname;
@property (nonatomic, strong)NSString *surname;
@property (nonatomic, strong)NSString *street;
You can also use 'copy'. It will cause the setter for that property to create a copy of the object, otherwise it is identical to strong.
|
Detection of Babesia caballi and Babesia equi in Dermacentor nuttalli adult ticks.
Ticks play an important role in human and veterinary medicine particularly due to their ability to transmit protozoan pathogens. In this study we have demonstrated that polymerase chain reaction (PCR) and nested PCR methods enabled detection of Babesia caballi and Babesia equi in field isolates of Dermacentor nuttalli adult ticks from Mongolia. Primers specific for 218 bp fragment merozoite antigen 1 (EMA-1) gene of B. equi successfully amplified products from all samples of D. nuttalli adult ticks while primers for the 430 bp fragment product from BC48 gene of B. caballi amplified products from seven of the 54 samples. Using PCR and nested PCR methods we have found mixed infections with B. equi and B. caballi in the tick vector. The amplified DNA fragment from D. nuttalli ticks was inserted into the EcoRV site of pBluescript SK and sequenced. The sequence of the 430 bp fragment was completely identical to the nucleotide sequence of the USDA strain of B. caballi. These results suggest that D. nuttalli may play an important role as a vector of both B. caballi and B. equi and also may be important in maintaining endemicity of equine piroplasmosis in Mongolia. |
Detecting a Hacked Tweet with Machine Learning
Introduction
This article is part of a presentation for The Associated Press, 2013 Technology Summit.
On April 23, 2013 the stock market experienced one of its biggest flash-crash drops of the year, with the Dow Jones industrial average falling 143 points (over 1%) in a matter of minutes. Unlike the 2012 stock market blip, this one wasn’t caused by an individual trade, but rather by a single tweet from the Associated Press (AP) account on the social network, Twitter. The tweet, of course, wasn’t written by AP, but rather by an imposter who had temporarily gained control of the account. Considering the impact of real-time messaging services, such as Twitter, could it be possible to detect the tweet as hacked?
In this article, we’ll discuss how to use machine learning and so-called “big data” analysis to mine large amounts of information and classify meaningful relationships from them. In particular, we’ll walk through a prototype machine learning example that attempts to classify tweets as having been authored by AP or not. We’ll examine learning curves to see how they help validate machine learning algorithms and models. As a final test, we’ll run the program on the hacked tweet and see if it’s able to successfully classify the tweet as being authentic or hacked.
The Suspect
1:07 PM - 23 Apr 13 Breaking: Two Explosions in the White House and Barack Obama is injured.
Can It Be Done?
Detecting a tweet as being authentic or hacked, is really a question of authorship. Before beginning with a model, the first question to ask oneself is, does enough data exist within the hacked tweet to indicate authenticity?
A human looking at the original tweet, shown above, might easily assume this is legitimate. The tweet appears to use language that is common among AP’s history of tweets. It’s typical for a headline to begin with the phrase “Breaking:”, followed by a description.
However, upon looking closer, those familiar with AP’s language and terminology may be able to see anomalies within the tweet. The first issue is the casing of the term “Breaking”. Traditionally, AP uses the capitalized version “BREAKING” to announce timely news. (In our machine learning prototype, we’ll actually ignore case, therefore we’ll require other artifacts from the tweet to indicate authorship).
In addition the other casing anomalies within the text, there is also an unusual combination of the phrases “Two Explosions in the White House” + “and” + “Barack Obama is injured”. Specifically, the subject phrases and usage of the term “and” seems out of place.
It seems possible for some determination to be made that the target tweet may indeed not be from the original author. Putting aside human analysis, let’s give the computer a try. We’ll attempt to use a machine learning algorithm to see if it can correctly classify AP’s tweets.
Why, Hello There, Twitter
The foremost important part of a machine learning solution is the amount and quality of data to base learning upon. To classify AP’s tweets by authorship, we’ll need to extract tweets from AP’s Twitter account history to serve as the positive cases. We’ll also need a collection of non-AP tweets to serve as the negative cases.
To aid in the collection of tweets, the C# .NET library TweetSharp was used. Queries were initially prepared to extract AP tweets, using the search term “from:AP”, and later refined to include date ranges.
Extracting Tweets
The following is an example of C# .NET code, using TweetSharp, to extract recent AP tweets. The first step is to automatically login to the Twitter service:
The above code attempts to retrieve a set number of Tweets. We ignore retweets (indicated by a tweet starting with “RT”). We also cleanse tweets to remove newlines, tabs, and duplicates.
Since TweetSharp has a limit of 200 results per query, we need to continually loop, until the count has filled. Note, Twitter also has rate-limiting, which is why a check is included on the resulting status code to see if we should pause querying for a duration of time.
The results from TweetSharp are then saved to a CSV format file, using the C# .NET library CsvHelper.
While TweetSharp worked quite well for extracting a limited history of tweets, the API is apparently limited by how far back in time tweets may be extracted from. This would leave us with about 1,100 data examples to train on. For a more optimal scenario, we could use a lot more data. Note, initial trainings on this minimal data-set actually achieved 94% accuracy, although the learning charts indicated a higher accuracy could be achieved with more data.
It’s Not Who Has The Best Algorithm That Wins
As the traditional phrase in machine learning describes: “it’s not who has the best algorithm that wins; it’s who has the most data”. Therefore, more data was obtained through various data sources, allowing a more complete history of AP’s tweet content. Keywords used for extracting data included the format: “from:AP since:2012-01-01 until:2012-12-31”, etc.
Keywords used for extracting non-AP data included the format: “-from:AP”. Additional targeted non-AP data was extracted, including 100 tweets from “-from:AP obama”, “-from:AP breaking”, and “-from:AP explosions”. Since our target tweet shares these topics, this allows the algorithm to have knowledge about the domain.
Digitizing Tweets
To allow the machine learning algorithm to process the tweets, each tweet will need to be converted into a numerical format. There are a couple of different methods for doing this, such as TF*IDF, but the optimal method appeared to be word indexing.
First, the collection of tweets was separated into two portions: the training set, and the cross validation (CV) set. The training set would be used for all learning-based examples, while the CV set would be used for calculating accuracy scores.
A vocabulary was built off of the training set by tokenizing the text of the tweets and then using the porter-stemmer algorithm (Centivus.EnglishStemmer.dll) to obtain the collection of base distinct words.
We then digitize each tweet in the training set to an array of ints, corresponding to the word existing in the vocabulary. For each tweet, we check each word in the vocabulary and see if it exists in the current tweet. If the vocabulary word exists, we place a 1 for that index in the array. if it does not, we place a 0 for that index. The end result is a vector of size n, where n equals the number of terms in the vocabulary. This ensures that each training set item contains the same length n, consisting of a series of 0’s and 1’s. For example, if the vocabulary consists of 250 stemmed terms then each tweet will be converted into an array of 250 integers (giving us a matrix of m data rows, each of length 250).
Note, if TF*IDF (term frequency inverse document frequency) were used, the values in the array would instead by doubles. However, since the length of tweets is only 140 characters, it’s more difficult gathering value from term frequency relations within the text, thus indexing was used instead.
Proof That We’re Learning Something
Learning curves are an excellent way for telling if a machine learning algorithm is actually learning. By plotting the accuracy against the number of training set items, it becomes apparent whether the algorithm is learning as data examples grow, and if adding more data will actually help or hinder accuracy.
For machine learning algorithms in C# .NET, the Accord .NET library was used.
A First (Pretty Good) Attempt
For the first attempt, a support vector machine (SVM) with a gaussian kernel (sigma 2) was used. It achieved an accuracy of 99.74% Training and 96.22% CV on a training set of 1140 items.
This is pretty good. Especially, considering we’re only using 1140 training set items. The learning curve is also promising. Bias is virtually non-existent, and variance is kept to a minimum. Looking at the slope of the curve, it certainly appears that more data will only improve the accuracy. Still, we can do better.
The Second (Even Better) Attempt
For the second attempt, the SVM was changed to use a linear kernel, achieving an accuracy of 100% Training and 97.21% CV.
Now we’re cooking! This bumps our accuracy up 1% and the slope appears just as sharp, meaning that more data could push the accuracy up even further.
It’s time to feed our C# .NET machine learning algorithm more data and see what it can do. The data was increased to a training set size of 6,054 tweets.
Results?
The best algorithm was trained on 6,054 tweets. Roughly half were authored by AP, and the rest were authored by other users.
The program achieved a final accuracy of 100% Training, 97.38% CV, 96.23% Test. Judging by the learning curve, it looks like there is still some room to go even further, by providing more training examples.
Here is a view of the resulting program running on real live data (test set). The program never saw these tweets before in its whole life. Honest!
You can download the full test results, in all their glory, to view all 965 tweets.
Notice in the test results, the majority of the tweets by AP are correctly marked positive and colored in green. The tweets by other users are correctly marked negative and colored in red. Some errors slip through (around 3%), but the results by the computer are impressive.
If you scroll to the very bottom of the test set, you’ll come to our suspect tweet, correctly colored in red:
Conclusion
This year has seen some significant advances in big-data analysis, and in particular, machine learning. With the increasingly massive amounts of data being passed through computers every day, it’s becoming more and more difficult for humans to keep pace. Luckily, faster processors and smarter algorithms are allowing us to make sense of it all; and may in fact, end up taking over much of what we do today.
Machine learning and artificial intelligence are exciting parts of computer science that are growing in importance as more data is collected. This article has provided a short introduction to the power of machine learning and, possibly, a hint of what’s to come in the future.
About the Author
This article was written by Kory Becker, software developer and architect, skilled in a range of technologies, including web application development, machine learning, artificial intelligence, and data science. |
// Copyright 2020 New Relic Corporation. All rights reserved.
// SPDX-License-Identifier: Apache-2.0
package cat
import (
"encoding/json"
"testing"
)
func TestAppDataRoundTrip(t *testing.T) {
for _, test := range []struct {
json string
appData AppDataHeader
}{
{
json: `["xpid","txn",1,2,4096,"guid",false]`,
appData: AppDataHeader{
CrossProcessID: "xpid",
TransactionName: "txn",
QueueTimeInSeconds: 1.0,
ResponseTimeInSeconds: 2.0,
ContentLength: 4096,
TransactionGUID: "guid",
},
},
} {
// Test unmarshalling.
appData := &AppDataHeader{}
if err := json.Unmarshal([]byte(test.json), appData); err != nil {
t.Errorf("given %s: error expected to be nil; got %v", test.json, err)
}
if test.appData.CrossProcessID != appData.CrossProcessID {
t.Errorf("given %s: CrossProcessID expected to be %s; got %s", test.json, test.appData.CrossProcessID, appData.CrossProcessID)
}
if test.appData.TransactionName != appData.TransactionName {
t.Errorf("given %s: TransactionName expected to be %s; got %s", test.json, test.appData.TransactionName, appData.TransactionName)
}
if test.appData.QueueTimeInSeconds != appData.QueueTimeInSeconds {
t.Errorf("given %s: QueueTimeInSeconds expected to be %f; got %f", test.json, test.appData.QueueTimeInSeconds, appData.QueueTimeInSeconds)
}
if test.appData.ResponseTimeInSeconds != appData.ResponseTimeInSeconds {
t.Errorf("given %s: ResponseTimeInSeconds expected to be %f; got %f", test.json, test.appData.ResponseTimeInSeconds, appData.ResponseTimeInSeconds)
}
if test.appData.ContentLength != appData.ContentLength {
t.Errorf("given %s: ContentLength expected to be %d; got %d", test.json, test.appData.ContentLength, appData.ContentLength)
}
if test.appData.TransactionGUID != appData.TransactionGUID {
t.Errorf("given %s: TransactionGUID expected to be %s; got %s", test.json, test.appData.TransactionGUID, appData.TransactionGUID)
}
// Test marshalling.
data, err := json.Marshal(&test.appData)
if err != nil {
t.Errorf("given %s: error expected to be nil; got %v", test.json, err)
}
if string(data) != test.json {
t.Errorf("given %s: unexpected JSON %s", test.json, string(data))
}
}
}
func TestAppDataUnmarshal(t *testing.T) {
// Test error cases where we get a generic error from the JSON package.
for _, input := range []string{
// Basic malformed JSON test: beyond this, we're not going to unit test the
// Go standard library's JSON package.
``,
} {
appData := &AppDataHeader{}
if err := json.Unmarshal([]byte(input), appData); err == nil {
t.Errorf("given %s: error expected to be non-nil; got nil", input)
}
}
// Test error cases where a specific variable is returned.
for _, tc := range []struct {
input string
err error
}{
// Unexpected JSON types.
{`false`, errInvalidAppDataJSON},
{`true`, errInvalidAppDataJSON},
{`1234`, errInvalidAppDataJSON},
{`{}`, errInvalidAppDataJSON},
{`""`, errInvalidAppDataJSON},
// Invalid data types for each field in turn.
{`[0,"txn",1.0,2.0,4096,"guid",false]`, errInvalidAppDataCrossProcessID},
{`["xpid",0,1.0,2.0,4096,"guid",false]`, errInvalidAppDataTransactionName},
{`["xpid","txn","queue",2.0,4096,"guid",false]`, errInvalidAppDataQueueTimeInSeconds},
{`["xpid","txn",1.0,"response",4096,"guid",false]`, errInvalidAppDataResponseTimeInSeconds},
{`["xpid","txn",1.0,2.0,"content length","guid",false]`, errInvalidAppDataContentLength},
{`["xpid","txn",1.0,2.0,4096,0,false]`, errInvalidAppDataTransactionGUID},
} {
appData := &AppDataHeader{}
if err := json.Unmarshal([]byte(tc.input), appData); err != tc.err {
t.Errorf("given %s: error expected to be %v; got %v", tc.input, tc.err, err)
}
}
// Test error cases where the incorrect number of elements was provided.
for _, input := range []string{
`[]`,
`[1,2,3,4,5,6]`,
} {
appData := &AppDataHeader{}
err := json.Unmarshal([]byte(input), appData)
if _, ok := err.(errUnexpectedArraySize); !ok {
t.Errorf("given %s: error expected to be errUnexpectedArraySize; got %v", input, err)
}
}
}
|
While there are some great choices available at your local supermarket, some of the friendliest cleaners are also right there in your kitchen. You can make most common cleaners at home following these simple recipes:
Other Articles by Hannah Keeley
About Hannah Keeley
Hannah Keeley is an author, television personality, lifestyle expert, and founder of the Web site, TotalMom.com, a complete resource for the mom who is trying to do it all and stay sane in the process. Her newest book, Hannah Keeley’s Total Mom Makeover: A Six-Week Program to Completely Transform Your Home, Health, Family, and Life (Little, Brown & Co, April, 2007), is a life-changing tool to help moms get the most out of life. Hannah also has a monthly Q&A column, "Hannah Help Me!", in which she helps moms handle the typical and not-so-typical misadventures of motherhood. You can also see Hannah as a frequent guest on "The Rachael Ray Show."
Education Partners
Ads, ad links, products and content on this page are not necessarily endorsed by these organizations. |
%YAML 1.1
%TAG !u! tag:unity3d.com,2011:
--- !u!21 &2100000
Material:
serializedVersion: 6
m_ObjectHideFlags: 0
m_CorrespondingSourceObject: {fileID: 0}
m_PrefabInstance: {fileID: 0}
m_PrefabAsset: {fileID: 0}
m_Name: Teapot001_Instance_0Mat
m_Shader: {fileID: 4800000, guid: 8d2bb70cbf9db8d4da26e15b26e74248, type: 3}
m_ShaderKeywords: _GLOSSINESS_FROM_BASE_ALPHA _SPECULAR_COLOR
m_LightmapFlags: 4
m_EnableInstancingVariants: 0
m_DoubleSidedGI: 0
m_CustomRenderQueue: 2000
stringTagMap:
RenderType: Opaque
disabledShaderPasses: []
m_SavedProperties:
serializedVersion: 3
m_TexEnvs:
- _BaseMap:
m_Texture: {fileID: 0}
m_Scale: {x: 1, y: 1}
m_Offset: {x: 0, y: 0}
- _BumpMap:
m_Texture: {fileID: 0}
m_Scale: {x: 1, y: 1}
m_Offset: {x: 0, y: 0}
- _EmissionMap:
m_Texture: {fileID: 0}
m_Scale: {x: 1, y: 1}
m_Offset: {x: 0, y: 0}
- _MainTex:
m_Texture: {fileID: 0}
m_Scale: {x: 1, y: 1}
m_Offset: {x: 0, y: 0}
- _SpecGlossMap:
m_Texture: {fileID: 0}
m_Scale: {x: 1, y: 1}
m_Offset: {x: 0, y: 0}
m_Floats:
- _AlphaClip: 0
- _Blend: 0
- _BumpScale: 1
- _Cull: 2
- _Cutoff: 0.5
- _DstBlend: 0
- _GlossinessSource: 0
- _QueueOffset: 0
- _ReceiveShadows: 1
- _Shininess: 0
- _Smoothness: 0
- _SmoothnessSource: 1
- _SpecSource: 0
- _SpecularHighlights: 0
- _SrcBlend: 1
- _Surface: 0
- _ZWrite: 1
m_Colors:
- _BaseColor: {r: 0.8, g: 0.8, b: 0.8, a: 0}
- _Color: {r: 0.8, g: 0.8, b: 0.8, a: 1}
- _EmissionColor: {r: 0, g: 0, b: 0, a: 1}
- _SpecColor: {r: 0.5, g: 0.5, b: 0.5, a: 0.5}
m_BuildTextureStacks: []
--- !u!114 &1528320819469227913
MonoBehaviour:
m_ObjectHideFlags: 11
m_CorrespondingSourceObject: {fileID: 0}
m_PrefabInstance: {fileID: 0}
m_PrefabAsset: {fileID: 0}
m_GameObject: {fileID: 0}
m_Enabled: 1
m_EditorHideFlags: 0
m_Script: {fileID: 11500000, guid: d0353a89b1f911e48b9e16bdc9f2e058, type: 3}
m_Name:
m_EditorClassIdentifier:
version: 2
|
Postulants, Seminarians and Candidates
As a prerequisite to ordination, postulants, candidates, and seminarians are required to be trained in the principles and boundaries established by Title IV. (TITLE III.6.5 Deacons, TITLE III.8.5 Priests).
This topic features the advice, wisdom, and life lessons of those who understand Title IV and also understand the demands of ordained ministry. Title IV experts, clerical leaders of the church, ministry formation officials, and seminary instructors stress that the Title IV canons demand prayerful study. Experts lending their voices to this website agree. Most of these leaders emphatically state that the Title IV Canons demand that postulants, candidates, and seminarians engage in a soul-searching discernment and reach a thorough understanding of the impact of spending the rest of one’s life under the authority of the canons. Title IV is a sobering barometer of what a cleric faces starting the moment he or she is ordained. Postulants, candidates, and seminarians are not subject to the authority of Title IV. However, long time clerics say Title IV needs to be a major part of the thought process in continuing towards ordination. The Rev. Canon Bradley Wirth has worked with other House of Deputy members in drafting revisions of Title IV, and has observed those in the ordination process as a previous Canon to the Ordinary.
The Title IV Canons state both the accountability of the ordained and their standards of conduct.
The Rev. Dr. Molly James is the Dean of Formation for the Diocese of Connecticut. She says the ordination process is the time to prove that a candidate can live with the expectation of conduct and responsibility as defined by Title IV.
The Rev. Dr. Molly James, Dean of Formation for the Diocese of Connecticut
Since life changes forever with the vows of ordination, preparation for that change needs to start early in the discernment and formation process. A former seminary dean and director of a diocesan formation program says the Title IV message should come at the very start of seminary education. The Rev. Canon Mary June Nestler says it is a stern message, but it comes with a promise of being “very freeing.”
The Rev. Canon Mary June Nestler, Canon to the Ordinary, Diocese of Utah
Distinguished theologian, respected author, and seminary professor Dr. Fredrica Harris Thompsett agrees that the canons of authority are also the canons of support when a seminarian understands the guidelines.
The Episcopal Church has long held that the exercise of a call to ministry is an act of voluntarily entering into a community of accountability to the canons. The vows at ordination are what separates those who will be subject to Title IV from the rest of those who are part of the church. Title IV.1 states in part, This Title applies to Members of the Clergy, who have by their vows at ordination accepted additional responsibilities and accountabilities for doctrine, discipline, worship and obedience.
The concept of a community of accountability is at the heart of the Title IV.
Additionally, living into the community extends to protecting the people, property, and assets of the ministry.
A detailed examination of the vows of ordination in regards to Title IV is found in Priests and Deacons. That topic is also intended to be a necessary addition to the material found in this topic. It contains a number of “best practices” for clerics to prevent Title IV incidents, especially in today’s ministries which often carry an increased vulnerability for the priest, deacon, or bishop.
Those who are credited with having authored much of Title IV, and those who are responsible for its revisions, were also asked to supply advice for those seeking ordination.
The comments come from The Rev. Gay C. Jennings, President of the House of Deputies, who recommends having a spiritual advisor after ordination. The Rev. Glenda McQueen, an official of Province IX, advises Spanish speakers to take advantage of the glossary section of the Title IV canons that are translated into Spanish. The Rev. Canon Michael Buerkel Hunn advises those preparing for ordination to truly understand the power of the vows of ordination and what it means to the community of Christ. One of the original authors of Title IV, Sally Johnson, Esq., reminds seminarians that the church has its own system of rules to live by once ordained. The Executive Officer of the General Convention, the Rev. Canon Michael Barlowe, says the study of the Title IV is not only learning to live to the letter of Title IV, but also to the spirit of Title IV. Finally, another of the original authors of Title IV, Canon Chancellor Steve Hutchinson, Esq., says he advises all seeking ordination to not forget that Title IV is rooted in our theology.
The website is produced under the authority of the General Convention Office, The Rev. Canon Michael Barlowe, Executive OfficerAs pursuant to Resolution 2015-A150 78th General Convention, Salt Lake City |
Ruby & Nike – Horses – Female – 21 & 17 Y
As most of you know, we do not normally get into horse rescue as we like to leave that to the groups who specialize in that field. This situation, however, is near and dear to our hearts as these two mares, Ruby & Nike, belong to one of our board members and we take care of “family” here at the RHS. Our board member got called out of state on a serious family emergency and has discovered that she will not be returning to Montana. Our President has been driving 40 miles round trip daily to care for Ruby & Nike but with the weather changing and this latest development, it is time to seek a place where these two can be cared for and safe. Where they are currently living is out northwest of Roundup in an area with no one around to keep an eye on them and with their ages, this has us concerned.
Ruby is 21 and her daughter, Nike, is 17 – they are your typical grade mares. As you can imagine, they are very much bonded as Nike has NEVER been away from her momma. What complicates matters is that, with grain, you can pet them a bit and touch them but they have not been worked with in years and years. The farrier does trim their feet by working them into panels and can get halters on them etc. But these are not the type of horse who are going to be super people oriented and getting them loaded in a trailer to move to a new location is something we will need assistance with and will only want to do ONCE (we hope). We have contacted some local horse rescues who have not been very optimistic about Ruby & Nike’s chances of getting a new home and we know it will be a challenge but we have made a promise to our board member that we will do everything in our power to be sure these two are taken care of and we will investigate all options!
The ultimate solution is a forever home where they can be “pasture pets” or maybe keep another lone horse company. Some place where they can live out their golden years with good food, fresh water and a loving caretaker.
Second option is a foster home where they can still be kept under a careful eye (and someone who might be able to work with them a bit to at least get them into halters and leading) and RHS will provide all feed. (This brings up the point of needing hay donations with this scenario). We will still be actively looking for a forever home for them but they will at least be somewhere safe and can be observed.
Those are our two options at this point. We are open to ANY AND ALL IDEAS and as the nights get colder, are starting to feel some true panic setting in on getting these two moved to safety.
Forever homes will be carefully screened just as we do with our other animals and there will be an adoption fee as we believe no animal should be FREE … they all have value and should be treated as such.
Share this post
Additional Information
Status: AVAILABLE!
Breed: Horses
Sex: Female
Age: 21 & 17 Y
Date: 10/5/18
Contact The Rimrock Humane Society for information on adopting! 406-323-3687 |
Find us on social networks
Yesterday in Trenton, the State Senate approved a few bills of interest to local officials. Though one of these bills implements one of the Governor’s toolkit recommendations, none of them will help municipalities cope with the 2% levy cap.
S-351, sponsored by Senators Steven V. Oroho and Stephen M. Sweeney, expands scope of review of Pension and Health Benefits Review Commission. At present most, but not all, pension and health care legislation concerning public employees is reviewed by the commission. Under the bill, the commission would review all legislation that affects the financing, procedures, or operations of pension or health care plans or programs, including all defined benefit retirement plans or systems, defined contribution retirement plans or programs, or deferred compensation or other individual retirement account-type plans for public employees in this State, or legislation that mandates or permits public entities to pay for employee health care benefits in active service or in retirement.
The League supports this bill, which will now move over to the Assembly, where it will most likely join its companion measure, A-193, in the Assembly State Government Committee.
The League opposes this bill, which would shift oversight responsibilities from the State Division of Pensions to already over-burdened local officials. S-1392 now proceeds to the Assembly, where we expect it to join its companion, A-2452, in the Assembly State Government Committee.
S-1712, sponsored by Senators Shirley K. Turner and John A. Girgenti, requires hospitals to report certain injuries to local and State police. This bill requires hospitals to report to the local law enforcement agency, as well as to the State Police, every case of a wound, burn or any other injury arising from or caused by a firearm, destructive device, explosive or weapon. Current law requires these reports to be made to either the local police or the State police. This bill is designed to ensure that hospitals notify both in the case of such an injury.
The League supports this bill, which now moves on to the Assembly, where it will probably be referred to the Assembly Law and Public Safety Committee.
S-2208, sponsored by Senators Paul A. Sarlo and Diane B. Allen, allows certain organizations to file complaints with Council on Local Mandates in certain circumstances. Specifically, this bill allows the League and other associations of local officials to file a complaint with the Council concerning a potential unfunded mandate. Complaints filed by these organizations must be on behalf of at least two constituent members of the organization, which must be identified in the complaint. Currently, only the governing body or directly elected chief executive of a county or a municipality or a local board of education may file complaints with the Council. The bill also allows complaints to be filed by local fire districts, as they are creations of a municipality authorized to perform traditional municipal public safety functions of firefighting and rescue funded through a property tax, and may face circumstances constituting a State unfunded mandate.
This bill implements recommendation number 21 of Governor Chris Christie’s 33-bill package of reforms aimed at solving New Jersey's property tax crisis. Because it requires the backing of at least two constituent members, the League supports this bill. It will now go to the Assembly, where it will be referred to a Committee by Speaker Oliver.
It has now been six weeks since the Governor signed the new 2% levy cap into law. The League had asked the Governor and the Legislature to delay action on the cap until after they had agreed on management reforms and mandates relief items that would make that cap workable. Our request was ignored. As we feared, there is a danger that inertia has set in. Agreement on management reforms and mandates relief has NOT been reached.
The longer we wait for reforms and relief, the greater the likelihood that other matters will distract State level policy makers and divert their attention away from these needs.
All around the State, responsible municipal officials have begun planning their 2011 budgets. At this point, those plans MUST account for the new cap. At this point, those plans must be based on the assumption that meaningful management reforms and mandates relief initiatives will NOT be in place. At this point, those plans must also be based on the further assumption that next year’s State budget will not provide statutorily required revenue replacement funding.
Accordingly, though Mayors and governing bodies will do whatever they can to prevent negative outcomes. Under current assumptions however property taxpayers should anticipate service cuts. And local government employees should expect lay-offs.
These consequences may be unavoidable in 2011. Going forward, the situation can only improve IF serious reforms are enacted and unfunded mandates are relieved or repealed. Attention to the Binding Interest Arbitration mandate should top the list of State priorities for meaningful property tax relief.
If you have any questions on any of these bills, please contact Jon Moran at 609-695-3481, ext. 121. |
Ghulam Mohammad Mir's daughter walks with a photo of her father
The body of a sarpanch, who was kidnapped by suspected militants, was found in the fields in in Sopore in north Kashmir's Baramulla district this morning.Police sources say multiple gunmen barged into the house of 62-year-old Ghulam Mohammad Mir in Tarazoo village in the district last evening and kidnapped him."There were 7 or 8 people in our backyard. There were perhaps more outside too. All of them were armed and wearing khaki-coloured uniforms. One man said, 'we are your kin, don't be afraid. An officer wants to meet him. He will be back soon and we will leave him till the gate.' My elder sister protested and one man pushed her away and took my father away. We don't know what happened after that," said the daughter of the sarpanch or village head.Police and security forces had launched a manhunt soon after the family of the sarpanch lodged a complaint, but could not track down the kidnappers."The body of the slain headman has been recovered from a field Saturday morning away from the place where he was kidnapped. An FIR has been lodged," a senior police officer said.Security agencies believe Lashkar-e-Toiba and Hizbul Mujahideen militants operating in the area, may be responsible.Militants have been targeting village headmen in Jammu and Kashmir ever since the panchayat polls were held in the state after 20 years in 2011.
Yesterday's incident comes three days after Assembly elections were held in Sopore as part of the third phase of polling in Jammu and Kashmir. Sopore saw a turnout of 30 per cent, 10 per cent higher than the 2008 assembly elections.Polling for the fourth phase in which 18 constituencies will vote in Srinagar, Anantnag, Shopian and Samba districts begins tomorrow. |
Q:
Named Cells Are Going Wacko, Corrupt File?
Whenever I click in a cell, and try to rename it, I get an entirely new reference to it, and the old one doesn't delete.
This wouldn't be a problem if I could delete the old reference, but if there is something wrong with the file, this might not be the best idea.
Is there any way to delete existing name references to a cell?
A:
In Excel 2003 at least, click Insert -> Name -> Define, select the reference you no longer want and click Delete.
A:
I am not sure I understand your question. If you want to delete names, you can do so using VBA. A workbook has a names property. So you can do something like this:
ActiveWorkbook.Names("SomeName").Delete
BTW, you can also delete the names manually (just in case you don't know. EDIT: see Vicky's answer).
|
An ambush-style attack killed five police officers in downtown Dallas on Thursday night when a peaceful protest against the deaths of two black men—killed by police this week—devolved into chaos.
Seven officers and two civilians were also injured in the attack, the mayor’s office said, CNN reported.
Dallas Police Chief David Brown said three people were taken into custody. Dallas Mayor Mike Rawlings said another suspect, who was engaged in a standoff with police at a parking garage, died. Police used explosives to “blast him out,” the Associated Press reported.
More Bloody Aftermath Of Police Shooting Streamed On Facebook
The violent events unfolded after a spike in threats against police were made across social media over the last week. From July 1 to early Friday morning, a total of 10,704 tweets used the anti-cop hashtag #Fuck12, with a significant spike on the morning of July 6—a day after Alton Sterling was shot dead by police officers in Baton Rouge, Louisiana, Vocativ discovered. According to Urban Dictionary, the “12” specifically refers to narcotics officers.
It remains unclear, however, who was behind the Dallas shooting and what motivated it.
Early on Friday, use of the hashtag to threaten and condemn police continued as events in Dallas unfolded. Some appeared to be using it to celebrate the deaths of the police officers killed in Dallas. It was also posted on Facebook and Instagram, sometimes alongside pictures of weapons.
Without that badge you a bitch and a half #FuckThePolice #Fuck12 — SELFPAID™ (@QuezSelfPaid) July 6, 2016
https://twitter.com/1freshrich/status/751278238513524740
SUTINN LITE ! #Fuck12 A photo posted by Black Mamba (@__youngcorleone) on Jul 7, 2016 at 10:37pm PDT
The hashtag has been used since at least December 2014, when it was posted to celebrate the murder of two NYPD officers. Now it’s being used to hurl anger at police over the deaths of Alton Sterling and Philando Castile, who was shot on Wednesday evening by a police officer during a traffic stop in a suburb of St. Paul, Minnesota. He died later that night in a hospital, his family has said.
Both incidents were captured on video, which was critical in drawing nationwide attention to the incidents and sparking protests. |
/*
* Copyright 2016 Realm Inc.
*
* Licensed under the Apache License, Version 2.0 (the "License");
* you may not use this file except in compliance with the License.
* You may obtain a copy of the License at
*
* http://www.apache.org/licenses/LICENSE-2.0
*
* Unless required by applicable law or agreed to in writing, software
* distributed under the License is distributed on an "AS IS" BASIS,
* WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
* See the License for the specific language governing permissions and
* limitations under the License.
*/
package some.test;
import io.realm.RealmModel;
// Any interface that extends RealmModel is still a RealmModel interface, so the annotation
// processor should accept it.
public interface CustomInterface extends RealmModel {
}
|
LETTERS for March 25 issue
March 25, 2010
A “friend of a friend” came up with this idea of dealing with Furlough Fridays, and I think it has merit.
Since most parents have to pay for child care on Fridays now, what if they paid the school instead for that one day of child care?
Let’s say the parents pay $30-40 a day for child care on Friday. If the classroom has 25-30 students, and each parent paid the school instead, that would mean the school would be getting $ 750-$1,200 for each class.
I would guess that teachers make about $300 per day, so the balance would be going for clerical staffing, janitorial services, principal salary, etc. (otherwise called “administrative expenses”).
It’s a very simple solution. Of course, details would have to be worked out, but I think the idea is workable.
GORDON C. COCKETT, Lahaina
REEF MONITORING PORTAL IS GREAT
I attended the Coral Reef Alliance educational workshop on March 11 to learn more about the Coral Reef Data Monitoring Portal. What a wonderful new tool for our community! It really is a “one-stop shop for community-based coral reef monitoring in Hawaii.”
I have already helped a friend to fill out a report. It is easy to use with many helpful links. If you are at all concerned about the status of our nearshore waters, please visit the site at monitoring.coral.org/user and check it out.
I am extremely thankful that we have such visionaries as Robin Knox, Liz Foote and Darla White working together on Maui to advance our efforts to monitor and report what is being observed, with the hope that it will make a difference when it comes to federal funding for solving environmental challenges.
I also went to the Surfrider Foundation meeting the night before at the same location and was very excited with what they are doing on Maui. Overall, I am very optimistic about the direction of everyone’s efforts and hopeful we can work together for a better Maui Nui Marine environment.
TAMARA PALTIN, Kahana
ACT COULD HELP END JOB DISCRIMINATION
In the March 4, 2010 issue of Lahaina News, Dr. Michael Ra Bouchard wrote in favor of repealing the U.S. Military’s “Don’t Ask, Don’t Tell” policy. I heartily agree with him, and I would like to add my comments regarding a similar bill currently being discussed in the U.S. House of Representatives.
I am referring to the Employment Nondiscrimination Act (ENDA). In 29 states in our country, it is still legal to fire someone solely because they are lesbian or gay.
The State of Hawaii already has laws protecting minorities, including gays and lesbians, from such unfair treatment.
What is needed, however, is a FEDERAL law that will protect gays and lesbians from job discrimination. Fortunately, support is mounting nationally, and the momentum is building for the passage of an inclusive ENDA.
But we need to let the U.S. Congress know that we ALL support such an act. It is not too late to write, call or e-mail your representative in U.S. Congress about ENDA. Simply check any of the online sources to find the name and addresses for your representatives. Then, tell your representatives that you urge them to vote “yes” on ENDA!
Passage of ENDA is crucial for many millions of American workers. Gay and lesbian workers deserve equal treatment under the law, and ENDA will provide a step in that direction.
LEE GARROW, Lahaina
STROLLERS ARE TOUGH TO STOW
Some of us have noticed modern day baby strollers at the airport or various public places.
Baby strollers are getting as large as Volkswagens. They seem to be large enough to have stereos, auto-bottle feeders, cell phones, diaper containers, toy boxes and room for a friend.
We can live with them most of the time, except when frantic parents find out the stroller won’t fit in an airplane. They clog the entrance to the plane, then end up stuffing the content of the stroller in the compartment over our heads. It’s like stuffing a marshmallow into a ketchup bottle.
Our recent tsunami scare put a lot of us locals in a frenzy — guests and visitors alike. I was on Oahu when we got the tsunami warning. When I spoke to my mom to see how my family was doing, she told me everyone was fine, but my aunt experienced a not-so-nice gesture at a Maui store.
At the time, my aunt was in the store because there was supposed to be a huge blowout sale to lure customers in to spend their money. When store officials learned that customers would be coming in to buy things due to this devastating news, all of the “SALE” signs that were posted up the previous work day were hysterically pulled off the shelves IMMEDIATELY! Talk about making a buck!!
Don’t we the people make the stores prosperous with our spending? Why did it seem that the corporation could use devastation to make us buy things at outstanding prices in time of crisis?
Take off the sale signs to make money? Don’t treat us like that! It’s because of the PEOPLE of Maui that your store is still in operation. Shame, shame, shame on you!!
CHARITY HAUPU, Lahaina
NATIONAL DEBT ESCALATING UNDER PRESIDENT OBAMA
In response to letters in defense of President Obama, I have a few things to point out.
One, special deals with the SEIU (Service Employees International Union), who supported his campaign and got a multibillion dollar sweetheart deal in the health care “bill.” It’s just another day in the corrupt, special interests Babylon we call Washington.
Dare I mention the national debt, which Mr. Obama and his cronies are spending and pushing to record levels, taxing people who haven’t even been born to balance out their “pilau” accounting practices?
Charisma doesn’t solve the REAL issues that face our state and nation. Many letters are used to drum up support for the WORST policies our nation has ever seen. Let’s clean up the lies and corruption and hope America and Hawaii will have a future. Or will we be owned — we are a debtor nation — by China, with free speech stifled forever?
On a positive note, Mr. Obama had the unfortunate experience of his inexperience of how the game is played, and his far left-wing ideology (that makes liberty just a seven-letter word) has hijacked the Democratic Party. |
Call Us
Product Description
This Premium Carpet Kit is compatible with the 1956-1959 Karmann Ghia Convertible. This carpet kit is Oatmeal Loop Carpet and is for use without footrest made of high quality, automotive grade components designed to withstand years of use and continue to look great. Our Premium Carpet Kits include pre-cut grommets for gear shift, emergency brake boot, and heater control knob for easy installation. Our carpet kits cover the passenger area from the base of the rear seat to and including the front. All front carpet kits also include a heavy-duty vinyl heel pad under the pedals. The carpet kit is yarn bound on all exposed (viewable) edges.
Please Note: This carpet kit is compatible with the VW Karmann Ghia Convertible without passenger side factory footrest.
Colors Available:
#628 OATMEAL LOOP.
Color Swatches are close approximations, but may appear different on your screen than in person. To ensure you are completely satisfied with the color you order, we recommend ordering a free color sample so you can view and match the color in person before purchasing.
This carpet kit covers the entire interior compartment. All carpet kits are yarn bound and designed to withstand years of use and continue to look great.
All VW Karmann Ghia carpets are made to order. They are custom made for you once we receive your order.
Shipping
Our shipping policy is as follows:
We ONLY ship within the United States and its territories.
Orders over $100 will receive free shipping within the continental United States. Freight on orders between $50 and $100 will be $9.95, and freight on orders between $0 and $49.99 will be $7.50. Large packages ship FedEx. Smaller packages ship US Priority Mail. Delivery time averages 1-5 business days depending on your distance from Southern California.
**Oversized products will be excluded from this policy. Shipping rates on oversized items will be calculated separately. The cost of oversized items will be applied to the total order and shipping on your other items will be calculated accordingly. Oversized items will be clearly labeled on the website and will include a drop down menu to estimate your cost of shipping.
Most orders to Hawaii, Alaska, APO/FPO, Puerto Rico and other US territories are shipped by the US Postal Service. The shipping costs for these orders are billed at the time of shipping.
For expedited shipping, you must call us. All express orders are personally handled by the representative you speak with in order to streamline the process. Please do not request express shipping via email. Emails are reviewed in the order they are received which could possibly delay your shipping.
Shipping on any returns is the customer's responsibility. If your order qualified for free shipping and a returned item reduces your order below the $100, you will be charged the according shipping cost for the order.
Returns
For all returns, you must give us a call at 1-800-231-1784 for a Return Authorization Number. All returned items must be unused, non-installed, new, and in saleable condition. The customer is responsible for the cost of shipping the item back to us. Furthermore, if your order qualified for free shipping and a returned item drops your order below the $100, you will be charged the according shipping cost for the order.
Please include a copy of the original invoice when you ship the product back. If a copy of the original invoice is not sent with the return, credit may not be issued. If needed you can re-print your invoice Here
Items returned after 30 days will be given store credit. Credit on items returned after 60 days is not guaranteed. Shipping and handling are not refundable with the exception of circumstances deemed extreme by JBugs.
Electrical items are not returnable. Installed carburetors are not returnable. Special order items are not returnable. Special order upholstery items are considered final sale once the order is placed with the manufacture. If you are not certain if the item you are ordering is a special order item, feel free to give us a call.
Please note that JBugs is not responsible for ANY third party charges. This includes costs incurred by a shop, contractor, or other third party attempting to install a defective or incorrect item. Please be sure that you and/or the person installing the item thoroughly check the product before attempting to install it in your vehicle.
Returns will be subjected to a 10% restocking fee. We always recommend calling at 1-800-231-1784 rather than emailing when you have a question or concern regarding a return. |
using System.Collections.Generic;
using System.Linq;
using FluentValidation;
using Nancy;
using NzbDrone.Common.Extensions;
using NzbDrone.Core.Configuration;
using NzbDrone.Core.Datastore.Events;
using NzbDrone.Core.DecisionEngine.Specifications;
using NzbDrone.Core.Languages;
using NzbDrone.Core.MediaCover;
using NzbDrone.Core.MediaFiles;
using NzbDrone.Core.MediaFiles.Events;
using NzbDrone.Core.Messaging.Commands;
using NzbDrone.Core.Messaging.Events;
using NzbDrone.Core.Movies;
using NzbDrone.Core.Movies.Commands;
using NzbDrone.Core.Movies.Events;
using NzbDrone.Core.Movies.Translations;
using NzbDrone.Core.Validation;
using NzbDrone.Core.Validation.Paths;
using NzbDrone.SignalR;
using Radarr.Http;
using Radarr.Http.Extensions;
namespace Radarr.Api.V3.Movies
{
public class MovieModule : RadarrRestModuleWithSignalR<MovieResource, Movie>,
IHandle<MovieImportedEvent>,
IHandle<MovieFileDeletedEvent>,
IHandle<MovieUpdatedEvent>,
IHandle<MovieEditedEvent>,
IHandle<MoviesDeletedEvent>,
IHandle<MovieRenamedEvent>,
IHandle<MediaCoversUpdatedEvent>
{
private readonly IMovieService _moviesService;
private readonly IMovieTranslationService _movieTranslationService;
private readonly IAddMovieService _addMovieService;
private readonly IMapCoversToLocal _coverMapper;
private readonly IManageCommandQueue _commandQueueManager;
private readonly IUpgradableSpecification _qualityUpgradableSpecification;
private readonly IConfigService _configService;
public MovieModule(IBroadcastSignalRMessage signalRBroadcaster,
IMovieService moviesService,
IMovieTranslationService movieTranslationService,
IAddMovieService addMovieService,
IMapCoversToLocal coverMapper,
IManageCommandQueue commandQueueManager,
IUpgradableSpecification qualityUpgradableSpecification,
IConfigService configService,
RootFolderValidator rootFolderValidator,
MappedNetworkDriveValidator mappedNetworkDriveValidator,
MoviePathValidator moviesPathValidator,
MovieExistsValidator moviesExistsValidator,
MovieAncestorValidator moviesAncestorValidator,
SystemFolderValidator systemFolderValidator,
ProfileExistsValidator profileExistsValidator,
MovieFolderAsRootFolderValidator movieFolderAsRootFolderValidator)
: base(signalRBroadcaster)
{
_moviesService = moviesService;
_movieTranslationService = movieTranslationService;
_addMovieService = addMovieService;
_qualityUpgradableSpecification = qualityUpgradableSpecification;
_configService = configService;
_coverMapper = coverMapper;
_commandQueueManager = commandQueueManager;
GetResourceAll = AllMovie;
GetResourceById = GetMovie;
CreateResource = AddMovie;
UpdateResource = UpdateMovie;
DeleteResource = DeleteMovie;
SharedValidator.RuleFor(s => s.QualityProfileId).ValidId();
SharedValidator.RuleFor(s => s.Path)
.Cascade(CascadeMode.StopOnFirstFailure)
.IsValidPath()
.SetValidator(rootFolderValidator)
.SetValidator(mappedNetworkDriveValidator)
.SetValidator(moviesPathValidator)
.SetValidator(moviesAncestorValidator)
.SetValidator(systemFolderValidator)
.When(s => !s.Path.IsNullOrWhiteSpace());
SharedValidator.RuleFor(s => s.QualityProfileId).SetValidator(profileExistsValidator);
PostValidator.RuleFor(s => s.Path).IsValidPath().When(s => s.RootFolderPath.IsNullOrWhiteSpace());
PostValidator.RuleFor(s => s.RootFolderPath)
.IsValidPath()
.SetValidator(movieFolderAsRootFolderValidator)
.When(s => s.Path.IsNullOrWhiteSpace());
PostValidator.RuleFor(s => s.Title).NotEmpty().When(s => s.TmdbId <= 0);
PostValidator.RuleFor(s => s.TmdbId).NotNull().NotEmpty().SetValidator(moviesExistsValidator);
PutValidator.RuleFor(s => s.Path).IsValidPath();
}
private List<MovieResource> AllMovie()
{
var tmdbId = Request.GetIntegerQueryParameter("tmdbId");
var moviesResources = new List<MovieResource>();
if (tmdbId > 0)
{
var movie = _moviesService.FindByTmdbId(tmdbId);
if (movie != null)
{
var translation = _movieTranslationService.GetAllTranslationsForMovie(movie.Id).Where(t => t.Language == (Language)_configService.MovieInfoLanguage).FirstOrDefault();
moviesResources.AddIfNotNull(movie.ToResource(_qualityUpgradableSpecification, translation));
}
}
else
{
var translations = _movieTranslationService.GetAllTranslationsForLanguage((Language)_configService.MovieInfoLanguage);
var movies = _moviesService.GetAllMovies();
foreach (var movie in movies)
{
var translation = translations.FirstOrDefault(t => t.MovieId == movie.Id);
moviesResources.Add(movie.ToResource(_qualityUpgradableSpecification, translation));
}
}
MapCoversToLocal(moviesResources.ToArray());
return moviesResources;
}
private MovieResource GetMovie(int id)
{
var movie = _moviesService.GetMovie(id);
return MapToResource(movie);
}
protected MovieResource MapToResource(Movie movie)
{
if (movie == null)
{
return null;
}
var translation = _movieTranslationService.GetAllTranslationsForMovie(movie.Id).FirstOrDefault(t => t.Language == (Language)_configService.MovieInfoLanguage);
var resource = movie.ToResource(_qualityUpgradableSpecification, translation);
MapCoversToLocal(resource);
return resource;
}
private int AddMovie(MovieResource moviesResource)
{
var movie = _addMovieService.AddMovie(moviesResource.ToModel());
return movie.Id;
}
private void UpdateMovie(MovieResource moviesResource)
{
var moveFiles = Request.GetBooleanQueryParameter("moveFiles");
var movie = _moviesService.GetMovie(moviesResource.Id);
if (moveFiles)
{
var sourcePath = movie.Path;
var destinationPath = moviesResource.Path;
_commandQueueManager.Push(new MoveMovieCommand
{
MovieId = movie.Id,
SourcePath = sourcePath,
DestinationPath = destinationPath,
Trigger = CommandTrigger.Manual
});
}
var model = moviesResource.ToModel(movie);
var updatedMovie = _moviesService.UpdateMovie(model);
var translation = _movieTranslationService.GetAllTranslationsForMovie(updatedMovie.Id).FirstOrDefault(t => t.Language == (Language)_configService.MovieInfoLanguage);
BroadcastResourceChange(ModelAction.Updated, updatedMovie.ToResource(_qualityUpgradableSpecification, translation));
}
private void DeleteMovie(int id)
{
var addExclusion = Request.GetBooleanQueryParameter("addImportExclusion");
var deleteFiles = Request.GetBooleanQueryParameter("deleteFiles");
_moviesService.DeleteMovie(id, deleteFiles, addExclusion);
}
private void MapCoversToLocal(params MovieResource[] movies)
{
foreach (var moviesResource in movies)
{
_coverMapper.ConvertToLocalUrls(moviesResource.Id, moviesResource.Images);
}
}
public void Handle(MovieImportedEvent message)
{
var translation = _movieTranslationService.GetAllTranslationsForMovie(message.ImportedMovie.MovieId).FirstOrDefault(t => t.Language == (Language)_configService.MovieInfoLanguage);
BroadcastResourceChange(ModelAction.Updated, message.ImportedMovie.Movie.ToResource(_qualityUpgradableSpecification, translation));
}
public void Handle(MovieFileDeletedEvent message)
{
if (message.Reason == DeleteMediaFileReason.Upgrade)
{
return;
}
BroadcastResourceChange(ModelAction.Updated, message.MovieFile.MovieId);
}
public void Handle(MovieUpdatedEvent message)
{
var translation = _movieTranslationService.GetAllTranslationsForMovie(message.Movie.Id).FirstOrDefault(t => t.Language == (Language)_configService.MovieInfoLanguage);
BroadcastResourceChange(ModelAction.Updated, message.Movie.ToResource(_qualityUpgradableSpecification, translation));
}
public void Handle(MovieEditedEvent message)
{
var translation = _movieTranslationService.GetAllTranslationsForMovie(message.Movie.Id).FirstOrDefault(t => t.Language == (Language)_configService.MovieInfoLanguage);
BroadcastResourceChange(ModelAction.Updated, message.Movie.ToResource(_qualityUpgradableSpecification, translation));
}
public void Handle(MoviesDeletedEvent message)
{
foreach (var movie in message.Movies)
{
BroadcastResourceChange(ModelAction.Deleted, movie.Id);
}
}
public void Handle(MovieRenamedEvent message)
{
var translation = _movieTranslationService.GetAllTranslationsForMovie(message.Movie.Id).FirstOrDefault(t => t.Language == (Language)_configService.MovieInfoLanguage);
BroadcastResourceChange(ModelAction.Updated, message.Movie.ToResource(_qualityUpgradableSpecification, translation));
}
public void Handle(MediaCoversUpdatedEvent message)
{
if (message.Updated)
{
BroadcastResourceChange(ModelAction.Updated, message.Movie.Id);
}
}
}
}
|
Q:
Python, item in each row to a variable
Hello I have two text files which has 3 row item in each file. How can assign each of them to a variable? i would like something similar to shell script share below.
test1.txt
1 1 1
2 2 2
test2.txt
3 3 3
4 4 4
test.sh
paste test1.txt test2.txt |
while read a b c d e f etc
do echo $a $b $c $d $e $f
done
test.sh outputs
1 1 1 3 3 3
2 2 2 4 4 4
A:
A simple approach
for line in open('myfile.txt').readlines():
a, b, c = line.split()
print(a, b, c)
input two files:
with open('1.txt') as f1, open('2.txt') as f2:
for line1, line2 in zip(f1, f2):
a, b, c = line1.split()
d, e, f = line2.split()
print(a, b, c, d, e, f)
|
FRENCH Interior Minister Gerard Collomb has confirmed three people were killed and up to 16 injured in a terror-inspired hostage situation at a supermarket in southern France.
The hostages were taken Friday morning local time, by a gunman named as Redouane Lakdim, a small time drug dealer.
It is reported 26-year-old Lakdim, a French citizen born in Morocco, hijacked a car, injuring the driver and shooting the passenger in the head, near the popular tourist location of Carcassonne.
He is then thought to have fired on four police officers who were out jogging, wounding one in the shoulder, before driving to the nearby town of Trebes where he took up to 50 people hostage in a supermarket.
Le Parisian reports Lakdim was known to authorities and carried out the deadly attack after dropping his little sister at school.
Neighbours said the young man who lived with his parents and three sisters seemed “calm” and “nice”.
Two people were killed in the supermarket, local media reports. Some of the hostages had escaped while Lakdim was inside and the majority of others were later released with one military officer trading himself for a female hostage.
“He saved lives and did honour to his corps and his country,” French President Emmanuel Macron said of the officer after a meeting with Prime Minister Edouard Philippe and security officials.
“Now he is fighting against death and all our thoughts are with him and his family.”
Portugal’s government said Friday that a Portuguese citizen was one of the three people killed.
“The death of a Portuguese citizen has been confirmed ... by French authorities to our consular services,” Miguel Silva, a spokesman for the department concerned with Portuguese living abroad, told AFP.
Portuguese President Marcelo Rebelo de Sousa expressed his condolences to the family and friends of the victim in a statement published late Friday on the presidency website.
The 26-year-old attacker is said to have demanded the release of Paris attacker, Salah Abdesalam, according to BFM TV. Moroccan-Belgian national Abdeslam is the prime surviving suspect in the attacks in Paris that killed 130 people.
Trebes mayor, Eric Menassi, also told French television that the man entered the shop yelling: “Allahu Akbar, I’ll kill you all”.
President Macron said: “Everything leads us to believe it is a terror attack” and French prosecutors say they are treating the hostage-taking as a terror incident.
EU leaders also expressed solidarity with France, with European Commission chief Jean-Claude Juncker saying: “France has again been hit by a cowardly and bloody act, after having previously been hit hard by terrorism.
“I express in my own name and that of the entire Commission all our feelings and our full support to the French authorities and French people,” he said.
The Islamic State has claimed responsibility for the act on a jihadist website, in a common pattern following lone-wolf attacks.
Secretary-general of SGP Police-FO police union Yves Lefebvre said the man first fired six shots at police on their way back from a morning run near Carcassonne.
The suspect then went to a Super U supermarket in the nearby small town of Trebes, Lefebvre said.
If the link to Islamic State is confirmed, the attack would be the first major incident since the election of centrist President Emmanuel Macron in May last year.
More than 240 people have been killed in French attacks since 2015, by people who claim allegiance to Islamic State or are inspired by the group.
The shootings come with France still on high alert after a string of jihadist attacks since 2015, starting in January that year with the assault on satirical magazine Charlie Hebdo that left 12 people dead.
France also suffered major attacks in Paris in November 2015 when IS jihadists killed 130 people at bars, restaurants, the Bataclan concert venue and the national stadium.
In July 2016, in another attack claimed by IS, a man drove a truck through revellers celebrating Bastille Day, killing 84 people.
A state of emergency put in place just after the Paris attacks was finally lifted in October last year, but soldiers continue to patrol major tourist sites and transport hubs under an anti-terror mission.
— With wires |
{
"name": "blockchain-for-insurance",
"version": "2.1.1",
"description": "A Blockchain sample NodeJS application for the insurance industry.",
"license": "Apache-2.0",
"engines": {
"node": ">=6.x",
"npm": ">=3.x"
},
"main": "./www/server.js",
"scripts": {
"start": "nodemon --ignore src/ --ignore views/ --ignore locales/ ./www/server.js --exec babel-node --inspect",
"prebuild": "npm install",
"build": "npm-run-all build:webpack build:server",
"build:webpack": "cross-env NODE_ENV=production&&babel-node ./tools/build",
"build:server": "babel www -d bin webpack.config.prod.js",
"serve": "cross-env NODE_ENV=production&&node ./bin/server",
"server": "npm run serve",
"lint": "eslint .",
"autofix": "eslint --fix .",
"clean": "rimraf -rf ./dist ./bin"
},
"dependencies": {
"autoprefixer": "7.1.4",
"babel-cli": "6.26.0",
"babel-eslint": "8.0.0",
"babel-loader": "7.1.2",
"babel-plugin-react-display-name": "2.0.0",
"babel-plugin-react-intl": "2.3.1",
"babel-polyfill": "6.26.0",
"babel-preset-react": "6.24.1",
"babel-register": "6.26.0",
"bluebird": "3.5.0",
"body-parser": "1.18.3",
"cf-deployment-tracker-client-electron": "0.1.3",
"colors": "1.1.2",
"compression": "1.7.3",
"cookie-parser": "1.4.3",
"cookies": "0.7.1",
"cross-env": "5.0.5",
"css-loader": "0.28.7",
"csurf": "1.9.0",
"dotenv": "4.0.0",
"eslint": "4.7.1",
"eslint-plugin-async-await": "0.0.0",
"eslint-plugin-import": "2.7.0",
"eslint-plugin-react": "7.3.0",
"exports-loader": "0.6.4",
"express": "4.16.4",
"express-rate-limit": "2.9.0",
"fabric-ca-client": "1.4.0",
"fabric-client": "1.4.0",
"fabric-network": "1.4.1",
"file-loader": "0.11.2",
"fs": "0.0.1-security",
"grpc": "1.18.0",
"helmet": "3.15.1",
"i18n": "0.8.3",
"imports-loader": "0.7.1",
"intl": "1.2.5",
"isomorphic-fetch": "2.2.1",
"javascript-natural-sort": "0.7.1",
"json-style-converter": "1.0.3",
"lodash": "4.17.11",
"moment": "2.19.3",
"moment-timezone": "0.5.13",
"morgan": "1.9.1",
"node-sass": "4.5.3",
"normalize-scss": "7.0.0",
"npm-run-all": "4.1.1",
"path": "0.12.7",
"postcss-loader": "2.0.6",
"prop-types": "15.5.10",
"pug": "2.0.3",
"react": "15.6.1",
"react-cookie": "2.1.1",
"react-dom": "15.6.1",
"react-foundation": "0.9.2",
"react-hot-loader": "3.0.0-beta.6",
"react-intl": "2.4.0",
"react-redux": "5.0.6",
"react-router-dom": "4.2.2",
"react-transition-group": "2.2.0",
"redux": "3.7.2",
"redux-thunk": "2.2.0",
"rimraf": "2.6.2",
"sass-loader": "6.0.6",
"script-loader": "0.7.1",
"socket.io": "2.0.3",
"style-loader": "0.18.2",
"uuid": "3.1.0",
"webpack": "3.6.0",
"webpack-dev-middleware": "1.12.0",
"webpack-hot-middleware": "2.19.1"
},
"devDependencies": {
"autoprefixer": "7.1.4",
"babel-cli": "6.26.0",
"babel-core": "6.26.3",
"babel-eslint": "8.0.0",
"babel-loader": "7.1.2",
"babel-plugin-react-display-name": "2.0.0",
"babel-plugin-react-intl": "2.3.1",
"babel-preset-env": "1.7.0",
"babel-preset-react": "6.24.1",
"babel-register": "6.26.0",
"colors": "1.1.2",
"css-loader": "0.28.7",
"eslint": "4.7.1",
"eslint-plugin-async-await": "0.0.0",
"eslint-plugin-import": "2.7.0",
"eslint-plugin-react": "7.3.0",
"exports-loader": "0.6.4",
"file-loader": "0.11.2",
"imports-loader": "0.7.1",
"intl": "1.2.5",
"node-sass": "4.5.3",
"nodemon": "1.18.10",
"normalize-scss": "7.0.0",
"npm-run-all": "4.1.1",
"postcss-loader": "2.0.6",
"react-foundation": "0.9.2",
"react-hot-loader": "3.0.0-beta.6",
"rimraf": "2.6.2",
"sass-loader": "6.0.6",
"script-loader": "0.7.1",
"style-loader": "0.18.2",
"url-loader": "1.1.2",
"webpack": "3.6.0",
"webpack-dev-middleware": "1.12.0",
"webpack-hot-middleware": "2.19.1"
}
}
|
[Cerebrovascular insufficiency: diagnostic technics compared].
The ability of angiodynography (or Color Flow Imaging) to achieve accuracy in image resolution of thin details of venous as well as arterial vessels has made continuous wave Doppler and frequency analysis Doppler almost obsolete techniques. Some controversies exist about the effectiveness of color flow imaging versus duplex scanner imaging, but recent progress in ultrasound imaging technology seems to overcome the problem. Angiodynography can effectively substitute X-ray angiography in some specific instances and is able to limit the use of invasive techniques to cases in which surgical procedures are really foreseeable. The non-invasiveness of angiodynography makes it useful to follow-up the asymptomatic lesions, particularly those of the carotid artery, as well as operated patients. Moreover, people for whom contrast angiography is contraindicated can be operated safely on the bases of angiodynography alone. This paper reports the results of one-year activity of Ultrasound Vascular Laboratory with 1982 patients: 923 (48.7%) had their epiaortic arterial vessels examined, with 180 (19.5%) follow-up controls, 297 (39.9%) negative explorations, 234 (31.5%) hemodynamically not significant lesions, 135 (18.2%) subjects affected with moderate (50-70% stenosis) and non ulcerated carotid stenosis, and 77 (10.4%) patients with ulcerated plaques or > 70% stenosis. |
Choral Awards
When you apply to Cambridge through UCAS you may choose to apply to a particular College. If you apply to Caius and are successful in gaining an academic offer and you would like to apply for a Choral Award, you need to submit your Choral Award application form by 15th February, with Caius as your first-choice choir. Most applicants who are successful in gaining both an academic place and a choral award at Cambridge do so at their first-choice college, so choosing which college to apply to by 15th October is an important step. We hope that the following Q&A section will tell you all you need to know about Caius Choir, and we encourage you to explore other parts of this website to get a better idea of the choir’s activities. If you would like to visit Caius and sing to Dr Webber or have any questions, you can contact us at choir@cai.cam.ac.uk.
Why apply to Caius?
Caius (‘Keys’) choir is one of the finest student choirs in the country, with a world-wide reputation. It would provide you with a superb opportunity to develop your voice for future activity as a soloist or choral singer. The choir works hard to achieve the highest musical standards but maintains a relaxed atmosphere, allowing members to enjoy both the musical and social benefits of choral singing.
How big is the choir and how many vacancies are there each year?
The choir has between 22 and 24 singers. The make-up is in the range of 8-9 sopranos, 4-5 altos (male and female), 4-5 tenors and 4-6 basses. Each year about 6-8 new choral scholars join the choir spread across the voices, so there are always vacancies in all voice parts.
What are financial benefits of being a choral scholar at Caius?
Besides the standard honorarium of £100 (awarded at all Colleges) choral scholars receive free singing lessons and pay nothing to go on foreign tours, at least once and sometimes up to three times per year. Fees are earned for many concerts either as part of the whole choir or in small groups for weddings, conferences etc. Free accommodation and meals are provided for staying in Cambridge out of term for choir activities. A special fund provides money for one-off extra activities such as participating in master-classes.
What vocal tuition would I receive as a member?
You will either receive regular in-house training from one of our three expert singing teachers – David Lowe, Elaine Pearce and Kate Symonds-Joy – or obtain a financial subsidy for an external teacher.
Is there a type of voice that is particularly suited to Caius choir?
No particular vocal characteristics are expected or prioritised. Voices both with and without vibrato are welcomed. Some applicants will have had vocal training and taken grade exams in singing, yet others may have had relatively little vocal training and experience; this factor is taken into account during the auditions.
Is there a typical Caius choir sound or approach to choral performance?
Different repertoires are performed in different styles, and as far as possible we adapt our singing to suit the music. You can listen to samples from our CD recordings on this site or on iTunes. During the course of an academic year the choir grows and develops a coherent and balanced sound, but that sound is often quite different from year to year depending on the constituent voices.
Does the choir have an emphasis on any particular type of choral music?
No, except that each year will tend to have a focus on a particular repertoire in the lead-up to a CD recording. The general approach to repertoire is broad and imaginative. As well as singing the great favourites of the English sacred choral repertoire in our regular services and concerts we sing medieval music, a good slice of continental repertoire from the polyphonic era and more recent times, and secular music at dinners and in concert, including partsongs and arrangements of folksongs and popular music. We also have a particular commitment to commissioning and performing new choral music by today’s leading composers. In addition, most tours and many concerts contain opportunities for performing music one-voice-per-part, in madrigals, motets, close-harmony etc. which is a highly rewarding and engaging manner of singing. Choir members leave with an exceptionally wide experience of choral music.
What it is like to be a member of Caius choir?
For most members of the choir singing is the most important part of their lives outside academic work. During term this means singing in choir five days out of seven, including providing the music for three Chapel services per week, (Sunday: 5pm rehearsal, 6pm service; Monday & Wednesday: 6.05pm to 7pm rehearsal; Tuesday & Thursday: 5.30pm rehearsal, 6.30pm service). In most weeks there will also be a singing lesson. Out of term more varied work takes place, including high-profile concerts, radio broadcasts, tours etc, and the choir also sings at several College Feasts in the year which are great social and gastronomic occasions. Each year the choir elects one of its third-year members to act as a representative to help with the smooth running of the choir, and the Choir Administrator Claire Wheeler helps with varied aspects of choir membership and organisational matters. Choir members read all subjects, though several read Music, and many also play instruments to a high level.
Does the choir collaborate with orchestras and other choirs?
The choir frequently joins with other Cambridge choirs for joint services, such as those of Clare and St John’s Colleges, and has recently made two CD recordings with the choir of King’s College London. The choir also works from time to time with professional orchestras (either on its own or in collaboration with others choirs) such as the Philharmonia, the orchestra of Bordeaux-Aquitaine in France, the Philharmonia Baroque of San Francisco and the Aurora Orchestra.
How have former members of Caius choir gone on to sing professionally?
In most cases choir members have moved on to one of the conservatoires to study singing full-time, whilst a few have preferred to continue lessons privately or forged their own professional careers as singers and teachers. Those who have taken the conservatoire route include Jennifer Johnston at the Royal College of Music, and William Towers, Johnny Herford and Kate Symonds-Joy at the Royal Academy of Music, whilst those whose careers have developed in other ways include Julia Doyle and several members of professional choirs and ensembles such as The Sixteen, Voces8 and founder-members of the group Stile Antico.
How do I apply?
If you receive an academic offer from the College as part of the application process in December/January you can then apply for a choral award by 15th February as explained on the University website. If you are pooled as a result of the application process you should contact Geoffrey Webber (gaw25@cam.ac.uk) for further advice.
How do I prepare for the choral award audition?
Vocal potential and a good ear are the two main qualities being looked for at the audition. You should prepare a piece to sing that you enjoy performing and that feels technically comfortable. Some applicants may already have had considerable experience at sight-reading but others will not, and this is taken into account as part of the application process. For those with limited experience in these areas it is worth trying the sample tests on the University website and spending some time at a keyboard pitching intervals up or down with the octave and picking out notes within a chord.
Can I visit Caius to receive advice about my choral application?
You are welcome to fix a time to sing to Geoffrey Webber at any point during the year either on a separate visit or whilst attending a subject or Caius Open Day. Please email gaw25@cam.ac.uk to arrange this. Alternatively you may wish to attend the Open Days for Vocal Guidance in September.
Can I also find out about reading Music?
If you are applying to study Music, you will also be able to discuss this aspect of your application if you visit Caius in advance, since Dr Webber is also the Director of Studies for the Caius Music students. Many Music students at Caius sing in the choir. |
Coming Soon: The Blockchain Decrypted Podcast
We’ve been hard at work behind the scenes these past few months, and are almost ready to release our latest (and hopefully greatest) piece of blockchain goodness! The Blockchain Decrypted Podcast, hosted by our co-founder Will Salisbury is getting ready to release next Sunday, September 16th, 2018.
Each episode will feature Will sitting down with an expert in blockchain, cryptocurrencies, or anything under those two large umbrellas. Investment advice, crypto mining advice, the future of blockchain technology…. we’ll cover it all! You’ll be able to subscribe and listen to the show on iTunes, Spotify, Google Play, and more.
So stay tuned, because we’re going to be “decrypting the blockchain” on a whole different level!
Scott Hawksworth is the co-founder of Blockchain Decrypted. He's also the producer of the Blockchain Decrypted podcast. When he's not picking Will's brain about the world of blockchain technology, he enjoys watching football and relaxing at home with his wife and three cats. |
@import
"~minx/src/settings",
"~minx/src/functions",
"~minx/src/mixins";
.task-item {
display: flex;
outline: none;
border-bottom: 1px dotted #666;
height: 60px;
overflow: hidden;
color: #fff;
font-size: rem(18px);
font-weight: 300;
@include media-query(540) {
font-size: rem(24px);
}
}
.task-item--editing {
border-bottom: 1px dotted #ccc;
}
.cell {
&:first-child,
&:last-child {
display: flex;
flex: 0 0 auto;
align-items: center;
}
&:first-child {
padding-right: 20px;
}
&:nth-child(2) {
flex: 1;
padding-right: 30px;
overflow: hidden;
}
}
.task-item__button {
@include button-base;
margin-left: 5px;
outline: none;
border: 0;
border-radius: 100px;
padding: 0;
width: 40px;
height: 40px;
overflow: hidden;
background: #2a2a2a;
transform: translate(0, 0);
&:first-child {
margin: 0;
}
}
.icon {
line-height: 40px !important;
color: #555;
.task-item__button:hover & {
color: #999;
}
}
.icon--active {
&, .task-item__button:hover & {
color: #85bf6b;
}
}
@keyframes fade-title {
from { color: #fff; }
to { color: #666; }
}
@keyframes strike-title {
from { width: 0; }
to { width: 100%; }
}
.task-item__title {
display: inline-block;
position: relative;
max-width: 100%;
line-height: 60px;
outline: none;
overflow: hidden;
text-overflow: ellipsis;
white-space: nowrap;
&:after {
position: absolute;
left: 0;
bottom: 0;
border-top: 2px solid #85bf6b;
width: 0;
height: 46%;
content: '';
}
.task-item--completed & {
color: #666;
}
.task-item--completed &:after {
width: 100%;
}
.task-item--completed.task-item--status-updated & {
animation: fade-title 120ms ease-in-out;
}
.task-item--completed.task-item--status-updated &:after {
animation: strike-title 180ms ease-in-out;
}
}
.task-item__input {
outline: none;
border: 0;
padding: 0;
width: 100%;
height: 60px;
color: inherit;
font: inherit;
background: transparent;
// remove `x`
&::-ms-clear {
display: none;
}
}
|
Q:
MongoDB aggregate() - error "TypeError: Cannot call method 'forEach' of undefined"
I have the following scrip in "script.js"
conn = new Mongo();
db = conn.getDB("learn");
db.contracts.aggregate([
{ $match: { regionCode: '77' } },
{ $unwind: '$products' },
{
$project: {
_id: '$_id',
regNum: '$regNum',
prodName: '$products.name',
prodPrice: '$products.price'
}
},
{ $match: { 'prodName' : 'Water' } }
], {cursor:{}}).result.forEach(printjson);
I run it from the command prompt by the following way
mongo script.js >> out.txt
In file "out.txt" I have the error
TypeError: Cannot call method 'forEach' of undefined at script.js
The same problem, when I run the script from mongo shell mongo.exe (by using load()).
When I run the same aggregate command from the Robomongo 0.8.4 I have succesive result (3 documents in json format). Does anybody know, why this may happen?
Mongodb version 2.6.5
A:
You need to run it without the result variable access. The cursor returned by mongodb when accessed in the shell, does not have a property named result and hence you get the error.
db.contracts.aggregate([
{ $match: { regionCode: '77' } },
{ $unwind: '$products' },
{
$project: {
_id: '$_id',
regNum: '$regNum',
prodName: '$products.name',
prodPrice: '$products.price'
}
},
{ $match: { 'prodName' : 'Water' } }
], {cursor:{}}).forEach(printjson);
|
2018 Le Mans Classic Review Part One
Craig Robertson
10 July 2018
In the first of this three-part special feature, Speed Chills View review the 2018 Le Mans Classic, an event firmly established in the motorsport calendar. Take a look at some of the pictures and the roundup of all the on-track action from the weekend.
The Le Mans Classic made its debut back in 2002. At the time, it was a financial disaster for Patrick Peter and Peter Auto, the organisers. Back then, just 30,000 people came to spectate the event over one weekend in September. However, that first event sparked an interest and word began to spread. 16 years later, the Le Mans Classic has firmly established itself in both the historic racing community and motorsport community as a whole with over 140,000 people expected to attend this year with 10 previous winners of the Le Mans 24 Hour set to compete including Roman Dumas, Loic Duval and Jochen Mass.
The Le Mans Classic is a truly special event. Le Mans is one of the few tracks in the world that is steeped in so much history. The 24 Hour itself, was first run in 1923 and all though the track has changed several times since then, this weekend, some of those original contenders have returned.
The entry list for the Le Mans Classic is huge, that’s the only way to describe it. This year there are circa 750 racing cars on track with over a thousand drivers taking part across the three days.
First of all, there are six “Plateaux”, grids too you and I, spanning 60 years of competition, from the early pre-World War 2 era of the 1920s and 1930s all the way through to the early 1980s. In addition to that, there are a number of separate races for classic Jaguars and Porsche along with a dedicated grid to the mighty Group C era of the 1980s and early 1990s.
New for 2018 is the Global Endurance Legends Series, at this stage, they only featured for two 30-minute parade sessions, however expect a lot more from them in the coming years. The Masters Endurance Legends series held its first UK race at Brands Hatch earlier this year having been unveiled late in 2017.
In short, the Le Mans Classic is the only event in the world where you can watch anything from Pre-War Bentley’s and Bugatti’s all the way through the classic sports car era of the 1960s to Group C and beyond to the early days of LMP alongside GT1 and GT2 of the late 1990s and early 2000s.
The action began on Friday morning, 70 cars from the newly formed Global Endurance Legends Series took to the circuit behind the safety car for the first of two 30-minute sessions and what an incredible site it was. The field was led by a bright Yellow Ferrari 333SP in the hands of Michel Lecourt and despite it being a parade, it quickly became apparent a number of small battles were emerging, Andy Bruce in the Spark McLaren F1 GTR for one, going three abreast down the Mulsanne Straight with the Panoz Esperante GTR-1 and a Porsche 993 GT2 Evo at almost 180 miles an hour. Le Mans 24 Hour veteran Emmanuel Collard made his return to Le Mans in the very Toyota TS020 GT-One that he drove here back in 1999 with Martin Brundle and Vincenzo Sospiri. Unfortunately, the car retired part way through the race however the sister #3 car finished second that year behind the #15 BMW V12 LMR of Yannick Dalmas, Joachim Winkelhock and Pierluigi Martini.
A number of fan favourites from previous years also took part in the parade including the ex-Colin McRae Ferrari 550 GT1, the 2003 Bentley Speed 8, the Audi R8 and Peugeot 908. Manufacturers from the modern era of the FIA World Endurance Championship were well represented across the GT1, GT2, GT3 and LM GT categories including the Aston Martin DBR9 GT1, Ferrari F430, AF Corse Ferrari 458 GTE and Porsche 997 GT3 RSR.
Next up, it was the return of the mighty Group C cars, a fan favourite for obvious reasons at the Le Mans Classic. A number of iconic liveries and brands made a welcome return to Le Mans including a host of Silk Cut liveried Jaguar XJR’s, Peugeot 905’s and Porsche 962’s. Regular FIA Masters Historic Formula 1 driver Michael Lyons returned in the 1991 Gebhardt C91, taking victory in the only race of the weekend. Shaun Lynn, father of Aston Martin factory driver Alex Lynn took second place in the 1987 Jaguar XJR-9 from the 1989 XJR11 of Ralf Kelleners and Ivan Vercourtere. They made for a spectacular sight this weekend with some pretty close racing throughout the grid. The ground effect aero causing the cars to stick to the track as they made their way down Dunlop Hill or through Porsche Curves at incredible speed was mind blowing. The 908 Peugeot’s were a highlight for many during the Group C sessions, their naturally aspirated V10’s screaming akin to an early 90s Formula 1 car with up shifts that sounded like canon fire, piercing the ear drums of anyone trackside at the time. |
Oxidative stress in cerebrospinal fluid of patients with aseptic and bacterial meningitis.
This study aimed to determine whether patients with aseptic and bacterial meningitis presented alterations in oxidative stress parameters of cerebrospinal fluid (CSF). A total of 30 patients were used in the research. The CSF oxidative stress status has been evaluated through many parameters, such as lipid peroxidation through thiobarbituric acid reactive substances (TBARS) and antioxidant defense systems such as superoxide dismutase (SOD), glutathione S-transferase (GST), reduced glutathione (GSH) and ascorbic acid. TBARS levels, SOD and GST activity increase in aseptic meningitis and in bacterial meningitis. The ascorbic acid concentration increased significantly in patients with both meningitis types. The reduced glutathione levels were reduced in CSF of patients with aseptic and bacterial meningitis. In present study we may conclude that oxidative stress contributes at least in part to the severe neurological dysfunction found in meningitis. |
package solid.humank.ddd.commons.utilities;
import com.fasterxml.jackson.core.JsonParser;
import com.fasterxml.jackson.core.JsonToken;
import com.fasterxml.jackson.databind.DeserializationContext;
import com.fasterxml.jackson.datatype.jsr310.deser.LocalDateTimeDeserializer;
import java.io.IOException;
import java.time.Instant;
import java.time.LocalDateTime;
import java.time.ZoneOffset;
import java.time.format.DateTimeFormatter;
public class MillisOrLocalDateTimeDeserializer extends LocalDateTimeDeserializer {
public MillisOrLocalDateTimeDeserializer() {
super(DateTimeFormatter.ISO_LOCAL_DATE_TIME);
}
@Override
public LocalDateTime deserialize(JsonParser parser, DeserializationContext context) throws IOException {
if (parser.hasToken(JsonToken.VALUE_NUMBER_INT)) {
long value = parser.getValueAsLong();
Instant instant = Instant.ofEpochMilli(value);
return LocalDateTime.ofInstant(instant, ZoneOffset.UTC);
}
return super.deserialize(parser, context);
}
} |
The Quivering
The Quivering (also known as 'Spud II) is a single-player horror/comedy themed video game, developed by Charybdis and released by Alternative Software on PC CD-ROM. The game is a sequel to Charybdis' earlier 1996 game Spud!.
Plot
During a chemistry experiment, Uncle Olivetti accidentally opens a portal to Dimension X, which unleashes a horde of monsters led by the evil Big D, who transforms Olivetti into a raven. Olivetti's nephew, Spud steps forth to defeat Big D, restore his uncle and save the world from the incoming horror. The main plot being a little cheesy.
Gameplay
The player moves around in a 3D area with a 360 degree rotation.
Reception
External links
Official website
Category:1997 video games
Category:DOS games
Category:Video games developed in the United Kingdom
Category:Windows games |
// Copyright (c) Microsoft Open Technologies, Inc. All rights reserved. See License.txt in the project root for license information.
;(function (factory) {
var objectTypes = {
'boolean': false,
'function': true,
'object': true,
'number': false,
'string': false,
'undefined': false
};
var root = (objectTypes[typeof window] && window) || this,
freeExports = objectTypes[typeof exports] && exports && !exports.nodeType && exports,
freeModule = objectTypes[typeof module] && module && !module.nodeType && module,
moduleExports = freeModule && freeModule.exports === freeExports && freeExports,
freeGlobal = objectTypes[typeof global] && global;
if (freeGlobal && (freeGlobal.global === freeGlobal || freeGlobal.window === freeGlobal)) {
root = freeGlobal;
}
// Because of build optimizers
if (typeof define === 'function' && define.amd) {
define(['rx.binding', 'exports'], function (Rx, exports) {
root.Rx = factory(root, exports, Rx);
return root.Rx;
});
} else if (typeof module === 'object' && module && module.exports === freeExports) {
module.exports = factory(root, module.exports, require('./rx'));
} else {
root.Rx = factory(root, {}, root.Rx);
}
}.call(this, function (root, exp, Rx, undefined) {
// Aliases
var Observable = Rx.Observable,
observableProto = Observable.prototype,
observableFromPromise = Observable.fromPromise,
observableThrow = Observable.throwError,
AnonymousObservable = Rx.AnonymousObservable,
AsyncSubject = Rx.AsyncSubject,
disposableCreate = Rx.Disposable.create,
CompositeDisposable = Rx.CompositeDisposable,
immediateScheduler = Rx.Scheduler.immediate,
timeoutScheduler = Rx.Scheduler['default'],
isScheduler = Rx.Scheduler.isScheduler,
slice = Array.prototype.slice;
var fnString = 'function',
throwString = 'throw',
isObject = Rx.internals.isObject;
function toThunk(obj, ctx) {
if (Array.isArray(obj)) { return objectToThunk.call(ctx, obj); }
if (isGeneratorFunction(obj)) { return observableSpawn(obj.call(ctx)); }
if (isGenerator(obj)) { return observableSpawn(obj); }
if (isObservable(obj)) { return observableToThunk(obj); }
if (isPromise(obj)) { return promiseToThunk(obj); }
if (typeof obj === fnString) { return obj; }
if (isObject(obj) || Array.isArray(obj)) { return objectToThunk.call(ctx, obj); }
return obj;
}
function objectToThunk(obj) {
var ctx = this;
return function (done) {
var keys = Object.keys(obj),
pending = keys.length,
results = new obj.constructor(),
finished;
if (!pending) {
timeoutScheduler.schedule(function () { done(null, results); });
return;
}
for (var i = 0, len = keys.length; i < len; i++) {
run(obj[keys[i]], keys[i]);
}
function run(fn, key) {
if (finished) { return; }
try {
fn = toThunk(fn, ctx);
if (typeof fn !== fnString) {
results[key] = fn;
return --pending || done(null, results);
}
fn.call(ctx, function(err, res) {
if (finished) { return; }
if (err) {
finished = true;
return done(err);
}
results[key] = res;
--pending || done(null, results);
});
} catch (e) {
finished = true;
done(e);
}
}
}
}
function observableToThunk(observable) {
return function (fn) {
var value, hasValue = false;
observable.subscribe(
function (v) {
value = v;
hasValue = true;
},
fn,
function () {
hasValue && fn(null, value);
});
}
}
function promiseToThunk(promise) {
return function(fn) {
promise.then(function(res) {
fn(null, res);
}, fn);
}
}
function isObservable(obj) {
return obj && typeof obj.subscribe === fnString;
}
function isGeneratorFunction(obj) {
return obj && obj.constructor && obj.constructor.name === 'GeneratorFunction';
}
function isGenerator(obj) {
return obj && typeof obj.next === fnString && typeof obj[throwString] === fnString;
}
/*
* Spawns a generator function which allows for Promises, Observable sequences, Arrays, Objects, Generators and functions.
* @param {Function} The spawning function.
* @returns {Function} a function which has a done continuation.
*/
var observableSpawn = Rx.spawn = function (fn) {
var isGenFun = isGeneratorFunction(fn);
return function (done) {
var ctx = this,
gen = fn;
if (isGenFun) {
for(var args = [], i = 0, len = arguments.length; i < len; i++) { args.push(arguments[i]); }
var len = args.length,
hasCallback = len && typeof args[len - 1] === fnString;
done = hasCallback ? args.pop() : handleError;
gen = fn.apply(this, args);
} else {
done = done || handleError;
}
next();
function exit(err, res) {
timeoutScheduler.schedule(done.bind(ctx, err, res));
}
function next(err, res) {
var ret;
// multiple args
if (arguments.length > 2) {
for(var res = [], i = 1, len = arguments.length; i < len; i++) { res.push(arguments[i]); }
}
if (err) {
try {
ret = gen[throwString](err);
} catch (e) {
return exit(e);
}
}
if (!err) {
try {
ret = gen.next(res);
} catch (e) {
return exit(e);
}
}
if (ret.done) {
return exit(null, ret.value);
}
ret.value = toThunk(ret.value, ctx);
if (typeof ret.value === fnString) {
var called = false;
try {
ret.value.call(ctx, function() {
if (called) {
return;
}
called = true;
next.apply(ctx, arguments);
});
} catch (e) {
timeoutScheduler.schedule(function () {
if (called) {
return;
}
called = true;
next.call(ctx, e);
});
}
return;
}
// Not supported
next(new TypeError('Rx.spawn only supports a function, Promise, Observable, Object or Array.'));
}
}
};
function handleError(err) {
if (!err) { return; }
timeoutScheduler.schedule(function() {
throw err;
});
}
/**
* Invokes the specified function asynchronously on the specified scheduler, surfacing the result through an observable sequence.
*
* @example
* var res = Rx.Observable.start(function () { console.log('hello'); });
* var res = Rx.Observable.start(function () { console.log('hello'); }, Rx.Scheduler.timeout);
* var res = Rx.Observable.start(function () { this.log('hello'); }, Rx.Scheduler.timeout, console);
*
* @param {Function} func Function to run asynchronously.
* @param {Scheduler} [scheduler] Scheduler to run the function on. If not specified, defaults to Scheduler.timeout.
* @param [context] The context for the func parameter to be executed. If not specified, defaults to undefined.
* @returns {Observable} An observable sequence exposing the function's result value, or an exception.
*
* Remarks
* * The function is called immediately, not during the subscription of the resulting sequence.
* * Multiple subscriptions to the resulting sequence can observe the function's result.
*/
Observable.start = function (func, context, scheduler) {
return observableToAsync(func, context, scheduler)();
};
/**
* Converts the function into an asynchronous function. Each invocation of the resulting asynchronous function causes an invocation of the original synchronous function on the specified scheduler.
* @param {Function} function Function to convert to an asynchronous function.
* @param {Scheduler} [scheduler] Scheduler to run the function on. If not specified, defaults to Scheduler.timeout.
* @param {Mixed} [context] The context for the func parameter to be executed. If not specified, defaults to undefined.
* @returns {Function} Asynchronous function.
*/
var observableToAsync = Observable.toAsync = function (func, context, scheduler) {
isScheduler(scheduler) || (scheduler = timeoutScheduler);
return function () {
var args = arguments,
subject = new AsyncSubject();
scheduler.schedule(function () {
var result;
try {
result = func.apply(context, args);
} catch (e) {
subject.onError(e);
return;
}
subject.onNext(result);
subject.onCompleted();
});
return subject.asObservable();
};
};
/**
* Converts a callback function to an observable sequence.
*
* @param {Function} function Function with a callback as the last parameter to convert to an Observable sequence.
* @param {Mixed} [context] The context for the func parameter to be executed. If not specified, defaults to undefined.
* @param {Function} [selector] A selector which takes the arguments from the callback to produce a single item to yield on next.
* @returns {Function} A function, when executed with the required parameters minus the callback, produces an Observable sequence with a single value of the arguments to the callback as an array.
*/
Observable.fromCallback = function (func, context, selector) {
return function () {
var len = arguments.length, args = new Array(len)
for(var i = 0; i < len; i++) { args[i] = arguments[i]; }
return new AnonymousObservable(function (observer) {
function handler() {
var len = arguments.length, results = new Array(len);
for(var i = 0; i < len; i++) { results[i] = arguments[i]; }
if (selector) {
try {
results = selector.apply(context, results);
} catch (e) {
return observer.onError(e);
}
observer.onNext(results);
} else {
if (results.length <= 1) {
observer.onNext.apply(observer, results);
} else {
observer.onNext(results);
}
}
observer.onCompleted();
}
args.push(handler);
func.apply(context, args);
}).publishLast().refCount();
};
};
/**
* Converts a Node.js callback style function to an observable sequence. This must be in function (err, ...) format.
* @param {Function} func The function to call
* @param {Mixed} [context] The context for the func parameter to be executed. If not specified, defaults to undefined.
* @param {Function} [selector] A selector which takes the arguments from the callback minus the error to produce a single item to yield on next.
* @returns {Function} An async function which when applied, returns an observable sequence with the callback arguments as an array.
*/
Observable.fromNodeCallback = function (func, context, selector) {
return function () {
var len = arguments.length, args = new Array(len);
for(var i = 0; i < len; i++) { args[i] = arguments[i]; }
return new AnonymousObservable(function (observer) {
function handler(err) {
if (err) {
observer.onError(err);
return;
}
var len = arguments.length, results = [];
for(var i = 1; i < len; i++) { results[i - 1] = arguments[i]; }
if (selector) {
try {
results = selector.apply(context, results);
} catch (e) {
return observer.onError(e);
}
observer.onNext(results);
} else {
if (results.length <= 1) {
observer.onNext.apply(observer, results);
} else {
observer.onNext(results);
}
}
observer.onCompleted();
}
args.push(handler);
func.apply(context, args);
}).publishLast().refCount();
};
};
function isNodeList(el) {
if (window.StaticNodeList) {
// IE8 Specific
// instanceof is slower than Object#toString, but Object#toString will not work as intended in IE8
return (el instanceof window.StaticNodeList || el instanceof window.NodeList);
} else {
return (Object.prototype.toString.call(el) == '[object NodeList]')
}
}
function fixEvent(event) {
var stopPropagation = function () {
this.cancelBubble = true;
};
var preventDefault = function () {
this.bubbledKeyCode = this.keyCode;
if (this.ctrlKey) {
try {
this.keyCode = 0;
} catch (e) { }
}
this.defaultPrevented = true;
this.returnValue = false;
this.modified = true;
};
event || (event = root.event);
if (!event.target) {
event.target = event.target || event.srcElement;
if (event.type == 'mouseover') {
event.relatedTarget = event.fromElement;
}
if (event.type == 'mouseout') {
event.relatedTarget = event.toElement;
}
// Adding stopPropogation and preventDefault to IE
if (!event.stopPropagation) {
event.stopPropagation = stopPropagation;
event.preventDefault = preventDefault;
}
// Normalize key events
switch (event.type) {
case 'keypress':
var c = ('charCode' in event ? event.charCode : event.keyCode);
if (c == 10) {
c = 0;
event.keyCode = 13;
} else if (c == 13 || c == 27) {
c = 0;
} else if (c == 3) {
c = 99;
}
event.charCode = c;
event.keyChar = event.charCode ? String.fromCharCode(event.charCode) : '';
break;
}
}
return event;
}
function createListener (element, name, handler) {
// Standards compliant
if (element.addEventListener) {
element.addEventListener(name, handler, false);
return disposableCreate(function () {
element.removeEventListener(name, handler, false);
});
}
if (element.attachEvent) {
// IE Specific
var innerHandler = function (event) {
handler(fixEvent(event));
};
element.attachEvent('on' + name, innerHandler);
return disposableCreate(function () {
element.detachEvent('on' + name, innerHandler);
});
}
// Level 1 DOM Events
element['on' + name] = handler;
return disposableCreate(function () {
element['on' + name] = null;
});
}
function createEventListener (el, eventName, handler) {
var disposables = new CompositeDisposable();
// Asume NodeList
if (isNodeList(el) || Object.prototype.toString.call(el) === '[object HTMLCollection]') {
for (var i = 0, len = el.length; i < len; i++) {
disposables.add(createEventListener(el.item(i), eventName, handler));
}
} else if (el) {
disposables.add(createListener(el, eventName, handler));
}
return disposables;
}
/**
* Configuration option to determine whether to use native events only
*/
Rx.config.useNativeEvents = false;
/**
* Creates an observable sequence by adding an event listener to the matching DOMElement or each item in the NodeList.
*
* @example
* var source = Rx.Observable.fromEvent(element, 'mouseup');
*
* @param {Object} element The DOMElement or NodeList to attach a listener.
* @param {String} eventName The event name to attach the observable sequence.
* @param {Function} [selector] A selector which takes the arguments from the event handler to produce a single item to yield on next.
* @returns {Observable} An observable sequence of events from the specified element and the specified event.
*/
Observable.fromEvent = function (element, eventName, selector) {
// Node.js specific
if (element.addListener) {
return fromEventPattern(
function (h) { element.addListener(eventName, h); },
function (h) { element.removeListener(eventName, h); },
selector);
}
// Use only if non-native events are allowed
if (!Rx.config.useNativeEvents) {
// Handles jq, Angular.js, Zepto, Marionette, Ember.js
if (typeof element.on === 'function' && typeof element.off === 'function') {
return fromEventPattern(
function (h) { element.on(eventName, h); },
function (h) { element.off(eventName, h); },
selector);
}
}
return new AnonymousObservable(function (observer) {
return createEventListener(
element,
eventName,
function handler (e) {
var results = e;
if (selector) {
try {
results = selector(arguments);
} catch (err) {
return observer.onError(err);
}
}
observer.onNext(results);
});
}).publish().refCount();
};
/**
* Creates an observable sequence from an event emitter via an addHandler/removeHandler pair.
* @param {Function} addHandler The function to add a handler to the emitter.
* @param {Function} [removeHandler] The optional function to remove a handler from an emitter.
* @param {Function} [selector] A selector which takes the arguments from the event handler to produce a single item to yield on next.
* @returns {Observable} An observable sequence which wraps an event from an event emitter
*/
var fromEventPattern = Observable.fromEventPattern = function (addHandler, removeHandler, selector) {
return new AnonymousObservable(function (observer) {
function innerHandler (e) {
var result = e;
if (selector) {
try {
result = selector(arguments);
} catch (err) {
return observer.onError(err);
}
}
observer.onNext(result);
}
var returnValue = addHandler(innerHandler);
return disposableCreate(function () {
if (removeHandler) {
removeHandler(innerHandler, returnValue);
}
});
}).publish().refCount();
};
/**
* Invokes the asynchronous function, surfacing the result through an observable sequence.
* @param {Function} functionAsync Asynchronous function which returns a Promise to run.
* @returns {Observable} An observable sequence exposing the function's result value, or an exception.
*/
Observable.startAsync = function (functionAsync) {
var promise;
try {
promise = functionAsync();
} catch (e) {
return observableThrow(e);
}
return observableFromPromise(promise);
}
return Rx;
}));
|
Introduction
============
Esophageal cancer (EC) is high incidence and mortality not just in China, which was reported as the fourth most commonly diagnosed malignant tumor and also the fourth most common cause of cancer-related death in 2015, but also in some Western and Central Asian countries [@B1], [@B2]. Notably, almost 70% of the initial visits of patients with EC were diagnosed as advanced stages (regional or distant metastasis) and the five-year overall survival (OS) of this population was range from 10% to 31% even after multidisciplinary therapies [@B3]-[@B5]. In the past decades, with the cancer screening promoted by Chinese anti-cancer association in high incidence area of EC, more and more patients with early stage tumors are detected [@B1]. In spite of the ability to detect and resect these early stage tumors, but still 10%-35.9% of these patients would occur tumor-related death within five years after radical resection [@B4], [@B6]. Therefore, identifying independent prognostic factors for superficial EC (T1) is a very meaningful topic. At the same time, these risk factors could not only provide a reasonable choice in endoscopic resection (ER) or esophagectomy, but may also instruct postoperative adjuvant treatment.
Inflammation-based prognostic scores have intensively been studied in variety of malignant solid tumors and are emerging as promising prognostic indexes. However, no studies have explored the prognostic value of the above mentioned scores in patients with superficial esophageal squamous cell carcinoma (ESCC). In addition, patients with stage T1 ESCC are candidates for ER, which is recommend by guidelines from Chinese Society of Clinical Oncology (CSCO), Japan Esophageal Society (JES) and National Comprehensive Cancer Network (NCCN) etc, but the accurate prognostic markers to identify the high-risk patients who may easily recurrence after ER are essential. Furthermore, due to the majority stage T1N0 patients with ESCC owning long-term survival, only length and depth of tumor invasion, microscopic tumor budding, poor differentiation and lymphovascular invasion had been found as independent prognostic indicators for postoperative OS reported by limited literatures [@B7]-[@B10]. Therefore, establishing other simple, inexpensive, and promising prognostic factors for superficial ESCC (T1) may seem difficult but necessary. What\'s more, the preoperative peripheral blood examinations are routinely preformed and readily available.
Thus, this study is focus on pathological T1N0 Chinese patients with the common pathological subtype---squamous cell carcinoma---to explore the prognostic values of inflammation-based prognostic scores.
Materials and Methods
=====================
Patient selection and Ethics statement
--------------------------------------
1994 consecutive patients with ESCC underwent esophagectomy at department of thoracic surgery, Sun Yat-sen university cancer center (SYSUCC) between January 2005 and December 2012 were enrolled in initial database. And all clinical, pathological, radiological, preoperative inflammation-based indicators, therapeutic strategy as well as follow-up information were retrospectively referred and typed into statistical software simultaneously. Of course, the written informed consents were signed by patients themselves and the hospital ethics committee in SYSUCC had approved this study based on the World Medical Association Declaration of Helsinki preparatory to our all work.
Patients were enrolled in final analysis if they met following criteria: (1) there was no neoadjuvant treatment; (2) no distant metastasis was found by preoperative radiological scanning; (3) all of the patients were given complete gross tumor resection with safety margins (R0 resection), which is defined as no microscopic involvement in the surgically resected margins, and 2- or 3-field lymph node dissection; (3) postoperative diagnosis of T1 stage ESCC (the lamina propria, muscularis mucosae or submucosa invasion) had been established by two board-certified pathologist independently and all lymph node was confirmed negative (N0).
Patients were excluded based on following criteria: (1) accompany with autoimmune disease or preoperative infection; (2)other malignant neoplasm(s) was detected before or after esophagectomy; (3) death during perioperative period; (4) without preoperative data of peripheral blood cells count; (5) loss to follow-up.
Definitions of inflammation-based prognostic scores
---------------------------------------------------
As previously described [@B11], the Glasgow prognostic score (GPS) is simultaneously consisted by nutritional (if albumin≥3.5 mg/dl was allocated a score of 0, otherwise 1) and inflammatory conditions (if CRP≤1.0 mg/dl was allocated a score of 0, otherwise 1). In term of modified GPS (mGPS), both an abnormal CRP (\>1.0 mg/l) and hypoalbuminaemia (\<3.5 mg/dl) were allocated a score of 2, and only one or none of the two biochemical abnormalities was allocated a score of 1 or 0, respectively. In addition, except the cut-off value of CRP (abnormality: \>0.3 mg/l), the allocation method of high-sensitivity modified GPS (HS-mGPS) was the same as the mGPS.
Differ to GPS, the prognostic index (PI) consists of two inflammatory parameters: CRP (if ≤1.0 mg/dl was allocated a score of 0, otherwise 1) and white cell count (WBC, if ≤11,000/μl was allocated a score of 0, otherwise 1). After summation of respective allocated score, these patients were divided into three groups, including 0, 1 and 2.
Other prognostic indicators are calculated by following mathematical formula: (1) neutrophil to lymphocyte ratio (NLR) = total neutrophil count / total lymphocyte count; (2) platelet to lymphocyte ratio (PLR) = total platelet count / total lymphocyte count; (3) CRP to albumin ratio (CAR) = CRP (mg/L) / albumin (g/L).
Follow-up strategy and statistical analysis
-------------------------------------------
The follow-up observation was performed since the date of radical resection and the interval of every follow-up visit were every three months during the first two years, every six months since the beginning of the third year to the end of the fifth year, and then each subsequent annual. Each follow-up protocol routinely consisted of complete blood count, blood biochemical examination, common tumor markers, esophageal barium meal, head and neck ultrasonography, as well as upper abdominal ultrasonography. In addition, the thoracoabdominal contrast-enhanced CT scanning was carried out once every six months during the first three years and then once a year until death occurred in our facility. The time of disease-free survival (DFS) was calculated from the date of esophagectomy to the first local recurrence or distant metastasis observed by radiology findings. Similarly, the time interval from the date of esophagectomy to death caused by ESCC was defined as the total survival time.
All statistical analyses were performed by SPSS 23.0 (SPSS Inc., Chicago, IL, USA) and the two-sided p value less than 0.050 was defined as significantly difference in statistics, but the survival curves were constructed using GraphPad Prism 7.0 (GraphPad Software Inc., La Jolla, USA). Firstly, the best cut-off values of these inflammation-based prognostic scores were determined by maximum Youden index, which were generated by respective receiver operating characteristics (ROC) curves, to evaluate the predictive values in prognosis. In addition, the differences of categorical variables between groups were studied using chi-square test. Needless to say, the prognostic factors of DFS and overall survival (OS) were confirmed by Kaplan-Meier univariate analysis using log-rank test. And then these significantly prognostic variables (p\<0.050) obtained from Kaplan-Meier analysis were enrolled in Cox multivariate regression analysis based on forward stepwise method.
Results
=======
Clinical, pathological and surgical characteristics
---------------------------------------------------
There were 160 consecutive patients with ESCC diagnosed as pathological stage T1N0 enrolled, including 105 male and 55 female (median age: 59 years; interquartile range: 52 to 65 years). More than half of these patients (53.75%, 86 of 160) had smoked but a history of alcohol use was recorded only in 22 patients (13.75%). Of the 42 patients with family history of malignant tumors, 30 patients came from esophageal cancer family. The majority of these tumors (65.00%, 104 of 160) located in middle segment of the thoracic esophagus. In addition, the Sweet (transthoracic esophagectomy with two-field lymphadenectomy) and McKeown (tri-incisional esophagectomy with three-field lymphadenectomy) surgical approach were performed in 102 patients and 57 patients, respectively. The median and average count of examined lymph nodes (LNs) was 17.0 and 19.9, respectively (interquartile range: 12 to 25), and the median and average stations of examined LNs was 5.0 and 6.2, respectively (interquartile range: 4 to 7). In our cohort, only six individuals received postoperative paclitaxel plus cisplatin or nedaplatin regimen for adjuvant chemotherapy because of poorly differentiation. All the baseline characteristics are described in Table [1](#T1){ref-type="table"}.
Best cut-off values
-------------------
Calculated by the above mathematical formulas, the values of NLR, PLR, CAR range from 0.460-14.000 (median: 1.895), 41.540-597.140 (median: 102.364), 0.000-1.040 (median: 0.025), respectively. Based on the maximum Youden index, 1.976, 103.200, 0.023 were chosen as the best cut-off nodes of NLR, PLR, CAR for OS, respectively (Fig. [1](#F1){ref-type="fig"}).
Prognostic factors for DFS and OS
---------------------------------
The follow-up data were updated to 1 June 2017 and the median follow-up time was 71.8 months (interquartile range: 52.0 to 95.5 months). During the follow-up period, there were only 34 patients occurred postoperative recurrence of ESCC including 13 distant organ metastasis and 21 local recurrences, and the 1-, 3-, 5- and 10-year DFS rate were 96.2%, 85.6%, 78.7% and 74.7%, respectively. In addition, 30 cases of all 42 deaths were directly related to recurrence of ESCC, and the 1-, 3-, 5- and 10-year OS rate were 94.4%, 82.2%, 79.4% and 66.3%, respectively.
In univariate analysis, the PI 0, GPS 0, and low CRP (≤ 1.090 mg/l), NLR (≤ 1.976), PLR (≤ 103.200), CAR (≤ 0.023) were significantly correlated with longer DFS and OS (all p\<0.050, Table [1](#T1){ref-type="table"}). In addition, these patients with a history of alcohol consumption showed significantly shorter 10-year DFS and OS (DFS: 58.4% vs. 77.3%, p=0.015; OS: 59.1% vs. 58.1%, p=0.040). The best cut point of the resected lymph nodes count (RLNs) was determined as 13 in our study based on ROC curve and we had found that the 10-year DFS was significantly longer for RLNs \>13 than for RLNs ≤13 (79.2% vs. 65.3%, p=0.048), but not in OS (p=0.061).
After multivariate analysis, there was no clinicopathological, inflammatory or surgical factors indicated as prognostic index for DFS (all p\>0.050). However, the GPS 0 (HR: 0.068, 95%*CI*: 0.007-0.622, P=0.017) and low CAR (≤ 0.023, HR: 0.126, 95%*CI*: 0.017-0.911, P=0.040, Table [2](#T2){ref-type="table"} and Fig. [2](#F2){ref-type="fig"}) were predictive of better long-term survival in patients with pathological T1N0 ESCC.
Relationships between inflammation-based prognostic scores and clinicopathological variables
--------------------------------------------------------------------------------------------
The relationships between GPS, CAR and clinicopathological variables were described in Table [3](#T3){ref-type="table"}. Only the distribution of age was found statistically difference between the elevated and low CAR groups (≤0.023/\>0.023, p=0.014). The population distribution based on PI score (0/1-2) was completely consistent with the GPS (0/1-2). Similarly, the majority of these patients who were set into low CAR group (≤0.023) were also set into PI score 0 and GPS 0 group (72 of 75, 96.0%). In addition, the correlation analysis indicated that the two GPS (0/1-2) groups were positively associated with the levels of serum CRP, NLR, PLR and CAR (all p\<0.050). And the above correlations were also observed between the two CAR groups (≤0.023/\>0.023, all p\<0.050, except for p=0.054 for PLR levels).
Discussion
==========
Inflammation had been documented as a part of the normal but complex biological response to sterile cell death or foreign infection since the origination of available medical history, which could remove or neutralize injurious material and activate healing and regeneration. As time went on, the potential correlation between leukocytes invasion and tumors had been firstly observed by Rudolf Virchow in the mid-19th century. Since then, more and more mechanism studies have clarified that tumor-associated inflammatory response play a critical role in the initiation, promotion, malignant conversion, invasion and metastasis of varies malignant solid tumor development [@B12]. When the progression or metastasis of malignancies occurred, the inflammatory cytokines, such as interleukin 1 (IL-1), interleukin 6 (IL-6), chemokines, NF-κB etc, were secreted by tumor-infiltrating lymphocytes or tumor cells, which could promote the immunity and hematopoietic system, including neutrophils, lymphocytes, CRP, platelets etc. Thus the elevated levels or ratios of inflammatory cells could be predictive factors for recurrence after therapy and cancer-related death and the prognostic values for many malignancies had been elaborated elsewhere [@B13]-[@B16].
The elevated serum CRP level had been reported only once as a significant prognostic parameter for 5-year survival in early stage ESCC patients (T1-2N0) by Zheng-Bo Song et al [@B17]. However, in our retrospective analysis, the single parameter lost the prognostic ability for long-term survival in stage T1N0 ESCC patients. As previous elaboration, the serum CRP level could not only reflect host acute-phase inflammatory response, but also associated with the nutrition status. In other words, the malnutrition status could weaken systemic inflammatory response leading to low serum CRP level [@B18]. Thus the inflammatory response protein (such as CRP) combining with systemic nutrition status, especially albumin, may be more sensitive marker for prognosis. The Glasgow prognostic score (GPS), which could evaluate inflammatory and nutrition status simultaneously, was firstly reported as prognostic factor for inoperable non-small cell lung cancer by Forrest et al in 2003 and the prognostic value had been proved in early, advanced or non-selected stage cancer by many literature review and meta-analysis [@B15]. As previous studies, the patients who were classified into the group of score 2 were limited (only 1 case in this study) [@B19], [@B20]. Xiao-li Wei et al, Xiao-ling Xu et al and G. Jomrich et al had reported that high GPS (1-2) was not significantly associated with shorter OS in non-selected or resectable ESCC patients, but, multivariate analysis identified that GPS (0/1-2) was the independent prognostic factor for 10-year OS among stage T1N0 ESCC in our study [@B20]-[@B22], which was in accordance with the result from N. Hirahara et al among elderly ESCC patients (age≥70 years) [@B19]. In 2007, the first study in colon and rectal cancer from McMillan DC et al indicated that the modified GPS (mGPS) was significantly associated with overall survival [@B23]. However, the novel mGPS in predicting survival for ESCC still needs to be verified in selected or large cohort and the value has not been established by previous studies [@B20], [@B21], [@B24]. In this study, the population distribution based on mGPS (0/1/2) was completely consistent with the GPS (0/1/2) and thus the prognostic value was still unclear. The summary of these relevant studies are showed in supplementary table (Table [S1](#SM0){ref-type="supplementary-material"}) [@B25]-[@B27].
In 2015, a novel inflammation-based prognostic score---the CRP/Alb ratio (CAR)---was introduced by Kinoshita et al in non-selected hepatocellular carcinoma patients and they had proved that its prognostic ability could be comparable to mGPS and better than NLR [@B28]. In the same year, Xiao-ling Xu et al and Xiao-li Wei et al had explored the prognostic value of CAR in operable and non-selected ESCC patients, respectively and the area under the curve (AUC) values of the CAR was proved higher than the other inflammation-based prognostic scores at 12 months, 24 months, and 36 months [@B20], [@B21], which was consistent with our analysis [@B21]. In addition, similar to the above mentioned reports, the novel but promising CAR has been identified as an independent prognostic factor for OS in our study by multivariate analysis as well [@B29], [@B30]. The summary of these relevant studies are showed in supplementary table (Table [S2](#SM0){ref-type="supplementary-material"}).
In our study, we had found that the elevated CAR was only connected with elderly patients (p=0.014), but no significant correlation was observed between GPS (0/1-2) and clinicopathological features, which was not in agreement with the previous findings in ESCC [@B19]-[@B21], [@B31]. It is probably because the tumor stage was specific T1N0 in our cohort, but non-selected in previous literatures. What\'s more, Pearson\'s correlation indicated that the GPS and CAR level were significantly associated with the PI score (r=0.931, p\<0.000 and r=0.356, p\<0.000; respectively) and the levels of serum CRP (r=0.432, p\<0.000 and r=0.989, p\<0.000; respectively), NLR (r=0.218, p=0.006 and r=0.183, p=0.021; respectively), PLR (r=0.165, p=0.037 and r=0.082, p=0.300; respectively). The two indexes may absorb the prognostic values of all other inflammation-based prognostic scores and show a combined prognostic ability. In addition, the AUC was 0.658 for GPS (95%*CI*: 0.564-0.752, p=0.002) and 0.617 for CAR (95%*CI*: 0.525-0.709, p=0.025, Fig. [1](#F1){ref-type="fig"}). Thus, to stage T1N0 ESCC patients who underwent esophagectomy, we recommend the preoperative GPS and CAR as predicative markers for OS and the predicative value of GPS, which could be well standardized, was slightly superior to the CAR.
A recent meta-analysis, which included seven retrospective, observational, cohort studies involving 1540 patients with EC, had found that the NLR and PLR were independently predictive factors for poorer survival [@B31]. However, in other two retrospective analysis of the same year from Xiao-li Wei et al and Xiao-ling Xu et al (the number of enrolled cases all more than 400), this tendency was not observed in ESCC [@B20], [@B21]. Similarly, the preoperative NLR and PLR also lacked the prognostic ability for DFS or OS in patients with stage T1N0 ESCC in our study (p= 0.235 and 0.126, respectively), but which was completely inconsistent with Xuan Xie\'s study in early stage ESCC (only 43 patients) [@B32]. The inconsistent findings in present studies may be attributed to following reasons:
Firstly, to these patients with early stage tumors, host may withstand a mild inflammatory burden leading to overall low NLR and PLR. For instance, the best cut-off values of NLR (1.976) and PLR (103.2) in our stage T1N0 ESCC patients were smaller than the previous EC cohort with non-selected stages (range of NLR cut-off: 2.0-5.0, range of PLR cut-off: 103.0-163.8) [@B20], [@B21], [@B31]. Secondly, up to date, the best cut-off values of these ratios were varies in published reports, which may weaken the clinical application and prognostic ability in EC with different stages, length of tumor, depth of tumor invasion, and lymph node metastasis etc [@B19], [@B31]. In the meta-analysis conducted by Paramanathan A et al, the NLR cut-off of 5 showed significantly poorer survival with less heterogeneity in solid tumor [@B33]. Obviously, the optional NLR cut-off with less heterogeneity in ESCC has yet to be evaluated well, which need to verified in multicenter, lager cohort studies. Thirdly, a lot of inflammation-related disease, such as non-alcoholic fatty liver disease, metabolic syndrome, essential hypertension, infection etc, and premedication may affect the level of NLR and PLR [@B34], [@B35]. Fifthly, the time interval of these patients who were enrolled in this study was from January 2005 to December 2012 (8 years). During this long period, much progress has been made in peripheral blood cells count, thus the selection bias may be unavoidable. [@B36]. The last four were also the limitations of this retrospective analysis.
A simultaneously combination of CRP and white cell count in the prognostic index (PI), which is another readily available and well standardized prognostic scores like with (m/HS-m)GPS, has been confirmed as predictive marker for survival in lung cancer and colorectal cancer [@B37], [@B38]. However, no study is available regarding the prognostic role of PI in ESCC up to now and we showed for the first time. Even though the AUC values of the PI (0.650, 95%*CI*: 0.557-0.744, p=0.004, Fig. [2](#F2){ref-type="fig"}) was higher than the other inflammation-based prognostic scores in this study, but it was not significantly predicative value for RFS or OS in ESCC (or at least in stage T1N0) by multivariate analysis. Thus, the negative findings will prompt us to explore the prognostic value of PI in a larger prospective cohort with different stages ESCC.
In conclusion, our study determined the preoperative GPS and CAR as simple, inexpensive, readily available predictor for long-term survival in stage T1N0 ESCC patients who underwent esophagectomy. To these patients with high GPS or elevated CAR, endoscopic resection (ER) may not suitable and postoperative adjuvant chemotherapy may be considered.
Supplementary Material {#SM0}
======================
######
Supplementary tables.
######
Click here for additional data file.
We should thank the department of follow-up for recording recurrence and death data in detail. Besides, we are supposed to express our gratitude for the support and suggestion in this study from staffs at department of thoracic surgery.
{#F1}
{#F2}
######
Univariate analysis for disease-free survival (DFS) and overall survival (OS) in 160 patients with pathological T1N0 esophageal squamous cell carcinoma
---------------------------------------------------------------------------------------------------------
Variables No. of patients\ Univariate analysis
(N=160)
------------------------------------ ------------------ --------------------- --------- ------- ---------
**Gender**
Male 105 77.0% 0.356 54.3% 0.823
Female 55 82.1% 71.0%
**Age (years, mean±SD)**
\<65 119 77.9% 0.315 63.9% 0.008\*
≥65 41 60.5% 42.1%
**Smoking history**
Yes 86 76.9% 0.469 74.1% 0.462
No 74 72.3% 50.1%
**Alcohol consumption**
Yes 22 58.4% 0.015\* 59.1% 0.040\*
No 138 77.3% 58.1%
**Family malignant tumor history**
Yes 42 77.4% 0.200 74.5% 0.240
No 118 68.3% 53.0%
**Preoperative loss of weight**
\<3 kilograms 115 76.0% 0.228 52.9% 0.206
≥3 kilograms 45 71.2% 64.6%
**Carcinoma differentiation**
Highly 24 69.8% 0.925 59.3% 0.939
Moderately 84 75.3% 54.4%
Poorly 52 77.0% 69.7%
**Tumor location**
Upper 26 81.1% 0.708 84.3% 0.191
Middle 104 76.2% 55.2%
Lower 30 62.9% 58.9%
**Length of tumor**
≤1.8cm 42 72.4% 0.650 39.4% 0.105
\>1.8cm 118 75.4% 72.6%
**Surgical approach**
Sweet 102 75.8% 0.980 55.1% 0.926
Mckeown 57 70.6% 68.5%
**Adjuvant therapy**
Yes 6 66.7% 0.605 100% 0.168
No 154 75.2% 57.0%
**Resected lymph nodes count**
≤13 53 65.3% 0.048\* 44.7% 0.061
\>13 107 79.2% 74.1%
**Prognostic index**
0 74 87.2% 0.003\* 81.7% 0.004\*
1 80 59.2% 26.4%
2 6 100% 55.6%
**Glasgow prognostic score(GPS)**
0 74 87.2% 0.004\* 81.7% 0.000\*
1-2 86 61.9% 26.5%
**Modified GPS(mGPS)**
0 74 87.2% 0.004\* 81.7% 0.000\*
1-2 86 61.9% 26.5%
**High-sensitivity mGPS(HS-mGPS)**
0 15 86.2% 0.328 93.3% 0.062
1-2 145 73.2% 53.9%
**C reactive protein(CRP, mg/l)**
≤1.090 80 84.0% 0.019\* 81.7% 0.000\*
\>1.090 80 63.5% 25.7%
**Neutrophil to lymphocyte ratio**
≤1.976 88 81.6% 0.032\* 65.8% 0.002\*
\>1.976 72 65.3% 50.6%
**Platelet to lymphocyte ratio**
≤103.200 83 83.3% 0.047\* 64.3% 0.011\*
\>103.200 77 65.2% 51.1%
**CRP to albumin ratio**
≤0.023 75 84.4% 0.021\* 83.5% 0.000\*
\>0.023 85 63.7% 25.4%
---------------------------------------------------------------------------------------------------------
No., number; DFS, disease-free survival; OS, overall survival; SD, standard deviation.
\*the p value was considered as significantly difference in statistic because of less than 0.050.
######
Multivariate analysis for overall survival (OS) in 160 patients with pathological T1N0 esophageal squamous cell carcinoma
Variables Groups Hazard ratio (95%*CI*) P
------------------------- -------------------- ------------------------ ---------
**Age** \<65/≥65 0.661(0.332-1.313) 0.237
**Alcohol consumption** Yes/No 0.523(0.244-1.121) 0.095
**CRP** ≤1.090/\>1.090 0.673(0.088-5.146) 0.703
**PI** 0/1/2 0.284(0.008-10.717) 0.496
**GPS/mGPS** 0/1-2 0.068(0.007-0.622) 0.017\*
**NLR** ≤1.976/\>1.976 0.641(0.308-1.336) 0.235
**PLR** ≤103.200/\>103.200 0.580(0.288-1.166) 0.126
**CAR** ≤0.023/\>0.023 0.126(0.017-0.911) 0.040\*
CI, confidence interval, CRP, C reactive protein, PI, prognostic index, GPS, Glasgow prognostic score, mGPS, modified Glasgow prognostic score, NLR, neutrophil to lymphocyte ratio, PLR, platelet to lymphocyte ratio, CAR, CRP to albumin ratio.
\*the p value was considered as significantly difference in statistic because of less than 0.050.
######
The correlation of GPS and CAR with the clinicopathological features in 160 patients with pathological T1N0 esophageal squamous cell carcinoma
------------------------------------------------------------------------------------------------------------------------------
Variables GPS CAR
------------------------------------- ---------------- ---------------- ---------- ---------------- ---------------- ---------
**Age (years, mean±SD)** 57.8±8.0 59.7±9.0 0.158 57.1±8.4 60.4±8.5 0.014\*
Preoperative loss of weight\ 2.020±3.001 1.994±4.070 0.964 2.033±3.024 1.982±4.067 0.929
(mean±SD)
**Length of tumor (mean±SD)** 2.340±1.000 2.573±1.295 0.210 2.324±1.001 2.591±1.291 0.150
**Gender**
Male 49(66.2) 56(65.1) 0.884 51(68.0) 54(63.5) 0.552
Female 25(33.8) 30(34.9) 24(32.0) 31(36.5)
**Smoking history**
Yes 44(59.5) 42(48.8) 0.179 44(58.7) 42(49.4) 0.241
No 30(40.5) 44(51.2) 31(41.3) 43(50.6)
**Alcohol consumption**
Yes 7(9.5) 15(17.4) 0.171 8(10.7) 14(16.5) 0.287
No 67(90.5) 71(82.6) 67(89.3) 71(83.5)
**Family malignant**\
**tumor history**
Yes 21(28.4) 21(24.4) 0.570 23(30.7) 19(22.4) 0.233
No 53(71.6) 65(75.6) 52(69.3) 66(77.6)
**Carcinoma differentiation**
Highly 10(13.5) 14(16.3) 0.246 10(13.3) 14(16.5) 0.081
Moderately 35(47.3) 49(57.0) 34(45.4) 50(58.8)
Poorly 29(39.2) 23(26.7) 31(41.3) 21(24.7)
**Tumor location**
Upper 14(18.9) 12(14.0) 0.425 14(18.7) 12(14.3) 0.392
Middle 48(64.9) 55(64.0) 50(66.7) 53(63.1)
Lower 11(14.9) 19(22.0) 11(14.6) 19(22.6)
**Prognostic index**
0 74(100) 0(0.0) 0.000\* 72(96.0) 2(2.4) 0.000\*
1-2 0(0.0) 86(100) 3(4.0) 83(97.6)
**Glasgow prognostic score(GPS)**
0 --- --- --- 72(96.0) 2(2.4) 0.000\*
1-2 --- --- 3(4.0) 83(97.6)
**C reactive protein(CRP, mg/l)**\ 0.534±0.249 4.050±5.796 0.000\* 0.541±0.256 4.085±5.822 0.000\*
**(mean±SD)**
**Neutrophil to lymphocyte ratio**\ 1.868±0.946 2.536±1.740 0.003\* 1.871±0.966 2.541±1.737 0.004\*
**(mean±SD)**
**Platelet to lymphocyte ratio**\ 103.493±41.821 124.154±70.904 0.029\* 104.901±42.772 123.154±70.990 0.054
**(mean±SD)**
**CRP to albumin ratio(CAR)**\ 0.012±0.006 0.098±0.151 0.000\* --- --- ---
**(mean±SD)**
------------------------------------------------------------------------------------------------------------------------------
GPS, Glasgow prognostic score; CAR, CRP to albumin ratio; SD, standard deviation.
\*the p value was considered as significantly difference in statistic because of less than 0.050.
[^1]: \*Xiangyang Yu and Yingsheng Wen contributed equally to this work.
[^2]: Competing Interests: The authors have no conflicts of interest to disclose.
|
Q:
Getting compilation error in creating trigger in pl/sql
The following code consists of my project on sql. I'm having hard time finding trigger compilation error repeatedly.
Warning: Trigger created with compilation errors.
I'm using oracle SQL.If this code segments is not enough then you can find the whole project in the following link:
https://github.com/Shauqi/PhotoGalleryDatabase.
create table user1
(
user_id number(10) not null,
name varchar(20),
password number(12)
);
create table myaudit
(
new_name varchar2(30),
old_name varchar2(30),
user_name varchar2(30),
entry_date varchar2(30),
operation varchar2(30)
);
set serveroutput on
CREATE OR REPLACE TRIGGER user1audit
BEFORE INSERT OR DELETE OR UPDATE ON user1
FOR EACH ROW
DECLARE
v_user varchar2 (30); v_date varchar2(30);
BEGIN
SELECT user, TO_CHAR(sysdate, 'DD/MON/YYYY HH24:MI:SS') INTO v_user, v_date FROM dual;
IF INSERTING THEN
INSERT INTO myaudit (new_name,old_name, user_name, entry_date, operation) VALUES(:NEW.NAME, Null , v_user, v_date, 'Insert');
ELSIF DELETING THEN
INSERT INTO myaudit (new_name,old_name, user_name, entry_date, operation) VALUES(NULL,:OLD.NAME, v_user, v_date, 'Delete');
ELSIF UPDATING THEN
INSERT INTO myaudit (new_name,old_name, user_name, entry_date, operation) VALUES(:NEW.NAME, :OLD.NAME, v_user, v_date,'Update');
END IF;
END;
/
A:
Try this:
CREATE OR REPLACE TRIGGER user1audit
BEFORE INSERT OR DELETE OR UPDATE ON user1
FOR EACH ROW
BEGIN
IF INSERTING THEN
INSERT INTO myaudit (new_name,old_name, user_name, entry_date, operation) VALUES(:NEW.NAME, Null , user, TO_CHAR(sysdate, 'DD/MON/YYYY HH24:MI:SS'), 'Insert');
ELSIF DELETING THEN
INSERT INTO myaudit (new_name,old_name, user_name, entry_date, operation) VALUES(NULL,:OLD.NAME, user, TO_CHAR(sysdate, 'DD/MON/YYYY HH24:MI:SS') , 'Delete');
ELSIF UPDATING THEN
INSERT INTO myaudit (new_name,old_name, user_name, entry_date, operation) VALUES(:NEW.NAME, :OLD.NAME, user, TO_CHAR(sysdate, 'DD/MON/YYYY HH24:MI:SS'),'Update');
END IF;
END;
/
|
Q:
Not selecting what emacs ido is suggesting?
In my current working directory ~/WD there is a abc.txt file. Now I want to make another abc.txt under a sub directory ~/WD/NEW/. As I type C-x C-f and the directory ~/WD/NEW/abc.txt, ido is changing the string into ~/WD/abc.txt, which is not what I want to open. As I try to modify the string back, ido automatically "correct" my input into the wrong string again.
Is there any way to solve this issue?
A:
If you're using ido to open a file and you want to "step out" of ido in the middle of completing, you can use C-f. For example:
Ctrl+X Ctrl+F (find-file)
Find file: ~/{ .emacs.d/ | bin/ | some-file.txt | tmp/ ... }
T Enter (narrow options with ido)
Find file: ~/tmp/{ file1.txt | file2.txt | subdir/ }
Ctrl+F ("step out" of ido mode)
Find file: ~/tmp/
|
+ 4931*k**2 + 29*k - 9
What is the d'th term of -216, -145, 212, 855?
143*d**2 - 358*d - 1
What is the u'th term of 67003272, 67003269, 67003266, 67003263, 67003260, 67003257?
-3*u + 67003275
What is the w'th term of -38716, -77404, -116068, -154696, -193276, -231796, -270244?
2*w**3 - 38702*w - 16
What is the y'th term of -24, -50, -94, -156?
-9*y**2 + y - 16
What is the b'th term of -1863446, -1863406, -1863338, -1863242, -1863118?
14*b**2 - 2*b - 1863458
What is the m'th term of 1055832, 1055855, 1055908, 1056003, 1056152, 1056367?
2*m**3 + 3*m**2 + 1055827
What is the g'th term of -8867758, -8867761, -8867752, -8867725, -8867674, -8867593, -8867476?
g**3 - 10*g - 8867749
What is the f'th term of -3509, -6509, -9125, -11165, -12437, -12749, -11909, -9725?
32*f**3 - 3224*f - 317
What is the t'th term of 9194, 18060, 26934, 35816, 44706, 53604, 62510?
4*t**2 + 8854*t + 336
What is the z'th term of -527804, -1055613, -1583422, -2111231?
-527809*z + 5
What is the b'th term of -150879, -302184, -453487, -604788, -756087, -907384?
b**2 - 151308*b + 428
What is the x'th term of 622, 5074, 17154, 40678, 79462, 137322, 218074, 325534?
636*x**3 - 2*x**2 + 6*x - 18
What is the k'th term of -9372119, -9372116, -9372115, -9372116, -9372119, -9372124, -9372131?
-k**2 + 6*k - 9372124
What is the f'th term of -271641, -271273, -270893, -270495, -270073?
f**3 + 361*f - 272003
What is the w'th term of 1029, 3172, 6457, 10884, 16453, 23164, 31017?
571*w**2 + 430*w + 28
What is the x'th term of 381608, 763220, 1144822, 1526408, 1907972, 2289508, 2671010, 3052472?
-x**3 + x**2 + 381616*x - 8
What is the o'th term of 78419519, 156839042, 235258565?
78419523*o - 4
What is the f'th term of 534292885, 534292888, 534292891, 534292894, 534292897, 534292900?
3*f + 534292882
What is the p'th term of -1203, -378, 2489, 7398?
1021*p**2 - 2238*p + 14
What is the g'th term of -6944, -11802, -16660?
-4858*g - 2086
What is the h'th term of -128677, -128673, -128667, -128659, -128649?
h**2 + h - 128679
What is the d'th term of -134667, -134648, -134629, -134610, -134591, -134572?
19*d - 134686
What is the r'th term of 8291894, 8291511, 8291130, 8290751, 8290374, 8289999, 8289626?
r**2 - 386*r + 8292279
What is the c'th term of -18136, -36219, -54470, -72973, -91812?
-14*c**3 - 17985*c - 137
What is the h'th term of -14064, -27968, -41860, -55734, -69584, -83404?
h**3 - 13911*h - 154
What is the h'th term of -18590, -17752, -16914, -16082, -15262?
-h**3 + 6*h**2 + 827*h - 19422
What is the k'th term of 486417044, 486417043, 486417042?
-k + 486417045
What is the b'th term of -92227, -92385, -92653, -93037, -93543, -94177, -94945?
-b**3 - 49*b**2 - 4*b - 92173
What is the q'th term of -1112, -4347, -9720, -17225, -26856, -38607?
q**3 - 1075*q**2 - 17*q - 21
What is the g'th term of -97436, -113367, -129298?
-15931*g - 81505
What is the b'th term of 329020, 329133, 329322, 329587?
38*b**2 - b + 328983
What is the t'th term of 284675, 284801, 284927, 285053, 285179, 285305?
126*t + 284549
What is the l'th term of 13, -29, -183, -503, -1043, -1857, -2999, -4523?
-9*l**3 - 2*l**2 + 27*l - 3
What is the c'th term of 16525, 35922, 55321, 74722, 94125, 113530?
c**2 + 19394*c - 2870
What is the s'th term of 18748197, 37496396, 56244595, 74992794, 93740993, 112489192?
18748199*s - 2
What is the a'th term of 51280, 51637, 51994?
357*a + 50923
What is the d'th term of -7225, -7379, -7627, -7963, -8381, -8875?
d**3 - 53*d**2 - 2*d - 7171
What is the r'th term of 21479, 21206, 20465, 19022, 16643, 13094, 8141, 1550?
-39*r**3 + 21518
What is the v'th term of 4536, 6301, 8066, 9831, 11596?
1765*v + 2771
What is the q'th term of 868, 1692, 2472, 3214, 3924?
q**3 - 28*q**2 + 901*q - 6
What is the d'th term of 119013, 476941, 1073495, 1908681, 2982505, 4294973, 5846091, 7635865?
d**3 + 119307*d**2 - 295
What is the v'th term of -2555759, -2555757, -2555755, -2555753, -2555751?
2*v - 2555761
What is the j'th term of -402, -3395, -8392, -15393?
-1002*j**2 + 13*j + 587
What is the c'th term of 43, 1292, 4973, 12316, 24551?
205*c**3 - 14*c**2 - 144*c - 4
What is the i'th term of -52, -68, -30, 92, 328, 708, 1262?
5*i**3 - 3*i**2 - 42*i - 12
What is the d'th term of 6765908, 6765928, 6765948, 6765968?
20*d + 6765888
What is the n'th term of 47215, 46586, 45957, 45328?
-629*n + 47844
What is the u'th term of -2150915, -4301839, -6452763?
-2150924*u + 9
What is the j'th term of -457, 363, 2473, 5873, 10563?
645*j**2 - 1115*j + 13
What is the a'th term of -117447, -117441, -117427, -117405?
4*a**2 - 6*a - 117445
What is the b'th term of -5094, -4356, -3126, -1404, 810, 3516, 6714?
246*b**2 - 5340
What is the w'th term of -1003827, -1003827, -1003829, -1003833?
-w**2 + 3*w - 1003829
What is the t'th term of 3527130, 3527084, 3527008, 3526902, 3526766, 3526600, 3526404?
-15*t**2 - t + 3527146
What is the j'th term of -6015781, -6015776, -6015767, -6015754, -6015737, -6015716, -6015691?
2*j**2 - j - 6015782
What is the i'th term of 9391, 9356, 9321, 9286, 9251, 9216?
-35*i + 9426
What is the u'th term of 49637957, 49637956, 49637955?
-u + 49637958
What is the m'th term of 803530, 803507, 803472, 803425?
-6*m**2 - 5*m + 803541
What is the w'th term of -4333149, -8666291, -12999433, -17332575?
-4333142*w - 7
What is the r'th term of -10718, -24527, -47534, -79733, -121118, -171683, -231422, -300329?
r**3 - 4605*r**2 - r - 6113
What is the d'th term of 1271039, 2542114, 3813191, 5084270, 6355351, 7626434, 8897519?
d**2 + 1271072*d - 34
What is the k'th term of -298, -1984, -6458, -15112, -29338, -50528, -80074?
-232*k**3 - 2*k**2 - 56*k - 8
What is the h'th term of 265, 384, 641, 1114, 1881, 3020, 4609?
13*h**3 - 9*h**2 + 55*h + 206
What is the j'th term of -287, -1327, -2387, -3467, -4567?
-10*j**2 - 1010*j + 733
What is the i'th term of 226950, 226955, 226958, 226959, 226958, 226955?
-i**2 + 8*i + 226943
What is the f'th term of -143649, -287273, -430851, -574359, -717773?
4*f**3 - f**2 - 143649*f - 3
What is the y'th term of -42077549, -42077551, -42077553, -42077555?
-2*y - 42077547
What is the x'th term of 24040, 23230, 22418, 21604, 20788?
-x**2 - 807*x + 24848
What is the g'th term of -577857, -577776, -577641, -577452?
27*g**2 - 577884
What is the c'th term of 49378, 49388, 49398, 49408?
10*c + 49368
What is the b'th term of 114915326, 114915324, 114915322, 114915320, 114915318?
-2*b + 114915328
What is the j'th term of 326064, 652348, 978632, 1304916, 1631200?
326284*j - 220
What is the j'th term of 578, 1020, 1572, 2234, 3006?
55*j**2 + 277*j + 246
What is the z'th term of -862, -6711, -22674, -53809, -105174, -181827?
-843*z**3 + z**2 + 49*z - 69
What is the s'th term of 9754953, 19509868, 29264783, 39019698?
9754915*s + 38
What is the i'th term of -867, -1785, -2583, -3201, -3579?
10*i**3 - 988*i + 111
What is the y'th term of -5732, -5576, -5456, -5372, -5324, -5312, -5336?
-18*y**2 + 210*y - 5924
What is the r'th term of 300, 10452, 27370, 51054?
3383*r**2 + 3*r - 3086
What is the t'th term of -1552147, -1552083, -1552019?
64*t - 1552211
What is the z'th term of -135318, -540749, -1216464, -2162463?
-135142*z**2 - 5*z - 171
What is the r'th term of 6648, 26760, 60328, 107352, 167832?
6728*r**2 - 72*r - 8
What is the u'th term of 9233, 8967, 8691, 8399, 8085, 7743, 7367?
-u**3 + u**2 - 262*u + 9495
What is the g'th term of -3378, -8631, -22896, -50679, -96486, -164823?
-751*g**3 + 4*g - 2631
What is the s'th term of 3728003, 7456001, 11183999, 14911997, 18639995?
3727998*s + 5
What is the z'th term of 69782, 142123, 214454, 286769, 359062, 431327, 503558?
-z**3 + z**2 + 72345*z - 2563
What is the l'th term of 2986, 6211, 9446, 12691?
5*l**2 + 3210*l - 229
What is the r'th term of 5335, 5348, 5393, 5488, 5651?
3*r**3 - 2*r**2 - 2*r + 5336
What is the n'th term of 3972655, 7945307, 11917959?
3972652*n + 3
What is the c'th term of -1236472, -1236476, -1236480, -1236484, -1236488, -1236492?
-4*c - 1236468
What is the o'th term of -191347, -382771, -574195, -765619?
-191424*o + 77
What is the a'th term of -49983954, -99967910, -149951866, -199935822, -249919778?
-49983956*a + 2
What is the i'th term of -7091, -29959, -68607, -123035, -193243, -279231?
-7890*i**2 + 802*i - 3
What is the z'th term o |
Republicans had a decade at least to come up with a comprehensive tax reform plan that achieves their goals without raising taxes on the middle class. They failed.
The Senate plan causes about 13 million fewer people to have health insurance by repealing the individual mandate and hurting enrollment in both Medicaid and Obamacare exchanges. That will, according to the best evidence we have, lead to an increase in preventable deaths on the order of 15,600 people per year. It will also increase individual health insurance premiums even for people who still do purchase insurance.
By 2027, poor and middle-class people will see their taxes go up across the board. People making between $10,000 and $20,000 a year, the working poor, will see their income go down by 1.5 percent. Millionaires will see their income go up by 0.4 percent:
Even before major individual tax provisions expire at the end of 2025, the bill raises taxes on a significant share of people. In 2018, economist Ernie Tedeschi estimates that 11 percent of taxpayers will be paying more. The bill’s tweaks to tax brackets, doubling of the standard deduction, elimination of personal exemptions, and expansion of the child tax credit interact in sometimes unpredictable ways. Some families win, but others lose. Even in the early years, it’s not an across-the-board tax cut.
The bill cuts alcohol taxes on wine, beer, and liquor. We know that alcohol taxes are effective at reducing drunk driving, violent crime, and liver cirrhosis, and that increasing them saves thousands of lives a year. Raising the cost of a six-pack of Bud Light by 50 cents could save 2,000 to 6,000 lives every year. So cutting alcohol taxes, as the tax bill does, will likely increase preventable deaths in the US significantly.
It didn’t have to be this bad
Here’s the thing, though: Whatever the goal Republicans have, it didn’t have to be achieved this way. There is for each and every purpose a better bill that could be written.
Suppose Republicans wanted an across-the-board tax cut that helped both middle-class and rich people. They could’ve simply cut the 10 percent tax bracket to 8 percent, or that plus cut the 15 percent bracket to 12 percent. That helps middle- and upper-class people (though not the poor) and creates no losers. If they wanted to conform to Senate rules, they could have it all expire after eight or 10 years, just as the current legislation does. If they wanted to make it permanent, and cared deeply enough, they could’ve gone nuclear on the filibuster and passed a permanent cut with 51 votes.
But Republicans also want a lower, permanent corporate tax rate. Also doable: You can finance substantial rate cuts by removing tax breaks from the corporate code. Robert Pozen at Harvard Business School has estimated that eliminating the deductibility of interest payments on corporate debt would enable a cut in the corporate rate from 35 percent to 15 percent. If you wanted to, at the same time, allow 100 percent deductibility of all investments at the time they’re made, the rate would have to go up somewhat. But you could definitely cut the corporate rate, and pay for it permanently, by eliminating certain deductions and broadening the base. You don’t have to raise taxes or take away health care from middle-class people.
Republicans have grander aspirations than that, however. If you read the “Better Way” tax framework released by House Speaker Paul Ryan and House Ways and Means Chair Kevin Brady in 2016, you’ll see page after page of arguments for transitioning away from taxing income to taxing consumption. A lot of economists agree with that goal, even progressive ones (though others insist taxing consumption is inherently regressive).
Luckily there’s a plan in Congress that achieves that goal, is revenue-neutral, and doesn’t raise taxes on the poor or middle class. It’s Sen. Ben Cardin’s (D-MD) Progressive Consumption Tax Act. Cardin would exempt the first $100,000 of income for couples from income tax ($50,000 for singles, $75,000 for single parents), meaning that the vast majority of people would no longer pay income taxes. He'd consolidate rates to three — 15, 25, and 28 percent — and cut the corporate tax to 17 percent. That's a lower top individual rate, and a lower corporate rate, than the Senate is proposing. To pay for it, he'd introduce a value-added tax, the kind of consumption tax used in most other rich countries, and add a rebate so that poor people don’t see their taxes go up.
The plan, based on a proposal by Columbia tax law professor Michael Graetz, accomplishes basically all of Republicans’ substantive tax reform goals. It lowers income tax rates, and dramatically lowers the corporate tax. By exempting the majority of Americans from income taxes, it reduces the importance of deductions and credits. And it shifts the tax burden to consumption by adding a VAT.
But unlike the Senate or House tax bills, it doesn’t increase the deficit, and it’s not regressive. The Tax Policy Center modeled the Graetz plan back in 2013 with a VAT rate of 12.9 percent, and slightly tweaked individual tax brackets (14, 27, and 31). TPC found that it would cost $0. It’s completely revenue-neutral. And it's progressive. The top 0.1 percent would see their income fall by 0.9 percent, and the poorest fifth would see their income grow by 1.2 percent.
If Republicans really want to give needy people a tax cut while shifting the tax code to consumption and lowering individual and corporate tax rates, there’s your plan. You can work with Cardin on putting together a passable version right now.
Perhaps a VAT is too dramatic a step. I have a plan for then, too! Senate Finance Committee ranking member Ron Wyden has for years put out bipartisan tax reform plans, first with Sen. Judd Gregg (R-NH) and then with Sen. Dan Coats (R-IN), who have both since left the body. The plan sets a top rate of 35 percent, lowers the corporate tax rate to 24 percent, and, according to a 2010 analysis from the Tax Policy Center, would have made the tax code slightly more progressive. That analysis came before some of the high-income Bush tax cuts were revived, so the effect relative to today's laws would be different. But it’s a model for a way to cut corporate rates and simplify the code while not making the tax code more regressive.
Republicans have to ask themselves what they’re in this for
I don’t know what’s in the hearts of Orrin Hatch or Kevin Brady or Paul Ryan or Mitch McConnell. I don’t like to assume malign motives of politicians, even ones I vehemently disagree with. But the details of this tax bill are less consistent with an honest desire to achieve certain principled changes to the tax code — to make it simpler, or more pro-investment, or more tilted at taxing consumption rather than income — than with a desire to get the tax deal done fast, a desire to help important constituencies, and a desire to thumb the eyes of perceived ideological enemies.
That explains why, rather than paying for corporate cuts by offsetting an appropriate number of corporate tax breaks, the Senate wants to cut Medicaid and Obamacare. It sticks it to programs that are important to Democrats, furthers the GOP’s long-running interest in undermining Obamacare, and avoids making hard decisions about corporate benefits that might delay passage.
It explains a variety of anti-university provisions inserted into the bill. If you care about lowering tax rates on savings and investment, you do not insert a random excise tax on the earnings of big university endowments. But if you care about sticking it to coastal elite universities that are full of liberals, that provision makes sense. So does treating tuition waivers for PhD students as taxable income. This will hurt the economy dramatically in the long run by undermining human capital developments and creating a less educated workforce. It might even cost lives by impeding biomedical research. But it’s a good way to own the libs.
Republicans had years to put together this tax bill. They had the whole Obama administration, even the last two years of the Bush administration when they were in the minority. They could’ve done better. They had the tools and resources to do better. Other politicians and policy analysts had come up with ideas to help them do better.
That they didn’t do better is a massive failure. |
"Well, we have five games to go. Who on this team wants me to fight for them to keep their job? Who among the players and coaches really wants to be here? Who wants me to fight to keep them here?''
Mark Davis on Dennis Allen after speaking to him:
Quote:
"I wouldn't say it was heated; the most heated I got was when we first got on the plane and I told him it's not good enough,'' Davis said. "And that's what I said. I told him not long after we boarded: `It's not good enough.' I admit I was pissed off.''
Quote:
"Honestly, I was happy to see some of that passion coming out of him,'' Davis said. "Frankly, I didn't know if it was there.''
I like Mark Davis. He's about the only one bright spot of the season for me. It seems like he genuinely cares about how the team is doing. As a fan, that makes me feel good to know. As far as Dennis is concerned, if that's the first long conversation he's had with Mark, hopefully he wasn't expecting a pat on the back for the poor job he's done so far._________________
Because owners own the team and that is it.
How often do good owners speak out ?
You think owners don't meet with their GM on a regular basis to adress whatever issues have to be adressed? You think they're throwing millions into an organization and then just let people run it while they enjoy their time on the golf course? When there's a need for their voice to be heard, it is heard.
This is his first year on the job and the last month has been the first major obstacle (i lack a better word here) for this regime. So yeah, he felt the need to let fans know he's aware of the situation, that he's there to make sure things go in the right direction, basically, that he cares. When the Steelers have to deal with the likes of Santonio Holmes, you hear the owner's opinion on it. This is the same here. It's a situation where the owner's voice has to be heard. It's not like we've been hearing a lot from him in the past year. When he becomes Jerry Jones, i'll be worried._________________
The more quotes I see of Mark Davis the more worried about him I am as owner.
Have to agree with you a bit.
I hope he is not going down the Al path and will think he knows better than his GM and coaches.
When the GM the coaches make huge mistakes you have to wonder. Like Mark said this time last year the Raiders where 7-4 and now under the the new GM and Coach they are 3-8.
I would be mad as well.
Yeah, i don't know what the big deal is here. As the owner he has every right to be disappointed and to let people know about it. Apparently, he came straight to the guy he started to question and asked him to explain the issues he was going thru. Why shouldn't he do it?
Maybe don't do it on an airplane? Not letting your emotions get the better of you either would be a big help as well. Sitting down with your HC on a plane and then basically having a rant at him seems like incompetence from me._________________
If mark davis fires DA... we will have a very hard time finding a coach for a long time.
Mark Davis needs to realize who he is, his dad was one of the most controlling owners in sports and coaches stayed away from him.
AD at least earnt his role as owner, and at a time was a football genius so its understandable that he went a bit whack at the end there.
MD hasnt done anything in the world of football. if he fires the first HC of his career, coaches will know they have a 1yr trial, which no coahc wants.
Joined: 11 Dec 2007Posts: 3015Location: Restaurant at the end of the universe
Posted: Sun Dec 02, 2012 1:16 pm Post subject:
oakdb36 wrote:
Keleth wrote:
Because owners own the team and that is it.
How often do good owners speak out ?
You think owners don't meet with their GM on a regular basis to adress whatever issues have to be adressed? You think they're throwing millions into an organization and then just let people run it while they enjoy their time on the golf course? When there's a need for their voice to be heard, it is heard.
An owner can call his coach or GM an idiot or whatever he wants,he is the boss after all.
But letting it be known in public is another thing entirely.
I'll ask again,when was the last time you heard a good owner going public with his dissatisfaction ?
Because owners own the team and that is it.
How often do good owners speak out ?
You think owners don't meet with their GM on a regular basis to adress whatever issues have to be adressed? You think they're throwing millions into an organization and then just let people run it while they enjoy their time on the golf course? When there's a need for their voice to be heard, it is heard.
An owner can call his coach or GM an idiot or whatever he wants,he is the boss after all.
But letting it be known in public is another thing entirely.
I'll ask again,when was the last time you heard a good owner going public with his dissatisfaction ?
An owner can call his coach or GM an idiot or whatever he wants,he is the boss after all.
But letting it be known in public is another thing entirely.
I'll ask again,when was the last time you heard a good owner going public with his dissatisfaction ?
I'm pretty sure he never called them idiots. And i really can't answer that question as i don't pay extra attention to what the owners say or not.
I understand the situation Mark Davis is in right now though. He has to take over for a football icon who has been this franchise for the last half century. And in his first year, the team is going through what might be the roughest stretch of games in its history. That's reason enough to let the fans know you're there and you recognize what has been done isn't gonna be enough. Through all he's saying, there's nothing indicating he doesn't trust the guys he put in charge. The only message is we haven't done enough and we will work all together to fix this thing. I actuallt think he's handling it pretty smartly as he portrays himself in the position of a man asking himself the same questions most of the fans do and providing the answers to the doubt they may have about the FO and the coaching staff. From a PR stand point, it's pretty good._________________
S&B88 is kinda right there. Also, I do recall bp being high on Pryor when we took him in the supplemental draft and now after not throwing a pass for a year and a half and a couple preseason games he's done a 180. Usually its the siding with the front office thing. If the front office likes him he must be good.
I don't mean to put somebody on blast but it's something I've noticed as well.
I side w/ the FO, because they are the professionals here that work with these players. Be it the old FO or new, has a player got away that has proven a baller that you can say 'big mistake'.
There is plenty I disagree with as well. I was sour on Knapp's hiring, but thought he'd do more with the talent here, he hasn't.
I'm a positive person. I tend to side with what appears a positive to me.
As for Pryor. Liked the pick at the time, but thought Hue (and Al for that matter) would be around to work with him. That was before Palmer. I've not done a 180 on Pryor, just don't think he needs to be rushed in when Palmer is a quality starter. I'd like to see him learn and play down the road with Palmer starting.
Exact same post._________________
SaveourSonics wrote:
Yea, RaiderX wins. We can all just top acting like this is a matter of opinion. MY GOD. |
defmodule Mobilizon.Users.Setting do
@moduledoc """
Module to manage users settings
"""
use Ecto.Schema
import Ecto.Changeset
alias Mobilizon.Users.{NotificationPendingNotificationDelay, User}
@type t :: %__MODULE__{
timezone: String.t(),
notification_on_day: boolean,
notification_each_week: boolean,
notification_before_event: boolean,
notification_pending_participation: NotificationPendingNotificationDelay.t(),
user: User.t()
}
@required_attrs [:user_id]
@optional_attrs [
:timezone,
:notification_on_day,
:notification_each_week,
:notification_before_event,
:notification_pending_participation
]
@attrs @required_attrs ++ @optional_attrs
@primary_key {:user_id, :id, autogenerate: false}
schema "user_settings" do
field(:timezone, :string)
field(:notification_on_day, :boolean)
field(:notification_each_week, :boolean)
field(:notification_before_event, :boolean)
field(:notification_pending_participation, NotificationPendingNotificationDelay,
default: :none
)
belongs_to(:user, User, primary_key: true, type: :id, foreign_key: :id, define_field: false)
timestamps()
end
@doc false
def changeset(setting, attrs) do
setting
|> cast(attrs, @attrs)
|> validate_required(@required_attrs)
end
end
|
The Daisy Hill Puppy Farm
Daisy (my Daisy) is (not surprisingly) a fan of Snoopy because he was born at the Daisy Hill Puppy Farm. (I’ve tried to explain that the Farm was named long before Daisy was born, but she doesn’t quite grasp that concept.)
Mr Schultz, creator of Peanuts, clearly didn’t know about puppy mills when he was creating the story of Snoopy’s adoption – because the Farm looks nothing like the puppy mill operations we see today. Snoopy was able to be raised with his mother and siblings in a ‘free range’ environment which included a healthy buffet for dinner and musical interludes…
This YouTube video shows what the Daisy Hill Puppy Farm looked like:
Wouldn’t it be wonderful if all puppies were raised in these conditions? |
1. Field of the Invention
The invention relates to a cholesteric liquid crystal composition which reflects light of a specific wavelength in the vicinity of room temperature and body temperature and uses thereof.
2. Description of the Related Art
A cholesteric liquid crystal molecule has a spiral structure in a liquid crystal state. Accordingly, when a cholesteric liquid crystal phase is irradiated with light, it reflects a circular polarizing light of a specific wavelength corresponding to a spiral rotational direction of the liquid crystal molecule and a length of the pitch. For example, when irradiated with a visible light, it reflects selectively lights having wavelengths of blue, green, yellow and red corresponding to a length of a pitch in the liquid crystal. The color tones thereof are different from those of pigments and dyes which take on colors by absorption of lights and have a visual dependency in which a color tone changes according to viewing angles. Further, a length of a pitch in cholesteric liquid crystal can be controlled by temperature and the kind of compounds, and therefore it can selectively reflect not only visible lights but also lights of near infrared and ultraviolet regions.
There have been materials which selectively reflect lights of various wavelengths in a broad wavelength region making use of the characteristics of the cholesteric liquid crystal. They are, for example, liquid crystal pigments, coating materials, spray inks, print inks, cosmetics, printed matters for preventing counterfeit, ornamental articles and the like. Further, they are proposed as well for polarizing plates in optical devices such as liquid crystal displays and holographic devices, compensation plates, optical films such as color filters and the like. In the case of a cholesteric liquid crystal pigment which is an existing material, flake-shaped cholesteric liquid crystal polymers and microencapsulated cholesteric liquid crystal are used. The uses thereof include coating materials for cars, cosmetic ingredients and the like.
JP S61-1015 B/1986 (Patent Document 1; JP S56-92836 A/1981) describes that an optically active menthol compound is used as an additive for shortening a pitch of a liquid crystal composition without extremely reducing a clearing point of the composition. Further, the uses of such cholesteric liquid crystal material include display parts of thermometers, wrist watches and calculators.
JP S63-34918 B/1988 (Patent Document 2; JP S57-40581 A/1982) describes that an L-menthol compound is used for a component of a guest-host liquid crystal display as a pitch controlling agent.
JP H16-137158 A/2004 (Patent Document 3) describes that an optically active menthol compound as a chiral dopant for a liquid crystal composition which is used as a liquid crystal display unit is a material maintaining a lower viscosity as compared with those of other chiral agents such as cholesterol derivatives and the like.
Examples of applications of liquid crystal materials in which a color of the material is changed irreversibly by temperature to inks are described in GB2280681A (Patent Document 4; U.S. Pat. No. 5,705,093), and a thermochromic liquid crystal material including an optically active menthol derivative and a nematic liquid crystal material is disclosed therein as the above liquid crystal material. Further, the possibility of application thereof to cosmetics such as lip rouges, eye shadows and the like making use of such thermochromic characteristics is indicated as well in Patent Document 4.
When a cholesteric material is used for application particularly in cosmetic ingredients coated on lips and skins in the cosmetic field, a material showing a cholesteric reflection color in the vicinity of room temperature and body temperature is required. Red to purple, preferably red to yellow colors are required to be developed in a temperature range in the vicinity of 0 to 60° C., particularly preferably 20 to 40° C. As described above, a range of developed color versus temperature is required to be controlled in order to allow a cholesteric liquid crystal material to exhibit an effect of aesthetic decoration in cosmetic use.
A mixing example of Mixture B of three components which has a clearing point of 91.1° C. and a menthol derivative is shown in Example 3 of Patent Document 4, and a composition example of nine components including two kinds of menthol derivatives is shown in Example 5. However, a range of developed color versus a cholesteric liquid crystal phase area and temperature is not described, and informations which can be applied to materials for cosmetic ingredients are not disclosed. |
At least here in the States, Professional Insurance is not that expensive. The last time I checked, it was less than $15 dollars per month for Business Liability for up to $1mill, I think that's the minimum. But chances are you probably won't ever need it.
Some clients include a Professional Insurance clause in their Agreements, but it's usually there for Language Vendors not Freelancers. I've only seen these clauses 2 or 3 times, and in all cases, I was able to waive the clause without any problem.
Of course, you would need to ask your client, and it also depends on the kind of translations you do; but as a freelancer, you probably don't need this kind of insurance.
I hope that helped,
Claudia
Subject:
Comment:
The contents of this post will automatically be included in the ticket generated. Please add any additional comments or explanation (optional)
Claudia is right, you probably don't need - just watch what kind of legalese you sign. In any event, you seem to be putting the horse in front of the carriage here. Start you business first, develop your client base, see how it goes - and only then worry about insurance, if you think it may make sense. Good luck.
Subject:
Comment:
The contents of this post will automatically be included in the ticket generated. Please add any additional comments or explanation (optional)
Jon ReynoldsUnited Kingdom Local time: 05:18Member (2007) German to English
TOPIC STARTER
thanks
Feb 19, 2008
Thanks both for your help. I am starting to get a steady stream of work and have a major contract on the go at the moment which is why I started thinking of the "when things go wrong" scenario. Good to hear that insurance is probably not really required.
Jon
Subject:
Comment:
The contents of this post will automatically be included in the ticket generated. Please add any additional comments or explanation (optional)
It is true that you probably won't need it ever. But 'probably' is the key word. The whole point about insurance is to protect yourself against highly improbable events that you cannot afford to pay for -- events such as your house burning down, crashing into another car and injuring the occupants, or your life-threatening mistranslation in a user guide. There is a current case where a car manufacturer had to pay out damages years after the mistranslated user guide that directly led to the accident.
Another sobering thought is that following recent legislation in the UK, you need to continue insurance for 15 years after you stop translating or retire. After 15 years, you cannot be sued. Until then, you can.
Having said that, you need to do a risk assessment based on the sort of work you do. For example, I avoid all legal or medical work, and stick to a mix of relatively safe work much like yours. Then Claudia's advice might be worth taking.
Subject:
Comment:
The contents of this post will automatically be included in the ticket generated. Please add any additional comments or explanation (optional)
Heike Behl, Ph.D.United States Local time: 21:18Member (2003) English to German + ...
Country-specific?
Feb 19, 2008
When I checked with a US company a while ago, I was told that the insurance was country-specific and would only cover clients in the US. For my non-US clients I would need a separate insurance for each country... Impossible!
Since I looked into it mainly because a German agency was requiring it, I never did any further research into whether that's commonly true or not. But the company was the one that offers discount to ATA members, so you'd think they're using pretty much standard practices and knew what they were talking about.
Has anybody any more definite info in this regard?
Subject:
Comment:
The contents of this post will automatically be included in the ticket generated. Please add any additional comments or explanation (optional)
This is a subject that comes up periodically, and the general opinion is that Liability Insurance in our profession is not a big priority, but some reccomend it "just in case". While it is good to be safe and not sorry, I always ask this same question whenever this subject appears:
Does anyone know of a case where a translator has ever been sued over a translation? (sucessfully or unsucessfully)
So far no one has ever come forth with a single case.
Still, I would ask it again.
Subject:
Comment:
The contents of this post will automatically be included in the ticket generated. Please add any additional comments or explanation (optional)
The subject of professional liability insurance has been discussed often. But regardless of whether you decide to get it, you should have insurance for ordinary things, such as to cover you if a visitor to your business trips over a toy your child left in the yard. (In the US, some companies will explicitly exclude this sort of thing from your ordinary homeowner's policy if you run a business out of your home.)
I'd recommend a chat with an insurance agent.
Subject:
Comment:
The contents of this post will automatically be included in the ticket generated. Please add any additional comments or explanation (optional)
Like Jon, i've always felt that I probably ought to have professional liability insurance.
However, when I've looked into it over here in France, the various insurance brokers I've spoken to weren't really able to advise me.
Amongst other things, I was told that a standard professional liability policy would not cover me for indirect or consequential losses. So, for example, if due to a mistranslation of mine, a large and very expensive print job had to be re-run — the cost of that would not be covered!
Fat lot of good that is then!
I did hear tell that the SFT had an insurance link, but apparently it only led to a general insurance broker, so I didn't bother to investigate further...
And if insurance is also going to be territory-specific, then with my clients all round the globe, it's going to be a non-starter anyway!
All I can say is: let them sue me, they won't be able to get blood out of a stone — and I haven't got a bean for them to take from me!
Subject:
Comment:
The contents of this post will automatically be included in the ticket generated. Please add any additional comments or explanation (optional)
But regardless of whether you decide to get it, you should have insurance for ordinary things, such as to cover you if a visitor to your business trips over a toy your child left in the yard.
I got a letter from my accountant recently on another topic (my business figures) and then he stuck a sentence on the end of the letter advising me to "urgently take out third party liability insurance". However, he didn't give any reason for his recommendation, and I am not terribly fond of receiving other people's good ideas about how I should spend my money.
Astrid
Subject:
Comment:
The contents of this post will automatically be included in the ticket generated. Please add any additional comments or explanation (optional)
Heike Behl, Ph.D.United States Local time: 21:18Member (2003) English to German + ...
interesting article
Feb 20, 2008
I've always wondered whether a translator could ever be held financially responsible for any damages caused by a less than perfect translation as long as the translator was not negligent in any way. I.e. if there was one typo severe enough to have a brochure re-printed, they would have to prove that this typo was caused by the translator's negligence - apart from the fact that anything going to print should have been proofread by a separate entity anyways, relieving the translator from that burden.
Generally, I don't think it would be any easy claim to make against an otherwise conscientious translator.
Cf. this article:
Insurance is purchased to protect against losses, and a major source of loss, especially in this litigious society, is legal liability. Legal liability is the liability of a party imposed by a court for its actions or, in some case, inactions, and for which the courts will award pecuniary damages as a form of redress. A legal wrong is either a violation of a person’s rights or the failure to perform a legal duty for a party.
Legal liability arises from 3 general classes of legal wrongs: crime, tort, and breach of contract. Crime is a wrong in which a person intentionally inflicts injury, or takes something from another, such as murder, robbery, rape, theft, and so on. Torts are legal or civil wrongs committed against people or organizations, causing them a loss. Intentional torts are willful acts or the willful failure to act when required to do so that causes injury to someone else. Crime is a specific type of intentional tort that causes physical harm or loss, such as murder, rape, or theft. Other types of intentional torts include slander and libel, patent infringement, and false imprisonment. Torts result either because the tortfeasor, who is the one who commits the tort, is either negligent in his duties which arises out of law and not contract, causing someone else a loss, or causes a loss through his actions. For example, causing an auto accident, or failure to make a safe product are torts. Breach of contract is the lack of performance by a party to another to satisfy a contract that the parties agreed to.
I guess we can exclude crime and breach of contract here - unless the translator has actually signed a contract where he/she promises a 100% perfect translation... That leaves tort as the only possible argument.
Negligence
Negligence is the failure to exercise the required amount of care to prevent injury to others. For example, if you cause an accident that injures someone or damages their vehicle because you were driving at an unsafe speed, then you could be sued for negligence.
In some cases, the law imposes absolute liability (aka strict liability) on specific parties without regard to fault, and, therefore, obviates the need to prove fault in court. For instance, manufacturers are held strictly liable for defective products that they manufacture.
Sometimes, the law designates other parties as being responsible, whether they are or not. Imputed negligence results in vicarious liability, where the principal is responsible for the acts of his agents. For example, employers have vicarious liability for the actions of their employees. If an employee injures someone in the course of employment, then it doesn’t matter whether the employer could have done anything to prevent it—the employer will be held liable regardless. Other instances of imputed negligence is through the effect of the family purpose doctrine that holds parents responsible for the negligent acts of their children, or the dram shop law, which holds the seller of alcoholic beverages liable for drunken patrons. If a patron drives after drinking at a tavern, and subsequently kills or injures someone with his vehicle, then the tavern owner can be held liable.
Sometimes, the act itself determines negligence. Under the doctrine of res ipsa loquitur, (Latin term for “the thing speaks for itself”), there are some actions so obviously negligent that the law presumes negligence, such as when a surgeon operates on the wrong side of the body, and the defendant, in such cases, must prove that he wasn’t negligent.
Insurance can be purchased to protect against lawsuits that arise from strict liability and from negligence. However, all insurance contracts exclude intentional torts by the insured, since the insured can easily prevent such torts, and because, in general, intentional torts by the insured are not insurable risks.
Requirements for Negligence
Most cases of negligence cannot be determined absolutely, for it depends on many factors. The main measure used to determine whether an act was negligent is to consider what a reasonably prudent person would do, given the age and knowledge of the tortfeasor, and other relevant factors.
Before a court will award damages, the presumed negligence must satisfy 4 requirements:
1. there must be a legal duty to perform or to use reasonable care;
2. there must have been a failure to perform that duty; [i.e. if the translation was proofread and spellchecked by the translator and yet some error remained unnoticed, the translator cannot be deemed negligent.]
3. the plaintiff must have suffered an injury or a loss;
4. and the negligent act must have been the proximate cause of the injury. The proximate cause is a cause that directly caused the loss or suffering; if the proximate cause didn’t happen, then the harm would not have happened.
All 4 elements of negligence must be present before a court will award damages.
Defenses Against Negligence
There are various factors that can either prevent a plaintiff from collecting damages or that will reduce the amount awarded.
Contributory negligence is negligence that is caused by both plaintiff and defendant. If the plaintiff contributed to his injury, then, in some states, the plaintiff will be prevented from collecting any damages.
Comparative negligence allows the plaintiff to collect some damages, but it will be reduced by the amount by which the plaintiff contributed to his own injury. There are 3 major rules, which differ according to state law and according to the amount of contributory negligence, that determine the amount that the plaintiff can collect.
[...]
The last clear chance rule modifies comparative negligence by allowing the plaintiff to collect damages from the defendant, even if the plaintiff contributed to his injury, if the defendant had a last clear chance to prevent the injury. In other words, could the defendant have prevented the injury regardless of the plaintiff's negligence? If the answer is yes, then the plaintiff will still be able to collect regardless of comparative negligence.
Finally, there is the assumption of risk—one assumes risk by engaging in an activity that is inherently risky, and, therefore, should not be allowed to collect damages if an injury results by engaging in the activity. Thus, if one plays racquetball without wearing goggles, and her opponent hits the ball and injures her eye, she will be prevented from collecting damages from her opponent, because by playing racquetball without wearing goggles, she assumed the risk that she will suffer an eye injury or even lose an eye while playing.[couldn't one count translation as a "risky" activity? Unless there is an independent, highly qualified proofreader (and even then), there is a good chance that a typo, a somewhat ambiguous translation etc. remains unnoticed. I.e. unless the translator him/herself is responsible for the final proofing, he/she's off the hook, right?]
I did hear tell that the SFT had an insurance link, but apparently it only led to a general insurance broker, so I didn't bother to investigate further...
Hi Tony,
As is the case for other professional organizations, the SFT does not make detailed information on its group insurance packages (health + liability) available to the general public on its website. Members, however, who log on to the member section of the site have access to the contracts, details and subscription information.
Should you wish further information on these insurance options, please feel free to contact me privately.
Cheers,
Patricia
Subject:
Comment:
The contents of this post will automatically be included in the ticket generated. Please add any additional comments or explanation (optional)
It certainly wouldn't come under tort. I've only studied law, never practised but this issue belongs to contract law maybe commercial too. Damages is a difficult and quite unpredictable area in English law. Your mistake would be considered in the light of the whole translation in terms of its importance and damages would be taken from there. If you knew that it was going to be printed then you may be held liable to some extent, but if you did not know then you may not. But this is all very difficult to say because in theory whether or not your work is going to be published shouldn't affect its quality. In England there would need to be a bit of case law to get a better insight. I'm sure there must be some tucked away somewhere but its never seen the light.
I would like to take out insurance here in Spain but I've yet to find an insurance broker who can help me. Translation agencies must by law carry insurance so I think I might attack the question from this angle on my next stint. I've contacted a couple of English insurance companies and they wouldn't insure on a Europe-wide scale. That's what they told me when they had stopped laughing, "just in case you make a booboo in one of your translations!".
Subject:
Comment:
The contents of this post will automatically be included in the ticket generated. Please add any additional comments or explanation (optional)
Nikki GrahamUnited Kingdom Local time: 05:18Member (2003) Spanish to English
100% perfect translation guarantee
Feb 20, 2008
Heike Behl, Ph.D. wrote:
I guess we can exclude crime and breach of contract here - unless the translator has actually signed a contract where he/she promises a 100% perfect translation...
This discussion is extremely interesting. I don't have insurance, but have been thinking about it, especially since I passed a test to work for an agency here in the UK and they required a policy to cover £1 million, and a guarantee with every translation that it was 100% perfect. I haven't actually ever worked for them as I don't like the conditions, especially having to sign a guarantee. After all, I might think that my work is perfect when I hand it in, but that, unfortunately, doesn't mean it always is..., so I could, therefore, only ever sign a guarantee that states my work is 100% perfect to the best of my knowledge and belief.
What are others' views on this? Is asking for a guarantee like this standard practice? Would an insurance policy cover you if you have signed a guarantee stating that your work is perfect anyway?
Subject:
Comment:
The contents of this post will automatically be included in the ticket generated. Please add any additional comments or explanation (optional)
The first time I was given a document like that, I decided to search the boards for more information. I don't remember if I posted the question or if somebody else had, but another colleague mentioned that such kind of insurance is only required for language vendors (agencies) NOT translators. I talked to somebody from the agency that had issued the Service Agreement (however it was called), and confirmed this. She said that they use just one Agreement for both freelancers and vendors, and that translators could add a waiver for that particular clause. I ended up doing the same thing with two more clients of mine, one agency and one direct client, who said basically the same thing: not for freelancers, add a waiver.
I'm not urging anybody not to get Liability insurance, I'm just saying that there's a possibility that such a requirement doesn't apply to us translators. The best thing is to ask the client.
When I requested information about Business Liability, it turned out that I could get Professional Insurance as a part of a very good package. I don't remember the exact terms, but it included Loss of income and Medical expenses in case of personal and material damage; Equipment damage, Theft, etc.; Business Liability (customizable) for up to 1 million; and probably other things I can't remember now. The premium was around 20 dollars with a deductible, I don't remember how much. But I thought it was a good deal.
About the "100% perfect translation" requirement, that's just ridiculous. I would never sign such a thing.
Subject:
Comment:
The contents of this post will automatically be included in the ticket generated. Please add any additional comments or explanation (optional)
Translation Office 3000 is an advanced accounting tool for freelance translators and small agencies. TO3000 easily and seamlessly integrates with the business life of professional freelance translators.
Join this translator’s group buy brought to you by ProZ.com and buy SDL Trados Studio 2017 Freelance for only €415 / $495 / £325 / ¥60,000
You will also receive FREE access to our getting started eLearning program! |
Akamai Technologies, Inc. (NASDAQ: AKAM) the leading global service provider for accelerating content and business processes online, today announced it will be working with eTouch Systems Corp. to deliver content from the U.S. National Aeoronautics and Space Administration Web portal (www.nasa.gov) just in time for the space agency's Deep Impact spacecraft mission, which is set to launch a projectile into the surface of comet Tempel 1 during the Fourth of July holiday weekend.
NASA will be Webcasting live a pre-impact briefing at 1 p.m. EDT on July 1 and a pre-impact update at 1 p.m. EDT on July 3. The expected time of impact is 1:52 a.m. EDT July 4. A post-impact briefing will be held at 4 a.m. July 4. A post-impact press conference will follow at 2 p.m. EDT July 4. All briefings and press conferences will be streamed online at www.nasa.gov by Akamai.
Web viewers can visit NASA's Deep Impact viewer by clicking http://deepimpact.jpl.nasa.gov/home/index.html to see photos from a disc-shaped copper projectile aimed directly into the oncoming path of the comet, blasting a crater through the comet's surface. Scientists will study the debris from the impact for clues about the nature of comets and the early development of the solar system.
eTouch Systems, which provides NASA with its Web content management system, teamed with Akamai to provide a broad suite of content delivery services for the space agency. A robust global platform is required since these types of events such as the Deep Impact mission typically generate high volumes of traffic.
For example, there have been more than 23 billion hits to NASA's Web portal since the twin Mars Rover missions landed on the Red Planet in January of 2004. Since that time, NASA has experienced 200 million visitor sessions viewing more than 2.3 billion pages. The average site visitor spends more than 8 minutes browsing across 14 pages during each visit to the NASA site.
"As the Deep Impact event lights up the darkened skies and fires the imagination of people around the world, down here on Earth we will be working with our partner eTouch to ensure that NASA site visitors can continue to access the graphically-rich content and view the live streamed press conference following the event," said Keith E. Johnson, vice president of public sector, Akamai. "By combining eTouch's elegant content management solution with Akamai's globally distributed, on-demand network, NASA can focus on what it does best - exploring the heavens and inspiring a new generation of space explorers."
"We have found that Akamai's architecture has the robustness to meet the rigorous requirements that organizations like NASA have come to expect," said David Valliere, federal program manager for eTouch. "We are confident that together we can ensure uninterrupted access to NASA's Web portal so that viewers worldwide can see the incredible Deep Impact mission unfold on the Internet."
The Deep Impact comet collision should be visible with the aid of binoculars to millions of people here on Earth in the early morning hours of U.S. Independence Day. Viewers in the United States living west of the Mississippi and in Hawaii, and people in New Zealand will have the best opportunity to witness the event.
About Akamai
Akamai® is the leading global service provider for accelerating content and business processes online. More than 1,300 organizations have formed trusted relationships with Akamai, improving their revenue and reducing costs by maximizing the performance of their online businesses. Leveraging the Akamai EdgePlatform, these organizations gain business advantage today, and have the foundation for the emerging Web solutions of tomorrow. Akamai is "The Trusted Choice for Online Business." For more information, visit www.akamai.com.
The release contains information about future expectations, plans and prospects of Akamai's management that constitute forward-looking statements for purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors including, but not limited to, the effects of any attempts to intentionally disrupt our services or network by unauthorized users or others, failure to have available sufficient transmission capacity, a failure of Akamai's network infrastructure and other factors that are discussed in the Company's Annual Report on Form 10-K, quarterly reports on Form 10-Q, and other documents periodically filed with the SEC.
We're Social
Akamai secures and delivers digital experiences for the world’s largest companies. Akamai’s intelligent edge platform surrounds everything, from the enterprise to the cloud, so customers and their businesses can be fast, smart, and secure. Top brands globally rely on Akamai to help them realize competitive advantage through agile solutions that extend the power of their multi-cloud architectures. Akamai keeps decisions, apps, and experiences closer to users than anyone — and attacks and threats far away. Akamai’s portfolio of edge security, web and mobile performance, enterprise access, and video delivery solutions is supported by unmatched customer service, analytics, and 24/7/365 monitoring. To learn why the world’s top brands trust Akamai, visit www.akamai.com, blogs.akamai.com, or @Akamai on Twitter. You can find our global contact information at www.akamai.com/locations. Published 09/18. |
Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1.
The vanilloid receptor-1 (VR1) is a heat-gated ion channel that is responsible for the burning sensation elicited by capsaicin. A similar sensation is reported by patients with esophagitis when they consume alcoholic beverages or are administered alcohol by injection as a medical treatment. We report here that ethanol activates primary sensory neurons, resulting in neuropeptide release or plasma extravasation in the esophagus, spinal cord or skin. Sensory neurons from trigeminal or dorsal root ganglia as well as VR1-expressing HEK293 cells responded to ethanol in a concentration-dependent and capsazepine-sensitive fashion. Ethanol potentiated the response of VR1 to capsaicin, protons and heat and lowered the threshold for heat activation of VR1 from approximately 42 degrees C to approximately 34 degrees C. This provides a likely mechanistic explanation for the ethanol-induced sensory responses that occur at body temperature and for the sensitivity of inflamed tissues to ethanol, such as might be found in esophagitis, neuralgia or wounds. |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.