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The Rif1 protein, originally identified as a telomere-binding factor in yeast, has recently been implicated in DNA replication control from yeast to metazoans. Here, we show that budding yeast Rif1 protein inhibits activation of prereplication complexes (pre-RCs). This inhibitory function requires two N-terminal motifs, RVxF and SILK, associated with recruitment of PP1 phosphatase (Glc7). In G1 phase, we show both that Glc7 interacts with Rif1 in an RVxF/SILK-dependent manner and that two proteins implicated in pre-RC activation, Mcm4 and Sld3, display increased Dbf4-dependent kinase (DDK) phosphorylation in rif1 mutants. Rif1 also interacts with Dbf4 in yeast two-hybrid assays, further implicating this protein in direct modulation of pre-RC activation through the DDK. Finally, we demonstrate Rif1 RVxF/SILK motif-dependent recruitment of Glc7 to telomeres and earlier replication of these regions in cells where the motifs are mutated. Our data thus link Rif1 to negative regulation of replication origin firing through recruitment of the Glc7 phosphatase.	How does Rif1 regulate DNA replication?	Rif1 also interacts with Dbf4 in yeast two-hybrid assays, further implicating this protein in direct modulation of pre-RC activation through the DDK. Finally, we demonstrate Rif1 RVxF/SILK motif-dependent recruitment of Glc7 to telomeres and earlier replication of these regions in cells where the motifs are mutated. Our data thus link Rif1 to negative regulation of replication origin firing through recruitment of the Glc7 phosphatase.
Capnocytophaga canimorsus is a fastidious, slow-growing, gram-negative, rod-shaped bacterium that belongs to the normal oral flora of dogs and cats. Human septicemic infections are associated with a high mortality; most cases occur in immunocompromised patients with a history of dog bite. The fifth case of cat-associated septicemia caused by Capnocytophaga canimorsus is described. The six case reports presented here point out the characteristics reported previously: (a) cats are a source of human infection; (b) alcohol abuse is an important risk factor for the development of septicemic Capnocytophaga canimorsus infection; (c) septicemic infection often manifests with disseminated intravascular consumption coagulopathy or purpura; and (d) some cases of septicemia in humans result from pets that lick skin ulcers.	Which animal bite can cause Capnocytophaga canimorsus infection?	Capnocytophaga canimorsus is a fastidious, slow-growing, gram-negative, rod-shaped bacterium that belongs to the normal oral flora of dogs and cats. Human septicemic infections are associated with a high mortality; most cases occur in immunocompromised patients with a history of dog bite.
Single-cell prokaryotes represent a simple and primitive cellular life form. The identification of the essential genes of bacteria and the minimal genome for the free-living cellular life could provide insights into the origin, evolution, and essence of life forms. The principles, methodology, and recent progresses in the identification of essential genes and minimal genome and the creation of synthetic cells are reviewed and particularly the strategies for creating the minimal genome and the potential applications are introduced.	What is the minimal genome build?	The identification of the essential genes of bacteria and the minimal genome for the free-living cellular life could provide insights into the origin, evolution, and essence of life forms.
Morton's neuroma is a frequent cause of pain in the forefoot that commonly occurs in the third intermetatarsal space. It is a type of nerve compression syndrome which involves the common digital plantar nerves. The diagnosis is typically made on the basis of history and careful physical exam. Imaging procedures may be useful to diagnose an atypical case or postoperative recurrence. Conservative treatments are successful in most cases, but when they fail surgery may be considered.	What is Morton's Neuroma?	Morton's neuroma is a frequent cause of pain in the forefoot that commonly occurs in the third intermetatarsal space.
Immune-regulatory mechanisms are used by cancer to hide from the immune system. Advances and in-depth understanding of the biology of melanoma and its interaction with the immune system have led to the development of some of antagonistic antibodies to the programmed death 1 pathway (PD-1) and one of its ligands, programmed death ligand 1 (PD-L1), which are demonstrating high clinical benefit rates and tolerability. Blocking the immune-regulatory checkpoints that limit T-cell responses to melanoma upon PD-1/PD-L1 modulation has provided clinically validated targets for cancer immunotherapy. Combinations with other anti-melanoma agents may result in additional benefits. Nivolumab, pembrolizumab (formerly known as MK-3475 and lambrolizumab), and pidilizumab are anti-PD-1 antibodies in clinical development for melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancers, lymphoma, and several other cancers. Long-term survivors already have been reported with these therapies. In this review, we discuss the current state of anti-PD-1 agents, the evidence in the literature to support the combination of anti-PD-1 antibodies with other anti-cancer agents and discuss the future directions for rational design of clinical trials that keep on increasing the number of long-term survivors.	What is the target of a drug pidilizumab?	Nivolumab, pembrolizumab (formerly known as MK-3475 and lambrolizumab), and pidilizumab are anti-PD-1 antibodies in clinical development for melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancers, lymphoma, and several other cancers.
CD4 T cells, especially T-helper (Th) cells (Th1, Th2 and Th17) and regulatory T cells (Treg) play pivotal role in the pathogenesis of multiple sclerosis (MS), a demyelinating autoimmune disease occurring in central nervous system (CNS). Astragaloside IV (ASI, CAS: 84687-43-4) is one of the saponins isolated from Astragalus membranceus, a traditional Chinese medicine with immunomodulatory effect. So far, whether ASI has curative effect on experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and how it affects the subsets of CD4 T cells, as well as the underlying mechanism have not been clearly elucidated. In the present study, ASI was found to ameliorate the progression and hamper the recurrence of EAE effectively in the treatment regimens. It significantly reduced the demyelination and inflammatory infiltration of CNS in EAE mice by suppressing the percentage of Th1 and Th17 cells, which was closely associated with the inhibition of JAK/STAT and NF-κB signaling pathways. ASI also increased the percentage of Treg cells in spleen and CNS, which was accompanied by elevated Foxp3. However, in vitro experiments disclosed that ASI could regulate the differentiation of Th17 and Treg cells but not Th1 cells. In addition, it induced the apoptosis of MOG-stimulated CD4 T cells probably through modulating STAT3/Bcl-2/Bax signaling pathways. Together, our findings suggested that ASI can modulate the differentiation of autoreactive CD4 T cells and is a potential prodrug or drug for the treatment of MS and other similar autoimmune diseases.	Which human disease is experimental autoimmune encephalomyelitis (EAE) model for?	experimental autoimmune encephalomyelitis (EAE), an animal model of MS
Recently, we have demonstrated that sensory neurons of rat lumbar dorsal root ganglia (DRG) respond to hypoxia with an activation of endothelial nitric oxide (NO) synthase (eNOS) resulting in enhanced NO production associated with mitochondria which contributes to resistance against hypoxia. Extracellular calcium is essential to this effect. In the present study on rat DRG slices, we set out to determine what types of calcium channels operate under hypoxia, and which upstream events contribute to their activation, thereby focusing upon mitochondrial complex II. Both the metallic ions Cd2+ and Ni2+, known to inhibit voltage-gated calcium channels and T-type channels, respectively, and verapamil and nifedipine, typical blocker of L-type calcium channels completely prevented the hypoxic neuronal NO generation. Inhibition of complex II by thenoyltrifluoroacetone at the ubiquinon binding site or by 3-nitropropionic acid at the substrate binding site largely diminished hypoxic-induced NO production while having an opposite effect under normoxia. An additional blockade of voltage-gated calcium channels entirely abolished the hypoxic response. The complex II inhibitor malonate inhibited both normoxic and hypoxic NO generation. These data show that complex II activity is required for increased hypoxic NO production. Since succinate dehydrogenase activity of complex II decreased at hypoxia, as measured by histochemistry and densitometry, we propose a hypoxia-induced functional switch of complex II from succinate dehydrogenase to fumarate reductase, which subsequently leads to activation of voltage-gated calcium channels resulting in increased NO production by eNOS.	Does nifedipine inhibit L-type calcium channels?	Both the metallic ions Cd2+ and Ni2+, known to inhibit voltage-gated calcium channels and T-type channels, respectively, and verapamil and nifedipine, typical blocker of L-type calcium channels completely prevented the hypoxic neuronal NO generation.
The viral gene for the killer protein 4 (KP4) has been explored for its antifungal effect in genetically modified wheat to defeat specifically the seed-transmitted smut and bunt diseases. In vitro both important seed-transmitted diseases of wheat, loose smut (Ustilago tritici) and stinking smut (Tilletia caries), are susceptible to KP4, whereas all other organisms tested so far proved to be not susceptible to KP4. For studies in planta we used stinking smut as a model fungus. In greenhouse experiments, two KP4-transgenic wheat lines showed up to 30% lower symptom development as compared to the nontransgenic control. As the last step in the proof of concept, field-testing has shown for the first time increased fungal resistance of a transgene in wheat. Due to its specificity against smuts and bunts, KP4 presents a very low risk to humans and the environment. Field-testing in Switzerland is regulated by a strong law, which for research is acceptable if legally and scientifically correctly applied.	What is the function of the viral KP4 protein?	The viral gene for the killer protein 4 (KP4) has been explored for its antifungal effect
Mutations of the gene SOD-1, which encodes the enzyme copper-zinc superoxide dismutase, occur in patients with a familial form of amyotrophic lateral sclerosis (ALS). We investigated 71 families with more than one individual affected by ALS for clinical features and SOD-1 mutations. Mutations were identified in 14 families, indicating the presence of SOD-1 mutations in around 20% of this population. There were 10 different heterozygote missense point mutations in eight different codons, and a novel two-base frameshift insertion (132insTT), which leads to substitution of aspartic acid for glutamic acid at codon 132, and a premature stop codon at 133, with predicted truncation of the protein. SOD enzyme activity was reduced to around 50% of normal in individuals with SOD-1 mutations, and may be a useful predictor for the presence of these mutations. A predilection for disease onset in the lower limbs appears to be a distinguishing feature of familial ALS with SOD-1 mutations, and accords with findings in transgenic mouse models. In general, the finding of an SOD-1 mutation does not accurately predict a prognosis or disease severity.	Can Amyotrophic Lateral Sclerosis (ALS) be associated with a mutation of the Super Oxide Dismutase 1 (SOD) gene?	A predilection for disease onset in the lower limbs appears to be a distinguishing feature of familial ALS with SOD-1 mutations, and accords with findings in transgenic mouse models.
Tissue samples in biobanks are typically formalin-fixed and paraffin-embedded (FFPE), in which form they are preserved for decades. It has only recently been shown that proteins in FFPE tissues can be identified by mass spectrometry-based proteomics but analysis of post-translational modifications is thought to be difficult or impossible. The filter aided sample preparation (FASP) method can analyze proteomic samples solubilized in high concentrations of SDS and we use this feature to develop a simple protocol for FFPE analysis. Combination with simple pipet-tip based peptide fractionation identified about 5000 mouse liver proteins in 24 h measurement time-the same as in fresh tissue. Results from the FFPE-FASP procedure do not indicate any discernible changes due to storage time, hematoxylin staining or laser capture microdissection. We compared fresh against FFPE tissue using the SILAC mouse and found no significant qualitative or quantitative differences between these samples either at the protein or the peptide level. Application of our FFPE-FASP protocol to phosphorylation and N-glycosylation pinpointed nearly 5000 phosphosites and 1500 N-glycosylation sites. Analysis of FFPE tissue of the SILAC mouse revealed that these post-translational modifications were quantitatively preserved. Thus, FFPE biobank material can be analyzed by quantitative proteomics at the level of proteins and post-translational modifications.	Is it possible to determine the proteome of a formalin fixed and paraffin embedded (FFPE) tissue?	Thus, FFPE biobank material can be analyzed by quantitative proteomics at the level of proteins and post-translational modifications.
The multicentre phase III CORAL study aims to guide choice of salvage chemotherapy in diffuse large B-cell lymphoma (DLBCL) and assess the role of rituximab maintenance after autologous stem cell transplantation (ASCT). Patients are first randomised between ICE (ifosfamide, carboplatin, etoposide) and DHAP (dexamethasone, ara-C and cisplatin), both combined with rituximab (R-ICE or R-DHAP). After three courses, responders are treated by ASCT with BEAM. A second randomisation then allocates patients to maintenance treatment with rituximab 375 mg/m(2), one injection every 2 months six times, or observation. Accrual to the study is now proceeding well and the planned 400 patients are likely to be enrolled within the next 1.5 years. Results to date are very preliminary but suggest encouraging rates of response. However, they also indicate that initial exposure to rituximab may increase the difficulty of salvaging patients who fail first-line therapy.	List drugs included in the DHAP-R chemotherapy regiment.	Patients are first randomised between ICE (ifosfamide, carboplatin, etoposide) and DHAP (dexamethasone, ara-C and cisplatin), both combined with rituximab (R-ICE or R-DHAP).
Recent human genetic discoveries have increased our understanding of rheumatoid arthritis (RA) susceptibility. Genome-wide association studies have expanded the number of validated RA risk loci beyond HLA-DRB1 "shared epitope" alleles to include additional major histocompatibility complex (MHC) risk alleles and more than 10 regions outside the MHC. The newly discovered risk alleles are common in the general population, have a modest effect on RA risk, and together explain less than 5% of the variance in disease risk. Whereas the actual causal mutation and causal gene for most loci remain to be determined, these studies are beginning to reveal general themes: many risk loci are associated with other autoimmune diseases; many genes fall within discrete biological pathways (eg, the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway); and human genetics can group diseases into clinically meaningful subset categories (eg, presence or absence of autoantibodies). This review discusses recent RA genetic discoveries in terms of their potential to improve patient care.	How many genes outside of the MHC locus have been genetically associated to Rheumatoid Arthritis through GWAS?	Genome-wide association studies have expanded the number of validated RA risk loci beyond HLA-DRB1 "shared epitope" alleles to include additional major histocompatibility complex (MHC) risk alleles and more than 10 regions outside the MHC.
Based on the anatomical and functional commonality between singing and speech, various types of musical elements have been employed in music therapy research for speech rehabilitation. This study was to develop an accent-based music speech protocol to address voice problems of stroke patients with mixed dysarthria. Subjects were 6 stroke patients with mixed dysarthria and they received individual music therapy sessions. Each session was conducted for 30 minutes and 12 sessions including pre- and post-test were administered for each patient. For examining the protocol efficacy, the measures of maximum phonation time (MPT), fundamental frequency (F0), average intensity (dB), jitter, shimmer, noise to harmonics ratio (NHR), and diadochokinesis (DDK) were compared between pre and post-test and analyzed with a paired sample t-test. The results showed that the measures of MPT, F0, dB, and sequential motion rates (SMR) were significantly increased after administering the protocol. Also, there were statistically significant differences in the measures of shimmer, and alternating motion rates (AMR) of the syllable /K$\inve$/ between pre- and post-test. The results indicated that the accent-based music speech protocol may improve speech motor coordination including respiration, phonation, articulation, resonance, and prosody of patients with dysarthria. This suggests the possibility of utilizing the music speech protocol to maximize immediate treatment effects in the course of a long-term treatment for patients with dysarthria.	Which are the major types of the motor speech disorder dysarthria?	address voice problems of stroke patients with mixed dysarthria
Enzymes required for de novo lipogenesis are induced in mammalian liver after a meal high in carbohydrates. In addition to insulin, increased glucose metabolism initiates an intracellular signaling pathway that transcriptionally regulates genes encoding lipogenic enzymes. A cis-acting sequence, the carbohydrate response element (ChoRE), has been found in the promoter region of several of these genes. ChREBP (carbohydrate response element-binding protein) was recently identified as a candidate transcription factor in the glucose-signaling pathway. We reported that ChREBP requires the heterodimeric partner Max-like factor X (Mlx) to bind to ChoRE sequences. In this study we provide further evidence to support a direct role of Mlx in glucose signaling in the liver. We constructed two different dominant negative forms of Mlx that could dimerize with ChREBP but block its binding to DNA. When introduced into hepatocytes, both dominant negative forms of Mlx inhibited the glucose response of a transfected ChoRE-containing promoter. The glucose response was rescued by adding exogenous wild type Mlx or ChREBP, but not MondoA, a paralog of ChREBP that can also form a heterodimer with Mlx. Furthermore, dominant negative Mlx blocked the induction of glucose-responsive genes from their natural chromosomal context under high glucose conditions. In contrast, genes induced by the insulin and thyroid hormone-signaling pathways were unaffected by dominant negative Mlx. Mlx was present in the glucose-responsive complex of liver nuclear extract from which ChREBP was purified. In conclusion, Mlx is an obligatory partner of ChREBP in regulating lipogenic enzyme genes in liver.	Which are the major transcription factors regulating glycolysis in mammals?	ChREBP (carbohydrate response element-binding protein) was recently identified as a candidate transcription factor in the glucose-signaling pathway
The amino acid selenocysteine is encoded by UGA, usually a stop codon, thus requiring a specialized machinery to enable its incorporation into selenoproteins. The machinery comprises the tRNA(Sec), a 3'-UTR mRNA stem-loop termed SElenoCysteine Insertion Sequence (SECIS), which is mandatory for recoding UGA as a Sec codon, the SECIS Binding Protein 2 (SBP2), and other proteins. Little is known about the molecular mechanism and, in particular, when, where, and how the SECIS and SBP2 contact the ribosome. Previous work by others used the isolated SECIS RNA to address this question. Here, we developed a novel approach using instead engineered minimal selenoprotein mRNAs containing SECIS elements derivatized with photoreactive groups. By cross-linking experiments in rabbit reticulocyte lysate, new information could be gained about the SBP2 and SECIS contacts with components of the translation machinery at various translation steps. In particular, we found that SBP2 was bound only to the SECIS in 48S pre-initiation and 80S pretranslocation complexes. In the complex where the Sec-tRNA(Sec) was accommodated to the A site but transpeptidation was blocked, SBP2 bound the ribosome and possibly the SECIS element as well, and the SECIS had flexible contacts with the 60S ribosomal subunit involving several ribosomal proteins. Altogether, our findings led to broadening our understanding about the unique mechanism of selenocysteine incorporation in mammals.	What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?	3'-UTR mRNA stem-loop termed SElenoCysteine Insertion Sequence (SECIS)
BORIS (CTCFL) is the paralog of CTCF (CCCTC-binding factor; NM_006565), a ubiquitously expressed DNA-binding protein with diverse roles in gene expression and chromatin organisation. BORIS and CTCF have virtually identical zinc finger domains, yet display major differences in their respective C- and N-terminal regions. Unlike CTCF, BORIS expression has been reported only in the testis and certain malignancies, leading to its classification as a "cancer-testis" antigen. However, the expression pattern of BORIS is both a significant and unresolved question in the field of DNA binding proteins. Here, we identify BORIS in the cytoplasm and nucleus of a wide range of normal and cancer cells. We compare the localization of CTCF and BORIS in the nucleus and demonstrate enrichment of BORIS within the nucleolus, inside the nucleolin core structure and adjacent to fibrillarin in the dense fibrillar component. In contrast, CTCF is not enriched in the nucleolus. Live imaging of cells transiently transfected with GFP tagged BORIS confirmed the nucleolar accumulation of BORIS. While BORIS transcript levels are low compared to CTCF, its protein levels are readily detectable. These findings show that BORIS expression is more widespread than previously believed, and suggest a role for BORIS in nucleolar function.	Are CTCF and BORIS involved in genome regulation and cancer?	Unlike CTCF, BORIS expression has been reported only in the testis and certain malignancies, leading to its classification as a "cancer-testis" antigen.
LC, survival, and complication rates in our series are comparable to those in previous reports of radiosurgery for intracranial meningiomas. Also, LC rates with radiosurgery are at least comparable to those of surgical series for radiation-induced meningiomas. Radiosurgery is a safe and effective treatment option for radiation-induced intracranial tumors, most of which are typical meningiomas.	Can radiation induced meningiomas be treated with radiosurgery?	Also, LC rates with radiosurgery are at least comparable to those of surgical series for radiation-induced meningiomas
Duchenne and Becker muscular dystrophy (DBMD) are allelic, X-linked recessive, neuromuscular disorders characterized by progressive loss of muscle function. Despite technological advances in diagnostic genetic testing, the mean age at diagnosis (4.7 years) has remained unchanged for decades. The purpose of the study was to characterize parental perceptions of the diagnostic process and identify factors that influence the timeline. Data collection for this qualitative study consisted of six individual and five group interviews. Participants (N = 30) included Hispanic, non-Hispanic black, and non-Hispanic white parents whose son was diagnosed with DBMD. The "help-seeking behavior model" provided an analytical framework to analyze the data. Parents did not move through help-seeking stages unidirectionally as described in other studies. Delays existed at each stage. We identified personal, familial, social, cultural, and provider factors that impeded earlier diagnosis. These barriers prolonged movement through a stage or led families to repeat previous stages. Results should initiate debate among system administrators, patient advocates, and healthcare providers regarding which barriers may be most modifiable and which interventions may reduce the time to diagnosis and limit parental emotional distress.	What is usually the age of diagnosis in Duchenne muscular dystrophy?	ive loss of muscle function. Despite technological advances in diagnostic genetic testing, the mean age at diagnosis (4.7 years) has re
There was no clinical difference in the time interval to respiratory rate > or =10 breaths/min between naloxone 0.8 mg s.q. and naloxone 0.4 mg i.v. for the out-of-hospital management of patients with suspected opioid overdose. The slower rate of absorption via the s.q. route was offset by the delay in establishing an i.v.	Which medication should be administered when managing patients with suspected acute opioid overdose?	There was no clinical difference in the time interval to respiratory rate > or =10 breaths/min between naloxone 0.8 mg s.q. and naloxone 0.4 mg i.v. for the out-of-hospital management of patients with suspected opioid overdose.
Methotrexate's mechanism of action affects both the inflammatory and immunosuppressive aspects of response. Its kinetics are defined and include variable absorption, intracellular metabolism, and both renal and biliary excretion. Methotrexate is clearly effective in the treatment of rheumatoid arthritis and may be able to decrease the rate of formation of new bony erosions. It is also effective in psoriatic arthritis and is being used in a multiplicity of other rheumatic diseases. The most common toxicities ascribed to methotrexate are gastrointestinal (e.g. stomatitis) and central nervous system (e.g. headache, fatigue, malaise). Methotrexate-induced hepatic cirrhosis is less common in rheumatoid arthritis than previously thought, although its occurrence in psoriasis is probably higher than in rheumatoid arthritis. Haematological, renal and pulmonary toxicity occur, but are rare, while teratogenicity is well documented. A new and disturbing adverse event, pseudolymphomas are being reported at present.	Is methotrexate used for the treatment of Rheumatoid Arthritis (RA)?	Methotrexate is clearly effective in the treatment of rheumatoid arthritis and may be able to decrease the rate of formation of new bony erosions.
The NovoTTF™-100A system is a portable device that delivers intermediate frequency alternating electric fields (TTFields, tumor treating fields) through transducer arrays arranged on the scalp. An ongoing trial is assessing its efficacy for newly diagnosed glioblastoma multiforme (GBM) and it has been FDA-approved for recurrent GBM.The fields are believed to interfere with formation of the mitotic spindle as well as to affect polar molecules at telophase, thus preventing cell division. The position of the four arrays is unique to each patient and optimized based on the patient's imaging. We present three patients with GBM in whom the fields were adjusted at recurrence and the effects of each adjustment. We believe there may be a higher risk of treatment failure on the edges of the field where the field strength may be lower. The first patient underwent subtotal resection, radiotherapy with temozolomide (TMZ), and then began NovoTTF Therapy with metronomic TMZ. She had good control for nine months; however, new bifrontal lesions developed, and her fields were adjusted with a subsequent radiographic response. Over the next five months, her tumor burden increased and death was preceded by a right insular recurrence. A second patient underwent two resections followed by radiotherapy/TMZ and NovoTTF Therapy/TMZ. Six months later, two new distal lesions were noted, and he underwent further resection with adjustment of his fields. He remained stable over the subsequent year on NovoTTF Therapy and bevacizumab. A third patient on NovoTTF Therapy/TMZ remained stable for two years but developed a small, slow growing enhancing lesion, which was resected, and his fields were adjusted accordingly. Interestingly, the pathology showed giant cell GBM with multiple syncitial-type cells. Based on these observations, we believe that field strength may play a role in 'out of field' recurrences and that either the presence of a certain field strength may select for cells that are of a different size or that tumor cells may change size to avoid the effects of the TTFields.	Tumor-treating fields are effective for treatment of which cancers?	A second patient underwent two resections followed by radiotherapy/TMZ and NovoTTF Therapy/TMZ. Six months later, two new distal lesions were noted, and he underwent further resection with adjustment of his fields. He remained stable over the subsequent year on NovoTTF Therapy and bevacizumab. A third patient on NovoTTF Therapy/TMZ remained stable for two years but developed a small, slow growing enhancing lesion, which was resected, and his fields were adjusted accordingly.
DNA damage response and repair pathways are important barriers to carcinogenesis. Here, we show that promyelocytic leukaemia (PML, also known as TRIM19), involved in sensing DNA damage and executing homologous recombination repair, is down-regulated in non-tumour liver cells surrounding hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). No PML mutation or deletion was found in HBV-infected liver or HCC cells. Immunohistochemical analysis of liver biopsies from patients with breast or liver cancer and HBV reactivation after chemotherapy revealed PML up-regulation and HBV exacerbation in normal liver tissue in response to DNA damage (functional PML), PML down-regulation in HCC peritumour cells associated with high HBsAg accumulation and low HBV replication activity (suppressive PML), and heterogeneous nuclear PML expression in HCC cells that lost HBV DNA and HBsAg and were non-reactive to DNA damage (dysregulated PML). Loss of PML in HBsAg-transgenic mice promoted chromosome breaks in liver cells and accelerated the accumulation of body and liver fat and the development of a liver steatosis-dysplasia-adenoma-carcinoma sequence in an inflammation-independent and male-predominant manner, compared to PML knock-out or HBsAg-transgenic mice during the same time period. These results indicate that PML deficiency facilitates genomic instability and promotes HBsAg-related hepatocarcinogenesis, which also involves androgen and lipid metabolism. These findings uncover a novel PML link between HBV-related tumourigenesis, DNA repair, and metabolism.	Are defects in recombination repair involved in carcinogenesis?	damage response and repair pathways are important barriers to carcinogenesis.
The challenges of research into brain-computer interfaces (BCI) include significant individual differences in learning pace and in the effective operation of BCI devices. The use of neurofeedback training is a popular method of improving the effectiveness BCI operation. The purpose of the present study was to determine to what extent it is possible to improve the effectiveness of operation of sensorimotor rhythm-based brain-computer interfaces (SMR-BCI) by supplementing user training with elements modifying the characteristics of visual feedback. Four experimental groups had training designed to reinforce BCI control by: visual feedback in the form of dummy faces expressing emotions (Group 1); flashing the principal elements of visual feedback (Group 2) and giving both visual feedbacks in one condition (Group 3). The fourth group participated in training with no modifications (Group 4). Training consisted of a series of trials where the subjects directed a ball into a basket located to the right or left side of the screen. In Group 1 a schematic image a face, placed on the controlled object, showed various emotions, depending on the accuracy of control. In Group 2, the cue and targets were flashed with different frequency (4 Hz) than the remaining elements visible on the monitor. Both modifications were also used simultaneously in Group 3. SMR activity during the task was recorded before and after the training. In Group 3 there was a significant improvement in SMR control, compared to subjects in Group 2 and 4 (control). Differences between subjects in Groups 1, 2 and 4 (control) were insignificant. This means that relatively small changes in the training procedure may significantly impact the effectiveness of BCI control. Analysis of behavioural data acquired from all participants at training showed greater effectiveness in directing the object towards the right side of the screen. Subjects with the greatest improvement in SMR control showed a significantly lower difference in the accuracy of rightward and leftward movement than others.	What is a SMR based BCI?	sensorimotor rhythm-based brain-computer interfaces (SMR-BCI)
Since 1992 PredictProtein (https://predictprotein.org) is a one-stop online resource for protein sequence analysis with its main site hosted at the Luxembourg Centre for Systems Biomedicine (LCSB) and queried monthly by over 3,000 users in 2020. PredictProtein was the first Internet server for protein predictions. It pioneered combining evolutionary information and machine learning. Given a protein sequence as input, the server outputs multiple sequence alignments, predictions of protein structure in 1D and 2D (secondary structure, solvent accessibility, transmembrane segments, disordered regions, protein flexibility, and disulfide bridges) and predictions of protein function (functional effects of sequence variation or point mutations, Gene Ontology (GO) terms, subcellular localization, and protein-, RNA-, and DNA binding). PredictProtein's infrastructure has moved to the LCSB increasing throughput; the use of MMseqs2 sequence search reduced runtime five-fold (apparently without lowering performance of prediction methods); user interface elements improved usability, and new prediction methods were added. PredictProtein recently included predictions from deep learning embeddings (GO and secondary structure) and a method for the prediction of proteins and residues binding DNA, RNA, or other proteins. PredictProtein.org aspires to provide reliable predictions to computational and experimental biologists alike. All scripts and methods are freely available for offline execution in high-throughput settings.	Are there any tools that could predict protein structure considering amino acid sequence?	PredictProtein (https://predictprotein.org) is a one-stop online resource for protein sequence analysis
Acute necrotizing encephalopathy (ANE) presents in children after common viral infections. Most cases of ANE are non-familial and non-recurrent and have been mainly reported in Asian patients, although ANE affects children worldwide. Recently, missense mutations in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2) have been found in several families with familial or recurrent cases of ANE. We describe a Spanish family with familial and recurrent ANE without mutations in RANBP2. Mutations in RANBP2 are not the sole susceptibility alleles for familial or recurrent ANE.	Is Acute Necrotizing Encephalopathy (ANE) which typically affects young, healthy children usually triggered by exposure to air pollution?	Acute necrotizing encephalopathy (ANE) presents in children after common viral infections
Leishmania major causes leishmaniasis and is grouped within the Trypanosomatidae family, which also includes the etiologic agent for African sleeping sickness, Trypanosoma brucei. Previous studies on T. brucei showed that acyl carrier protein (ACP) of mitochondrial fatty acid synthase type 2 (FASII) plays a crucial role in parasite survival. Additionally, 3-oxoacyl-ACP synthase TbKASIII as well as TbHTD2 representing 3-hydroxyacyl-ACP dehydratase were also identified; however, 3-oxoacyl-ACP reductase TbKAR1 has hitherto evaded positive identification. Here, potential Leishmania FASII components LmjF07.0440 and LmjF07.0430 were revealed as 3-hydroxyacyl-ACP dehydratases LmHTD2-1 and LmHTD2-2, respectively, whereas LmjF27.2440 was identified as LmKAR1. These Leishmania proteins were ectopically expressed in Saccharomyces cerevisiae htd2Delta or oar1Delta respiratory deficient cells lacking the corresponding mitochondrial FASII enzymes Htd2p and Oar1p. Yeast mutants producing mitochondrially targeted versions of the parasite proteins resembled the self-complemented cells for respiratory growth. This is the first identification of a FASII-like 3-oxoacyl-ACP reductase from a kinetoplastid parasite.	What causes leishmaniasis?	Leishmania major causes leishmaniasis and is grouped within the Trypanosomatidae family, which also includes the etiologic agent for African sleeping sickness, Trypanosoma brucei.
These results suggested that rates of vitamin D deficiency are higher among women with IGT/GDM, and the relationship between vitamin D status and glucose tolerance in pregnancy needs further study.	Is Vitamin D deficiency in pregnant women associated with gestational diabetes?	These results suggested that rates of vitamin D deficiency are higher among women with IGT/GDM, and the relationship between vitamin D status and glucose tolerance in pregnancy needs further study.
Two regulatory genes, acpA and atxA, have been reported to control expression of the Bacillus anthracis capsule biosynthesis operon capBCAD. The atxA gene is located on the virulence plasmid pXO1, while pXO2 carries acpA and the cap genes. acpA has been viewed as the major regulator of the cap operon because it is essential for capsule gene expression in a pXO1(-) pXO2(+) strain. atxA is essential for toxin gene transcription but has also been implicated in control of the cap genes. The molecular functions of the regulatory proteins are unknown. We examined cap gene expression in a genetically complete pXO1(+) pXO2(+) strain. Our results indicate that another pXO2 gene, acpB (previously called pXO2-53; accession no. NC002146.1:49418-50866), has a role in cap expression. The predicted amino acid sequence of AcpB is 62% similar to that of AcpA and 50% similar to that of AtxA. Assessment of cap gene transcription revealed that cap expression was not affected in a pXO1(+) pXO2(+) acpB-null mutant and was slightly reduced in an isogenic acpA mutant. However, cap gene expression was abolished in an acpA acpB double mutant. Microscopic examination of capsule synthesis by the mutants corroborated these findings. acpA and acpB expression is controlled by atxA; capsule synthesis and transcription of acpA and acpB were markedly reduced in an atxA mutant. The data suggest that, in a strain containing both virulence plasmids, atxA is the major regulator of capsule synthesis and controls capBCAD expression indirectly, via positive regulation of acpA and acpB.	What is the function of the AtxA pleiotropic regulator?	The atxA gene is located on the virulence plasmid pXO1, while pXO2 carries acpA and the cap genes
Seven patients, six suffering from amyotrophic lateral sclerosis (ALS) and one from Friedreich ataxia, were treated with a placebo i.v. infusion during the first day and with TRH-T i.v. infusion at a rate of 2 mg/h for 8 h daily (total daily dosage 16 mg) on the 2 consecutive days. Continuous blood pressure (BP) and EKG monitorings were performed during 3 days infusion. Blood samples were collected for endocrinological evaluations. The neurological evaluation after acute TRH-T treatment showed an objective improvement in 3 of the 8. We found significantly higher values of systolic (max. difference of 10.1 mm Hg) and diastolic (max. difference of 8.8 mm Hg) BP than during placebo, beginning from the 5th h of the infusion (p less than 0.05). A trend in progressive increase of the heart rate (HR) reached statistical significance (p less than 0.01) at the 8th h of the second TRH-T infusion. The cardiovascular changes during the i.v. continuous TRH-T infusions were clinically irrelevant and never required the interruption of the treatment.	Is there any data to suggest that TRH (thyrotropin releasing hormone) administration can improve symptom severity of amyotrophic lateral sclerosis patients?	The neurological evaluation after acute TRH-T treatment showed an objective improvement in 3 of the 8.
Since the CD44 variant 6(v6) molecule has been noted as a marker for tumor metastasis and prognosis in several tumors, we examined whether or not v6 is a useful marker for evaluating the prognosis of pancreatic cancer patients. In addition, we attempted to assess the clinicopathological implications for pancreatic cancer of the variant 2 (v2) isoform using a recently developed monoclonal antibody against a v2 epitope. The expression of CD44 variants was evaluated immunohistochemically in paraffin-embedded pancreatic cancer tissues from 42 patients who were confirmed surgically and histologically to have received curative resection. An indirect immunoperoxidase method was used with monoclonal antibodies against epitopes of the standard (CD44s) portion, v6 and v2. Protein expression data were evaluated statistically for any correlations with the length of survival or with histological parameters. The expression of CD44v6 and v2 was observed only in tumor cells, if at all. On the other hand, expression of total CD44 (including CD44v, as well as CD44s) was observed in both tumors and adjacent normal sites. Tumor tissue from 21 (50%) and 16 (38%) patients showed positive immunoreactivity with mAb 2F10 (anti-CD44v6) and mAb M23.6.1 (anti-CD44v2), respectively. The expression of CD44v6 and v2 was correlated with decreased overall survival (P = 0.0160 and P = 0.0125, respectively). A significant correlation was obtained between CD44v2 peptide expression and vessel invasion (P = 0.026). These results suggest that CD44v2 and CD44v6 may be useful markers for poor prognosis in curatively resected primary pancreatic cancer.	Are CD44 variants (CD44v) associated with poor prognosis of metastasis?	CD44v2 and CD44v6 may be useful markers for poor prognosis in curatively resected primary pancreatic cancer
Coronaviruses are pathogens with a serious impact on human and animal health. They mostly cause enteric or respiratory disease, which can be severe and life threatening, e.g., in the case of the zoonotic coronaviruses causing severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) in humans. Despite the economic and societal impact of such coronavirus infections, and the likelihood of future outbreaks of additional pathogenic coronaviruses, our options to prevent or treat coronavirus infections remain very limited. This highlights the importance of advancing our knowledge on the replication of these viruses and their interactions with the host. Compared to other +RNA viruses, coronaviruses have an exceptionally large genome and employ a complex genome expression strategy. Next to a role in basic virus replication or virus assembly, many of the coronavirus proteins expressed in the infected cell contribute to the coronavirus-host interplay. For example, by interacting with the host cell to create an optimal environment for coronavirus replication, by altering host gene expression or by counteracting the host's antiviral defenses. These coronavirus-host interactions are key to viral pathogenesis and will ultimately determine the outcome of infection. Due to the complexity of the coronavirus proteome and replication cycle, our knowledge of host factors involved in coronavirus replication is still in an early stage compared to what is known for some other +RNA viruses. This review summarizes our current understanding of coronavirus-host interactions at the level of the infected cell, with special attention for the assembly and function of the viral RNA-synthesising machinery and the evasion of cellular innate immune responses.	Please list 2 human diseases caused by a coronavirus.	They mostly cause enteric or respiratory disease, which can be severe and life threatening, e.g., in the case of the zoonotic coronaviruses causing severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) in humans.
Necrobiosis lipoidica diabeticorum is a rare skin disorder, usually considered a marker for diabetes mellitus. More than half of the patients with necrobiosis lipoidica diabeticorum have diabetes mellitus, but less than one per cent of diabetes mellitus patients have necrobiosis lipoidica diabeticorum. In the diabetes and dermatology literature, we find the position that there is no effect of glucose control on either the appearance of necrobiosis lipoidica diabeticorum or the clinical course of the lesion. We base our challenge to this position on a critical review of the original data. And conclude on the contrary, that necrobiosis lipoidica diabeticorum is usually associated with poor glucose control and that tighter glucose control, as currently practised, might improve or prevent the disorder.	Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?	More than half of the patients with necrobiosis lipoidica diabeticorum have diabetes mellitus, but less than one per cent of diabetes mellitus patients have necrobiosis lipoidica diabeticorum.
Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.	What are common variants at 12q14 and 12q24 associated with?	Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794).
Auxin/indole-3-acetic acid (Aux/IAA) proteins are transcriptional regulators that mediate many aspects of plant responses to auxin. While functions of most Aux/IAAs have been defined mainly by gain-of-function mutant alleles in Arabidopsis thaliana, phenotypes associated with loss-of-function mutations have been scarce and subtle. We report here that the downregulation of IAA9, a tomato (Solanum lycopersicum) gene from a distinct subfamily of Aux/IAA genes, results in a pleiotropic phenotype, consistent with its ubiquitous expression pattern. IAA9-inhibited lines have simple leaves instead of wild-type compound leaves, and fruit development is triggered before fertilization, giving rise to parthenocarpy. This indicates that IAA9 is a key mediator of leaf morphogenesis and fruit set. In addition, antisense plants displayed auxin-related growth alterations, including enhanced hypocotyl/stem elongation, increased leaf vascularization, and reduced apical dominance. Auxin dose-response assays revealed that IAA9 downregulated lines were hypersensitive to auxin, although the only early auxin-responsive gene that was found to be upregulated in the antisense lines was IAA3. The activity of the IAA3 promoter was stimulated in the IAA9 antisense genetic background, indicating that IAA9 acts in planta as a transcriptional repressor of auxin signaling. While no mutation in any member of subfamily IV has been reported to date, the phenotypes associated with the downregulation of IAA9 reveal distinct and novel roles for members of the Aux/IAA gene family.	Which genes belong to the AUX/IAA family of transcription repressors in plants?	We report here that the downregulation of IAA9, a tomato (Solanum lycopersicum) gene from a distinct subfamily of Aux/IAA genes, results in a pleiotropic phenotype, consistent with its ubiquitous expression pattern
The collection of fetal genetic materials is required for the prenatal diagnosis of fetal genetic diseases. The conventional methods for sampling fetal genetic materials, such as amniocentesis and chorionic villus sampling, are invasive in nature and are associated with a risk of fetal miscarriage. For decades, scientists had been pursuing studies with goals to develop non-invasive methods for prenatal diagnosis. In 1997, the existence of fetal derived cell-free DNA molecules in plasma of pregnant women was first demonstrated. This finding provided a new source of fetal genetic material that could be obtained safely through the collection of a maternal blood sample and provided a new avenue for the development of non-invasive prenatal diagnostic tests. Now 15 years later, the diagnostic potential of circulating fetal DNA analysis has been realized. Fruitful research efforts have resulted in the clinical implementation of a number of non-invasive prenatal tests based on maternal plasma DNA analysis and included tests for fetal sex assessment, fetal rhesus D blood group genotyping and fetal chromosomal aneuploidy detection. Most recently, research groups have succeeded in decoding the entire fetal genome from maternal plasma DNA analysis which paved the way for the achievement of non-invasive prenatal diagnosis of many single gene diseases. A paradigm shift in the practice of prenatal diagnosis has begun.	How can the fetal Rhesus be determined with non-invasive testing?	Fruitful research efforts have resulted in the clinical implementation of a number of non-invasive prenatal tests based on maternal plasma DNA analysis and included tests for fetal sex assessment, fetal rhesus D blood group genotyping and fetal chromosomal aneuploidy detection.
Amblyopia is a developmental disorder resulting in poor vision in one eye. The mechanism by which input to the affected eye is prevented from reaching the level of awareness remains poorly understood. We recorded simultaneously from large populations of neurons in the supragranular layers of areas V1 and V2 in 6 macaques that were made amblyopic by rearing with artificial strabismus or anisometropia, and 1 normally reared control. In agreement with previous reports, we found that cortical neuronal signals driven through the amblyopic eyes were reduced, and that cortical neurons were on average more strongly driven by the non-amblyopic than by the amblyopic eyes. We analyzed multiunit recordings using standard population decoding methods, and found that visual signals from the amblyopic eye, while weakened, were not degraded enough to explain the behavioral deficits. Thus additional losses must arise in downstream processing. We tested the idea that under monocular viewing conditions, only signals from neurons dominated by - rather than driven by - the open eye might be used. This reduces the proportion of neuronal signals available from the amblyopic eye, and amplifies the interocular difference observed at the level of single neurons. We conclude that amblyopia might arise in part from degradation in the neuronal signals from the amblyopic eye, and in part from a reduction in the number of signals processed by downstream areas.	Does Amblyopia affect the eye?	Amblyopia is a developmental disorder resulting in poor vision in one eye.
Li-Fraumeni syndrome (LFS) is a rare, autosomal dominant, hereditary cancer predisposition disorder. In Brazil, the p.R337H TP53 founder mutation causes the variant form of LFS, Li-Fraumeni-like syndrome. The occurrence of cancer and age of disease onset are known to vary, even in patients carrying the same mutation, and several mechanisms such as genetic and epigenetic alterations may be involved in this variability. However, the extent of involvement of such events has not been clarified. It is well established that p53 regulates several pathways, including the thymine DNA glycosylase (TDG) pathway, which regulates the DNA methylation of several genes. This study aimed to identify the DNA methylation pattern of genes potentially related to the TDG pathway (CDKN2A, FOXA1, HOXD8, OCT4, SOX2, and SOX17) in 30 patients with germline TP53 mutations, 10 patients with wild-type TP53, and 10 healthy individuals. We also evaluated TDG expression in patients with adrenocortical tumors (ADR) with and without the p.R337H TP53 mutation. Gene methylation patterns of peripheral blood DNA samples assessed by pyrosequencing revealed no significant differences between the three groups. However, increased TDG expression was observed by quantitative reverse transcription PCR in p.R337H carriers with ADR. Considering the rarity of this phenotype and the relevance of these findings, further studies using a larger sample set are necessary to confirm our results.	Is Li–Fraumeni syndrome a rare, autosomal recessive, hereditary disorder that predisposes carriers to cancer development?	Li-Fraumeni syndrome (LFS) is a rare, autosomal dominant, hereditary cancer predisposition disorder.
Nucleotide 1138 in transmembrane domain of FGFR3 gene is the hot point for mutation in ACH and hence its major pathologic cause. PCR-DGGE is a sensitive and reliable technique for point mutation screening, especially for the heterozygotes.	Mutation of which gene is associated with Achondroplasia?	Nucleotide 1138 in transmembrane domain of FGFR3 gene is the hot point for mutation in ACH and hence its major pathologic cause.
Pheochromocytomas synthesize and release catecholamines, which subsequently are related to various clinical manifestations of the disease. However, pheochromocytomas are not innervated and the catecholamine release and synthesis are not initiated by neural impulses. It is still unknown how catecholamine synthesis is regulated in pheochromocytomas. As a first step toward understanding the molecular mechanisms by which catecholamine synthesis is controlled in the tumor, we measured the levels of mRNA coding for the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH) and catecholamines in 6 pheochromocytomas and 2 normal adrenal glands. The TH mRNA level was overexpressed and the catecholamine contents were high in 4 out of 6 pheochromocytomas. There was a close correlation between the TH mRNA level and the catecholamines content in the tumors. We also examined the gene expression of the messengers of other catecholamine synthesizing enzymes, dopamine beta-hydroxylase (DBH) and aromatic 1-amino acid decarboxylase (AADC) in pheochromocytomas. The expression of these genes was in parallel with that of TH mRNA in the tumors. These findings indicate that catecholamine overproduction in pheochromocytomas is mediated by the overexpression of genes coding for catecholamines synthesizing enzymes, TH, DBH, and AADC.	Which enzymes synthesize catecholamines in adrenal glands?	These findings indicate that catecholamine overproduction in pheochromocytomas is mediated by the overexpression of genes coding for catecholamines synthesizing enzymes, TH, DBH, and AADC.
Vedolizumab can be detected in the breast milk of nursing mothers. Although more data are imperative, the concentrations of vedolizumab in breast milk are minute and are therefore unlikely to result in systemic or gastro-intestinal immune-suppression of the infant.	Can therapeutic levels of Vedolizumab be found in the breast milk of nursing mothers following treatment for Inflammatory bowel disease?	Vedolizumab can be detected in the breast milk of nursing mothers. Although more data are imperative, the concentrations of vedolizumab in breast milk are minute and are therefore unlikely to result in systemic or gastro-intestinal immune-suppression of the infant.