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Updated
DOI
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2025-12-14 00:00:00
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10.1101/2025.03.24.644978
|
MiR-7a-Klf4 axis as a regulator and therapeutic target of neuroinflammation and ferroptosis in Alzheimer's disease
|
Ramesh, M.; Govindaraju, T.
|
Thimmaiah Govindaraju
|
Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR)
|
10.1101/2025.03.24.644978
|
2025-03-25
|
1
|
new results
|
cc_no
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/25/2025.03.24.644978.source.xml
|
Neuroinflammation and ferroptosis significantly contribute to neuronal death in Alzheimers disease (AD) and other neurodegenerative disorders. MicroRNAs (miRNAs) are crucial regulators of these pathological processes. We employed transcriptomic analysis in an APP/PSEN1 Tg AD mouse model to identify dysregulated miRNAs and construct a miRNA-mRNA-pathway network. We discovered increased miR7a expression in the AD brain, targeting Kruppel-like factor 4 (Klf4), a transcriptional factor implicated in A{beta} oligomer-induced neuroinflammation and RSL3-induced neuronal ferroptosis. Elevated Klf4 levels in AD mice brains suggest its involvement in AD pathology. The miR-7a mediated silencing of Klf4 alleviates neuroinflammation by modulating NF-{kappa}B, iNOS, and NLRP3 pathways, and inhibition of ferroptosis by targeting labile iron levels, GPX4, Nrf2 pathway, and mitochondrial damage. These findings highlight the neuroprotective role of miR-7a and its potential as RNA therapeutic. Pharmacological targeting of the miR-7a-Klf4 axis with blood-brain-barrier (BBB)-permeable compound effectively mitigates neuroinflammation and ferroptosis, suggesting the miR-7a-Klf4 axis as a novel therapeutic target for AD.
GRAPHICAL ABSTRACT
O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/644978v1_ufig1.gif" ALT="Figure 1">
View larger version (32K):
org.highwire.dtl.DTLVardef@804f96org.highwire.dtl.DTLVardef@1e91bc7org.highwire.dtl.DTLVardef@11ed0daorg.highwire.dtl.DTLVardef@21d02e_HPS_FORMAT_FIGEXP M_FIG C_FIG
|
10.1093/narmme/ugaf022
|
bioRxiv
|
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|
10.1101/2025.03.25.25324600
|
Deep learning approach for automatic assessment of schizophrenia and bipolar disorder in patients using R-R intervals
|
Ksiazek, K. M.; Masarczyk, W.; Głomb, P.; Romaszewski, M.; Buza, K.; Sekuła, P.; Cholewa, M.; Kołodziej, K.; Gorczyca, P.; Piegza, M.
|
Kamil Michał Książek
|
Jagiellonian University
|
10.1101/2025.03.25.25324600
|
2025-03-25
|
1
|
PUBLISHAHEADOFPRINT
|
cc_by_nc
|
psychiatry and clinical psychology
|
https://www.medrxiv.org/content/early/2025/03/25/2025.03.25.25324600.source.xml
|
Schizophrenia and bipolar disorder are severe mental illnesses that significantly impact quality of life. These disorders are associated with autonomic nervous system dysfunction, which can be assessed through heart activity analysis. Heart rate variability (HRV) has shown promise as a potential biomarker for diagnostic support and early screening of those conditions. This study aims to develop and evaluate an automated classification method for schizophrenia and bipolar disorder using short-duration electrocardiogram (ECG) signals recorded with a low-cost wearable device.
We conducted classification experiments using machine learning techniques to analyze R-R interval windows extracted from short ECG recordings. The study included 60 participants - 30 individuals diagnosed with schizophrenia or bipolar disorder and 30 control subjects. We evaluated multiple machine learning models, including Support Vector Machines, XGBoost, multilayer perceptrons, Gated Recurrent Units, and ensemble methods. Two time window lengths (about 1 and 5 minutes) were evaluated. Performance was assessed using 5-fold cross-validation and leave-one-out cross-validation, with hyperparameter optimization and patient-level classification based on individual window decisions. Our method achieved classification accuracy of 83% for the 5-fold cross-validation and 80% for the leave-one-out scenario. Despite the complexity of our scenario, which mirrors real-world clinical settings, the proposed approach yielded performance comparable to advanced diagnostic methods reported in the literature.
The results highlight the potential of short-duration HRV analysis as a cost-effective and accessible tool for aiding in the diagnosis of schizophrenia and bipolar disorder. Our findings support the feasibility of using wearable ECG devices and machine learning-based classification for psychiatric screening, paving the way for further research and clinical applications.
Author summaryMental health conditions such as schizophrenia and bipolar disorder can be challenging to diagnose, but early detection is crucial to better outcomes. In our study, we explored a simple but powerful idea: using heart rate variability (HRV), the natural fluctuations in time between heartbeats, as a potential indicator of these disorders. As HRV reflects the balance of the autonomic nervous system, research has shown that people with schizophrenia and bipolar disorder often have distinct HRV patterns, suggesting that heart activity analysis could support mental health screening. We tested whether a wearable heart monitor, similar to a fitness tracker, could help recognize these patterns using artificial intelligence. By analyzing heart activity records from 60 individuals, some with these conditions and others without, we trained several machine learning models to differentiate between them. Our approach successfully classified individuals with about 80% accuracy. Although not a replacement for clinical diagnosis, heart monitoring combined with artificial intelligence could help detect signs of mental illness, leading to faster interventions. Our work opens the door for further studies and, ultimately, the development of easy-to-use tools that could support doctors and improve patient care.
|
10.1371/journal.pcbi.1012983
|
medRxiv
|
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192,
72,
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|
10.1101/443119
|
The Cuon Enigma: Genome survey and comparative genomics of the endangered Dhole (Cuon alpinus)
|
Habib, B.; Ghaskadbi, P.; Nigam, P.; Modi, S.; Kumar, P. S.; Sharma, K.; Singh, V.; Kumar, B.; Tripathi, A.; Kothandaraman, H.; Yellaboina, S.; Baghel, D. S.; Mondol, S.
|
Bilal Habib
|
Wildlife Institute of India
|
10.1101/443119
|
2018-10-14
|
1
|
new results
|
cc_by_nc_nd
|
genomics
|
https://www.biorxiv.org/content/early/2018/10/14/443119.source.xml
|
The Asiatic wild dog is an endangered monophyletic canid restricted to Asia; facing threats from habitat fragmentation and other anthropogenic factors. Dholes have unique adaptations as compared to other wolf-like canids for large litter size (larger number of mammae) and hypercarnivory making it evolutionarily notable. Over evolutionary time, dhole and the subsequent divergent wild canids have lost coat patterns found in African wild dog. Here we report the first high coverage genome survey of Asiatic wild dog and mapped it with African wild dog, dingo and domestic dog to assess the structural variants. We generated a total of 124.8 Gb data from 416140921 raw read pairs and retained 398659457 reads with 52X coverage and mapped 99.16% of the clean reads to the three reference genomes. We identified ~13553269 SNVs, ~2858184 InDels, ~41000 SVs, ~1854109 SSRs and about 1000 CNVs. We compared the annotated genome of dingo and domestic dog with dhole genome sequence to understand the role of genes responsible in pelage pattern, dentition and mammary glands. Positively selected genes for these phenotypes were looked for SNP variants and top ranked genes for coat pattern, dentition and mammary glands were found to play a role in signalling and developmental pathways. Mitochondrial genome assembly predicted 35 genes, 11 CDS and 24 tRNA. This genome information will help in understanding the divergence of two monophlyletic canids, Cuon and Lycaon, and the evolutionary adaptations of dholes with respect to other canids.
|
NA
|
bioRxiv
|
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|
10.1101/2023.02.07.527553
|
Experience with mating receptivity cues affects sexual behaviour of male guppies, but not their strength of preference towards receptive females
|
Goberdhan, V.; Darolti, I.; van der Bijl, W.; Mank, J. E.; Corral-Lopez, A.
|
Alberto Corral-Lopez
|
Department of Zoology and Biodiversity Research Centre, University of British Columbia
|
10.1101/2023.02.07.527553
|
2023-09-29
|
2
|
new results
|
cc_by_nc
|
animal behavior and cognition
|
https://www.biorxiv.org/content/early/2023/09/29/2023.02.07.527553.source.xml
|
Females are traditionally presented as the choosier sex, selecting males based on the quality of their traits. Yet, there is increasing evidence that male mate choice is also important, even in species without male parental care. Social environment and learning are key factors in determining mate preference, and animals are able to use the information they gather from previous experience to potentially increase their odds of obtaining a high-quality mate. We examined how the social environment affects male mate choice in the guppy (Poecilia reticulata). We evaluated whether male guppies with previous social experience of female receptivity cues learn to prefer and adapt their behavioural repertoire towards females with higher receptiveness levels, as this represents an optimal use of time and energy and is more likely to result in insemination. For this, we measured sexual preference and behaviour for receptive females in no-choice and dichotomous choice tests using guppy males experienced or naive to female receptivity cues. Experience with receptivity cues did not change the strength of preference towards receptive females. However, male guppies that had previous experience with female receptivity cues adapted their mating tactic compared to naive males. The change in mating tactics but lack of preference towards receptive females shows that the influence of social learning is present but might be weaker than predicted in this species. Furthermore, these results provide further support to studies of female mate choice suggesting mating status is not a key factor driving the strength of sexual preferences in natural populations.
|
NA
|
bioRxiv
|
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|
10.1101/2021.12.27.474282
|
Booster vaccines protect hamsters with waning immunity from Delta VOC infection, disease, and transmission
|
Potts, K. G.; Noyce, R. S.; Gafuik, C.; John, C. M.; Todesco, H. M.; De Heuvel, E.; Favis, N.; Kelly, M. M.; Evans, D. H.; Mahoney, D. J.
|
Douglas J Mahoney
|
University of Calgary
|
10.1101/2021.12.27.474282
|
2021-12-28
|
1
|
new results
|
cc_by_nc_nd
|
immunology
|
https://www.biorxiv.org/content/early/2021/12/28/2021.12.27.474282.source.xml
|
Waning immunity to COVID-19 vaccination is associated with increased risk of breakthrough infection, especially with highly transmissible variants of concern (VOC). Booster vaccination generates rapid immune recall in humans, which real-world observational studies suggest protects against VOC infection and associated disease, and modeling studies suggest could mitigate community spread. We directly tested the impact of booster vaccination on protection against Delta VOC infection, disease, and transmission to naive cohorts in golden Syrian hamsters. Animals with waning immunity to bnt162b2 generated rapid immune recall and strong protection against upper- and lower-respiratory tract infection when boosted with bnt126b2, mRNA-1273 or AZD1222. Boosting with either mRNA vaccine generated moderate protection against lung inflammation and virus transmission to unvaccinated animals. Our data support booster vaccination as a tool to address emerging VOC in the COVID-19 pandemic.
One-Sentence SummaryA booster vaccine delivered 9 months after primary bnt162b2 vaccination protects hamsters from Delta VOC infection, disease, and transmission.
|
NA
|
bioRxiv
|
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|
10.1101/2023.03.27.534449
|
Alopecosa nagpag acts on cardiac ventricular myocytes to kill prey
|
huang, b.
|
biao huang
|
Chengdu Pepbiomedical Co.,Ltd.
|
10.1101/2023.03.27.534449
|
2023-03-29
|
1
|
new results
|
cc_by
|
pharmacology and toxicology
|
https://www.biorxiv.org/content/early/2023/03/29/2023.03.27.534449.source.xml
|
Spiders are excellent predator to kill their prey by peptide toxins from its venoms. Alopecosa nagpag (A. nagpag) is a new identified wolf spider distributing in Yunnan province and nothing has known about the venom. In this study, venom of A. nagpag showed mild toxicity to Kunming mouse with LD50 of 3.32 mg/kg. Action potential duration (APD) was prolonged in a frequency-dependent manner and whole currents of neonatal rat ventricular myocytes (NRVMs) were inhibited by venom. Meanwhile, venom of A. nagpag could largely increase L calcium currents (ICaL). Whereas sodium current (INa) and rapidly activating delayed rectifier potassium current (IKr) were significantly decreased by 100 g/mL venoms. No obvious inhibition was found on other ion channels such as rapidly activating and inactivating transient inward (IK1), rapid (IKr) and slow (IKs). As those ion channels play critical role in rhythm of cardiac ventricular myocytes, A. nagpag may lead prey to death by changing cardiac rhythm.
|
NA
|
bioRxiv
|
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|
10.1101/2023.06.01.543253
|
Maintenance of cooperation in a yeast population in a public-good driven system.
|
Raj, N.; Saini, S.
|
Supreet Saini
|
Indian Institute of Technology Bombay
|
10.1101/2023.06.01.543253
|
2023-06-05
|
1
|
new results
|
cc_by_nc_nd
|
evolutionary biology
|
https://www.biorxiv.org/content/early/2023/06/05/2023.06.01.543253.source.xml
|
The phenomenon of cooperation is prevalent at all levels of life. In microbial communities, some groups of cells exhibit cooperative behaviour by producing costly extracellular resources that are freely available to others. These resources are referred to as public goods. Saccharomyces cerevisiae secretes invertase (public good) in the periplasm to hydrolyse sucrose into glucose and fructose, which are further imported by the cells. After hydrolysis of sucrose, the cells retain only 1% of the monosaccharides, while 99% diffuse into the environment and can be utilised by all neighbouring cells. The non-producers of invertase (cheaters) exploit the invertase-producing cells (cooperators) by utilising the monosaccharides and paying nothing for the latter. In this work, we investigate the evolutionary dynamics of this cheater-cooperator system. If cheaters are selected for their higher fitness, the population will collapse. For cooperators to survive cheating and thrive in nature, they should have evolved some survival strategies. To understand the adaptation of cooperators in sucrose, we performed a coevolution experiment in sucrose. Our results show that cooperators increase in fitness as the experiment progresses. This phenomenon was not observed in environments which involved a non-public good system. Genome sequencing reveals the molecular basis for the cooperator adaptating is because of increased privatization of the public-good released carbon resource.
|
NA
|
bioRxiv
|
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|
10.1101/527762
|
IL-5Rα marks nasal polyp IgG4 and IgE-secreting cells in aspirin-exacerbated respiratory disease
|
Buchheit, K. M.; Dwyer, D. F.; Ordovas-Montanes, J.; Katz, H. R.; Lewis, E.; Bhattacharyya, N.; Shalek, A. K.; Barrett, N. A.; Boyce, J. A.; Laidlaw, T. M.
|
Tanya M. Laidlaw
|
Brigham and Women's Hospital, Boston, MA
|
10.1101/527762
|
2019-01-23
|
1
|
new results
|
cc_no
|
immunology
|
https://www.biorxiv.org/content/early/2019/01/23/527762.source.xml
|
BackgroundThe cause of nasal polyposis in aspirin-exacerbated respiratory disease (AERD) is unknown. Elevated antibody levels have been associated with disease severity in nasal polyps, but the upstream drivers and cellular mechanisms of local antibody production in AERD remain to be investigated.
ObjectiveWe sought to identify the upstream drivers and phenotypic properties of local antibody-secreting cells in nasal polyps and to understand their clinical relevance in AERD.
MethodsSinus tissue was obtained from subjects with AERD, aspirin-tolerant chronic rhinosinusitis with nasal polyps (CRSwNP), aspirin-tolerant chronic rhinosinusitis without nasal polyps (CRSsNP), and healthy controls. Tissue antibody levels were quantified via ELISA and immunohistochemistry, and were correlated with clinical markers of disease severity. Tissue cytokine mRNA levels were measured with quantitative PCR (qPCR). Antibody-secreting cells were profiled with a combination of single-cell RNA-sequencing (scRNA-seq), flow cytometry and immunofluorescence.
ResultsTissue IgE and IgG4 were elevated in AERD compared to controls (p<0.01 for IgE and p<0.001 for IgG4, vs. CRSwNP). Total IgG and IgG4 positively correlated with the number of polyp surgeries per subject (r=0.48, p=0.011 and r=0.58, p=0.0003, respectively). Polyp IL-10 mRNA expression was higher in AERD vs. CRSwNP (p<0.05), but there were no differences in mRNA expression of type 2 cytokines. ScRNA-seq revealed increased IL5RA, IGHG4, and IGHE in the antibody-associated cells of subjects with AERD compared to CRSwNP. Total plasma cells and IL-5R+ plasma cell numbers in the polyp tissue from AERD exceeded those in polyps from CRSwNP (p=0.0051 and p=0.026, respectively) by flow cytometry. With immunofluorescence, we determined that IL-5R and IgG4 are co-expressed in antibody-secreting cells in AERD.
ConclusionsOur study identifies unique clusters of antibody-secreting cells in AERD defined by enrichment of transcripts encoding IL5RA, IGHG4 and IGHE. We confirm surface expression of IL-5R on these cells, and identify T cells as a unique transcriptional source of IL-5. Tissue antibody levels are elevated in AERD and correlate with disease severity. Our findings suggest a role for IL-5 in facilitating local antibody production that may drive features of severe sinus disease.
Key MessagesO_LIIgG4 and IgE levels are markedly increased in nasal polyp tissue from subjects with AERD compared to aspirin-tolerant CRSwNP.
C_LIO_LITissue IgG4 levels positively correlate with disease recurrence.
C_LIO_LIIL-10 mRNA levels are significantly higher in AERD polyp tissue compared to CRSwNP tissue, but differences were not noted for type 2 cytokines or cytokines involved in class switch recombination.
C_LIO_LIIL-5R transcript and protein surface expression is elevated in antibody-secreting cells from subjects with AERD and may play a role in facilitating class switching and/or survival of antibody-secreting cells.
C_LI
Capsule SummarySingle-cell RNA-sequencing (scRNA-seq) of whole nasal polyp tissue identified increased IL5RA, IGHE, and IGHG4 expression in the antibody-secreting cell compartment of subjects with aspirin-exacerbated respiratory disease (AERD) compared to aspirin-tolerant chronic rhinosinusitis with nasal polyps (CRSwNP). IgE and IgG4 levels are elevated in nasal polyp tissue from subjects with AERD compared to CRSwNP and correlate with disease recurrence.
|
NA
|
bioRxiv
|
[
208,
220,
149,
110,
136,
161,
155,
140,
233,
5,
101,
237,
109,
114,
61,
47,
102,
225,
193,
18,
149,
167,
189,
195,
94,
119,
102,
91,
107,
237,
117,
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125,
200,
10,
29,
2,
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117,
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108,
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74,
24,
65,
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49,
214,
82,
250,
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36,
178,
38,
194,
181,
254,
125,
158,
160,
98,
33,
150,
53,
184,
141,
143,
218,
158,
4,
59,
249,
72,
10,
55,
189,
154,
200,
7,
216,
223,
192,
189,
248,
34,
70,
140,
3,
215,
176,
216,
188,
119,
183,
32,
203,
205,
70,
84,
30,
105,
30,
114,
184
]
|
10.1101/554709
|
The impact of distillery effluent irrigation on plant-growth-promoting traits and taxonomic composition of bacterial communities in agricultural soil
|
Kumari, P.; Tripathi, B. M.; Singh, R. N.; Saxena, A. K.; Kaushik, R.
|
Priyanka Kumari
|
Department of Environmental Health Sciences, Seoul National University, Republic of Korea
|
10.1101/554709
|
2019-02-19
|
1
|
new results
|
cc_by_nc_nd
|
microbiology
|
https://www.biorxiv.org/content/early/2019/02/19/554709.source.xml
|
Long-term irrigation of agricultural fields with distillery effluent (DE) may alter the physical, chemical and biological properties of the soil. Microorganisms are critical to the maintenance of soil health and productivity. However, the impact of DE irrigation on activity and taxonomy of soil microorganisms is poorly understood. Here we studied plant-growth-promoting (PGP) traits and taxonomic composition of bacterial communities in agricultural soil irrigated with DE in conjugation with irrigation water, using cultivation-dependent and - independent methods. Most of the bacterial isolates obtained from DE irrigated soil were found to display PGP traits (phosphate solubilization, siderophore, indolic compounds and ammonia production). Diverse bacterial taxa were found in both culturable bacterial community and 16S rRNA gene clone library, which belonged to bacterial phyla Proteobacteria (Alpha-, Beta- and Gamma- subdivisions), Firmicutes, Actinobacteria, Acidobacteria, Bacteroidetes and Gemmatimonadates. Overall, these results indicate that PGP traits and taxonomic diversity of soil bacterial communities were not severely impacted by DE irrigation.
|
NA
|
bioRxiv
|
[
100,
234,
13,
77,
142,
245,
24,
146,
200,
25,
98,
213,
125,
114,
44,
163,
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197,
124,
39,
55,
251,
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8,
154,
39,
127,
39,
176,
182,
65,
106,
196,
76,
245,
90,
70,
29
]
|
10.1101/2022.03.29.486331
|
Genetic surveillance of SARS-CoV-2 Mpro reveals high sequence and structural conservation prior to the introduction of protease inhibitor Paxlovid
|
Lee, J. T.; Yang, Q.; Gribenko, A.; Perrin, B. S.; Zhu, Y.; Cardin, R.; Liberator, P. A.; Anderson, A. S.; Hao, L.
|
Li Hao
|
Pfizer, Inc
|
10.1101/2022.03.29.486331
|
2022-03-30
|
1
|
new results
|
cc_no
|
genomics
|
https://www.biorxiv.org/content/early/2022/03/30/2022.03.29.486331.source.xml
|
SARS-CoV-2 continues to represent a global health emergency as a highly transmissible, airborne virus. An important coronaviral drug target for treatment of COVID-19 is the conserved main protease (Mpro). Nirmatrelvir is a potent Mpro inhibitor and the antiviral component of Paxlovid. The significant viral sequencing effort during the ongoing COVID-19 pandemic represented a unique opportunity to assess potential nirmatrelvir escape mutations from emerging variants of SARS-CoV-2. To establish the baseline mutational landscape of Mpro prior to the introduction of Mpro inhibitors, Mpro sequences and its cleavage junction regions were retrieved from [~]4,892,000 high-quality SARS-CoV-2 genomes in GISAID. Any mutations identified from comparison to the reference sequence (Wuhan-hu-1) were cataloged and analyzed. Mutations at sites key to nirmatrelvir binding and protease functionality (e.g., dimerization sites) were still rare. Structural comparison of Mpro also showed conservation of key nirmatrelvir contact residues across the extended Coronaviridae family (alpha-, beta-, and gamma-coronaviruses). Additionally, we showed that over time the SARS-CoV-2 Mpro enzyme remained under purifying selection and was highly conserved relative to the spike protein. Now, with the EUA approval of Paxlovid and its expected widespread use across the globe, it is essential to continue large-scale genomic surveillance of SARS-CoV-2 Mpro evolution. This study establishes a robust analysis framework for monitoring emergent mutations in millions of virus isolates, with the goal of identifying potential resistance to present and future SARS-CoV-2 antivirals.
ImportanceThe recent authorization of oral SARS-CoV-2 antivirals, such as Paxlovid, has ushered in a new era of the COVID-19 pandemic. Emergence of new variants, as well as selective pressure imposed by antiviral drugs themselves, raise concern for potential escape mutations in key drug binding motifs. To determine the potential emergence of antiviral resistance in globally circulating isolates and its implications for the clinical response to the COVID-19 pandemic, sequencing of SARS-CoV-2 viral isolates before, during, and after the introduction of new antiviral treatments is critical. The infrastructure built herein for active genetic surveillance of Mpro evolution and emergent mutations will play an important role in assessing potential antiviral resistance as the pandemic progresses and Mpro inhibitors are introduced. We anticipate our framework to be the starting point in a larger effort for global monitoring of the SARS-CoV-2 Mpro mutational landscape.
|
NA
|
bioRxiv
|
[
96,
197,
236,
78,
188,
177,
221,
206,
245,
11,
103,
85,
189,
99,
112,
191,
110,
229,
224,
21,
100,
167,
159,
33,
97,
68,
102,
107,
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214,
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39,
131,
3,
221,
72,
144,
35,
123,
77,
34,
73,
77,
200,
54,
156,
105,
63,
110,
184
]
|
10.1101/2023.09.14.557846
|
Ellagic acid ameliorates atherosclerosis by targeting the epidermal growth factor receptor
|
Huang, Y.-W.; Wang, L.-T.; Yin, H.-L.; Hu, D.-D.; Sheng, J.; Wang, X.-J.
|
Ye-Wei Huang
|
Yunnan Agriculture University
|
10.1101/2023.09.14.557846
|
2023-09-15
|
1
|
new results
|
cc_by_nc_nd
|
biochemistry
|
https://www.biorxiv.org/content/early/2023/09/15/2023.09.14.557846.source.xml
|
BACKGROUNDHigh levels of plasma low-density lipoprotein (LDL) are a key risk factor for atherosclerosis. Low-density lipoprotein receptor (LDLR) mediates the degradation of plasma LDL. Therefore, it may be possible to prevent and treat atherosclerosis by increasing the levels of LDLR. The natural polyphenolic compound ellagic acid (EA) has various biological activities. In mice, EA alleviated the progression of atherosclerosis; however, the underlying mechanism remains unclear.
METHODSMolecular interaction, cell, and animal experiments were used to explore the role and mechanism of EA in improving atherosclerosis.
RESULTSEA binds to the extracellular domain of the epidermal growth factor receptor (EGFR), thus activating the EGFR-extracellular signal-regulated kinase (EGFR-ERK) signaling pathway, stabilizing LDLR mRNA, and promoting the expression of LDLR protein. The development of EA-loaded human serum albumin nanoparticles enabled intravenous administration in animal experiments.
CONCLUSIONSThe research verified the in vivo effects of EA on the EGFR-ERK signaling pathway, LDLR levels, and atherosclerosis. EA may assist in the prevention and treatment of atherosclerosis.
|
NA
|
bioRxiv
|
[
117,
235,
25,
109,
168,
164,
91,
30,
220,
139,
53,
113,
75,
99,
52,
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193,
22,
21,
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86,
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116,
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2,
223,
220,
26,
133,
127,
124,
144,
72,
76,
198,
212,
68,
184,
56,
70,
52
]
|
10.1101/2023.02.20.529310
|
Biophysical characterization and modeling of SCN1A gain-of-function predicts interneuron hyperexcitability and a predisposition to network instability through homeostatic plasticity
|
Berecki, G.; Bryson, A.; Polster, T.; Petrou, S.
|
Steven Petrou
|
Praxis Precision Medicines
|
10.1101/2023.02.20.529310
|
2023-02-21
|
1
|
new results
|
cc_by
|
neuroscience
|
https://www.biorxiv.org/content/early/2023/02/21/2023.02.20.529310.source.xml
|
SCN1A gain-of-function variants are associated with early onset developmental and epileptic encephalopathies (DEEs) that possess distinct clinical features compared to Dravet syndrome caused by SCN1A loss-of-function. However, it is unclear how SCN1A gain-of-function may predispose to cortical hyper-excitability and seizures. Here, we first report the clinical features of a patient carrying a de novo SCN1A variant (T162I) associated with neonatal-onset DEE, and then characterize the biophysical properties of T162I and three other SCN1A variants associated with neonatal-onset or early infantile DEE (I236V, P1345S, R1636Q). In voltage clamp experiments, three variants (T162I, P1345S and R1636Q) exhibited changes in activation and inactivation properties that enhanced window current, consistent with gain-of-function. Dynamic action potential clamp experiments utilising model neurons incorporating Nav1.1. channels supported a gain-of-function mechanism for all four variants. Here, the T162I, I236V, P1345S, and R1636Q variants exhibited higher peak firing rates relative to wild type and the T162I and R1636Q variants produced a hyperpolarized threshold and reduced neuronal rheobase. To explore the impact of these variants upon cortical excitability, we used a spiking network model containing an excitatory pyramidal cell (PC) and parvalbumin positive (PV) interneuron population. SCN1A gain-of-function was modeled by enhancing the excitability of PV interneurons and then incorporating three simple forms of homeostatic plasticity that restored pyramidal cell firing rates. We found that homeostatic plasticity mechanisms exerted differential impact upon network function, with changes to PV- to-PC and PC-to-PC synaptic strength predisposing to network instability. Overall, our findings support a role for SCN1A gain-of-function and inhibitory interneuron hyperexcitability in early onset DEE. We propose a mechanism through which homeostatic plasticity pathways can predispose to pathological excitatory activity and contribute to phenotypic variability in SCN1A disorders.
|
NA
|
bioRxiv
|
[
208,
73,
8,
110,
152,
224,
217,
150,
193,
28,
19,
127,
13,
49,
116,
46,
39,
97,
200,
117,
246,
177,
255,
233,
16,
83,
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118,
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153,
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85,
140,
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98,
0,
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165,
137,
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183,
218,
204,
4,
63,
241,
198,
15,
53,
127,
154,
188,
157,
120,
242,
68,
167,
120,
36,
231,
156,
35,
205,
56,
144,
48,
119,
205,
162,
106,
95,
195,
80,
158,
249,
26,
26,
60
]
|
10.1101/2022.09.16.22279894
|
Intraoperative phrenic stimulation offsets diaphragm fiber weakness during cardiothoracic surgery
|
Bresciani, G. B.; Beaver, T.; Martin, A. D.; Van der Pijl, R.; Mankowski, R.; Leeuwenburgh, C.; Ottenheijm, C. A. C.; Martin, T.; Arnaoutakis, G. J.; Ahmed, S.; Mariani, V.; Xue, W.; Smith, B. K.; Ferreira, L. F.
|
Leonardo F Ferreira
|
University of Florida
|
10.1101/2022.09.16.22279894
|
2022-09-18
|
1
|
PUBLISHAHEADOFPRINT
|
cc_by_nc_nd
|
rehabilitation medicine and physical therapy
|
https://www.medrxiv.org/content/early/2022/09/18/2022.09.16.22279894.source.xml
|
RationaleMechanical ventilation rapidly induces slow and fast fiber contractile dysfunction in the human diaphragm, which could be attenuated by phrenic nerve stimulation. Here, we present data from a controlled trial of intraoperative phrenic stimulation to offset slow and fast fiber contractile dysfunction and myofilament protein derangements.
ObjectivesIn this study, we tested the hypothesis that intraoperative hemidiaphragm stimulation would mitigate slow and fast fiber loss of contractile function in the human diaphragm.
MethodsNineteen adults (9 females, age 59 {+/-}12 years) consented to participate. Unilateral phrenic twitch stimulation was applied for one minute, every 30 minutes during cardiothoracic surgery. Thirty minutes following the last stimulation bout, biopsies were obtained from the hemidiaphragms for single fiber force mechanics and quantitation of thin filament protein abundance. Effects of stimulation and fiber type on force mechanics were evaluated with linear mixed models with the subject treated as a random intercept effect.
Measurements and Main ResultsSubjects underwent 6 {+/-}2 hemidiaphragm stimulations at 17 {+/-}6 mA, during 278 {+/-}68 minutes of mechanical ventilation. In slow-twitch fibers, cross-sectional area (p<0.0001) and specific force (p<0.0005) were significantly greater on the stimulated side. Longer-duration surgeries were associated with lower slow-twitch specific force (p<0.001). Stimulation did not alter contractile function of fast-twitch fibers or calcium-sensitivity in either fiber type. There were no differences in abundance or phosphorylation of myofilament proteins.
ConclusionUnilateral phrenic stimulation during open chest surgery preserved contractile function of slow-twitch diaphragm fibers, but had no effect on relative abundance of sarcomeric proteins.
|
NA
|
medRxiv
|
[
212,
73,
217,
108,
138,
67,
184,
158,
209,
24,
118,
241,
45,
120,
101,
11,
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101,
65,
85,
212,
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247,
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86,
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29,
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66,
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79,
216,
76,
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253,
33,
223,
35,
179,
166,
88,
29,
185,
171,
57,
164,
27,
7,
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54,
216,
168,
81,
104,
121,
33,
75,
28,
34,
16,
31,
206,
18,
154,
155,
49,
240,
93,
176,
102,
64,
49,
175,
47,
158,
227,
34,
36,
27,
189,
168,
170,
159,
203,
232,
166,
43,
145,
154,
155,
19,
63,
250,
220,
158,
250,
166,
112,
159,
236,
52,
71,
12,
19,
223,
168,
152,
44,
119,
173,
0,
200,
92,
114,
210,
143,
171,
30,
118,
56
]
|
10.1101/2020.05.21.20074682
|
Leukopenia of Asymptomatic COVID-19 Infections under 18 Years Old in Recovery Stage
|
Zhang, W.; Yuan, Y.; Yang, Z.; Fu, J.; Zhang, Y.; Ma, M.; Wu, W.; Zhou, H.
|
Wei Zhang
|
Affiliated Hospital of Zunyi Medical University
|
10.1101/2020.05.21.20074682
|
2020-06-28
|
2
|
PUBLISHAHEADOFPRINT
|
cc_by_nc_nd
|
infectious diseases
|
https://www.medrxiv.org/content/early/2020/06/28/2020.05.21.20074682.source.xml
|
ObjectivesIn December, 2019, a type of novel coronavirus which was designated novel coronavirus 2019 (2019-nCoV) by World Health Organization (WHO) occurred in Wuhan, Hubei, China. The epidemiological and clinical characteristics of those patients under 18 years old in the recovery stage are limited. To compare the difference of epidemiological and clinical characteristics of COVID-19 involving 25 patients under 18 years old in recovery stage between confirmed and asymptomatic infections.
MethodsRetrospective, single-center cohort study of COVID-19 involving 25 patients under 18 years old in the recovery stage at Guizhou Provincial Staff Hospital in Guiyang, China, from January 29, to March 31, 2020; final date of follow-up was April 22. Epidemiological, demographic, clinical, laboratory, radiological, and treatment data were collected and analyzed. Epidemiological and clinical characteristics of confirmed COVID-19 infections and asymptomatic infections were compared.
ResultsAmong the 25 COVID infections under 18 years old, 16 (64%) were mild or moderate confirmed cases, and 9 (36%) were asymptomatic. The shortest treatment period was 6 days, the longest 26 days, and the average treatment period 14 days. Four cases (44.4%) had visited Wuhan or had a living story in the city. There were 9 (100%) asymptomatic cases were familial cluster outbreak, with an average infection number was 6 cases among all families. The number of asymptomatic COVID-19 infections with leukopenia were significantly more than confirmed cases (p=0.04).
ConclusionsLeukopenia mostly occurred in asymptomatic COVID-19 infections under 18 years old compared with the confirmed patients.
Key PointIn this single-center case series involving 25 cases under 18 years old with COVID-19 infections, leukopenia mostly occurred in asymptomatic infections.
|
NA
|
medRxiv
|
[
49,
200,
12,
76,
152,
181,
194,
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79,
121,
189,
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242,
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157,
121,
58,
114,
61
]
|
10.1101/2025.03.24.645017
|
Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation
|
Agarwal, G.; Antoszewski, M.; Xie, X.; Pershad, Y.; Arora, U. P.; Poon, C.-L.; Lyu, P.; Lee, A. J.; Guo, C.-J.; Ye, T.; Norford, L. B.; Neehus, A.-L.; della Volpe, L.; Wahlster, L.; Ranasinghe, D.; Ho, T.-C.; Barlowe, T. S.; Chow, A.; Schurer, A.; Taggart, J.; Durham, B. H.; Abdel-Wahab, O.; McGraw, K. L.; Allan, J. M.; Soldatov, R.; Bick, A. G.; Kharas, M. G.; Sankaran, V. G.
|
Vijay G. Sankaran
|
Boston Children's Hospital
|
10.1101/2025.03.24.645017
|
2025-03-26
|
1
|
new results
|
cc_by_nc_nd
|
genetics
|
https://www.biorxiv.org/content/early/2025/03/26/2025.03.24.645017.source.xml
|
Somatic mutations that increase hematopoietic stem cell (HSC) fitness drive their expansion in clonal hematopoiesis (CH) and predispose to blood cancers. Although CH frequently occurs with aging, it rarely progresses to overt malignancy. Population variation in the growth rate and potential of mutant clones suggests the presence of genetic factors protecting against CH, but these remain largely undefined. Here, we identify a non-coding regulatory variant, rs17834140-T, that significantly protects against CH and myeloid malignancies by downregulating HSC-selective expression and function of the RNA-binding protein MSI2. By modeling variant effects and mapping MSI2 binding targets, we uncover an RNA network that maintains human HSCs and influences CH risk. Importantly, rs17834140-T is associated with slower CH expansion rates in humans, and stem cell MSI2 levels modify ASXL1-mutant HSC clonal dominance in experimental models. These findings leverage natural resilience to highlight a key role for post-transcriptional regulation in human HSCs, and offer genetic evidence supporting inhibition of MSI2 or its downstream targets as rational strategies for blood cancer prevention.
|
NA
|
bioRxiv
|
[
240,
202,
25,
92,
142,
162,
89,
210,
237,
94,
243,
123,
109,
97,
124,
239,
100,
237,
192,
22,
116,
230,
151,
65,
214,
87,
102,
25,
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240,
230,
38,
69,
3,
221,
58,
28,
135,
119,
93,
160,
118,
72,
202,
214,
14,
121,
146,
103,
60
]
|
10.1101/2022.04.02.486850
|
A brain-inspired object-based attention network for multi-object recognition and visual reasoning
|
Adeli, H.; Ahn, S.; Zelinsky, G.
|
Hossein Adeli
|
Stony Brook University
|
10.1101/2022.04.02.486850
|
2022-04-26
|
2
|
new results
|
cc_by
|
animal behavior and cognition
|
https://www.biorxiv.org/content/early/2022/04/26/2022.04.02.486850.source.xml
|
The visual system uses sequences of selective glimpses to objects to support goal-directed behavior, but how is this attention control learned? Here we present an encoder-decoder model inspired by the interacting bottom-up and top-down visual pathways making up the recognitionattention system in the brain. At every iteration, a new glimpse is taken from the image and is processed through the "what" encoder, a hierarchy of feedforward, recurrent, and capsule layers, to obtain an object-centric (object-file) representation. This representation feeds to the "where" decoder, where the evolving recurrent representation provides top-down attentional modulation to plan subsequent glimpses and impact routing in the encoder. We demonstrate how the attention mechanism significantly improves the accuracy of classifying highly overlapping digits. In a visual reasoning task requiring comparison of two objects, our model achieves near-perfect accuracy and significantly outperforms larger models in generalizing to unseen stimuli. Our work demonstrates the benefits of object-based attention mechanisms taking sequential glimpses of objects.
|
NA
|
bioRxiv
|
[
192,
126,
12,
110,
136,
226,
86,
174,
96,
7,
82,
55,
245,
112,
209,
187,
93,
1,
70,
76,
84,
61,
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168,
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53,
162,
64,
205,
3,
86,
142,
123,
59,
6,
157
]
|
10.1101/2025.03.20.644436
|
High-throughput protein target mapping enables accelerated bioactivity discovery for ToxCast and PFAS compounds
|
Yang, D.; Wang, X.; Liu, J.; Nair, P.; Sun, J.; Gong, Y.; Qian, X.; Cui, C.; Zeng, H.; Dong, A.; Harding, R. J.; Burgess-Brown, N.; Beyett, T. S.; Song, D.; Krause, H.; Diamond, M. L.; Bolhuis, D. L.; Brown, N. G.; Arrowsmith, C. H.; Edwards, A. M.; Halabelian, L.; Peng, H.
|
Hui Peng
|
University of Toronto
|
10.1101/2025.03.20.644436
|
2025-03-25
|
1
|
new results
|
cc_by_nc_nd
|
pharmacology and toxicology
|
https://www.biorxiv.org/content/early/2025/03/25/2025.03.20.644436.source.xml
|
Chemical pollution is a global threat to human health, yet the toxicity mechanism of most contaminants remains unknown. Here, we applied an ultrahigh-throughput affinity-selection mass spectrometry (AS-MS) platform to systematically identify protein targets of prioritized chemical contaminants. After benchmarking the platform, we screened 50 human proteins against 481 prioritized chemicals, including 446 ToxCast chemicals and 35 per-and polyfluoroalkyl substances (PFAS). Among 24,050 interactions assessed, we discovered 35 novel interactions involving 14 proteins, with fatty acid-binding proteins (FABPs) emerging as the most ligandable protein family. Given this, we selected FABPs for further validation, which revealed a distinct PFAS binding pattern: legacy PFAS selectively bound to FABP1, whereas replacement compounds, PFECAs, unexpectedly interacted with all FABPs. X-ray crystallography further revealed that the ether group enhances molecular flexibility of alternative PFAS, to accommodate the binding pockets of FABPs. Our findings demonstrate that AS-MS is a robust platform for the discovery of novel protein targets beyond the scope of the ToxCast program and highlight the broader protein-binding spectrum of alternative PFAS as potential regrettable substitutes.
|
NA
|
bioRxiv
|
[
117,
171,
228,
110,
140,
177,
28,
24,
237,
140,
113,
209,
1,
112,
53,
41,
109,
73,
76,
30,
5,
246,
249,
83,
87,
95,
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221,
179,
125,
77,
133,
77,
201,
168,
84,
78,
248,
98,
102,
52
]
|
10.1101/2025.03.22.644563
|
Patient-derived liver biopsy organoids enable precision alcohol-associated liver disease modeling
|
Arino, S.; Zannatto, L.; Martinez-Garcia de la Torre, R. A.; Ferrer-Lorente, R.; Cratacos-Gines, J.; Belen Rubio, A.; Perez, M.; Aguilar-Bravo, B.; Serrano, G.; Atkinson, S.; Xu, Z.; Cantallops-Vila, P.; Sererols-Vinas, L.; Ruiz-Blazquez, P.; Rill, A.; Lozano, J. J.; Coll, M.; Ochoa, I.; Affo, S.; Moles, A.; Mereu, E.; Bataller, R.; Pose, E.; Sancho-Bru, P.
|
Pau Sancho-Bru
|
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
|
10.1101/2025.03.22.644563
|
2025-03-25
|
1
|
new results
|
cc_no
|
cell biology
|
https://www.biorxiv.org/content/early/2025/03/25/2025.03.22.644563.source.xml
|
Background & AimsAlcohol-associated liver disease (ALD) is a major cause of liver disease worldwide with scarce therapeutic options. Animal models poorly recapitulate advanced ALD precluding the development of new treatments. Organoids have emerged as a powerful human-based preclinical tool. However, current patient-derived liver organoids fail to recapitulate the epithelial heterogeneity and its generation requires liver surgical resections, thus limiting personalized disease modeling. Here, we report the development of organoids from liver needle biopsies (b-Orgs) from patients with ALD.
Methodsb-Orgs were generated from tru-cut biopsies from patients at early (n=28) and advanced (n=34) stages of ALD. b-Orgs were characterized by immunofluorescence, bulk and single cell RNA-sequencing and compared to parental tissues. b-Orgs were used to model ALD progression, identify pathogenic drivers, induce alcohol-associated hepatitis (AH) and evaluate response to prednisolone.
ResultsPhenotypic and functional analysis of b-Orgs showed hepatocyte- enriched features. Single-cell RNA-sequencing revealed a heterogeneous cell composition comprising hepatocyte, biliary and progenitor populations, mirroring the epithelial landscape found in patients with advanced ALD. Moreover, b-Orgs preserved disease-stage features and allowed to identify the association of ELF3 with cell plasticity and disease progression. Finally, stimulation of b-Orgs with drivers of ALD induced pathophysiological features of alcohol-associated hepatitis, including ROS production, lipid accumulation, inflammation and decreased cell proliferation, which were mitigated in response to prednisolone.
Conclusions
Overall, we provide a human-based model that recapitulates epithelial complexity and patient specific features, allowing to identify drivers of cell plasticity and expanding organoid-based liver disease modeling for personalized medicine.
Impact and implications
Here, we describe the generation of biopsy-derived organoids (b-Orgs) from patients with liver disease. b-Orgs reproduce the liver epithelial cell composition found in patients liver tissue and are efficiently generated from different stages of the disease, providing a platform for patient- tailored disease modeling and drug testing.
|
NA
|
bioRxiv
|
[
165,
75,
141,
124,
172,
160,
226,
156,
193,
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189,
77,
115,
236,
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92,
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26,
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56
]
|
10.1101/2023.07.03.23291969
|
Measuring up: A Comparison of Tapestation 4200 and Bioanalyzer 2100 as Measurement Tools for RNA Quality in Postmortem Human Brain Samples
|
Walker, J. E.; Oliver, J. C.; Stewart, A. M.; Beh, S. T.; Arce, R. A.; Glass, M. J.; Vargas, D. E.; Qiji, S. H.; Intorcia, A. J.; Borja, C. I.; Cline, M. P.; Hemmingsen, S. J.; Krupp, A. N.; McHattie, R. D.; Mariner, M. R.; Lorenzini, I.; Aslam, S.; Tremblay, C.; Beach, T. G.; Serrano, G. G.
|
Geidy G Serrano
|
Banner Health
|
10.1101/2023.07.03.23291969
|
2023-07-06
|
1
|
PUBLISHAHEADOFPRINT
|
cc_no
|
pathology
|
https://www.medrxiv.org/content/early/2023/07/06/2023.07.03.23291969.source.xml
|
Determining RNA integrity is a critical quality assessment tool for gene expression studies where the experiments success is highly dependent on sample quality. Since its introduction in 1999, the gold standard in the scientific community has been the Agilent 2100 Bioanalyzers RNA Integrity Number (RIN) which uses a 1-10 value system with 1 being the most degraded to 10 being the most intact. In 2015, Agilent launched the 4200 Tapestations RIN equivalent and reported a strong correlation of r2 of 0.936 and median error < {+/-} 0.4 RIN units. To evaluate this claim, we compared the Agilent 4200 Tapestations RIN equivalent (RINe) and DV200 to the Agilent 2100 Bioanalyzers RIN for 183 parallel RNA samples. In our study, using RNA from a total of 183 human postmortem brain samples, we found that the RIN and RINe values only weakly correlate with an r2 of 0.393 and an average difference of 3.2 RIN units. DV200 also only weakly correlated with RIN (r2 of 0.182) and RINe (r2 of 0.347). Finally, when applying a cut-off value of 6.5 for both metrics, we found that 95.6% of samples passed with RIN, while only 23.5% passed with RINe. Our results suggest that even though RIN (Bioanalyzer) and RINe (Tapestation) use the same 1-10 value system, they should not be used interchangeably, and cut-off values should be calculated independently.
|
NA
|
medRxiv
|
[
242,
232,
12,
94,
172,
161,
27,
218,
203,
13,
83,
177,
109,
99,
124,
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77,
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169,
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146,
237,
84,
194,
210,
158,
9,
58,
87,
54
]
|
10.1101/2024.01.17.575995
|
The Role of Rhizosphere Microorganisms and CNPS Genes in Shaping Nutritional Traits of Capsicum
|
Tao, Y.; Zhang, M.; Peng, S.; Long, S.; Zou, X.; Li, X.
|
Xin Li
|
1 Hunan Institute of Vegetables Research; 2 Hunan Engineering Research Center on Excavation and Utilization of the Endophytic Microbial Resources of Plants; 6 I
|
10.1101/2024.01.17.575995
|
2024-01-20
|
1
|
confirmatory results
|
cc_no
|
microbiology
|
https://www.biorxiv.org/content/early/2024/01/20/2024.01.17.575995.source.xml
|
The rhizosphere microbiota plays crucial roles in biogeochemical cycling and primary production. However, there is a lack of research exploring the complex relationships between microbiota and their functional traits in pepper rhizospheres, as well as their impact on nutrient cycling processes. Here, we investigated the effects of pepper species on the rhizomicrobiota and functional genes (C/N/P/S) on nutrient absorptions and accumulations in pepper organs. The results revealed that Pepper YZ/BE had higher N content in all compartments, which could be attributed to the presence of enriched N-metabolic microbes (Gaiellales/Leifsonia) and higher expression of N availability-promoting genes (ureC/amoA2/nxrA/napA) in rhizospheres. Additionally, we utilized co-occurrence network analysis and partial least squares path modeling (PLS-PM) to understand the interactions among the variables. The bacterial network exhibited more associations than the fungal network, and the abundance of certain modules positively correlated with the expression of CNPS genes, which thus significantly influenced pepper nutrient content. The PLS-PM analysis demonstrated that taxa abundance in network modules, functional genes, and rhizospheric soil properties collectively explained 92% of the variance in pepper nutrient content. Overall, this study provides valuable experimental and theoretical insights into the effects of rhizosphere microorganisms and CNPS genes on the nutritional traits of Capsicum.
HighlightThe rizho-bacterial community harbored more robust relationships than the fungal ones, which formed the functional clusters highly linking to the below- and aboveground nutrient properties of pepper species.
|
NA
|
bioRxiv
|
[
109,
233,
205,
76,
142,
152,
57,
220,
232,
58,
113,
221,
77,
115,
62,
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69,
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69,
127,
212,
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94,
33,
127,
47,
176,
98,
64,
98,
212,
77,
248,
81,
70,
53
]
|
10.1101/2024.01.16.575942
|
Dietary tryptophan and genetic susceptibility expand gut microbiota that promote systemic autoimmune activation
|
Ma, L.; Ge, Y.; Brown, J.; Choi, S. C.; Elshikha, A.; Kanda, N.; Terrell, M.; Six, N.; Garcia, A.; Mohamadzadeh, M.; Silverman, G. J.; Morel, L.
|
Laurence Morel
|
UT Health San Antonio
|
10.1101/2024.01.16.575942
|
2024-01-20
|
1
|
new results
|
cc_by_nc_nd
|
immunology
|
https://www.biorxiv.org/content/early/2024/01/20/2024.01.16.575942.source.xml
|
Tryptophan modulates disease activity and the composition of microbiota in the B6.Sle1.Sle2.Sle3 (TC) mouse model of lupus. To directly test the effect of tryptophan on the gut microbiome, we transplanted fecal samples from TC and B6 control mice into germ-free or antibiotic-treated non-autoimmune B6 mice that were fed with a high or low tryptophan diet. The recipient mice with TC microbiota and high tryptophan diet had higher levels of immune activation, autoantibody production and intestinal inflammation. A bloom of Ruminococcus gnavus (Rg), a bacterium associated with disease flares in lupus patients, only emerged in the recipients of TC microbiota fed with high tryptophan. Rg depletion in TC mice decreased autoantibody production and increased the frequency of regulatory T cells. Conversely, TC mice colonized with Rg showed higher autoimmune activation. Overall, these results suggest that the interplay of genetic and tryptophan can influence the pathogenesis of lupus through the gut microbiota.
|
NA
|
bioRxiv
|
[
119,
72,
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126,
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183,
184,
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217,
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80,
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27,
78,
188
]
|
10.1101/2024.01.15.575792
|
Single-cell RNA sequencing reveals recruitment of the M2-like CCL8high macrophages in Lewis lung carcinoma-bearing mice following hypofractionated radiotherapy
|
Yang, H.; Lei, Z.; He, J.; Zhang, L.; Lai, T.; Zhou, L.; Wang, N.; Tang, Z.; Sui, J.; Wu, Y.
|
Yongzhong Wu
|
Radiation Oncology Center, Chongqing University Cancer Hospital
|
10.1101/2024.01.15.575792
|
2024-01-17
|
1
|
new results
|
cc_by_nc
|
immunology
|
https://www.biorxiv.org/content/early/2024/01/17/2024.01.15.575792.source.xml
|
Tumor-associated macrophages (TAMs) are a crucial factor in reprogramming the tumor microenvironment following radiotherapy. The mechanisms underlying this process remain to be elucidated. Here, we seek to investigate the effects of hypofractionated radiotherapy on macrophages dynamics in a subcutaneous Lewis lung carcinoma murine model. Utilizing single-cell RNA sequencing, we identified a distinct M2-like population of macrophages with high Ccl8 expression level post-hypofractionated radiotherapy. Remarkbly, hypofractionated radiotherapy promoted CCL8high macrophages infiltration and reprogrammed them by upregulating immunosuppressive genes and downregulating antigen-presenting genes, leading to an immunosuppressive tumor microenvironment. Further, we demonstrated that hypofractionated radiotherapy amplified the CCL signaling pathway, enhancing the pro-tumorigenic functions of CCL8high macrophages and promoting macrophages recruitment. The combination therapy of hypofractionated radiotherapy with the CCL signal inhibitor Bindarit was effective in reducing M2 macrophages infiltration and extending the duration of local tumor control. This research highlights the potential of targeting TAMs and introduces a novel combination to improve the efficacy of hypofractionated radiotherapy.
|
NA
|
bioRxiv
|
[
176,
235,
221,
92,
142,
162,
216,
16,
220,
138,
247,
249,
77,
34,
108,
175,
36,
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66,
117,
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37,
217,
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87,
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28
]
|
10.1101/669457
|
Resting state functional connectivity in early post-anesthesia recovery is characterized by globally reduced anticorrelations
|
Nir, T.; Jacob, Y.; Huang, K.-H.; Schwartz, A. E.; Brallier, J. W.; Ahn, H.; Kundu, P.; Tang, C. Y.; Delman, B. N.; McCormick, P. J.; Sano, M.; Deiner, S. G.; Baxter, M. G.; Mincer, J. S.
|
Joshua S. Mincer
|
Memorial Sloan Kettering Cancer Center
|
10.1101/669457
|
2019-06-26
|
2
|
new results
|
cc_by_nc_nd
|
neuroscience
|
https://www.biorxiv.org/content/early/2019/06/26/669457.source.xml
|
Though a growing body of literature is addressing the possible longer-term cognitive effects of anesthetics, to date no study has delineated the normal trajectory of neural recovery due to anesthesia alone in older adults. We obtained resting state functional magnetic resonance imaging scans on 62 healthy human volunteers between ages forty and eighty before, during, and after sevoflurane (general) anesthesia, in the absence of surgery, as part of a larger study on cognitive function post-anesthesia. Resting state networks expression decreased consistently one hour after emergence from anesthesia. This corresponded to a global reduction in anticorrelated functional connectivity post-anesthesia, seen across individual regions-of-interest. Positively correlated functional connectivity remained constant across peri-anesthetic states. All measures returned to baseline 1 day later, with individual regions-of-interest essentially returning to their pre-anesthesia connectivity levels. These results define normal peri-anesthetic changes in resting state connectivity in healthy older adults.
|
NA
|
bioRxiv
|
[
209,
97,
105,
94,
184,
228,
10,
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161,
47,
41,
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50
]
|
10.1101/2023.11.08.566131
|
TNFa hinders FGF4 efficacy to mitigate ALS astrocyte dysfunction and cGAS-STING pathway-induced innate immune reactivity
|
Velasquez, E.; savchenko, e.; marmolejo, s.; challuau, d.; aebi, a.; Pomeshchik, Y.; Lamas, N.; Vihinen, M.; Rezeli, m.; schneider, b.; Raoul, c.; roybon, l.
|
laurent roybon
|
Van Andel Institute
|
10.1101/2023.11.08.566131
|
2023-11-12
|
1
|
new results
|
cc_by_nc
|
neuroscience
|
https://www.biorxiv.org/content/early/2023/11/12/2023.11.08.566131.source.xml
|
Astrocytes play an important role in the onset and progression of amyotrophic lateral sclerosis (ALS), a fatal disorder characterized by the relentless degeneration of motor neurons (MNs) in the central nervous system. Despite evidence showing that ALS astrocytes are toxic to MNs, little is understood about the earliest pathological changes that lead to their neurotoxic phenotype. In this study, we generated human astrocytes from induced pluripotent stem cells (iPSCs) harboring the ALS-associated A4V mutation in superoxide dismutase 1 (SOD1), to examine cellular pathways and network changes similar to early stages of the disease. By using proteomics as a molecular indicator, we observed significant alterations in the levels of proteins linked to ALS pathology and the cGAS-STING pathway-induced innate immunity. Interestingly, we found that the protein profile of reactive ALS astrocytes differed from that of wildtype astrocytes treated with the pro-inflammatory cytokine TNF. Notably, we showed that fibroblast growth factor 4 (FGF4) reversed ALS astrocyte dysfunction and reactivity, but failed to provide protection to MNs when expressed in the spinal cord of the SOD1G93A mouse model of ALS. Further analysis showed that ALS astrocyte reactivity which was rescued by FGF4 was abrogated by TNF. The latter is capable of exacerbating the dysfunction and reactivity of ALS astrocytes compared to control. Our data show that iPSC-derived ALS astrocytes are dysfunctional and spontaneously exhibit a reactive phenotype when generated from iPSCs. This suggests that this phenotype may resemble the early stages of the disease. Our data also demonstrate that reducing mutant astrocyte reactivity in vivo using FGF4 is not sufficient to prevent MN death in a mouse model of ALS. To mitigate ALS, future studies should investigate whether dual therapies that both lower astrocyte reactivity and reverse disease-associated cellular dysfunction could prevent MN death.
Graphic abstract
O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/566131v1_ufig1.gif" ALT="Figure 1">
View larger version (48K):
org.highwire.dtl.DTLVardef@9490b5org.highwire.dtl.DTLVardef@1a897e5org.highwire.dtl.DTLVardef@18c4578org.highwire.dtl.DTLVardef@24da7d_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights- ALS astrocytes are dysfunctional and reactive compared to wildtype astrocytes
- FGF4 reverses ALS astrocyte dysfunction and reactivity
- FGF4 lowers ALS astrocyte reactivity in vivo but fails to protect ALS motor neurons from death
- ALS astrocyte reactivity rescued by FGF4 is attenuated by TNF
|
NA
|
bioRxiv
|
[
84,
201,
141,
124,
168,
161,
146,
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225,
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59,
77,
49,
69,
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84,
213,
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]
|
10.1101/2022.01.07.475425
|
ARF small GTPases in the developmental function mediated by ARF regulators GNOM and VAN3
|
Adamowski, M.; Matijevic, I.; Friml, J.
|
Maciek Adamowski
|
IST Austria
|
10.1101/2022.01.07.475425
|
2022-01-10
|
1
|
new results
|
cc_no
|
plant biology
|
https://www.biorxiv.org/content/early/2022/01/10/2022.01.07.475425.source.xml
|
ARF small GTPases are molecular switches acting in intracellular trafficking. Their cycles of activity are controlled by regulators, ARF Guanine nucleotide Exchange Factors (ARF-GEFs) and ARF GTPase Activating Proteins (ARF-GAPs). The ARF-GEF GNOM (GN) and the ARF-GAP VAN3 share a prominent function in auxin-mediated developmental patterning, but the ARFs which they might control were not identified. We conducted a loss-of-function and localization-based screening of the ARF/ARF-LIKE gene family in Arabidopsis thaliana with the primary aim of identifying functional partners of GN and VAN3, while extending the limited understanding of this gene group as a whole. We identified a function of ARLA1 in branching angle control. Mutants lacking the variably localized ARLB1, ARFB1, ARFC1, ARFD1, and ARF3, even in high order combinations, do not exhibit any evident phenotypes. Loss of function arfa1 phenotypes support a major role of ARFA1 in growth and development overall, but patterning defects typical to gn loss of function are not found. ARFA1 are not localized at the plasma membrane, where GN and VAN3 carry out developmental patterning function according to current models. Taken together, putative ARF partners of GN and VAN3 in developmental patterning cannot be conclusively identified.
|
NA
|
bioRxiv
|
[
246,
234,
203,
108,
136,
250,
148,
216,
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85,
105,
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84,
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]
|
10.1101/2022.12.19.521138
|
Little pig, little pig, let me come in: The influence of landscape structure and La Nina climatic anomalies on the emergence of Japanese encephalitis virus in Australian piggeries in 2022
|
Walsh, M. G.; Webb, C. E.; Brookes, V.
|
Michael G Walsh
|
Faculty of Medicine, University of Sydney
|
10.1101/2022.12.19.521138
|
2022-12-20
|
1
|
new results
|
cc_by
|
ecology
|
https://www.biorxiv.org/content/early/2022/12/20/2022.12.19.521138.source.xml
|
The widespread activity of Japanese encephalitis virus (JEV) in previously unaffected regions of eastern and southern Australia in 2022 represents the most significant local arbovirus emergency in almost 50 years. Japanese encephalitis virus is transmitted by mosquitoes and maintained in wild ardeid birds and amplified in pigs, the latter of which suffer significant reproductive losses as a result of infection. The landscape of JEV outbreak risk in mainland Australia is almost entirely unknown, particularly in the eastern and southern parts of the country where the virus has not been previously documented. Although other areas with endemic JEV circulation in the Indo-Pacific region have demonstrated the importance of wild waterbird-livestock interface in agricultural-wetland mosaics, no such investigation has yet determined the configuration of pathogenic landscapes for Australia. Moreover, the recent emergence in Australia has followed substantial precipitation and temperature anomalies associated with the La Nina phase of the El Nino Southern Oscillation. This study investigated the landscape epidemiology of JEV outbreaks in Australian piggeries recorded between January and April of 2022 to determine the influence of ardeid habitat suitability, hydrogeography, hydrology, land cover and La Nina-associated climate anomalies in demarcating risk. Outbreaks of JEV in domestic pigs were associated with ardeid species richness, agricultural and riparian landscape mosaics, hydrological flow accumulation, and grasslands. This study has identified the composition and configuration of landscape features that delineated risk for piggeries during the 2022 emergence of JEV in Australia. Although preliminary, these findings can inform actionable strategies for the development of new One Health JEV surveillance specific to the needs of Australia.
|
NA
|
bioRxiv
|
[
67,
204,
28,
110,
128,
161,
57,
14,
69,
1,
229,
223,
159,
99,
45,
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176,
31,
31,
122
]
|
10.1101/291047
|
A deep learning approach for uncovering lung cancer immunome patterns
|
Hess, M.; Lenz, S.; Binder, H.
|
Moritz Hess
|
Faculty of Medicine and Medical Center of the University of Freiburg
|
10.1101/291047
|
2018-03-30
|
1
|
new results
|
cc_by_nc_nd
|
bioinformatics
|
https://www.biorxiv.org/content/early/2018/03/30/291047.source.xml
|
Tumor immune cell infiltration is a well known factor related to survival of cancer patients. This has led to deconvolution approaches that can quantify immune cell proportions for each individual. What is missing, is an approach for modeling joint patterns of different immune cell types. We adapt a deep learning approach, deep Boltzmann machines (DBMs), for modeling immune cell gene expression patterns in lung adenocarcinoma. Specifically, a partially partitioned training approach for dealing with a relatively large number of genes. We also propose a sampling-based approach that smooths the original data according to a trained DBM and can be used for visualization and clustering. The identified clusters can subsequently be judged with respect to association with clinical characteristics, such as tumor stage, providing an external criterion for selecting DBM network architecture and tuning parameters for training. We show that the hidden nodes of the trained networks cannot only be linked to clinical characteristics but also to specific genes, which are the visible nodes of the network. We find that hidden nodes that are linked to tumor stage and survival represent expression of T-cell and mast cell genes among others, probably reflecting specific immune cell infiltration patterns. Thus, DBMs, trained and selected by the proposed approach, might provide a useful tool for extracting immune cell gene expression patterns. In the case of lung adenocarcinomas, these patterns are linked to survival as well as other patient characteristics, which could be useful for uncovering the underlying biology.
|
NA
|
bioRxiv
|
[
200,
121,
141,
126,
152,
161,
130,
218,
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24,
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255,
101,
105,
124,
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73,
0,
212,
30,
125,
50,
116,
60
]
|
10.1101/2022.03.02.482203
|
Class-Controlled Copy-Paste Based Cell Segmentation for CoNIC Challenge
|
Ahn, H.; Hong, Y.
|
Yiyu Hong
|
Arontier
|
10.1101/2022.03.02.482203
|
2022-03-04
|
1
|
new results
|
cc_by_nc
|
pathology
|
https://www.biorxiv.org/content/early/2022/03/04/2022.03.02.482203.source.xml
|
Muti-class cell segmentation in histopathology images is a challenging task. Here, we propose a copy-paste augmentation-based method for CoNIC challenge. As the challenge train data is severely class imbalanced. To deal with it, we copy all cell objects of train data and paste them to the train image on the fly while training model. The paste strategy is that we paste more cell objects of the insufficient classes and paste less cell objects for the sufficient classes. We experimented the method by stratified splitting train data in 4:1 ratio, the result shows the copy paste method can reach PQ 64.84 and mPQ 53.72, which improved and 0.66 compared to without copy pasted. Moreover, the improvements in those insufficient classes is more obvious.
|
NA
|
bioRxiv
|
[
172,
234,
140,
60,
140,
169,
129,
184,
200,
9,
211,
151,
109,
98,
110,
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23,
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82,
77,
19,
212,
31,
57,
122,
102,
191
]
|
10.1101/300582
|
Nonlinear dynamics of chemotherapeutic resistance
|
Newton, P.; Ma, Y.
|
Paul Newton
|
USC
|
10.1101/300582
|
2018-04-12
|
1
|
new results
|
cc_by_nc_nd
|
cancer biology
|
https://www.biorxiv.org/content/early/2018/04/12/300582.source.xml
|
We use a three-component replicator dynamical system with healthy cells, sensitive cells, and resistant cells, with a prisoners dilemma payoff matrix from evolutionary game theory to understand the phenomenon of competitive release, which is the main mechanism by which tumors develop chemotherapeutic resistance. By comparing the phase portraits of the system without therapy compared to continuous therapy above a certain threshold, we show that chemotherapeutic resistance develops if there are pre-exisiting resistance cells in the population. We examine the basin boundaries of attraction associated with the chemo-sensitive population and the chemo-resistant population for increasing values of chemo-concentrations and show their spiral intertwined structure. We also examine the fitness landscapes both with and without continuous therapy and show that with therapy, the average fitness as well as the fitness functions of each of the subpopulations initially increases, but eventually decreases monotonically as the resistant subpopulation saturates the tumor.
|
NA
|
bioRxiv
|
[
248,
254,
12,
126,
136,
164,
49,
218,
224,
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119,
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242,
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190
]
|
10.1101/2022.02.23.481600
|
Direct and delayed synergistic effects of marine heatwaves, metals and food limitation on tropical reef-associated fish larvae
|
Le, M.-H.; Dinh, K. V.; Vo, X. T.; Pham, H. Q.
|
Khuong V. Dinh
|
Nha Trang University
|
10.1101/2022.02.23.481600
|
2022-02-25
|
1
|
new results
|
cc_by_nc_nd
|
ecology
|
https://www.biorxiv.org/content/early/2022/02/25/2022.02.23.481600.source.xml
|
Tropical fish are fast-growing and high energetic-demand organisms, which can be highly vulnerable to long-lasting effects of heat stress and pollution, particularly under food shortages. We tested this by assessing highly complex direct and delayed interactive effects of an extreme temperature (32{degrees}C) from a simulated marine heatwave (MHW), copper (Cu, 0, 100, 150 and 175 {micro}g L-1) and food availability (limited and saturated food) on larvae of a tropical, reef-associated seaperch (Psammoperca waigiensis). Cu, MHW, and food limitation independently reduced survival and growth, partly explained by reduced feeding. The negative effect of Cu on fish survival was more substantial under MHW, particularly under limited food. Delayed interactive effects of Cu, MHW, and food limitation were still lethal to fish larvae during the post-exposure period. These results indicate that reef-associated fish larvae are highly vulnerable to these dominant stressors, impairing their ecological function as predators in the coral reefs.
Graphical abstract
O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/481600v1_ufig1.gif" ALT="Figure 1">
View larger version (32K):
org.highwire.dtl.DTLVardef@1bc37aborg.highwire.dtl.DTLVardef@1eaedaeorg.highwire.dtl.DTLVardef@9a409eorg.highwire.dtl.DTLVardef@1087cc6_HPS_FORMAT_FIGEXP M_FIG C_FIG
|
NA
|
bioRxiv
|
[
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|
10.1101/204594
|
Use of a Neural Circuit Probe to Validate in silico Predictions of Inhibitory Connections
|
Liu, H.; Bridges, D.; Randall, C.; Solla, S. A.; Wu, B.; Hansma, P.; Yan, X.; Kosik, K. S.; Bouchard, K.
|
Kenneth S. Kosik
|
Neuroscience Research Institute, University of California, Santa Barbara, USA
|
10.1101/204594
|
2017-10-19
|
2
|
new results
|
cc_no
|
neuroscience
|
https://www.biorxiv.org/content/early/2017/10/19/204594.source.xml
|
Understanding how neuronal signals propagate in local network is an important step in understanding information processing. As a result, spike trains recorded with Multi-electrode Arrays (MEAs) have been widely used to study behaviors of neural connections. Studying the dynamics of neuronal networks requires the identification of both excitatory and inhibitory connections. The detection of excitatory relationships can robustly be inferred by characterizing the statistical relationships of neural spike trains. However, the identification of inhibitory relationships is more difficult: distinguishing endogenous low firing rates from active inhibition is not obvious. In this paper, we propose an in silico interventional procedure that makes predictions about the effect of stimulating or inhibiting single neurons on other neurons, and thereby gives the ability to accurately identify inhibitory causal relationships. To experimentally test these predictions, we have developed a Neural Circuit Probe (NCP) that delivers drugs transiently and reversibly on individually identified neurons to assess their contributions to the neural circuit behavior. With the help of NCP, three inhibitory connections identified by our in silico modeling were validated through real interventional experiments. Together, these methods provide a basis for mapping complete neural circuits.
|
NA
|
bioRxiv
|
[
88,
233,
76,
106,
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|
10.1101/2021.06.09.447659
|
Draft genome assembly data of Anoxybacillus sp. strain MB8 isolated from Tattapani hot springs, India
|
PRASOODANAN P K, V.; S. Menon, S.; Saxena, R.; Waiker, P.; Sharma, V. K.
|
Vineet K Sharma
|
Indian Institute of Science Education and Research Bhopal
|
10.1101/2021.06.09.447659
|
2021-06-10
|
1
|
new results
|
cc_no
|
genomics
|
https://www.biorxiv.org/content/early/2021/06/10/2021.06.09.447659.source.xml
|
Discovery of novel thermophiles has shown promising applications in the field of biotechnology. Due to their thermal stability, they can survive the harsh processes in the industries, which make them important to be characterized and studied. Members of Anoxybacillus are alkaline tolerant thermophiles and have been extensively isolated from manure, dairy-processed plants, and geothermal hot springs. This article reports the assembled data of an aerobic bacterium Anoxybacillus sp. strain MB8, isolated from the Tattapani hot springs in Central India, where the 16S rRNA gene shares an identity of 97% (99% coverage) with Anoxybacillus kamchatkensis strain G10. The de novo assembly and annotation performed on the genome of Anoxybacillus sp. strain MB8 comprises of 2,898,780 bp (in 190 contigs) with a GC content of 41.8% and includes 2,976 protein-coding genes,1 rRNA operon, 73 tRNAs, 1 tm-RNA and 10 CRISPR arrays. The predicted protein-coding genes have been classified into 21 eggNOG categories. The KEGG Automated Annotation Server (KAAS) analysis indicated the presence of assimilatory sulfate reduction pathway, nitrate reducing pathway, and genes for glycoside hydrolases (GHs) and glycoside transferase (GTs). GHs and GTs hold widespread applications, in the baking and food industry for bread manufacturing, and in the paper, detergent and cosmetic industry. Hence, Anoxybacillus sp. strain MB8 holds the potential to be screened and characterized for such commercially relevant enzymes.
Specifications Table
O_TBL View this table:
org.highwire.dtl.DTLVardef@46be2org.highwire.dtl.DTLVardef@46fbe2org.highwire.dtl.DTLVardef@42cc37org.highwire.dtl.DTLVardef@16d5912org.highwire.dtl.DTLVardef@1f2bcdc_HPS_FORMAT_FIGEXP M_TBL C_TBL Values of DataO_LIThe Anoxybacillus sp. strain MB8 genome assembly data provides insights into functional potential of thermophilic enzymes of this thermotolerant microbe.
C_LIO_LIThe presence of genes for Glycoside Hydrolase (GHs) like alpha-amylase, pullulanase, neopullulanase, alpha-glucosidase, beta-fructofuranosidase etc. and genes for Glycosyl Transferase (GTs) like sucrose synthase, maltodextrin phosphorylase, starch synthase, and glycogen phosphorylase were identified, which hold strong industrial values.
C_LIO_LIThe taxonomic annotation of Anoxybacillus sp. strain MB8 using different approaches indicates that the closest relatives were Anoxybacillus gonensis NZ CP012152T (96.86% ANI) and Anoxybacillus kamchatkensis G10 NZ CP025535 (96.83% ANI) obtained from. The strain MB8 most likely belongs to the same subspecies of Anoxybacillus gonensis NZ CP012152T.
C_LI
|
NA
|
bioRxiv
|
[
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110,
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]
|
10.1101/2023.04.28.538535
|
High-throughput ligand profile characterization in novel biosensor cell lines expressing seven heterologous olfactory receptors for the detection of volatile plant biomarkers
|
Zboray, K.; Toth, A. V.; Miskolczi, T. D.; Casanova, E.; Mike, A.; Sagi, L.; Lukacs, P.
|
Peter Lukacs
|
Centre for Agricultural Research, Martonvasar, Hungary
|
10.1101/2023.04.28.538535
|
2023-04-28
|
1
|
new results
|
cc_no
|
molecular biology
|
https://www.biorxiv.org/content/early/2023/04/28/2023.04.28.538535.source.xml
|
Agriculturally important crop plants emit a multitude of volatile organic compounds (VOCs), which are excellent indicators of their health status and/or their interaction with pathogens and pests. Here, we present the generation of a novel cellular biosensor panel for the recognition of fungal pathogen-related VOCs we had identified in the field as well as during controlled inoculations of several crop plants. The panel consists of seven stable HEK293 cell lines each expressing a functional Drosophila olfactory receptor as a biosensing element and a genetically encoded fluorescent calcium indicator protein. For high-throughput measurement of odorant binding by the cells, fluorescence response was detected in an automated 384-well microplate reader upon the injection of tester VOCs. Biosensor cell lines were characterized for their reference ligand binding in more detail, then a set of 66 VOCs was profiled on all cell lines over a concentration range of three orders of magnitude (1 M to 100 M). Forty-six VOCs (70%) evoked a response in at least one biosensor cell line and certain VOCs could activate the cell lines already from the nanomolar (ppb) concentration. Interaction profiles mapped in this study will support biosensor development for agricultural applications, but the olfactory receptor proteins may also be purified from these cell lines at sufficient yields for further processing including structure determination or coupling with artificial sensor devices.
|
NA
|
bioRxiv
|
[
38,
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78,
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]
|
10.1101/2022.05.23.492977
|
Revisiting Colocalization from the Perspective of Similarity
|
da F. Costa, L.
|
Luciano da F. Costa
|
Instituto de Fisica de Sao Carlos, USP
|
10.1101/2022.05.23.492977
|
2022-05-24
|
1
|
new results
|
cc_no
|
systems biology
|
https://www.biorxiv.org/content/early/2022/05/24/2022.05.23.492977.source.xml
|
Given two or more concentrations, an interesting and important related issue concerns the quantification of how strongly they are spatially interrelated. The concept of colocalization has been frequently considered as an indication of the tendency of the values of two concentrations to spatially vary together. While this frequently adopted approach presents several interesting characteristics, being a suitable choice for several situations, in the present work we study how multiset similarity indices can be applied for similar purposes, possibly allowing a complementation, in the sense of taking into account shared portions of the concentrations, of the colocalization characterization provided by the Pearson correlation methodology. The problem of colocalization is first addressed in terms of possible underlying mathematical models, and then the Pearson correlation coefficient-based approach, as well as the standardization procedure which is its intrinsic part, are presented and discussed. The particularly important issue of how to define the baseline of the concentrations is also approached and illustrated. The minmax alternative normalization scheme is presented next, followed by the description of the three considered multiset simiarlity indices -- namely the interiority, Jaccard, and coincidence similarity approaches. The characteristics of each of these methods is then illustrated respectively to 1D, and then to 2D concentrations under presence of several interesting and relevant effects including spatial displacement, as well as sharpening, presence of unrelated effects. The similarity indices, and in particular the coincidence approach, are found to present some interesting features when applied to the quantification of the colocalization between two or more concentrations, suggesting that it can provided complementary information when performing colocalization analysis.
|
NA
|
bioRxiv
|
[
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96,
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53
]
|
10.1101/2024.07.14.603444
|
SWR1 is recruited to activated ABA response genes to maintain gene body H2A.Z in Arabidopsis thaliana
|
Krall, E. G.; Deal, R. B.
|
Roger B Deal
|
Emory University
|
10.1101/2024.07.14.603444
|
2024-07-18
|
2
|
new results
|
cc_by_nc_nd
|
plant biology
|
https://www.biorxiv.org/content/early/2024/07/18/2024.07.14.603444.source.xml
|
The histone variant H2A.Z is important for transcriptional regulation across eukaryotes, where it can alternately promote or repress transcription. In plants, actively transcribed genes show H2A.Z enrichment in nucleosomes immediately downstream of the transcription start site (TSS), while silent genes show H2A.Z enrichment across the gene body. Previous work showed that silent genes responsive to temperature and far-red light lose gene body H2A.Z upon activation, but whether H2A.Z loss is generally required for transcription is not clear. We profiled H2A.Z and components of its deposition complex, SWR1, before and after treating Arabidopsis thaliana with the hormone abscisic acid (ABA). Our results show that transcribed genes with TSS-enriched H2A.Z have high SWR1 binding at steady-state, indicating continuous replacement of H2A.Z, while silent genes with gene body H2A.Z show lower SWR1 binding. Surprisingly, upon ABA treatment, thousands of previously silent genes activate, coincident with recruitment of SWR1 and retention of gene body H2A.Z enrichment. We also found that the SWR1-interacting protein MBD9 is not required for SWR1 recruitment to activated genes. These results provide new insights into the relationship between H2A.Z and transcription and the mechanics of H2A.Z targeting to chromatin.
|
NA
|
bioRxiv
|
[
116,
203,
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220,
134,
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181
]
|
10.1101/2022.04.07.487504
|
Dyslexia associated gene, KIAA0319, regulates cell cycle during human neuroepithelium development
|
Paniagua, S.; Cakir, B.; Hu, Y.; Kiral, F. R.; Tanaka, Y.; Xiang, Y.; Patterson, B.; Gruen, J. R.; Park, I.-H.
|
Jeffrey R. Gruen
|
Yale Medical School
|
10.1101/2022.04.07.487504
|
2022-04-08
|
1
|
new results
|
cc_by_nc_nd
|
developmental biology
|
https://www.biorxiv.org/content/early/2022/04/08/2022.04.07.487504.source.xml
|
Reading Disability (RD), also known as dyslexia, is defined as difficulty processing written language in individuals with normal intellectual capacity and educational opportunity. The prevalence of RD is between 5% and 17%, and the heritability ranges from 44% to 75%. Genetic linkage analysis and genome-wide association studies (GWAS) have identified several genes and regulatory elements linked to RD and reading ability. However, their functions and molecular mechanisms are not well understood. Prominent among these is KIAA0319, encoded in the DYX2 locus of human chromosome 6p22. Association of KIAA0319 has been independently replicated in multiple independent studies and languages. Rodent models suggest that KIAA0319 is involved in neuronal migration, but its precise function is unknown. This studies aim to determine the mechanisms by which KIAA0319 affects reading and language performance. We hypothesize that KIAA0319 plays a critical role in neuronal development. RT-qPCR and quantitative immunofluorescence in the cortical neurons differentiated from H7 hESC show regulatory effects on proliferation and differentiation of neuronal progenitor cells. Knockdown of KIAA0319 expression promotes early exit from the neuroepithelial cell stage and drives cells into cell cycle arrested neuronal progenitor cell stage. This suggests that KIAA0319 act by regulating neurogenesis in the reading related centers of the brain by targeting the cell cycle of proliferative cells. This demonstrates how subtle changes in expression could affect an isolated trait such as reading without global brain effects.
|
NA
|
bioRxiv
|
[
214,
194,
93,
124,
138,
160,
143,
158,
196,
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19,
127,
105,
35,
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]
|
10.1101/2021.03.21.21253999
|
Three-dimensional cranio-facial landmark detection in CT slices from a publicly available database, using multi-phased regression networks on a personal computer.
|
Nishimoto, S.; Saito, T.; Ishise, H.; Fujiwara, T.; Kawai, K.; Kakibuchi, M.
|
Soh Nishimoto
|
Hyogo College of Medicine
|
10.1101/2021.03.21.21253999
|
2021-03-26
|
1
|
PUBLISHAHEADOFPRINT
|
cc_by_nc
|
radiology and imaging
|
https://www.medrxiv.org/content/early/2021/03/26/2021.03.21.21253999.source.xml
|
AimGeometrical assessments to comprehend the shape of an object are done based on characteristic landmarks. Computer assisted tomography (CT) images, horizontal slices as two-dimensional pictures, can be digitally restructured into virtual three-dimensional objects. Automatic detection of the landmarks, if developed, will be a great help not only medically, but also for anthropologically. The aim of this study is to develop an automated system to predict three-dimensional coordinate values of cranio-facial landmarks in sequences of CT slices.
MethodsCT images were obtained from a publicly available database. Digital reconstruction was done to obtain three dimensional models. Sixteen landmarks were plotted on the models and coordinate values of them were recorded. Multi-phased deep learning system was constructed. For the first phase, 512 x 512 pixels images were resized to 96 x 96 pixels. A regression deep learning network was trained with 90 training data. For the second phase, for each landmark, 100 x 100 pixels images were cropped from the original images. Sixteen models were trained. For the third phase, 50 x 50 pixels images were cropped, and models were trained.
ResultsThree-dimensional error for the first phase, testing 30 data, was 11.60 pixels in average. (1 pixel = 500 / 512 mm) For the second phase, it was significantly improved to 4.66 pixels. For the third phase, it was significantly progressed to 2.89. This was comparable to the gaps between the landmarks, plotted by two experienced practitioners.
DiscussionThe calculation volume required to process three-dimensional pile of images is tremendous. One solution may be to compress the images, but detailed information may be lost during the process. Our proposing method of multi-phased prediction, coarse detection first and narrowing down the detection area, may be a possible solution, within the physical limitation of memory and computation.
|
NA
|
medRxiv
|
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]
|
10.1101/2021.12.01.470810
|
Development of Web Application for the Comparison of Segment Variability with Sequence Evolution and Immunogenic Properties for Highly Variable Proteins: An Application to Viruses.
|
Bala, S.; Ghosh, A.; Pradhan, S.
|
Ambarnil Ghosh
|
Independent Researcher
|
10.1101/2021.12.01.470810
|
2021-12-03
|
1
|
new results
|
cc_no
|
bioinformatics
|
https://www.biorxiv.org/content/early/2021/12/03/2021.12.01.470810.source.xml
|
High rate of mutation and structural flexibilities in viral proteins quickly make them resistant to the host immune system and existing antiviral strategies. For most of the pathogenic viruses, the key survival strategies lie in their ability to evolve rapidly through mutations that affects the protein structure and function. Along with the experimental research related to antiviral development, computational data mining also plays an important role in deciphering the molecular and genomic signatures of the viral adaptability. Uncovering conserved regions in viral proteins with diverse chemical and biological properties is an important area of research for developing antiviral therapeutics, though assigning those regions is not a trivial work. Advancement in protein structural information databases and repositories, made by experimental research accelerated the in-silico mining of the data to generate more integrative information. Despite of the huge effort on correlating the protein structural information with its sequence, it is still a challenge to defeat the high mutability and adaptability of the viral genomics structure. In this current study, the authors have developed a user-friendly web application interface that will allow users to study and visualize protein segment variabilities in viral proteins and may help to find antiviral strategies. The present work of web application development allows thorough mining of the surface properties and variabilities of viral proteins which in combination with immunogenicity and evolutionary properties make the visualization robust. In combination with previous research on 20-Dimensional Euclidian Geometry based sequence variability characterization algorithm, four other parameters has been considered for this platform: [1] predicted solvent accessibility information, [2] B-Cell epitopic potential, [3] T-Cell epitopic potential and [4] coevolving region of the viral protein. Uniqueness of this study lies in the fact that a protein sequence stretch is being characterized rather than single residue-based information, which helps to compare properties of protein segments with variability. In current work, as an example, beside presenting the web application platform, five proteins of SARS-CoV2 was presented with keeping focus on protein-S. Current web-application database contains 29 proteins from 7 viruses including a GitHub repository of the raw data used in this study. The web application is up and running in the following address: http://www.protsegvar.com.
|
NA
|
bioRxiv
|
[
228,
192,
72,
110,
28,
161,
56,
150,
209,
29,
103,
217,
109,
99,
124,
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20,
117,
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125,
59,
102,
188
]
|
10.1101/2023.03.25.534140
|
A phenotypically robust model of Spinal and Bulbar Muscular Atrophy in Drosophila
|
Richardson, K.; Sengupta, M.; Sujkowski, A.; Libohova, K.; Harris, A. C.; Wessells, R.; Merry, D. E.; Todi, S. V.
|
Sokol V. Todi
|
Wayne State University School of Medicine
|
10.1101/2023.03.25.534140
|
2023-03-27
|
1
|
new results
|
cc_by_nc_nd
|
neuroscience
|
https://www.biorxiv.org/content/early/2023/03/27/2023.03.25.534140.source.xml
|
Spinal and bulbar muscular atrophy (SBMA) is an X-linked disorder that affects males who inherit the androgen receptor (AR) gene with an abnormal CAG triplet repeat expansion. The resulting protein contains an elongated polyglutamine (polyQ) tract and causes motor neuron degeneration in an androgen-dependent manner. The precise molecular sequelae of SBMA are unclear. To assist with its investigation and the identification of therapeutic options, we report here a new model of SBMA in Drosophila melanogaster. We generated transgenic flies that express the full-length, human AR with a wild-type or pathogenic polyQ repeat. Each transgene is inserted into the same "safe harbor" site on the third chromosome of the fly as a single copy and in the same orientation. Expression of pathogenic AR, but not of its wild-type variant, in neurons or muscles leads to consistent, progressive defects in longevity and motility that are concomitant with polyQ-expanded AR protein aggregation and reduced complexity in neuromuscular junctions. Additional assays show adult fly eye abnormalities associated with the pathogenic AR species. The detrimental effects of pathogenic AR are accentuated by feeding flies the androgen, dihydrotestosterone. This new, robust SBMA model can be a valuable tool towards future investigations of this incurable disease.
|
NA
|
bioRxiv
|
[
244,
202,
145,
222,
138,
227,
144,
158,
194,
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215,
117,
109,
51,
117,
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232,
26,
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182
]
|
10.1101/2023.08.08.552536
|
Tail length in male versus female fox squirrels (Sciurus niger)
|
Nichols, H. K.; Smith, S. K.; Eddington, V. M.; Calistri-Yeh, A.; Kloepper, L. N.; Young, V. K. H.
|
Vanessa K Hilliard Young
|
Saint Mary's College
|
10.1101/2023.08.08.552536
|
2023-08-12
|
1
|
new results
|
cc_by_nc_nd
|
zoology
|
https://www.biorxiv.org/content/early/2023/08/12/2023.08.08.552536.source.xml
|
BackgroundArboreal mammals rely on their tails to aid in balance while maneuvering complex habitats. Females experience additional challenges to locomotion due to reproductive demands including altered body mass and/or body shape, which leads to shifts in center of mass. Without compensation, this may increase the risk of losing balance and falling out of trees. We tested the hypothesis that female squirrels have longer tails than males to offset shifts in center of mass that may result from pregnancy.
ResultsMorphological data were collected from 57 fox squirrels (Sciurus niger) in northern Indiana in summer 2019 and 2021. Although our initial t-test analysis of relative tail length (RTL) showed that female squirrels had longer tails than males (p = 0.02), a subsequent ANCOVA that controlled for effect of body length indicated no significant effect of sex on tail length (p = 0.42).
ConclusionsThe results of this study demonstrate the potential impacts of different analysis methods on overall understanding of organismal functional morphology and are an important addition to the literature on tail form and function, which remains poorly understood compared to other appendages.
|
NA
|
bioRxiv
|
[
229,
235,
221,
76,
174,
225,
33,
158,
195,
25,
205,
119,
15,
98,
85,
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167,
85,
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37,
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46,
64,
84,
132,
225,
27,
6,
58
]
|
10.1101/091629
|
BLISS: quantitative and versatile genome-wide profiling of DNA breaks in situ
|
Yan, W. X.; Mirzazadeh, R.; Garnerone, S.; Scott, D. A.; Schneider, M. W.; Kallas, T.; Custodio, J.; Wernersson, E.; Gao, L.; Li, Y.; Federova, Y.; Zetsche, B.; Zhang, F.; Bienko, M.; Crosetto, N.
|
Nicola Crosetto
|
Karolinska Institutet
|
10.1101/091629
|
2016-12-04
|
1
|
new results
|
cc_by_nc_nd
|
molecular biology
|
https://www.biorxiv.org/content/early/2016/12/04/091629.source.xml
|
We present a method for genome-wide DNA double-strand Breaks (DSBs) Labeling In Situ and Sequencing (BLISS) which, compared to existing methods, introduces several key features: 1) high efficiency and low input requirement by in situ DSB labeling in cells or tissue sections directly on a solid surface; 2) easy scalability by performing in situ reactions in multi-well plates; 3) high sensitivity by linearly amplifying tagged DSBs using in vitro transcription; and 4) accurate DSB quantification and control of PCR biases by using unique molecular identifiers. We demonstrate the ability to use BLISS to quantify natural and drug-induced DSBs in low-input samples of cancer cells, primary mouse embryonic stem cells, and mouse liver tissue sections. Finally, we applied BLISS to compare the specificity of CRISPR-associated RNA-guided endonucleases Cas9 and Cpf1, and found that Cpf1 has higher specificity than Cas9. These results establish BLISS as a versatile, sensitive, and efficient method for genome-wide DSB mapping in many applications.
|
NA
|
bioRxiv
|
[
252,
202,
205,
88,
140,
161,
23,
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207,
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115,
221,
45,
43,
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158,
157,
153,
117,
76,
178,
75,
77,
168,
84,
196,
124,
66,
111,
61
]
|
10.1101/2021.09.22.21263956
|
An artificial intelligence system for predicting mortality in COVID-19 patients using chest X-rays: a retrospective study
|
Nanivadekar, A.; Zirpe, K.; Dwivedi, A.; Patel, R.; Pant, R.; Gupte, T.; Lokwani, R.; Shende, D.; Kulkarni, V.; Kharat, A.
|
Richa Pant
|
DeepTek Medical Imaging Pvt Ltd
|
10.1101/2021.09.22.21263956
|
2021-09-23
|
1
|
PUBLISHAHEADOFPRINT
|
cc_no
|
radiology and imaging
|
https://www.medrxiv.org/content/early/2021/09/23/2021.09.22.21263956.source.xml
|
BackgroundEarly prediction of disease severity in COVID-19 patients is essential. Chest X-ray (CXR) is a faster, widely available, and less expensive imaging modality that may be useful in predicting mortality in COVID-19 patients. Artificial Intelligence (AI) may help expedite CXR reading times, and improve mortality prediction. We sought to develop and assess an artificial intelligence system that used chest X-rays and clinical parameters to predict mortality in COVID-19 patients.
MethodsA retrospective study was conducted in Ruby Hall Clinic, Pune, India. The study included patients who had a positive real-time reverse transcriptase-polymerase chain reaction (RT-PCR) test for COVID-19 and at least one available chest X-ray at the time of their initial presentation or admission. Features from CXR images and clinical parameters were used to train the Random Forest model.
ResultsClinical data from a total of 201 patients was assessed retrospectively. The average age of the cohort was 51.4{+/-}14.8 years, with 29.4% of the patients being over the age of 60. The model, which used CXRs and clinical parameters as inputs, had a sensitivity of 0.83 [95% CI: 0.7, 0.95] and a specificity of 0.7 [95% CI: 0.64, 0.77]. The area under the curve (AUC) on receiver operating characteristics (ROC) was increased from 0.74 [95% CI: 0.67, 0.8] to 0.79 [95% CI: 0.72, 0.85] when the model included features of CXRs in addition to clinical parameters.
ConclusionAn Artificial Intelligence (AI) model based on CXRs and clinical parameters demonstrated high sensitivity and can be used as a rapid and reliable tool for COVID-19 mortality prediction.
|
NA
|
medRxiv
|
[
233,
66,
52,
124,
184,
160,
24,
72,
208,
27,
243,
61,
93,
107,
117,
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24,
58,
127,
96,
163,
93,
93,
202,
212,
12,
255,
59,
126,
44
]
|
10.1101/2022.12.16.520780
|
Development of a high-throughput barrier function assay using primary human gut organoids
|
Wright, C. W.; Li, N.; Shaffer, L.; Hill, A.; Boyer, N.; Alves, S.; Venkat, S.; Biswas, K.; Lieberman, L. A.; Mohammadi, S.
|
Sina Mohammadi
|
Merck & Co., Inc., Cambridge, MA, 02141
|
10.1101/2022.12.16.520780
|
2022-12-19
|
1
|
new results
|
cc_no
|
immunology
|
https://www.biorxiv.org/content/early/2022/12/19/2022.12.16.520780.source.xml
|
Disruptions in the gut epithelial barrier can lead to the development of chronic indications such as inflammatory bowel disease (IBD). Historically, barrier function has been assessed in cancer cell lines, which do not contain all human intestinal cell types, leading to poor translatability. To bridge this gap, we adapted human primary gut organoids grown as monolayers to assess barrier function. In this work we describe and characterize a novel 96-well human gut organoid-derived monolayer system that enables medium/high-throughput quantitative assessment of candidate therapeutics. Normal human intestine differentiation patterns and barrier function were characterized and confirmed to recapitulate key aspects of in vivo biology. Next, cellular response to TNF- (a central driver of IBD) was determined using a diverse cadre of readouts.These outputs included transcription factor phosphorylation, target gene expression, cytokine/chemokine production, and barrier function. Additionally, we showed that TNF- pathway antagonists rescued damage caused by TNF- in a dose-dependent manner, indicating that this system is suitable for quantitative assessment of barrier modulating factors. Taken together, we have established a robust primary cell-based 96-well system capable of interrogating questions around mucosal response. This system is well suited to provide pivotal functional data to support translational target and drug discovery efforts.
|
NA
|
bioRxiv
|
[
213,
201,
157,
124,
172,
160,
218,
12,
201,
10,
195,
57,
109,
98,
52,
33,
37,
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87,
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24,
47,
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159,
130,
105,
72,
6,
212,
15,
125,
26,
122,
56
]
|
10.1101/2022.12.22.521639
|
Down regulation of the liver lipid metabolism induced by hypothyroidism in mice: metabolic flexibility favors compensatory mechanisms in white adipose tissue
|
Chamas, L.; Seugnet, I.; Tanve, O.; Enderlin, V.; Clerget-Froidevaux, M.-S.
|
Marie-Stephanie Clerget-Froidevaux
|
CNRS/MNHN UMR 7221 Phyma, Department of Life Adaptations, Museum National d Histoire Naturelle, 57, rue Cuvier CP 32, 75231, Paris, CEDEX 05, France
|
10.1101/2022.12.22.521639
|
2022-12-23
|
1
|
new results
|
cc_by_nc_nd
|
physiology
|
https://www.biorxiv.org/content/early/2022/12/23/2022.12.22.521639.source.xml
|
In mammals, the maintenance of energy homeostasis relies on complex mechanisms requiring tight synchronization between peripheral organs and the brain. Thyroid hormones (TH), among their pleiotropic actions, play a central role in these regulations. Hypothyroidism, which is characterized by low circulating TH levels, slows down the metabolism, leading to a reduction in energy expenditure, as well as in lipid and glucose metabolism, and to insulin resistance. Our objective was to evaluate whether metabolic deregulations induced by hypothyroidism could be avoid by regulatory mechanisms involved in metabolic flexibility. To this aim, we compared the response to hypothyroidism in two mouse strains, the wild-derived WSB/EiJ mouse strain characterized by a diet-induced obesity (DIO) resistance due to its high metabolic flexibility phenotype and the C57BL/6J mice, prone to DIO. Adult mice were fed with a low-iodine diet supplemented with 6-n-propyl-2-thiouracyl (PTU) for 7 weeks to induce hypothyroidism. Our results show that hypothyroidism, characterized by a decrease in serum T4 levels, led to metabolic deregulations, as an alteration of lipid metabolism in the liver of both strains. However, the decrease in hepatic lipid synthesis was compensated in WSB/EiJ mice by a mobilization of lipid reserves from white adipose tissue, but not in the C57BL/6J mice. No peripheral or hypothalamic inflammatory response to hypothyroidism was observed in both strains. Moreover, gene expression analysis showed that hypothyroidism stimulates the hypothalamic orexigenic circuit in both strains, but unchanged Mc4r and LepR expression in hypothyroid WSB/EiJ mice strain, which reflect their adaptability to maintain their body weight, contrary to C57BL/6J mice. Our results show that WSB/EiJ mice displayed a phenotype of resistance to metabolic dysregulations induced by hypothyroidism, by compensatory mechanisms. This response as well as their resistance to HFD-induced obesity highlights their adaptive capacities to maintain metabolic homeostasis, namely, their high metabolic flexibility, despite serum hypothyroidism. This model sheds light on the importance of local thyroid homeostasis to maintain lipid metabolism and metabolic homeostasis.
|
NA
|
bioRxiv
|
[
199,
73,
25,
76,
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160,
149,
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202,
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105,
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103,
184
]
|
10.1101/2023.03.03.530983
|
Addition of adjuvant to DTaP modulates vaccine-induced immunological responses but is insufficient to improve protection in CD-1 mice
|
Weaver, K. L.; Pyles, G. M.; Dublin, S. R.; Huckaby, A. B.; Miller, S. J.; Gutierrez, M. d. l. P.; Sen-Kilic, E.; Witt, W. T.; Boehm, D. T.; Damron, F. H.; Barbier, M.
|
Mariette Barbier
|
West Virginia University
|
10.1101/2023.03.03.530983
|
2023-03-04
|
1
|
new results
|
cc_by_nc_nd
|
immunology
|
https://www.biorxiv.org/content/early/2023/03/04/2023.03.03.530983.source.xml
|
3.1Pertussis is a vaccine-preventable respiratory disease caused by the Gram-negative bacterium Bordetella pertussis. While vaccination rates remain high in developed countries, incidence of pertussis has increased following the transition from wP vaccines to aP vaccines. The reemergence of pertussis is attributed, in part, to waning immunity induced by aP vaccination. Therefore, the objective of this work was to determine if addition of adjuvant to DTaP can modulate the immune response and improve protection compared to DTaP alone. In this study we immunized outbred, female CD-1 mice with 1/320th the human dose of vehicle control, DTaP, and DTaP supplemented with adjuvant. Markers of early vaccine-induced memory were measured using a chemokine assay or by flow cytometry. Protection was assessed by measuring serological responses and quantifying bacterial burden in the respiratory tract at day 3 post-challenge. From this work we identified a partially protective aP vaccine dose to use for vaccination and challenge studies. We observed that MPLA and SWE promote robust anti-B. pertussis antibody responses and stimulate significant increases in early markers of vaccine-induced memory such as CXCL13, FDCs, and TFH cells. Quil-A induced Th1 responses compared to DTaP alone, but none of the adjuvants improved protection against challenge with B. pertussis. Overall, the data suggests that addition of adjuvant modulates the protective immune responses induced by aPs. Further studies are needed to evaluate the B cell compartment and longevity of protection.
|
NA
|
bioRxiv
|
[
221,
85,
60,
79,
138,
225,
224,
24,
214,
1,
103,
219,
109,
114,
61,
161,
101,
237,
69,
84,
21,
175,
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]
|
10.1101/733105
|
Early post-zygotic mutations contribute to congenital heart disease
|
Hsieh, A.; Morton, S. U.; Willcox, J. A.; Gorham, J. M.; Tai, A. C.; Qi, H.; DePalma, S.; McKean, D.; Griffin, E.; Manheimer, K. B.; Bernstein, D.; Kim, R. W.; Newburger, J. W.; Porter, G. A.; Srivastava, D.; Tristani-Firouzi, M.; Brueckner, M.; Lifton, R. P.; Goldmuntz, E.; Gelb, B. D.; Chung, W. K.; Seidman, C.; Seidman, J. G.; Shen, Y.
|
Yufeng Shen
|
Columbia University
|
10.1101/733105
|
2019-08-13
|
1
|
new results
|
cc_by_nc_nd
|
bioinformatics
|
https://www.biorxiv.org/content/early/2019/08/13/733105.source.xml
|
BackgroundThe contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined.\n\nResultsWe developed a computational method, Expectation-Maximization-based detection of Mosaicism (EM-mosaic), to analyze mosaicism in exome sequences of 2530 CHD proband-parent trios. EM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The frequency of mosaic variants above 10% mosaicism was 0.13/person in blood and 0.14/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction.\n\nConclusionsWe estimate that ~1% of CHD probands have a mosaic variant detectable in blood that could contribute to cardiac malformations, particularly those damaging variants expressed at higher allele fraction compared to benign variants. Although blood is a readily-available DNA source, cardiac tissues analyzed contributed ~5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses.
|
NA
|
bioRxiv
|
[
112,
200,
4,
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190,
161,
67,
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]
|
10.1101/2021.09.24.461619
|
A phenotypic screen using splitCas9 identifies essential genes required for actin regulation during host cell egress and invasion by Toxoplasma gondii
|
Li, W.; Grech, J.; Stortz, J. F.; Gow, M.; Periz, J.; Meissner, M.; Jimenez-Ruiz, E.
|
Elena Jimenez-Ruiz
|
Experimental Parasitology, Department of Veterinary Sciences, Faculty of Veterinary Medicine, Ludwig-Maximilians-Universitaet, LMU. Munich, Germany.
|
10.1101/2021.09.24.461619
|
2021-09-24
|
1
|
new results
|
cc_no
|
microbiology
|
https://www.biorxiv.org/content/early/2021/09/24/2021.09.24.461619.source.xml
|
Apicomplexan parasites, such as Toxoplasma gondii, possess unique organelles, cytoskeletal structures, signalling cascades, replicate by internal budding within a specialised compartment and actively invade and exit the host cell, to name a few aspects of the unique biology that characterise this phylum. Due to their huge phylogenetic distance from well established model organisms, such as opisthokonts, comparative genomics has a limited capacity to infer gene functions and conserved proteins can fulfil different roles in apicomplexans. Indeed, approximately 30% of all genes are annotated as hypothetical and many had a crucial role during the asexual life cycle in genome-wide screens. While the current CRISPR/Cas9-based screens allow the identification of fitness conferring genes, only little information about the respective functions can be obtained. To overcome this limitation, and to group genes of interest into functional groups, we established a conditional Cas9-system in T. gondii that allows phenotypic screens. Using an indicator strain for F-actin dynamics and apicoplast segregation, we identified critical genes required for defined steps during the asexual life cycle. The detailed characterisation of two of these candidates revealed them to be critical for host cell egress and invasion and to act at different time points in the disassembly of the intravacuolar F-actin network. While the signalling linking factor (SLF) is an integral part of a signalling complex required for early induction of egress, a novel conoid protein (conoid gliding protein, CGP) acts late during egress and is required for the activation of gliding motility.
|
NA
|
bioRxiv
|
[
156,
200,
220,
108,
138,
243,
112,
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109,
240,
52,
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118,
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105,
81,
70,
180
]
|
10.1101/2023.02.28.23286362
|
First report of Plasmodium vivax in a semi-arid region of northern Kenya
|
Prudhomme O'Meara, W.; Maraga, L.; Meredith, H.; Esimit, D.; Lokoel, G.; Chepkwony, T.; Kipkoech, J.; Ambani, G.; Menya, D.; Freedman, E.; Taylor, S. M.; Obala, A.
|
Wendy Prudhomme O'Meara
|
Duke University
|
10.1101/2023.02.28.23286362
|
2023-03-01
|
1
|
PUBLISHAHEADOFPRINT
|
cc_by_nc_nd
|
infectious diseases
|
https://www.medrxiv.org/content/early/2023/03/01/2023.02.28.23286362.source.xml
|
Most malaria morbidity in Kenya is due to Plasmodium falciparum with no cases attributed to P.vivax. Little is known about the epidemiology in northern Kenya along the border with Ethiopia and Sudan. We found that 2% of household members of P.falciparum cases were infected with P.vivax, affecting all ages in urban and rural sites.
|
NA
|
medRxiv
|
[
124,
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231,
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50,
118,
0,
177,
162,
31,
57
]
|
10.1101/2022.10.27.514096
|
Tocilizumab treatment leads to early resolution of lymphopenia and myeloid dysregulation in patients hospitalized with COVID-19
|
Shivram, H.; Hackney, J. A.; Rosenberger, C. M.; Teterina, A.; Qamra, A.; Onabajo, O.; McBride, J.; Cai, F.; Bao, M.; Tsai, L.; Regev, A.; Rosas, I.; Bauer, R.
|
Rebecca Bauer
|
Genentech
|
10.1101/2022.10.27.514096
|
2023-02-22
|
2
|
new results
|
cc_no
|
immunology
|
https://www.biorxiv.org/content/early/2023/02/22/2022.10.27.514096.source.xml
|
High interleukin (IL)-6 levels are associated with more severe clinical manifestations in patients hospitalized with COVID-19, but the complex role of IL-6 in antiviral and inflammatory processes has made it difficult to decipher its involvement in the disease. IL-6 receptor blockade by tocilizumab (anti-IL6R; Actemra) is used globally for the treatment of severe COVID-19, yet a molecular understanding of the therapeutic benefit remains unclear. We characterized the immune profile and identified cellular and molecular pathways directly modified by tocilizumab in peripheral blood samples collected from patients enrolled in the COVACTA study, a phase 3, randomized, double-blind, placebo-controlled trial that assessed the efficacy and safety of tocilizumab in hospitalized patients with severe COVID-19 pneumonia. We identified factors predicting disease severity and clinical outcomes, including markers of inflammation, lymphopenia, myeloid dysregulation, and organ injury. Proteomic analysis confirmed a pharmacodynamic effect for tocilizumab in addition to identifying novel pharmacodynamic biomarkers. Transcriptomic analysis revealed that tocilizumab treatment leads to faster resolution of lymphopenia and myeloid dysregulation associated with severe COVID-19, indicating greater anti-inflammatory activity relative to standard of care and potentially leading to faster recovery in patients hospitalized with COVID-19.
One sentence summaryInterleukin-6 receptor blockade with tocilizumab accelerated resolution of myeloid dysfunction and lymphopenia in patients hospitalized with COVID-19
|
NA
|
bioRxiv
|
[
145,
199,
244,
76,
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30,
121,
58,
114,
52
]
|
10.1101/537225
|
Fetal stage melanopsin (OPN4) and GNAQ (Gαq) signaling regulates vascular development of the eye
|
Vemaraju, S.; Nayak, G.; Miller, W. E.; Copenhagen, D. R.; Lang, R. A.
|
Richard A Lang
|
Cincinnati Children's Hospital Medical Center
|
10.1101/537225
|
2019-01-31
|
1
|
new results
|
cc_no
|
developmental biology
|
https://www.biorxiv.org/content/early/2019/01/31/537225.source.xml
|
Maturation of sensory systems in mammals is regulated by appropriate sensory stimulation. Developmental refinement of the eye and visual system is regulated by light and visual stimulation. One compelling example is that fetal mouse pups deprived of light exhibit altered vascular development in their eyes. Previous work demonstrated that light activation of the photopigment melanopsin (Opn4), an atypical opsin expressed in intrinsically photosensitive retinal ganglion cells (ipRGCs), is crucial to normal vascular development. This suggested the unusual hypothesis that vascular development of the eye was regulated by ipRGC responses in the fetal eye by light that traveled through the body wall of the mother. Here, we test the requirement of OPN4 during fetal stages using genetic approaches. The G-protein GNAQ (Gq) is a candidate mediator of melanopsin signaling. We show that ipRGC-specific deletion of Gnaq phenocopies both hyaloid and retinal vascular development of the Opn4 null mouse. Furthermore, GNAQ gain-of-function in Opn4-expressing cells only during late gestation was sufficient to reverse the consequences for vascular development of either dark rearing or Opn4 loss-of-function. We conclude that melanopsin-dependent signaling in the fetal mouse eye is necessary and sufficient for vascular maturation.
|
NA
|
bioRxiv
|
[
145,
207,
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104,
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116,
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]
|
10.1101/304345
|
Inhibition of EV71 replication by an interferon-stimulated gene product L3HYPDH
|
Liu, J.; Liu, L.; Shinun Zeng, S.; Meng, X.; Lei, N.; Yang, H.; Li, R.; Mu, X.; Guo, X.
|
Xuemin Guo
|
Zhongshan School of Medicine, Sun Yat-Sen University
|
10.1101/304345
|
2023-02-14
|
2
|
confirmatory results
|
cc_by_nd
|
microbiology
|
https://www.biorxiv.org/content/early/2023/02/14/304345.source.xml
|
Enterovirus 71 (EV71) is the common causative agent of hand-foot-mouth disease (HFMD). Despite evidence in mice model suggested that the interferon (IFN) signaling pathways play a role in defending against this virus, knowledge on the IFN-mediated antiviral response is still limited. Here we identified an IFN-stimulated gene (ISG) called L3HYPHD, whose expression inhibits EV71 replication. Mapping assay indicated that amino acids 61-120 and 295-354 are critical for its optimal antiviral activity. Mechanismly, L3HYPDH specifically inhibits protein translation mediated by EV71 internal ribosome entry site (IRES). Our data thus uncovered a new mechanism utilized by the host cell to restrict EV71 replication.
|
10.1016/j.virusres.2024.199336
|
bioRxiv
|
[
29,
79,
164,
126,
142,
225,
209,
82,
72,
9,
97,
123,
5,
114,
125,
52,
103,
103,
69,
117,
69,
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210,
214,
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34,
71,
52
]
|
10.1101/327023
|
Alternative activation of macrophages is accompanied by chromatin remodeling and short-term dampening of macrophage secondary response
|
Tang, M. S.; Miraldi, E. R.; Girgis, N. M.; Bonneau, R. A.; Loke, P.
|
Mei San Tang
|
NYU School of Medicine
|
10.1101/327023
|
2020-03-08
|
3
|
new results
|
cc_by_nc
|
immunology
|
https://www.biorxiv.org/content/early/2020/03/08/327023.source.xml
|
Interleukin-4 (IL-4) activates macrophages to adopt a distinct phenotype associated with clearance of helminth infections and tissue repair. Here, we describe changes in the accessible chromatin landscape following IL-4 stimulation of terminally differentiated mouse peritoneal macrophages. This chromatin remodeling process occurs in both tissue resident and monocyte-derived macrophages, but the regions gaining accessibility post-stimulation are macrophage-specific. PU.1 motif is similarly associated with tissue resident and monocyte-derived IL-4 induced regions, but has macrophage-specific DNA shape and predicted co-factors. In addition, IL-4 stimulation leads to short-term dampening of macrophage secondary response. However, the degree of dampening differs between macrophages derived from different genetic backgrounds. Together, these results lead us to propose that DNA sequence variations can alter parts of the accessible chromatin landscape and differences in secondary responses due to host genetics can contribute to phenotypic variations in immune responses.
|
NA
|
bioRxiv
|
[
252,
72,
149,
92,
4,
165,
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249,
109,
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]
|
10.1101/578682
|
Embodiment is related to better performance on an immersive brain computer interface in head-mounted virtual reality: A pilot study
|
Juliano, J. M.; Spicer, R. P.; Vourvopoulos, A.; Lefebvre, S.; Jann, K.; Ard, T.; Santarnecchi, E.; Krum, D. M.; Liew, S.-L.
|
Sook-Lei Liew
|
University of Southern California
|
10.1101/578682
|
2019-06-19
|
2
|
new results
|
cc_no
|
neuroscience
|
https://www.biorxiv.org/content/early/2019/06/19/578682.source.xml
|
Brain computer interfaces (BCI) can be used to provide individuals with neurofeedback of their own brain activity and train them to learn how to control their brain activity. Neurofeedback-based BCIs used for motor rehabilitation aim to close the loop between attempted motor commands and sensory feedback by providing supplemental sensory information when individuals successfully establish specific brain patterns. Existing neurofeedback-based BCIs have used a variety of displays to provide feedback, ranging from devices that provide a more immersive and compelling experience (e.g., head-mounted virtual reality (HMD-VR) or CAVE systems) to devices that are considered less immersive (e.g., computer screens). However, it is not clear whether more immersive systems (i.e., HMD-VR) improve neurofeedback performance compared to computer screens, and whether there are individual performance differences in HMD-VR versus screen-based neurofeedback. In this pilot experiment, we compared neurofeedback performance in HMD-VR versus on a computer screen in twelve healthy individuals. We also examined whether individual differences in presence or embodiment correlated with neurofeedback performance in either environment. Participants were asked to control a virtual right arm by imagining right hand movements. Real-time brain activity indicating motor imagery, which was measured via electroencephalography (EEG) as desynchronized sensorimotor rhythms (SMR; 8-24 Hz) in the left motor cortex, drove the movement of the virtual arm towards (increased SMR desynchronization) or away from (decreased SMR desynchronization) targets. Participants performed two blocks of 30 trials, one for each condition (Screen, HMD-VR), with the order of conditions counterbalanced across participants. After completing each block, participants were asked questions relating to their sense of presence and embodiment in each environment. We found that, while participants performance on the neurofeedback-based BCI task was similar between conditions, the participants reported levels of embodiment was significantly different between conditions. Specifically, participants experienced higher levels of embodiment in HMD-VR compared to the computer screen. We further found that reported levels of embodiment positively correlated with neurofeedback performance only in the HMD-VR condition. Overall, these preliminary results suggest that embodiment may improve performance on a neurofeedback-based BCI and that HMD-VR may increase embodiment during a neurofeedback-based BCI task compared to a standard computer screen.
|
NA
|
bioRxiv
|
[
83,
90,
12,
78,
168,
196,
180,
154,
229,
48,
80,
181,
63,
113,
221,
107,
245,
69,
203,
69,
214,
179,
243,
5,
86,
87,
70,
251,
111,
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51,
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172,
103,
235,
151,
9,
76,
99,
22,
158,
250,
29,
26,
56
]
|
10.1101/452151
|
Risk aversion in macaques in a freely moving patch-leaving foraging task
|
Eisenreich, B.; Hayden, B. Y.
|
Benjamin Eisenreich
|
University of Minnesota
|
10.1101/452151
|
2018-10-25
|
1
|
new results
|
cc_no
|
animal behavior and cognition
|
https://www.biorxiv.org/content/early/2018/10/25/452151.source.xml
|
Animals, including humans, are risk-averse in most contexts. A major exception is the rhesus macaque (Macaca mulatta), which is robustly risk-seeking. Macaques unique preferences may reflect their unique evolutionary history. Alternatively, they may derive from elements of task design associated with the demands of physiological recording, the source of nearly all macaque risk preference data. To disambiguate these possibilities we assessed macaques risk attitudes in a somewhat more naturalistic environment: subjects foraged at four feeding stations in a large enclosure. Stations (i.e. patches) provided either stochastically or non-stochastically depleting rewards. Subjects patch residence times were longer at safe than at risky stations, indicating a preference for safe options. This preference was not attributable to a win-stay-lose-shift heuristic. These findings highlight the lability of risk attitudes in macaques and support the hypothesis that observed differences between macaques and other species are ephemeral, not evolved.
|
NA
|
bioRxiv
|
[
209,
70,
24,
126,
152,
128,
168,
158,
195,
44,
247,
251,
205,
114,
20,
169,
84,
77,
13,
69,
84,
163,
181,
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126,
81,
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160,
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30,
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58
]
|
10.1101/2022.01.27.477845
|
A Complete Set of Equations and Parameters for the Computational Model of Mitochondrial Function for the Proximal Convoluted Tubule and Medullary Thick Ascending Limb Cells in the Rat Kidney
|
Bell, W.; Layton, A.
|
Anita Layton
|
University of Waterloo
|
10.1101/2022.01.27.477845
|
2022-01-28
|
1
|
new results
|
cc_by_nc_nd
|
cell biology
|
https://www.biorxiv.org/content/early/2022/01/28/2022.01.27.477845.source.xml
|
To investigate mitochondrial function of renal epithelial cells under different tissue oxygenation levels, we have developed and applied computational models of mitochondrial function of the proximal convoluted tubule and medullary thick ascending limb cells. The models predict several key cellular quantities, including ATP generation, P/O (phosphate/oxygen) ratio, proton motive force, electrical potential gradient, oxygen consumption, the redox state of important electron carriers, and ATP consumption. The complete set of model equations and parameters are presented here, together with local and global sensitivity analysis results.
|
NA
|
bioRxiv
|
[
204,
234,
40,
110,
168,
241,
134,
158,
209,
58,
97,
57,
85,
114,
60,
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5,
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69,
117,
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]
|
10.1101/2022.06.05.494796
|
Development and application of an uncapped mRNA platform
|
Zheng, X.; Liu, B.; Ni, P.; Cai, L.; Shi, X.; Ke, Z.; Zhang, S.; Hu, B.; Yang, B.; Xu, Y.; Long, W.; Fang, Z.; Wang, Y.; Zhang, W.; Xu, Y.; Wang, Z.; Pan, K.; Zhou, K.; Wang, H.; Geng, H.; Hu, H.; Liu, B.
|
Binlei Liu
|
National "111" Centre for Cellular Regulation and Molecular Pharmaceutics,Hubei Provincial Cooperative Innovation Centre of Industrial Fermentation, College of
|
10.1101/2022.06.05.494796
|
2023-08-24
|
3
|
new results
|
cc_no
|
bioengineering
|
https://www.biorxiv.org/content/early/2023/08/24/2022.06.05.494796.source.xml
|
A novel uncapped mRNA platform was developed. Five lipid nanoparticle (LNP)-encapsulated mRNA constructs were made to evaluate several aspects of our platform, including transfection efficiency and durability in vitro and in vivo and the activation of humoral and cellular immunity in several animal models. The constructs were eGFP-mRNA-LNP (for enhanced green fluorescence mRNA), Fluc-mRNA-LNP (for firefly luciferase mRNA), S{delta}T-mRNA-LNP (for Delta strain SARS-CoV-2 spike protein trimer mRNA), gDED-mRNA-LNP (for truncated glycoprotein D mRNA coding ectodomain from herpes simplex virus type 2 (HSV2)) and gDFR-mRNA-LNP (for truncated HSV2 glycoprotein D mRNA coding amino acids 1[~]400). Quantifiable target protein expression was achieved in vitro and in vivo with eGFP-and Fluc-mRNA-LNP. S{delta}T-mRNA-LNP, gDED-mRNA-LNP and gDFR-mRNA-LNP induced both humoral and cellular immune responses comparable to those obtained by previously reported capped mRNA-LNP constructs. Notably, S{delta}T-mRNA-LNP elicited neutralizing antibodies in hamsters against the Omicron and Delta strains. Additionally, gDED-mRNA-LNP and gDFR-mRNA-LNP induced potent neutralizing antibodies in rabbits and mice. The mRNA constructs with uridine triphosphate (UTP) outperformed those with N1-methylpseudouridine triphosphate (N1m{psi}TP) in the induction of antibodies via S{delta}T-mRNA-LNP. Our uncapped, process-simplified, and economical mRNA platform may have broad utility in vaccines and protein replacement drugs.
|
NA
|
bioRxiv
|
[
52,
79,
180,
94,
175,
225,
89,
22,
86,
5,
103,
219,
141,
240,
61,
170,
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97,
197,
86,
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14,
242,
84,
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108,
26,
95,
189
]
|
10.1101/579276
|
Higher order analysis of gene correlations by tensor decomposition
|
Yahyanejad, F.
|
Farzane Yahyanejad
|
University of Illinois at Chicago
|
10.1101/579276
|
2019-03-16
|
1
|
new results
|
cc_by_nc
|
bioinformatics
|
https://www.biorxiv.org/content/early/2019/03/16/579276.source.xml
|
This study advances our understanding of inter- and intra-pathways higher order signaling in the cellular system and it leads to new discovery of multiple intracellular structures in signal transduction pathways in yeast Saccharomyces. We present a new tensor decomposition algorithm in reconstructing the pathways based on higher correlations among genes that compose a cellular system. The higher order gene correlation (HOGC) analysis has the power to elucidate genes higher interaction dependencies which has been barely understood. Recent studies i.e. [24] have experimentally revealed that multiple signaling proteins, yet sometimes infinite, may assemble to meaningful structure to transmit a receptor activation information. In this paper we reveal 3-order genomic correlations among significant component of the cellular system. This is the first time such a systematic and computational model provided for analysis of higher order correlations among genes. We use new fast algorithm to formulate a genes x genes x genes x decorrelated rank-1 sub-tensors (complexes) which can be associated with functionally independent pathways. Then we model higher order tensor decomposition [Formula] which is constructed by K tensors of genes x genes x genes. Each new tensor is constructed by an orthogonal projection of data signal onto a designated basis signal to keep common sub-tensors in both signals. Our model for decomposing tensor order-4 approximates series of tensors as linear components of deccorelated rank-1 sub-tensors over tensor of order-3 and rank-3 triplings among sub-tensors. The linear components represent intra-pathway in cell signaling and triplings implicate inter-pathways higher order signaling. Through structural studies of inter- and intra-higher order signaling pathways, we uncover different scenario that involves triple formation of signaling proteins into higher order signaling machines for transmission of receptor activation information to cellular responses.
|
NA
|
bioRxiv
|
[
120,
226,
12,
110,
142,
226,
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208,
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31,
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]
|
10.1101/2022.06.20.496866
|
Synthetic Coolant WS-23 increases E-Cigarette Generated Aerosolized Acellular Reactive Oxygen Species (ROS) Levels
|
Yogeswaran, S.; Manevski, M.; Chand, H.; Rahman, I.
|
Irfan Rahman
|
University of Rochester
|
10.1101/2022.06.20.496866
|
2022-06-21
|
1
|
new results
|
cc_no
|
pharmacology and toxicology
|
https://www.biorxiv.org/content/early/2022/06/21/2022.06.20.496866.source.xml
|
There has been a substantial rise in e-cigarette (e-cig) use or vaping in the past decade, prompting growing concerns about their adverse health effects. Recently, e-cig manufacturers have been using synthetic cooling agents, like WS-23 and WS-3, to provide a cooling sensation without the "menthol taste". Studies have shown that aerosols/vapes generated by e-cigs can contain significant levels of reactive oxygen species (ROS). However, studies investigating the role of synthetic coolants in modulating ROS levels generated by e-cigs are lacking. This study seeks to understand the potential of synthetic coolants, e-cigarette additives that have become increasingly prevalent in e-liquids sold in the United States (US), on acellular ROS production. Aerosols were generated from e-liquids with and without synthetic coolants through a single-puff aerosol generator; subsequently, acellular ROS was semi-quantified in H2O2 equivalents via fluorescence spectroscopy. Our data suggest that adding WS-3 to e-liquid base (PG:VG), regardless of nicotine content, has a minimal impact on modifying e-cigarette-generated acellular ROS levels. Additionally, our data also suggest that the addition of WS-23 to nicotine-containing e-liquid base significantly modifies e-cigarette-generated acellular ROS levels. Together, our data provide insight into whether adding synthetic coolants to e-liquids significantly impacts vaping-induced oxidative stress in the lungs.
|
NA
|
bioRxiv
|
[
89,
234,
252,
76,
168,
161,
152,
222,
212,
141,
119,
241,
79,
107,
84,
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]
|
10.1101/260844
|
MSIGNET: a Metropolis sampling-based method for global optimal significant network identification
|
Chen, X.; Xuan, J.
|
Xi Chen
|
Virginia tech
|
10.1101/260844
|
2018-02-06
|
1
|
new results
|
cc_by_nd
|
bioinformatics
|
https://www.biorxiv.org/content/early/2018/02/06/260844.source.xml
|
In this paper, we propose a novel approach namely MSIGNET to identify subnetworks with significantly expressed genes by integrating context specific gene expression and protein-protein interaction (PPI) data. Specifically, we integrate differential expression of each gene and mutual information of gene pairs in a Bayesian framework and use Metropolis sampling to identify functional interactions. During the sampling process, a conditional probability is calculated given a randomly selected gene to control the network state transition. Our method provides global statistics of all genes and their interactions, and finally achieves a global optimal sub-network. We apply MSIGNET to simulated data and have demonstrated its superior performance over comparable network identification tools. Using a validated Parkinson data set we show that the network identified using MSIGNET is consistent to previously reported results but provides more biology meaningful interpretation of Parkinsons disease. Finally, to study networks related to ovarian cancer recurrence, we investigate two patient data sets. Identified networks from independent data sets show functional consistence. And those common genes and interactions are well supported by current biological knowledge.
|
NA
|
bioRxiv
|
[
248,
233,
76,
78,
136,
160,
150,
210,
200,
26,
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239,
125,
225,
124,
41,
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199,
95,
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]
|
10.1101/2021.09.17.459817
|
Short-term assessment of subfoveal injection of AAV2-hCHM gene augmentation in choroideremia using adaptive optics ophthalmoscopy
|
Morgan, J. I. W.; Jiang, Y. Y.; Vergilio, G. K.; Serrano, L. W.; Pearson, D. J.; Bennett, J.; Maguire, A. M.; Aleman, T. S.
|
Jessica I.W. Morgan
|
University of Pennsylvania
|
10.1101/2021.09.17.459817
|
2021-09-20
|
1
|
new results
|
cc_no
|
neuroscience
|
https://www.biorxiv.org/content/early/2021/09/20/2021.09.17.459817.source.xml
|
Subretinal injection for gene augmentation in retinal degenerations forcefully detaches the neural retina from the retinal pigment epithelium (RPE), potentially damaging photoreceptors and/or RPE cells. Here, we use adaptive optics scanning light ophthalmoscopy (AOSLO) to assess the short-term integrity of the cone mosaic following subretinal injections of AAV2-hCHM gene augmentation in subjects with choroideremia (CHM). Nine adult CHM patients received uniocular subfoveal injections of low dose (5x1010 vector genome (vg) per eye, n=5) or high dose (1x1011 vg per eye, n=4) AAV2-hCHM. The macular regions of both eyes were imaged pre- and one-month post-injection using a custom-built, multimodal AOSLO. Post-injection cone inner segment mosaics were compared to pre-injection mosaics at multiple regions of interest (ROIs). Post-injection AOSLO images showed preservation of the cone mosaic in all 9 AAV2-hCHM injected eyes. Mosaics appeared intact and contiguous one-month post-injection, with the exception of foveal disruption in one patient. Co-localized optical coherence tomography showed foveal cone outer segment (COS) shortening post-injection (significant, n=4; non-significant, n=4; unchanged, n=1). Integrity of the cone mosaic is maintained following subretinal delivery of AAV2-hCHM, providing strong evidence in support of the safety of the injections. Minor foveal thinning observed following surgery corresponds with short-term COS shortening rather than cone cell loss.
|
NA
|
bioRxiv
|
[
208,
197,
148,
124,
12,
160,
209,
148,
210,
11,
55,
153,
125,
35,
116,
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]
|
10.1101/716746
|
The hormone neuroparsin seems essential in Lepidoptera but not in domesticated silkworms
|
Veenstra, J. A.
|
Jan Adrianus Veenstra
|
UMR 5287 CNRS, The University of Bordeaux
|
10.1101/716746
|
2019-07-28
|
1
|
new results
|
cc_no
|
evolutionary biology
|
https://www.biorxiv.org/content/early/2019/07/28/716746.source.xml
|
The primary sequence of the Arthropod neurohormone neuroparsin is so variable that so far no orthologs from moths and butterflies have been characterized, even though classical neurosecretory stains identify cells that are homologous to those producing this hormone in other insect species. Here Lepidopteran cDNAs showing limited sequence similarity to other insect neuroparsins are described. That these cDNAs do indeed code for authentic neuroparsins was confirmed by in situ hybridization in the wax moth, Galleria mellonella, which labeled the neuroparsin neuroendocrine cells. Although in virtually all genome assemblies from Lepidoptera a neuroparsin gene could be identified, the genome assembly from the silkworm, Bombyx mori, has a neuroparsin gene containing a 16 nucleotide deletion that renders this gene nonfunctional. Although only a small number of all silkworm strains carry this deletion, it suggests that the domestication of the silkworm has rendered the function of this neurohormone dispensable.
|
NA
|
bioRxiv
|
[
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]
|
10.1101/2023.04.06.23288270
|
The Prevalence of the Female Athlete Triad in Female Service Members
|
Mattison, C. S.; Wiese, J.
|
Cameron S Mattison
|
Medical College of Wisconsin
|
10.1101/2023.04.06.23288270
|
2023-04-12
|
1
|
PUBLISHAHEADOFPRINT
|
cc_by_nc_nd
|
sports medicine
|
https://www.medrxiv.org/content/early/2023/04/12/2023.04.06.23288270.source.xml
|
Osteoporosis, amenorrhea, and low energy with or without disordered eating (the female athlete triad) are frequent clinical outcomes associated with female athletes in constant low energy availability (LEA). The rigorous training demands of the Army and the strict weight limits suggest that female service members may be susceptible to states of LEA, where energy expenditure exceeds dietary energy intake.
To understand the prevalence of the female athlete triad among female service members and how restrictive weight requirements influence these symptoms, we compared survey responses measuring symptoms of the female athlete triad between female active-duty service members and female veterans.
The results indicated that female veterans had significantly higher female athlete triad and disordered eating scores. Therefore, female veterans are more likely to demonstrate female athlete triad symptoms than active-duty service members. Specifically, female veterans are more likely to demonstrate symptoms of low energy with or without disordered eating.
Female veterans unique stressors of no longer being in the military (reintegration into society and losing support system within the military) could be why they are more likely to present with female athlete triad symptoms than active-duty female service members.
|
NA
|
medRxiv
|
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]
|
10.1101/2022.03.24.22272861
|
Intubation and Inhospital mortality in trauma patients with Glasgow Coma Scale Score eight or less. A multicenter cohort study.
|
SONI, K. D.; Bansal, V.; Khajanchi, M.; Veetil, D. K.; Anderson, G.; Rayker, N.; Sarang, B.; David, S.; Gerdin Warnberg, M.; Roy, N.
|
KAPIL DEV SONI
|
All India Institute of Medical Sciences, New Delhi
|
10.1101/2022.03.24.22272861
|
2022-03-25
|
1
|
PUBLISHAHEADOFPRINT
|
cc_no
|
emergency medicine
|
https://www.medrxiv.org/content/early/2022/03/25/2022.03.24.22272861.source.xml
|
BackgroundMost trauma societies recommend intubation of trauma patients with Glasgow coma scale (GCS) [≤] 8, without robust evidence supporting it.
MethodsWe examined the association between intubation and inhopital 30 day mortality in trauma patients arriving with GCS [≤] 8. The data were obtained using the Towards Improved Trauma Care Outcomes (TITCO) registry in India cohort. We compared the outcomes of patients with GCS [≤] 8 who were intubated within one hour after arrival with those who were intubated later or not at all, using multiple analytical approaches to evaluate the consistency of the findings. We also examined the association in multiple subgroups to identify any variability of the effect.
ResultsOf 3476 patients who arrived with a GCS [≤] 8, 1671 (48.1%) were intubated within an hour and 1805 (51.9%) were intubated later or not intubated at all. Overall, 1957 (56.3%) patients died in whole cohort. A total of 947 (56.7%) patients died in intubation group and 1010 (56%) died in non intubation group. In the main analysis, there was no significant association between intubation within an hour and mortality(OR=1.18,[CI,0.76-1.84], p value = 0.467). This result was consistent across multiple sensitivity analysis.
ConclusionIn this observational study of trauma patients with GCS [≤] 8, who present to tertiary care hospitals, intubation within one hour after arrival was not associated with increased or decreased risk of inhospital mortality compared to intubation after one hour or no intubation. Further studies are needed to precisely evaluate the benefit of intubation and thus supporting the recommendations.
|
NA
|
medRxiv
|
[
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226,
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]
|
10.1101/2022.11.15.22282368
|
Selective prediction for extracting unstructured clinical data
|
Swaminathan, A.; Lopez, I.; Wang, W.; Srivastava, U.; Tran, E.; Bhargava-Shah, A.; Wu, J. Y.; Ren, A.; Caoili, K.; Bui, B.; Alkhani, L.; Lee, S.; Mohit, N.; Seo, N.; Macedo, N.; Cheng, W.; Liu, C.; Thomas, R.; Chen, J. H.; Gevaert, O.
|
Olivier Gevaert
|
Stanford Center for Biomedical Informatics Research
|
10.1101/2022.11.15.22282368
|
2022-11-18
|
1
|
PUBLISHAHEADOFPRINT
|
cc_by_nc_nd
|
health informatics
|
https://www.medrxiv.org/content/early/2022/11/18/2022.11.15.22282368.source.xml
|
Electronic health records represent a large data source for outcomes research, but the majority of EHR data is unstructured (e.g. free text of clinical notes) and not conducive to computational methods. While there are currently approaches to handle unstructured data, such as manual abstraction, structured proxy variables, and model-assisted abstraction, these methods are time-consuming, not scalable, and require clinical domain expertise. This paper aims to determine whether selective prediction, which gives a model the option to abstain from generating a prediction, can improve the accuracy and efficiency of unstructured clinical data abstraction. We trained selective prediction models to identify the presence of four distinct clinical variables in free-text pathology reports: primary cancer diagnosis of glioblastoma (GBM, n = 659), resection of rectal adenocarcinoma (RRA, n = 601), and two procedures for resection of rectal adenocarcinoma: abdominoperineal resection (APR, n = 601) and low anterior resection (LAR, n = 601). Data were manually abstracted from pathology reports and used to train L1-regularized logistic regression models using term-frequency-inverse-document-frequency features. Data points that the model was unable to predict with high certainty were manually abstracted. All four selective prediction models achieved a test-set sensitivity, specificity, positive predictive value, and negative predictive value above 0.91. The use of selective prediction led to sizable gains in automation (anywhere from 57% to 95% reduction in manual abstraction of charts across the four outcomes). For our GBM classifier, the selective prediction model saw improvements to sensitivity (0.94 to 0.96), specificity (0.79 to 0.96), PPV (0.89 to 0.98), and NPV (0.88 to 0.91) when compared to a non-selective classifier. Selective prediction using utility-based probability thresholds can facilitate unstructured data extraction by giving "easy" charts to a model and "hard" charts to human abstractors, thus increasing efficiency while maintaining or improving accuracy.
|
NA
|
medRxiv
|
[
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|
10.1101/2021.01.05.21249293
|
Modelling Decay of Population Immunity With Proposed Second Dose Deferral Strategy
|
Jurgens, G. T.
|
Graham T Jurgens
|
Unaffiliated
|
10.1101/2021.01.05.21249293
|
2021-01-06
|
1
|
PUBLISHAHEADOFPRINT
|
cc_by_nc
|
allergy and immunology
|
https://www.medrxiv.org/content/early/2021/01/06/2021.01.05.21249293.source.xml
|
A second dose deferred strategy has been proposed to increase initial population immunity as an alternative to the default two dose vaccine regimen with spacing of 21 or 28 days between vaccine doses for the mRNA vaccines from Pfizer and Moderna. This increased initial population immunity is only of value if one dose immunity does not decay so fast as to nullify the benefit. Because decay rates of one dose and two dose efficacy are currently unknown, a model to project population immunity between the two strategies was created. By evaluating the decay rate of one dose efficacy, two dose efficacy, and time until the second dose is given, the model shows that if there is an increased decay rate of one dose efficacy relative to the two dose decay rate, it is highly unlikely to nullify the benefit of increased population immunity seen in a second dose deferral strategy. Rather, all reasonable scenarios strongly favour a second dose deferral strategy with much higher projected population immunity in comparison to the default regimen.
|
NA
|
medRxiv
|
[
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]
|
10.1101/567297
|
Induction of the nicotinamide riboside kinase NAD+ salvage pathway in skeletal muscle of H6PDH KO mice
|
Doig, C. L.; Zielinska, A. E.; Oakey, L. A.; Fletcher, R. S.; El Hassan, Y. S.; Garten, A.; Cartwright, D.; Heising, S.; Alsheri, A.; Watson, D. G.; Adamski, J.; Tennant, D. A.; Lavery, G. G.
|
Gareth G Lavery
|
University of Birmingham
|
10.1101/567297
|
2019-04-05
|
2
|
new results
|
cc_by_nd
|
physiology
|
https://www.biorxiv.org/content/early/2019/04/05/567297.source.xml
|
BackgroundHexose-6-Phosphate Dehydrogenase (H6PDH) is a generator of NADPH in the Endoplasmic/Sarcoplasmic Reticulum (ER/SR). Interaction of H6PDH with 11{beta}-hydroxysteroid dehydrogenase type 1 provides NADPH to support oxo-reduction of inactive to active glucocorticoids, but the wider understanding of H6PDH in ER/SR NAD(P)(H) homeostasis is incomplete. Muscle specific lack of H6PDH results in a deteriorating skeletal myopathy, altered glucose homeostasis, ER stress and activation of the unfolded protein response. Here we further assess muscle responses to H6PDH deficiency to delineate pathways that may underpin myopathy and link SR redox status to muscle wide metabolic adaptation.\n\nMethodsWe analysed skeletal muscle from H6PDH knockout (H6PDKO), H6PDH and NRK2 double knockout (DKO) and wild-type (WT) mice. H6PDKO mice were supplemented with the NAD+ precursor nicotinamide riboside. Skeletal muscle samples were subject to biochemical analysis including NAD(H) measurement, LC/MS based metabolomics, Western immunoblotting, and high resolution mitochondrial respirometry. Genetic and supplement models were assessed for degree of myopathy compared to H6PDKO.\n\nResultsH6PDKO skeletal muscle showed adaptations in the routes regulating nicotinamide and NAD+ biosynthesis, with significant activation of the Nicotinamide Riboside Kinase 2 (NRK2) pathway. Associated with changes in NAD+ biosynthesis H6PDKO muscle had impaired mitochondrial respiratory capacity with altered mitochondrial acylcarnitine and acetyl CoA metabolism. Boosting NAD+ levels through the NRK2 pathway using the precursor nicotinamide riboside had no effect to mitigate ER stress and dysfunctional mitochondrial respiratory capacity or Acetyl-CoA metabolism. Similarly, H6PDKO/NRK2 double KO mice did not display an exaggerated timing or severity of myopathy or overt change in mitochondrial metabolism despite depression of NAD+ availability.\n\nConclusionsThese findings suggest a complex metabolic response to changes to muscle SR NADP(H) redox status that result in impaired mitochondrial energy metabolism and activation of cellular NAD+ salvage pathways. It is possible that SR can sense and signal perturbation in NAD(P)(H) that cannot be rectified in the absence of H6PDH. Whether NRK2 pathway activation is a direct response to changes in SR NAD(P)(H) availability or adaptation to deficits in metabolic energy availability remains to be resolved.
|
NA
|
bioRxiv
|
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|
10.1101/2023.04.11.535868
|
Targeting ABCB4 using mRNA-LNP for the treatment of rare liver diseases
|
Alsuraih, M.; LaViolette, B. M.; Lin, G.-Y.; Kovi, R.; Daurio, N.; Cheng, C.; Ahn, Y.; Sun, X.; Jiang, Z.; Wang, Y.; Li, S.; Cheng, Y.; Fan, X.; Haskins, J.; Ortiz, R.; Hunter, A.; Hirenallur Shanthappa, D.; Wu, Y.; Holsti, M.; Stewart, M.; Tadin Strapps, M.; Chiang, S.-H.
|
Mohammed Alsuraih
|
Pfizer
|
10.1101/2023.04.11.535868
|
2023-04-11
|
1
|
new results
|
cc_by_nc_nd
|
molecular biology
|
https://www.biorxiv.org/content/early/2023/04/11/2023.04.11.535868.source.xml
|
Mutations in the ABCB4 gene lead to a wide-spectrum of rare liver diseases including progressive familial intrahepatic cholestasis type 3 (PFIC3) and low-phospholipid associated cholelithiasis (LPAC) syndrome. PFIC3 patients develop symptoms during late infancy, including severe itching, jaundice, and failure to thrive. The condition may progress to liver failure during childhood or adulthood. This is a highly unmet medical condition where liver transplantation is the only option to correct this disease. Recently, exciting data suggested that restoration of the ABCB4 function via gene replacement could rescue liver phenotypes associated with ABCB4 dysfunction in a preclinical PFIC3 mouse model. Here, we used mRNA LNP platform to determine expression and durability of ABCB4 in the liver of wildtype mice. In addition, we generated Abcb4-/- mice to study the efficacy of systemic delivery of ABCB4 mRNA LNP. We observed a robust and durable expression of hABCB4 up to 72 hours post systemic dosing in the liver of wild-type mice. Systemic administration of hABCB4 mRNA achieved a remarkable restoration of phosphatidylcholine levels in bile, a significant decrease in liver stiffness as measured by shear wave elastography, and amelioration of liver histopathology including fibrosis and ductular reaction. We conclude that administration of hABCB4 mRNA LNPs was sufficient to ameliorate fibrosis markers in the PFIC3 mouse model. Our data suggests that gene replacement using mRNA LNP modality could provide an excellent opportunity for patients with biliary diseases.
|
NA
|
bioRxiv
|
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]
|
10.1101/530378
|
Deep learning enables accurate clustering and batch effect removal in single-cell RNA-seq analysis
|
Li, X.; Lyu, Y.; Park, J.; Zhang, J.; Stambolian, D.; Susztak, K.; Hu, G.; Li, M.
|
- Li
|
University of Pennsylvania
|
10.1101/530378
|
2019-01-25
|
1
|
new results
|
cc_by_nc_nd
|
genomics
|
https://www.biorxiv.org/content/early/2019/01/25/530378.source.xml
|
Single-cell RNA sequencing (scRNA-seq) can characterize cell types and states through unsupervised clustering, but the ever increasing number of cells imposes computational challenges. We present an unsupervised deep embedding algorithm for single-cell clustering (DESC) that iteratively learns cluster-specific gene expression signatures and cluster assignment. DESC significantly improves clustering accuracy across various datasets and is capable of removing complex batch effects while maintaining true biological variations.
|
10.1038/s41467-020-15851-3
|
bioRxiv
|
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]
|
10.1101/2024.02.01.24301771
|
Mapping domains of early-life determinants of future multimorbidity across three UK longitudinal cohort studies.
|
Stannard, S.; Berrington, A.; Fraser, S.; Paranjothy, S.; Hoyle, R.; Owen, R.; Akbari, A.; Shiranirad, M.; Chiovoloni, R.; Alwan, N. A.
|
Sebastian Stannard
|
University of Southampton
|
10.1101/2024.02.01.24301771
|
2024-02-03
|
1
|
PUBLISHAHEADOFPRINT
|
cc_by
|
public and global health
|
https://www.medrxiv.org/content/early/2024/02/03/2024.02.01.24301771.source.xml
|
Many studies use a reductionist approach to isolate the influence of one factor in childhood on multimorbidity rather than consider the combined effect of wider determinants. We explored how potential multiple early-life determinants of multimorbidity can be characterised across three UK cohort studies.
We used the National Child Development Study (NCDS), the 1970 British Cohort Study (BCS70), and the Aberdeen Children of the 1950s Study (ACONF) to identified early-life variables that fit into 12 domains of early-life determinants of multimorbidity. Variables were assigned into 12 domains; principal component analysis reduced the dimensionality of the data and structured variables into subgroups.
The data audit identified 7 domains in ACONF, 10 domains in NCDS and 12 domains in BCS70. Components included maternal fertility histories within the prenatal, antenatal and birth domain, long-term illnesses within the child health domain, educational ability within the child education and health literacy domain, ethnicity within the demography domain, parental health behaviours within the transgenerational domain, housing within the socioeconomic domain and parental-child interactions within the parental-family domain.
Conceptualising the risk of future multimorbidity as lifecourse domains composed of multiple factors can help challenge the existing understanding of disease aetiology and develop new ideas for prevention of multimorbidity.
|
10.1038/s41598-024-72275-5
|
medRxiv
|
[
99,
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51
]
|
10.1101/2022.09.24.509337
|
Small-molecule ketone esters treat brain network abnormalities in an Alzheimer's disease mouse model
|
Newman, J. C.; Ma, K.; Kroll, F.; Higgins, E.; Ulrich, S.; Palop, J. J.; Verdin, E.
|
John C Newman
|
Buck Institute for Research on Aging, Novato CA USA
|
10.1101/2022.09.24.509337
|
2022-09-26
|
1
|
new results
|
cc_by
|
neuroscience
|
https://www.biorxiv.org/content/early/2022/09/26/2022.09.24.509337.source.xml
|
Altered brain network activity and the resulting hypersynchrony are important for the pathogenesis of cognitive decline in Alzheimers disease (AD) mouse models. Treatments that reduce epileptiform discharges (EDs) or network hyperactivity improve cognition in AD models and humans. We first show that ketogenic diet, but not fasting, rapidly and persistently reduced EDs in the hAPPJ20 Alzheimers mouse model over timescales of hours to months. Then, to identify the specific mechanism of the pleiotropic ketogenic diet, we developed small molecule ketone esters to deliver ketone bodies pharmacologically. Two ketone esters recapitulate ED suppression without other dietary manipulation, over time scales of minutes to one week. This small molecule rescue was associated with reduced low-frequency oscillatory activity similar to the recently reported mechanism of an NMDA receptor modulator molecule in this model. Long-term KD resulted in cognitive improvement and in a sex-stratified analysis also improved survival in the more severely affected hAPPJ20 males. Agents that deliver ketone bodies via small molecules or act on downstream targets may hold therapeutic promise in AD through the mechanism of improved network function and reduced epileptiform activity.
|
NA
|
bioRxiv
|
[
211,
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110,
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]
|
10.1101/2022.09.01.506282
|
Identification of a novel HASPIN inhibitor and its synergism with the PLK1 inhibitor
|
Kwon, E.-J.; Mashelkar, K.; Seo, J.; Shin, Y.; Sung, K.; Jang, S. C.; Cheon, S. W.; Lee, H.; Han, B. W.; Jeong, L. S.; Cha, H.-J.
|
Lak Shin Jeong
|
Seoul National University
|
10.1101/2022.09.01.506282
|
2022-09-03
|
1
|
new results
|
cc_no
|
pharmacology and toxicology
|
https://www.biorxiv.org/content/early/2022/09/03/2022.09.01.506282.source.xml
|
BackgroundHASPIN, a mitotic kinase for Histone H3, is a promising target for anti-cancer therapy. However, as HASPIN is an atypical kinase with low similarity to eukaryotic protein kinases, development of a HASPIN inhibitor from the conventional pharmacophore of kinase inhibitors would be technically challenging.
MethodsChemical modifications of a cytotoxic 4-thioadenosine analogue with high genotoxicity and multiple kinomescan profiles were performed to produce a novel non-genotoxic kinase inhibitor, LJ4827. The mode of action of this inhibitor with clear anti-cancer activity was inferred based on transcriptomic and chemical similarity to known drugs.
ResultsThe specificity and potency of LJ4827 as a HASPIN inhibitor were validated by in vitro kinase screening and subsequent X-ray crystallography. As predicted, LJ4827 treatment delayed mitosis by clear inhibition of the recruitment of Aurora B at the centromere in cancer cells, without a genotoxic response. Through transcriptome analysis of lung cancer patients, PLK1 was predicted as a druggable synergistic partner to complement HASPIN inhibition. Cotreatment with the PLK1 inhibitor BI2536 and LJ4827 led to pronounced cytotoxicity of lung cancers in vitro and in vivo.
ConclusionSimultaneous inhibition of both HASPIN and PLK1 is a promising therapeutic strategy for lung cancers.
|
NA
|
bioRxiv
|
[
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]
|
10.1101/2023.05.04.539430
|
Dimensional clinical phenotyping using post-mortem brain donor medical records: Association with neuropathology
|
Vogelgsang, J. S.; Dan, S.; Lally, A. P.; Chatigny, M.; Vempatia, S.; Abston, J.; Durning, P. T.; Oakley, D. H.; McCoy, T. H.; Klengel, T.; Berretta, S.
|
Jonathan S. Vogelgsang
|
McLean Hospital
|
10.1101/2023.05.04.539430
|
2023-05-05
|
1
|
new results
|
cc_no
|
neuroscience
|
https://www.biorxiv.org/content/early/2023/05/05/2023.05.04.539430.source.xml
|
INTRODUCTIONTransdiagnostic dimensional phenotypes are essential to investigate the relationship between continuous symptom dimensions and pathological changes. This is a fundamental challenge to postmortem work, as assessment of newly developed phenotypic concepts needs to rely on existing records.
METHODSWe adapted well-validated methodologies to compute NIMH research domain criteria (RDoC) scores using natural language processing (NLP) from electronic health records (EHRs) obtained from post-mortem brain donors and tested whether RDoC cognitive domain scores were associated with hallmark Alzheimers disease (AD) neuropathological measures.
RESULTSOur results confirm an association of EHR-derived cognitive scores with hallmark neuropathological findings. Notably, higher neuropathological load, particularly neuritic plaques, was associated with higher cognitive burden scores in the frontal ({beta}=0.38, p=0.0004), parietal ({beta}=0.35, p=0.0008), temporal ({beta}=0.37, p=0. 0004) and occipital ({beta}=0.37, p=0.0003) lobes.
DISCUSSIONThis proof of concept study supports the validity of NLP-based methodologies to obtain quantitative measures of RDoC clinical domains from postmortem EHR.
|
NA
|
bioRxiv
|
[
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216,
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194,
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]
|
10.1101/2023.05.04.539515
|
RFP-CyanineDye Probe Pair for In vivo Neurovascular Multiphoton Imaging
|
Sun, Q.
|
Qinchao Sun
|
Shenzhen Institute of Advanced Technology
|
10.1101/2023.05.04.539515
|
2023-05-24
|
2
|
new results
|
cc_no
|
biophysics
|
https://www.biorxiv.org/content/early/2023/05/24/2023.05.04.539515.source.xml
|
In vivo imaging of the neurovascular network is considered to be one of the most powerful approaches for understanding brain functionality. Nevertheless, simultaneously imaging the neuron network and blood vessels in deeper brain layers in a non-invasive manner remains to be a major challenge due to the lack of appropriate labeling fluorescence probe pairs. Herein, we proposed a 2P and 3P fluorescence probe pair for neurovascular imaging. Specifically, the red fluorescence protein (RFP) with an absorption maximum around 550 nm is used as a 3P excited probe to label neurons, and a cyanine derivative dye Q820 has a NIR absorption maximum of 825 nm as a 2P excited probe to label the vasculature, enabling single wavelength excitation at 1650 nm for neurovascular imaging. In particular, the two-photon cross section of Q820 was found to be about 2-fold higher than that of indocyanine green (ICG), a commonly used red two-photon fluorescence labeling agent, at the same excitation wavelength. Benefited from the long wavelength advantage in reducing scattering in both 2 and 3-photon excitation of the fluorescence pairs, we demonstrated in vivo neurovascular imaging in intact mouse brains through white matter and deep into the hippocampus in somatosensory cortex.
|
NA
|
bioRxiv
|
[
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]
|
10.1101/2023.05.15.540833
|
Novel Curcuphenol Analogues Possess Anti-Metastatic Biologic Activity
|
Ellis, S. L. S.; Nohara, L. L.; Dada, S.; Saranchova, I.; Munro, L.; Choi, K. B.; Garrovillas, E.; Pfeifer, C. G.; Williams, D. E.; Cheng, P.; Andersen, R. J.; Jefferies, W.
|
Wilfred Jefferies
|
University of British Columbia
|
10.1101/2023.05.15.540833
|
2023-05-23
|
4
|
regular article
|
cc_no
|
biochemistry
|
https://www.biorxiv.org/content/early/2023/05/23/2023.05.15.540833.source.xml
|
For eons, turmeric and curcumin have been used as culinary spices and as traditional medicines and as vogue dietary supplements for a growing list of disorders, including arthritis, digestive disorders, respiratory infections, allergies, liver disease, depression and cancer. The activities of these spices are commonly attributed to curcuminoids; however, the medical applications of this class of compounds has been limited due to the low water solubility, chemical instability, acid lability, poor absorption, rapid catabolism by enzymes of the diverse curcuminoids contained in turmeric and curcumin extracts. Furthermore, identifying the bio-active curcuminoids with unique molecular entities responsible for specific medicinal benefit is at its infancy. To overcome these many issues and substantially advance this area of inquiry, we created a water-soluble achiral curcuphenol analogue and a water-soluble racemic analogue that have enhanced chemical characteristics and biological performance, and we subsequently demonstrated their ability to reverse the immune-escape phenotype, a process that enables tumours to hide from host immune responses and thereby provides tumours a significant growth advantage to metastatic tumours. The discovery that curcuphenols can reverse tumour immune-escape mechanisms and thereby reduce tumour growth, provides a rationale for the development of advanced dissecting nutraceuticals and bioceuticals for unique chemical entities as therapeutic building blocks to synthesize analogues with optimal chemical characteristics capable of harnessing the power of the immune system to extinguish metastatic cancers and beyond.
|
NA
|
bioRxiv
|
[
5,
207,
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76,
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]
|
10.1101/490524
|
Rapid functional divergence of grass duplicate genes
|
Jiang, X.; Assis, R.
|
Raquel Assis
|
Pennsylvania State University
|
10.1101/490524
|
2018-12-09
|
1
|
new results
|
cc_no
|
evolutionary biology
|
https://www.biorxiv.org/content/early/2018/12/09/490524.source.xml
|
Gene duplication has played an important role in the evolution and domestication of flowering plants. Yet little is known about how plant duplicate genes evolve and are retained over long timescales, particularly those arising from small-scale duplication (SSD) rather than whole-genome duplication (WGD) events. Here we address this question in the Poaceae (grass) family by analyzing gene expression data from nine tissues of Brachypodium distachyon, Oryza sativa japonica (rice), and Sorghum bicolor (sorghum). Consistent with theoretical predictions, expression profiles of most grass genes are conserved after SSD, suggesting that functional conservation is the primary outcome of SSD in grasses. However, we also uncover support for widespread functional divergence, much of which occurs asymmetrically via the process of neofunctionalization. Moreover, neofunctionalization preferentially targets younger (child) duplicate gene copies, is associated with RNA-mediated duplication, and occurs quickly after duplication. Further analysis reveals that functional divergence of SSD-derived genes is positively correlated with both sequence divergence and tissue specificity in all three grass species, and particularly with anther expression in B. distachyon. Therefore, as found in many animal species, SSD-derived grass genes often undergo rapid functional divergence that may be driven by natural selection on male-specific phenotypes.
|
NA
|
bioRxiv
|
[
244,
224,
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216,
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]
|
10.1101/571653
|
Targeted DNA transposition using a dCas9-transposase fusion protein
|
Bhatt, S.; Chalmers, R.
|
Ronald Chalmers
|
University of Nottingham
|
10.1101/571653
|
2019-04-12
|
2
|
new results
|
cc_no
|
biochemistry
|
https://www.biorxiv.org/content/early/2019/04/12/571653.source.xml
|
Homology directed genome engineering is limited by transgene size. Although DNA transposons are more efficient with large transgenes, random integrations are potentially mutagenic. Catalytically inactive Cas9 is attractive candidate for targeting a transposase fusion-protein because of its high specificity and affinity for its binding site. Here we demonstrate efficient Cas9 targeting of a mariner transposon. Targeted integrations were tightly constrained at two adjacent TA dinucleotides about 20 bp to one side of the gRNA binding site. Biochemical analysis of the nucleoprotein complexes demonstrated that the transposase and Cas9 moieties of the fusion protein can bind their respective substrates independently. In the presence of the Cas9 target DNA, kinetic analysis revealed a delay between first and second strand cleavage at the transposon end. This step involves a significant conformational change that may be hindered by the properties of the interdomainal linker. Otherwise, the transposase behaved normally and was proficient for integration in vitro and in vivo.
|
NA
|
bioRxiv
|
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]
|
10.1101/2023.06.22.23291740
|
Demography, hygiene and previous disease prevalence as plausible risk factors associated with Covid-19 deaths across Indian states
|
Chatterjee, B.; Mande, S. C.
|
Shekhar C Mande
|
Bioinformatics Centre, Savitribai Phule Pune University, Pune
|
10.1101/2023.06.22.23291740
|
2023-06-29
|
1
|
PUBLISHAHEADOFPRINT
|
cc_no
|
epidemiology
|
https://www.medrxiv.org/content/early/2023/06/29/2023.06.22.23291740.source.xml
|
Severity of Covid-19 diseases has been disproportionate with higher case-fatality ratio affecting developed nations. In India, states with higher income have reported more number of deaths compared to lower income states. The global burden of diseases India 2019 and the National Health Profile 2019 data was used to draw correlations with Covid-19 mortality at two different dates of peak Covid-19 cases in India. We explored correlation of mortality in different states of India with prevalence of different diseases, demography, development, sanitation etc. The study found a positive correlation with known demographic parameters such as percentage of elderly population(spearman correlation coefficient(rho) =0.44 and 0.46 with 1st and 2nd peak respectively). Similarly, percentage urbanization was seen to correlate well with mortality(rho=0.71 and 0.57) suggesting Covid-19 to be a predominantly urban disease. Prevalence of Autoimmune diseases, and Cancer show higher correlation with deaths. A surprising positive correlation emerged between improved sanitation parameters, such as closed drainage and indoor toilets, with COVID-19 deaths. Overall the multivariate regression model achieved by combining demography, sanitation, autoimmune diseases and cancer gave us the best prediction for Covid-19 mortality(adjusted R square value of 0.71 with peak 1 and 0.85 with peak 2). Analysis of the Covid-19 related data seems to indicate that as the wealth of a state increases, the states urban landscape changes often leading to better sanitation facilities. The lifestyle and prevalence to autoimmune diseases as well as cancer also increases. However, this may affect the states ability to fight pandemics due to lower exposure to pathogens and immune training.
|
NA
|
medRxiv
|
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|
10.1101/2022.07.18.500453
|
An integrase clade that repeatedly targets prophage late genes, yielding helper-embedded satellites
|
Tommasini, D.; Mageeney, C. M.; Williams, K. P.
|
Kelly P Williams
|
Sandia National Laboratories
|
10.1101/2022.07.18.500453
|
2022-07-19
|
1
|
new results
|
cc_by
|
bioinformatics
|
https://www.biorxiv.org/content/early/2022/07/19/2022.07.18.500453.source.xml
|
Satellites are mobile genetic elements that rely on helper phages for their mobilization. The many known satellite-helper interactions are trans-regulatory, with gene products from one partner modulating the nucleic acid or protein activities of the other. We discovered a satellite type with a more intimate cis-regulatory configuration: integrated within, and co-oriented with, a late gene of its lambdoid helper prophage. This helper-embedded satellite (HES) configuration would delay expression of the interrupted helper late gene until the satellite excises; it also offers potential passive components to both HES replication and late transcription, driven by the helper. Induction of a helper-satellite composite was monitored; precise excision of the entire composite was observed, followed by its replication, and the excision of the satellite from it. We mapped 491 HESs to one of 14 sites in cognates of phage lambda late genes A, B, C, E, V, T, H, L and J. The associated integrases form a single phylogenetic clade with subclades respecting the 14 site groups, while the attP attachment site regions contained a new doubled DNA sequence motif. This clade thus exhibits a repeated tropism for prophage late genes as it develops new integration sites. HESs bear close genomic similarities to gram-negative phage-induced chromosomal islands (PICIs, of which we found many more integrated into fis and hpt genes). We describe four ordered zones in a general HES/PICI genome organization: an integration zone encoding integrase and AlpA, a Bro zone encoding members of the Bro-N network of domain-swapping DNA-interactive proteins and immunity repressor RNAs, a replication zone, and a late zone in which clusters as large as 18 consecutive helper late genes have been captured. Like the late zone, the Bro zone is dynamic, perhaps due to activity of the Bro proteins themselves.
|
NA
|
bioRxiv
|
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|
10.1101/2022.08.31.505522
|
Natural and pathological aging distinctively impact the vomeronasal system and social behavior
|
Portales, A.; Chamero, P.; Jurado, S.
|
Sandra Jurado
|
Institute of Neuroscience CSIC-UMH, San Juan de Alicante, Alicante, Spain
|
10.1101/2022.08.31.505522
|
2022-09-25
|
4
|
new results
|
cc_no
|
neuroscience
|
https://www.biorxiv.org/content/early/2022/09/25/2022.08.31.505522.source.xml
|
Normal aging and many age-related disorders such as Alzheimers disease cause deficits in olfaction, however it is currently unknown how natural and pathological aging impact the detection of social odors which might contribute to the impoverishment of social behavior at old age further worsening overall health. Here, we investigated the effect of aging in the recognition of social cues and the display of social behavior. Our findings indicate that aging distinctively disrupts the processing of social olfactory cues decreasing social odor exploration, discrimination and habituation in both wild type senescent (2-year-old) mice and in 1-year-old double mutant model of Alzheimers disease (APP/PS1Het). Furthermore, social novelty was diminished in 1-year-old APP/PS1Het mice, indicating that alterations in the processing of social cues are accelerated during pathological aging. Analysis of the vomeronasal organ, the main gateway to pheromone-encoded information, indicated that natural and pathological aging distinctively reduce the neurogenic ability of the vomeronasal sensory epithelium. Cell proliferation remained majorly preserved in 1-year model of Alzheimers disease (APP/PS1Het), whereas naturally aged animals exhibited significant deficiencies in the number of mature, proliferative and progenitor cells. This study reveals fundamental differences in the cellular processes by which natural and pathological aging disrupt the exploration of social cues and social behavior.
|
NA
|
bioRxiv
|
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|
10.1101/749887
|
Experimental evolution reveals the genetic basis and systems biology of superoxide stress tolerance
|
Tan, J.; Olson, C. A.; Park, J. H.; Sastry, A. V.; Phaneuf, P.; Yang, L.; Szubin, R.; Hefner, Y.; Feist, A. M.; Palsson, B. O.
|
Bernhard O Palsson
|
University of California, San Diego
|
10.1101/749887
|
2019-08-29
|
1
|
new results
|
cc_no
|
systems biology
|
https://www.biorxiv.org/content/early/2019/08/29/749887.source.xml
|
Bacterial response to oxidative stress is of fundamental importance. Oxidative stresses are endogenous, such as reactive oxidative species (ROS) production during respiration, or exogenous in industrial biotechnology, due to culture conditions or product toxicity. The immune system inflicts strong ROS stress on invading pathogens. In this study we make use of Adaptive Laboratory Evolution (ALE) to generate two independent lineages of Escherichia coli with increased tolerance to superoxide stress by up to 500% compared to wild type. We found: 1) that the use of ALE reveals the genetic basis for and systems biology of ROS tolerance, 2) that there are only 6 and 7 mutations, respectively, in each lineage, five of which reproducibly occurred in the same genes (iron-sulfur cluster regulator iscR, putative iron-sulfur repair protein ygfZ, pyruvate dehydrogenase subunit E aceE, succinate dehydrogenase sucA, and glutamine tRNA glnX), and 3) that the transcriptome of the strain lineages exhibits two different routes of tolerance: the direct mitigation and repair of ROS damage and the up-regulation of cell motility and swarming genes mediated through phosphate starvation, which has been linked to biofilm formation and aggregation. These two transcriptomic responses can be interpreted as flight and fight phenotypes.\n\nImportanceBacteria encounter oxidative stress from multiple sources. During pathogenic infections, our bodys immune system releases ROS as a form of antimicrobial defense whilst bacteria used in industrial biotechnology are frequently exposed to genetic modifications and culture conditions which induce oxidative stress. In order to get around the bodys defences, pathogens have developed various adaptations to tolerate high levels of ROS, and these adaptive mechanisms are not always well understood. At the same time, there is a need to improve oxidative stress tolerance for industrially relevant strains in order to increase robustness and productivity. In this study we generate two strains of superoxide tolerant Escherichia coli and identify several adaptive mechanisms. These findings can be directly applied to improve production strain fitness in an industrial setting. They also provide insight into potential virulence factors in other pathogens, highlighting potential targets for antimicrobial compounds.
|
NA
|
bioRxiv
|
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