bluuebunny/crossref_metadata_2025 huggingface dataset:
The seroprevalence and trends of SARS-CoV-2 in Delhi, India: A repeated population-based seroepidemiological study
Authors: Sharma Nandini , Sharma Pragya , Basu Saurav , Saxena Sonal , Chawla Rohit , Dushyant Kumar , Mundeja Nutan , Marak Z SK , Singh Sanjay , Singh Gautam Kumar , Rustagi Ruchir
Published: December 2020

Background

Three rounds of a repeated cross-sectional serosurvey to estimate the seroprevalence and trends of SARS-CoV-2 were conducted from August-October’ 2020 in the state of Delhi in India in the general population aged ≥5 years.

Methods

The selection of participants was through a multi-stage sampling design from all the 11 districts and 280 wards of the city-state, with two-stage allocation proportional to population- size. Household selected was via systematic random sampling, and individual participant selection through the age-order procedure. The blood samples were screened using the IgG ELISA COVID-Kawach kit (August Round), and the ERBALISA COVID-19 IgG (September and October) rounds. The seroprevalence was estimated by applying the sampling weights based on age and sex with further adjustment for the assay-kit characteristics.

Results

A total of 4267 (n=15046), 4311 (n=17409), and 3829 (n=15015) positive tests indicative of the presence of IgG antibody to SARS-CoV-2 were observed during the August, September, and October 2020 serosurvey rounds, respectively. The adjusted seroprevalence declined from 28.39% (95% CI 27.65-29.14) (August) to 24.08% (95% CI 23.43-24.74) (September), and 24.71% (95% CI 24.01, 25.42%) (October). The antibody positivity was highest in the ≥50 and female age-group during all rounds of the serosurvey, while the decline was maximum among the younger age-group (5-17 years). On adjusted analysis, participants with lower per capita income, living in slums or overcrowded households, and those with diabetes comorbidity had significantly higher statistical odds of antibody positivity.

Conclusions

Despite high IgG seroprevalence, there was evidence for waning of antibody positivity with the progression of the COVID-19 epidemic, implying a potential reduction in population immunity, especially if also associated with the lack of trained T cell immunity.
Transcription factor network analysis identifies REST/NRSF as an intrinsic regulator of CNS regeneration
Authors: Cheng Yuyan , Yin Yuqin , Zhang Alice , Bernstein Alexander M. , Kawaguchi Riki , Gao Kun , Potter Kyra , Gilbert Hui-Ya , Ao Yan , Ou Jing , Fricano-Kugler Catherine J. , Goldberg Jeffrey L. , Woolf Clifford J. , Sofroniew Michael V. , Benowitz Larry I. , Geschwind Daniel H.
Published: December 2020

The inability of neurons to regenerate long axons within the CNS is a major impediment to improving outcome after spinal cord injury, stroke, and other CNS insults. Recent advances have uncovered an intrinsic program that involves coordinate regulation by multiple transcription factors that can be manipulated to enhance growth in the peripheral nervous system. Here, we used a system-genomics approach to characterize regulatory relationships of regeneration-associated transcription factors, identifying RE1-Silencing Transcription Factor (REST; Neuron-Restrictive Silencer Factor, NRSF) as a predicted upstream suppressor of a pro-regenerative gene program associated with axon regeneration in the CNS. We validate our predictions using multiple paradigms, showing that mature mice bearing cell type-specific deletions of REST or expressing dominant-negative mutant REST showed improved regeneration of the corticospinal tract and optic nerve, accompanied by upregulation of regeneration-associated genes in cortical motor neurons and retinal ganglion cells, respectively. These analyses identify a novel role for REST as an upstream suppressor of the intrinsic regenerative program in the CNS and demonstrate the power of a systems biology approach involving integrative genomics and bio-informatics to predict key regulators of CNS repair.
Distinct kinetics in antibody responses to 111 Plasmodium falciparum antigens identifies novel serological markers of recent malaria exposure
Authors: Yman Victor , Tuju James , White Michael T , Kamuyu Gathoni , Mwai Kennedy , Kibinge Nelson , Asghar Muhammad , Sundling Christopher , Sonden Klara , Murungi Linda , Kiboi Daniel , Kimathi Rinther , Chege Timothy , Chepsat Emily , Kiyuka Patience , Nyamako Lydia , Osier Faith H A , Farnert Anna
Published: December 2020

Strengthening malaria surveillance is a key intervention needed to reduce the global disease burden. Reliable serological markers of recent malaria exposure could dramatically improve current surveillance methods by allowing for accurate estimates of infection incidence from limited data. We studied the IgG antibody response to 111 Plasmodium falciparum proteins in travellers followed longitudinally after a natural malaria infection in complete absence of re-exposure. We identified a novel combination of five serological markers (GAMA, MSP1, MSPDBL1 C- and N-terminal, and PfSEA1) that detect exposure within the previous 3-months with >80% sensitivity and specificity. Using mathematical modelling, we examined the antibody kinetics and determined that responses informative of recent exposure display several distinct characteristics: rapid initial boosting and decay, less inter-individual variation in response kinetics, and minimal persistence over time. These serological exposure markers can be incorporated into routine malaria surveillance to guide efforts for malaria control and elimination.
SARS-CoV-2 among migrants and forcibly displaced populations: a rapid systematic review
Authors: Hintermeier Maren , Gencer Hande , Kajikhina Katja , Rohleder Sven , Santos-Hövener Claudia , Tallarek Marie , Spallek Jacob , Bozorgmehr Kayvan
Published: December 2020

The economic and health consequences of the COVID-19 pandemic pose a particular threat to vulnerable groups, such as migrants, particularly forcibly displaced populations. The aim of this review is (i) to synthesise the evidence on risk of infection and transmission among migrants, refugees, asylum seekers and internally displaced populations, and (ii) the effect of lockdown measures on these populations. We searched MEDLINE and WOS, preprint servers, and pertinent websites between 1st December 2019 and 26th June 2020. The included studies showed a high heterogeneity in study design, population, outcome and quality. The incidence risk of SARS-CoV-2 varied from 0·12% to 2·08% in non-outbreak settings and from 5·64% to 21·15% in outbreak settings. Migrants showed a lower hospitalisation rate compared to non-migrants. Negative impacts on mental health due to lockdown measures were found across respective studies. However, findings show a tenuous and heterogeneous data situation, showing the need for more robust and comparative study designs.
Impact of neoadjuvant chemoradiotherapy on postoperative clinically significant pancreatic fistula. A systemic review and updated meta-analysis.
Authors: VASAVADA BHAVIN , PATEL HARDIK
Published: December 2020

Background:
Pancreatic fistula is one of the main complications after pancreatic surgery and the leading cause of morbidity and mortality after pancreatic surgery. There are many pieces of evidence emerging out from retrospective studies and metanalysis that neoadjuvant chemoradiation decreases rates of clinically significant postoperative pancreatic fistula.
Aims and objectives:
The primary aim of our analysis was to do a systemic review and updated meta-analysis of literature published in the last 10 years and look for the association of neoadjuvant chemoradiation and risk of subsequent clinically significant pancreatic fistula.
Methods:
EMBASE, MEDLINE, and the Cochrane Database were searched for
Studies comparing outcomes in patients receiving neoadjuvant chemoradiotherapy first
with those patients who received surgery first in case of pancreatic cancer. A systemic review and Metanalysis were done according to MOOSE and PRISMA guidelines. Heterogeneity was measured using Q tests and I2, and p < 0.10 was determined as significant. The Odds ratios (OR) and Risk Ratios (RR) were calculated for dichotomous data as per the requirement, and weighted mean differences (WMD) were used for continuous variables. Nonrandomized trials were accessed for bias using the New Castle Ottawa scale. Publication bias was studied using funnel plots. The meta-analysis was conducted using Open Review Manager 5.4.
Results:
Twenty-six studies including 17021 patients finally included in the analysis. 339 patients out of a total of 3386 developed clinically significant pancreatic fistula in the neoadjuvant first group. 2342 patients out of 13335 patients developed clinically significant pancreatic fistula in the surgery first group. Neoadjuvant treatment significantly reduced the risk of subsequent clinically significant pancreatic fistula. (p= <0.0001). The number of patients with soft pancreas was significantly higher in the surgery first group. (p <0.0001). Pancreatic duct diameter mentioned in only two studies but there was no significant difference between both groups. [p=1].Blood loss was significantly more in the surgery first group.[ p <0.0001]. There was no difference in pancreaticoduodenectomy or distal pancreatectomy performed between both groups. (p=0.82). There was no difference in the number of borderline resectable pancreatic tumors between both groups. (p= 0.34). There was no difference in overall grade 3/grade 4 complications rate between both groups. (p= 0.39).
Conclusion:
Neoadjuvant treatments may be responsible for the lower rates of clinically significant pancreatic fistula after subsequent surgery.
Utility of COVID-19 Decision Rules Related to Consecutive Decline in Positivity or Hospitalizations: A Data-driven Simulation Study
Authors: Ejima Keisuke , Maki Kevin , Golzarri-Arroyo Lilian , Allison David B.
Published: December 2020

The White House issued Guidelines for Opening Up America Again to help state and local officials when reopening their economies. These included a 'downward trajectory of positive tests as a percent of total tests within a 14-day period.' To examine this rule, we computed the probability of observing continuous decline in positivity when true positivity is in decline using data-driven simulation. Data for COVID-19 positivity reported in New York state from April 14 to May 5, 2020, where a clear reduction was observed, were used. First, a logistic regression model was fitted to the data, considering the fitted values as true positivity. Second, we created observed positivity by randomly selecting 25,000 people per day from a population with those true positivity for 14 days. The simulation was repeated 1,000 times to compute the probability of observing a consecutive decline. As sensitivity analyses, we performed the simulation with different daily numbers of tests (10 to 30,000) and length of observation (7 and 21 days). We further used daily hospitalizations as another metric, using data from the state of Indiana. With 25,000 daily tests, the probability of a consecutive decline in positivity for 14 days was 99.9% (95% CI: 99.7% to 100%). The probability dropped with smaller numbers of tests and longer lengths of consecutive observation, because there is more chance of observing an increase in positivity with smaller numbers of tests and longer observation. The probability of consecutive decline in hospitalizations was ~0.0% regardless of the length of consecutive observation due to large variance. These results suggest that continuous declines in sample COVID-19 test positivity and hospitalizations may not be observed with sufficient probability, even when population probabilities truly decline. Criteria based on consecutive declines in metrics are unlikely to be useful for making decisions about relaxing COVID-19 mitigation efforts.
Active vaccine safety surveillance via a scalable, integrated system in Australian pharmacies.
Authors: Salter Sandra M , Singh Gurkamal , Nissen Lisa , Trentino Kevin , Murray Kevin , Lee Kenneth , Kop Benjamin , Peters Ian , Leeb Alan
Published: December 2020

ABSTRACT
Introduction: Active vaccine safety surveillance will be critical to COVID-19 vaccine deployment. Pharmacists have been identified as potential immunisers in COVID-19 policies, yet there are no reported active surveillance systems operating in pharmacies. We integrated an established participant-centred active vaccine safety surveillance system with a cloud-based pharmacy immunisation-recording program. We measured adverse events following immunisation (AEFI) reported via the new surveillance system in pharmacies, and compared these to AEFI reported via an existing surveillance system in non-pharmacy sites (general practice and other clinics).
Methods: A prospective cohort study of individuals>10 years receiving influenza immunisations from 22 pharmacies and 90 non-pharmacy sites between March and October, 2020, in Australia. Active surveillance was conducted using SMS and smartphone technology, via an opt-out system. Multivariable logistic regression (including a subgroup analysis of participants over 65 years) was used to assess differences in proportions of AEFI between participants immunised in pharmacies compared to non-pharmacy sites, adjusting for confounders of age, sex, and influenza vaccine brand.
Results: Of 101,440 influenza immunisation participants (6,992 from pharmacies; 94,448 from non-pharmacy sites), 77,498 (76.4%) responded; 96.1% (n=74,448) within 24 hours. Overall, 4.8% (n=247) pharmacy participants reported an AEFI, compared with 6.0% (n=4,356) non-pharmacy participants (adjusted odds ratio: 0.87; 95% confidence interval: 0.76 to 0.99; p=0.039). Similar proportions of AEFIs were reported in pharmacy (5.8%; n=31) and non-pharmacy participants (6.0; n=1617) aged over 65 years (adjusted odds ratio: 0.94, 95% confidence interval: 0.65 to 1.35; p=0.725).
Conclusion: High and rapid response rates demonstrate good participant engagement with active surveillance in both pharmacy and non-pharmacy participants. Significantly fewer AEFIs reported after pharmacist immunisations compared to non-pharmacy immunisations, with no difference in older adults, suggests different cohorts attend pharmacy and non-pharmacy immunisers. The integrated pharmacy system is rapidly scalable across Australia with global potential.
The SEQC2 Epigenomics Quality Control (EpiQC) Study: Comprehensive Characterization of Epigenetic Methods, Reproducibility, and Quantification
Authors: Foox Jonathan , Nordlund Jessica , Lalancette Claudia , Gong Ting , Lacey Michelle , Lent Samantha , Langhorst Bradley W. , Ponnaluri V K Chaithanya , Williams Louise , Padmanabhan Karthik Ramaswamy , Cavalcante Raymond , Lundmark Anders , Butler Daniel , Mozsary Chris , Gurvitch Justin , Greally John M. , Suzuki Masako , Menor Mark , Nasu Masaki , Alonso Alicia , Sheridan Caroline , Scherer Andreas , Bruinsma Stephen , Golda Gosia , Muszynska Agata , Łabaj Paweł P. , Campbell Matthew A. , Wos Frank , Raine Amanda , Liljedahl Ulrika , Axelsson Tomas , Wang Charles , Chen Zhong , Yang Zhaowei , Li Jing , Yang Xiaopeng , Wang Hongwei , Melnick Ari , Guo Shang , Blume Alexander , Franke Vedran , de Caceres Inmaculada Ibanez , Rodriguez-Antolin Carlos , Rosas Rocio , Davis Justin Wade , Ishii Jennifer , Megherbi Dalila B. , Xiao Wenming , Liao Will , Xu Joshua , Hong Huixiao , Ning Baitang , Tong Weida , Akalin Altuna , Wang Yunliang , Deng Youping , Mason Christopher E.
Published: December 2020

Cytosine modifications in DNA such as 5-methylcytosine (5mC) underlie a broad range of developmental processes, maintain cellular lineage specification, and can define or stratify cancer and other diseases. However, the wide variety of approaches available to interrogate these modifications has created a need for harmonized materials, methods, and rigorous benchmarking to improve genome-wide methylome sequencing applications in clinical and basic research. Here, we present a multi-platform assessment and a global resource for epigenetics research from the FDA’s Epigenomics Quality Control (EpiQC) Group. The study design leverages seven human cell lines that are designated as reference materials and publicly available from the National Institute of Standards and Technology (NIST) and Genome in a Bottle (GIAB) consortium. These samples were subject to a variety of genome-wide methylation interrogation approaches across six independent laboratories, with a primary focus was on 5-methylcytosine modifications. Each sample was processed in two or more technical replicates by three whole-genome bisulfite sequencing (WGBS) protocols (TruSeq DNA methylation, Accel-NGS MethylSeq, and SPLAT), oxidative bisulfite sequencing (TrueMethyl), one enzymatic deamination method (EMseq), targeted methylation sequencing (Illumina Methyl Capture EPIC), and single-molecule long-read nanopore sequencing from Oxford Nanopore Technologies. After rigorous quality assessment and comparison to Illumina EPIC methylation microarrays and testing on a range of algorithms (Bismark, BitmapperBS, BWAMeth, and GemBS), we found overall high concordance between assays (R=0.87-R0.93), differences in efficency of read mapping and CpG capture and coverage, and platform performance. The data provided herein can guide continued used of these reference materials in epigenomics assays, as well as provide best practices for epigenomics research and experimental design in future studies.
Sex difference in hip adduction during the stance phase of running: A swing phase problem?
Authors: Liu Jia , Salem George J , Powers Christopher M
Published: December 2020

Purpose

The purpose of the current study was to: 1) evaluate sex differences in peak hip adduction during the late swing and stance phases of running and 2) determine if peak hip adduction during late swing is predictive of peak hip adduction during stance.

Methods

15 female and 16 male heel strike runners ran over ground at a speed of 4 m/s. Hip joint kinematics during running were quantified using a 3D motion capture system. Sex differences in peak hip adduction during the late swing and stance phases were compared using independent sample t-tests. Linear regression analysis was used to determine the relationship between late swing and stance phase hip adduction.

Results

Compared to males, females exhibited significantly greater peak hip adduction during both the late swing (8.5 ± 2.6 vs 6.1 ± 2.8°, p = 0.019) and stance phases of running (13.3 ± 4.2 vs 9.6 ± 3.4°, p = 0.011). Furthermore, late swing peak hip adduction was predictive of subsequent stance phase peak hip adduction (r = 0.63, p < 0.001).

Conclusion

Sex differences in hip adduction during stance are influenced in part by late swing phase hip adduction. Further studies are needed to identify potential causes of excessive hip adduction during the late swing phase of running.
Genetic and Epigenetic Regulation of Skeletal Muscle Ribosome Biogenesis with Exercise
Authors: Figueiredo Vandré C. , Wen Yuan , Alkner Björn , Fernandez-Gonzalo Rodrigo , Norrbom Jessica , Vechetti Ivan J. , Valentino Taylor , Mobley C. Brooks , Zentner Gabriel E. , Peterson Charlotte A. , McCarthy John J. , Murach Kevin A. , von Walden Ferdinand
Published: December 2020

Ribosomes are the macromolecular engines of protein synthesis. Skeletal muscle ribosome biogenesis is stimulated by exercise, but the contribution of ribosomal DNA (rDNA) copy number and methylation to exercise-induced rDNA transcription is unclear. To investigate the genetic and epigenetic regulation of ribosome biogenesis with exercise, a time course of skeletal muscle biopsies was obtained from 30 participants (18 men and 12 women; 31 ±8 yrs, 25 ±4 kg/m2) at rest and 30 min, 3h, 8h, and 24h after acute endurance (n=10, 45 min cycling, 70% VO2max) or resistance exercise (n=10, 4 x 7 x 2 exercises); 10 control participants underwent biopsies without exercise. rDNA transcription and dosage were assessed using qPCR and whole genome sequencing. rDNA promoter methylation was investigated using massARRAY EpiTYPER, and global rDNA CpG methylation was assessed using reduced-representation bisulfite sequencing. Ribosome biogenesis andMYCtranscription were associated with resistance but not endurance exercise, indicating preferential up-regulation during hypertrophic processes. With resistance exercise, ribosome biogenesis was associated with rDNA gene dosage as well as epigenetic changes in enhancer and non-canonical MYC-associated areas in rDNA, but not the promoter. A mouse model ofin vivometabolic RNA labeling and genetic myonuclear fluorescent labeling validated the effects of an acute hypertrophic stimulus on ribosome biogenesis andMyctranscription, and corroborated rDNA enhancer and Myc-associated methylation alterations specifically in myonuclei. This study provides the first information on skeletal muscle genetic and rDNA gene-wide epigenetic regulation of ribosome biogenesis in response to exercise, revealing novel roles for rDNA dosage and CpG methylation.

GRAPHICAL ABSTRACT
Imaging of native transcription and transcriptional dynamicsin vivousing a tagged Argonaute protein
Authors: Toudji-Zouaz Amel , Bertrand Vincent , Barrière Antoine
Published: December 2020

Abstract

A flexible method to image unmodified transcripts and transcriptionin vivowould be a valuable tool to understand the regulation and dynamics of transcription. Here, we present a novel approach to follow native transcription, with fluorescence microscopy, in liveC. elegans. By using the fluorescently tagged Argonaute protein NRDE-3, programmed by exposure to defined dsRNA to bind to nascent transcripts of the gene of interest, we demonstrate transcript labelling of multiple genes, at the transcription site and in the cytoplasm. This flexible approach does not require genetic manipulation, and can be easily scaled up by relying on whole-genome dsRNA libraries. We apply this method to image the transcriptional dynamics of two transcription factors:ttx-3(a LHX2/9 orthologue) in embryos, andhlh-1(a MyoD orthologue) in larvae, respectively involved in neuronal and muscle development.
GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis
Authors: Wang Qiujie , Cheng Bin , Xue Qiang , Gao Qingzhu , Huang Ailong , Wang Kai , Tang Ni
Published: December 2020

Increasing evidence supports that ferroptosis plays an important role in tumor growth inhibition. Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, has been shown to induce ferroptosis in hepatocellular carcinoma (HCC). However, some hepatoma cell lines are less sensitive to sorafenib-induced ferroptotic cell death. Glutathione S-transferase zeta 1 (GSTZ1), an enzyme in the catabolism of phenylalanine, has been found to negatively regulate the master regulator of cellular redox homeostasis nuclear factor erythroid 2-related factor 2 (NRF2). This study aimed to investigate the role of GSTZ1 in sorafenib-induced ferroptosis in HCC cell lines and determine the involved molecular mechanisms. Mechanistically, GSTZ1 depletion enhanced the activation of the NRF2 pathway and increased the glutathione peroxidase 4 (GPX4) level, thereby suppressing sorafenib-induced ferroptosis. The combination of sorafenib and RSL3, a GPX4 inhibitor, significantly inhibited GSTZ1 deficient cell viability and promoted ferroptosis, accompanied with ectopic increases of iron and lipid peroxides. Anin vivoexperiment showed that the combination of sorafenib and RSL3 had a synergic therapeutic effect on HCC progression inGstz1−/−mice. In conclusion, GSTZ1 was significantly downregulated in sorafenib resistant hepatoma cells. GSTZ1 enhanced sorafenib-induced ferroptosis by inhibiting the NRF2/GPX4 axis in HCC cells. GSTZ1 deficiency was resistant to sorafenib-induced ferroptosis and is, therefore, a potential therapeutic approach for treating HCC by synergizing sorafenib and RSL3 to induce ferroptosis.
A simple technique to classify diffraction data from dynamic proteins according to individual polymorphs
Authors: Nguyen Thu , Phan Kim L , Kreitler Dale F , Andrews Lawrence C , Gabelli Sandra B , Kozakov Dima , Jakoncic Jean , Sweet Robert M , Soares Alexei S , Bernstein Herbert J
Published: December 2020

One often observes small but measurable differences in diffraction data measured from different crystals of a single protein. These differences might reflect structural differences in the protein and potentially reflect the natural dynamism of the molecule in solution. Partitioning these mixed-state data into single-state clusters is a critical step to extract information about the dynamic behavior of proteins from hundreds or thousands of single-crystal data sets. Mixed-state data can be obtained deliberately (through intentional perturbation) or inadvertently (while attempting to measure highly redundant single-crystal data). State changes may be expressed as changes in morphology, so that a subset of the polystates may be observed as polymorphs. After mixed-state data are deliberately or inadvertently measured, the challenge is to sort the data into clusters that may represent relevant biological polystates. Here we address this problem using a simple multi-factor clustering approach that classifies each data set using independent observables in order to assign each data set to the correct location in conformation space. We illustrate this method using two independent observables (unit cell constants and intensities) to cluster mixed-state data from chymotrypsinogen (ChTg) crystals. We observe that the data populate an arc of the reaction trajectory as ChTg is converted into chymotrypsin.
Neuroinvasion and encephalitis following intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice
Authors: Kumari Pratima , Rothan Hussin A. , Natekar Janhavi P. , Stone Shannon , Pathak Heather , Strate Philip G. , Arora Komal , Brinton Margo A. , Kumar Mukesh
Published: December 2020

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can cause neurological disease in humans, but little is known about the pathogenesis of SARS-CoV-2 infection in the central nervous system. Herein, using K18-hACE2 mice, we demonstrate that SARS-CoV-2 neuroinvasion and encephalitis is associated with mortality in these mice. Intranasal infection of K18-hACE2 mice with 105plaque-forming units of SARS-CoV-2 resulted in 100% mortality by day 6 after infection. The highest virus titers in the lungs were observed at day 3 and declined at days 5 and 6 after infection. In contrast, very high levels of infectious virus were uniformly detected in the brains of all the animals at days 5 and 6. Onset of severe disease in infected mice correlated with peak viral levels in the brain. SARS-CoV-2-infected mice exhibited encephalitis hallmarks characterized by production of cytokines and chemokines, leukocyte infiltration, hemorrhage and neuronal cell death. SARS-CoV-2 was also found to productively infect cells within the nasal turbinate, eye and olfactory bulb, suggesting SARS-CoV-2 entry into the brain by this route after intranasal infection. Our data indicate that direct infection of CNS cells together with the induced inflammatory response in the brain resulted in the severe disease observed in SARS-CoV-2-infected K18-hACE2 mice.
The Covid-19 containment effects of public health measures - A spatial difference-in-differences approach
Authors: Kosfeld Reinhold , Mitze Timo , Rode Johannes , Wälde Klaus
Published: December 2020

Since mid-March 2020 the Federal and state governments in Germany agreed on comprehensive public health measures to curb the spread of SARS-CoV-2 infections leading to the Covid-19 disease. We study the containment effects of these policy interventions on the progression of the pandemic in the first containment phase in spring 2020 before the easing of restrictions may become effective by the end of April. To exploit both the temporal and spatial dimension in the dissemination of the virus, we conduct a spatial panel data analysis for German NUTS-3 regions. Specifically, we employ a spatial difference-in-differences approach to identify the effects of six compound sets of public health measures. We find that contact restrictions and closure of schools substantially contributed to flattening the infection curve. Additionally, a strong treatment effect of mandatory wearing of face masks is established for the few treated regions during this containment phase. No incremental effect is evidenced for closure of establishments, such as museums, theaters, cinemas and parks, and the shutdown of shopping malls and other non-essential retail stores. These findings prove to be robust to changes in model specification. By contrast, the dampening effect of restaurant closure is sensitive to model variation.
Differential effects of PD-1 and CTLA-4 blockade on the melanoma-reactive CD8 T cell response
Authors: Gangaev Anastasia , Rozeman Elisa A. , Rohaan Maartje W. , Philips Daisy , Patiwael Sanne , van den Berg Joost H. , Ribas Antoni , Schadendorf Dirk , Schilling Bastian , Schumacher Ton N. , Blank Christian U. , Haanen John B.A.G. , Kvistborg Pia
Published: December 2020

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have revolutionized the treatment of melanoma patients. Based on early studies addressing the mechanism of action, it was assumed that PD-1 blockade mostly influences T cell responses at the tumor site. However, recent work has demonstrated that PD-1 blockade can influence the T cell compartment in peripheral. blood. If activation of circulating tumor-reactive T cells would form an important mechanism of action of PD-1 blockade, it may be predicted that such blockade would alter either the frequency and/or the breadth of the tumor-reactive CD8 T cell response. To address this question, we analyzed CD8 T cell responses towards 71 melanoma associated epitopes in peripheral blood of 24 melanoma patients. We show that both the frequency and the breadth of the melanoma-reactive CD8 T cell response in peripheral blood was unaltered upon PD-1 blockade. In contrast, a broadening of the melanoma-reactive CD8 T cell response was observed upon CTLA-4 blockade, in concordance with our prior data. On the basis of these results, we conclude that PD-1 and CTLA-4 blockade impact the tumor-reactive CD8 T cell response in a distinct manner. In addition, the data provide an argument in favor of the hypothesis that anti-PD-1 therapy may primarily act at the tumor site.

One sentence summary

We demonstrate that, contrary to CTLA-4 blockade, PD-1 blockade in melanoma patients does not lead to an increase in the breadth or magnitude of the melanoma-reactive CD8 T cell response in peripheral blood, thereby arguing for a dominant effect of PD-1 blockade at the tumor site.
Quantitative Genetic Scoring, or how to put a number on an arbitrary genetic region
Authors: Schoenmacker GH , Vlaming P , Pallesen J , Pikulina MY , Ghamarian AH , Demontis D , Børglum A , Galesloot TE , Poelmans G , Franke B , Claassen T , Heskes T , Buitelaar JK , Vásquez A Arias
Published: December 2020

Motivation

With the increasing availability of genome-wide genetic data, methods to combine genetic variables with other sources of data in statistical models are required. This paper introduces quantitative genetic scoring (QGS), a dimensionality reduction method to create quantitative genetic variables representing arbitrary genetic regions.

Methods

QGS is defined as the sum of absolute differences in the genetic sequence between a subject and a reference population. QGS properties such as distribution and sensitivity to region size were examined, and QGS was tested in six different existing genomic data sets of various sizes and various phenotypes.

Results

QGS can reduce genetic information by >98% yet explain phenotypic variance at low, medium, and high level of granularity. Associations based on QGS are independent of both size and linkage disequilibrium structure of the underlying region. In combination with stability selection, QGS finds significant results where a traditional genome-wide association approaches struggle. In conclusion, QGS preserves phenotypically significant genetic variance while reducing dimensionality, allowing researchers to include quantitative genetic information in any type of statistical analysis.

Availability

https://github.com/machine2learn/QGS

Contact

gido.schoenmacker@radboudumc.nl

Supplemental information

Supplemental data are available online.
Predicting compound activity from phenotypic profiles and chemical structures
Authors: Moshkov Nikita , Becker Tim , Yang Kevin , Horvath Peter , Dancik Vlado , Wagner Bridget K. , Clemons Paul A. , Singh Shantanu , Carpenter Anne E. , Caicedo Juan C.
Published: December 2020

Recent advances in deep learning enable using chemical structures and phenotypic profiles to accurately predict assay results for compounds virtually, reducing the time and cost of screens in the drug-discovery process. We evaluate the relative strength of three high-throughput data sources—chemical structures, images (Cell Painting), and gene-expression profiles (L1000)—to predict compound activity using a sparse historical collection of 16,170 compounds tested in 270 assays for a total of 585,439 readouts. All three data modalities can predict compound activity with high accuracy in 6-10% of assays tested; replacing million-compound physical screens with computationally prioritized smaller screens throughout the pharmaceutical industry could yield major savings. Furthermore, the three profiling modalities are complementary, and in combination they can predict 21% of assays with high accuracy, and 64% if lower accuracy is acceptable. Our study shows that, for many assays, predicting compound activity from phenotypic profiles and chemical structures might accelerate the early stages of the drug-discovery process.
Molecular topography of an entire nervous system
Authors: Taylor Seth R , Santpere Gabriel , Weinreb Alexis , Barrett Alec , Reilly Molly B. , Xu Chuan , Varol Erdem , Oikonomou Panos , Glenwinkel Lori , McWhirter Rebecca , Poff Abigail , Basavaraju Manasa , Rafi Ibnul , Yemini Eviatar , Cook Steven J , Abrams Alexander , Vidal Berta , Cros Cyril , Tavazoie Saeed , Sestan Nenad , Hammarlund Marc , Hobert Oliver , Miller David M.
Published: December 2020

Nervous systems are constructed from a deep repertoire of neuron types but the underlying gene expression programs that specify individual neuron identities are poorly understood. To address this deficit, we have produced an expression profile of all 302 neurons of theC. elegansnervous system that matches the single cell resolution of its anatomy and wiring diagram. Our results suggest that individual neuron classes can be solely identified by combinatorial expression of specific gene families. For example, each neuron class expresses unique codes of ∼23 neuropeptide-encoding genes and ∼36 neuropeptide receptors thus pointing to an expansive “wireless” signaling network. To demonstrate the utility of this uniquely comprehensive gene expression catalog, we used computational approaches to (1) identify cis-regulatory elements for neuron-specific gene expression across the nervous system and (2) reveal adhesion proteins with potential roles in synaptic specificity and process placement. These data are available at cengen.org and can be interrogated at the web application CengenApp. We expect that this neuron-specific directory of gene expression will spur investigations of underlying mechanisms that define anatomy, connectivity and function throughout theC. elegansnervous system.
Sestrins regulate age-induced deterioration of muscle stem cell homeostasis
Authors: Yang Benjamin A. , Castor-Macias Jesus , Fraczek Paula , Brown Lemuel A. , Kim Myungjin , Brooks Susan V. , Lee Jun Hee , Aguilar Carlos A.
Published: December 2020

The health and homeostasis of skeletal muscle is preserved by a population of tissue resident stem cells called satellite cells. Young healthy satellite cells maintain a state of quiescence, but aging or metabolic insults results in reduced capacity to prevent premature activation and stem cell exhaustion. As such, understanding genes and pathways that protect satellite cell maintenance of quiescence are needed. Sestrins are a class of stress-inducible proteins that act as antioxidants and inhibit the activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling complex. Despite these pivotal roles, the role of Sestrins has not been explored in adult stem cells. Herein, we show that Sestrin1,2 loss results in hyperactivation of the mTORC1 complex, increased propensity to enter the cell cycle and shifts in metabolic flux. Aging of Sestrin1,2 knockout mice demonstrated a loss of MuSCs and reduced ability to regenerate. These findings demonstrate Sestrins function to help maintain MuSC metabolism that supports quiescence and against aging.

Highlights

Sestrin deficiency alters mTORC1 signaling in muscle stem cells (MuSCs).

In young mice, Sestrins are dispensable for regenerative responses of MuSCs.

Sestrin deficiency accelerates age-dependent loss and dysfunction of MuSCs.
Statistically correcting dynamical electron scattering improves the refinement of protein nanocrystals, including charge refinement of coordinated metals
Authors: Blum Thorsten B. , Housset Dominique , Clabbers Max T. B. , van Genderen Eric , Bacia-Verloop Maria , Zander Ulrich , McCarthy Andrew A. , Schoehn Guy , Ling Wai Li , Abrahams Jan Pieter
Published: December 2020

Electron diffraction allows protein structure determination when only nanosized crystals are available. Nevertheless, multiple elastic (or dynamical) scattering, which is prominent in electron diffraction, is a concern. Current methods for modeling dynamical scattering by multi-slice or Bloch wave approaches are not suitable for protein crystals because they are not designed to cope with large molecules. Here, dynamical scattering of nanocrystals of insulin, thermolysin and thaumatin was limited by collecting data from thin crystals. To accurately measure the weak diffraction signal from the few unit cells in the thin crystals, a low-noise hybrid pixel Timepix electron-counting detector was used. The remaining dynamical component was further reduced in refinement using a likelihood-based correction, which was introduced previously for analyzing electron diffraction data of small-molecule nanocrystals and was adapted here for protein crystals. The procedure is shown to notably improve the structural refinement, in one case allowing the location of solvent molecules. It also allowed refinement of the charge states of bound metal atoms, an important element in protein function, through B-factor analysis of the metal atoms and their ligands. These results clearly increase the value of macromolecular electron crystallography as a complementary structural biology technique.
Effect of percutaneous aortic valve position on stress map in ascending aorta: A fluid‐structure interaction analysis
Authors: Ibanez Ivan , de Azevedo Gomes Bruno A. , Nieckele Angela O.
Published: December 2020

Transcatheter aortic valve implantation (TAVI) is an increasingly widespread procedure. Although this intervention is indicated for high and low surgical risk patients, some issues still remain, such as prosthesis positioning optimization in the aortic annulus. Coaxial positioning of the percutaneous prosthesis influences directly on the aortic wall stress map. The determination of the mechanical stress that acts on the vascular endothelium resulting from blood flow can be considered an important task, since TAVI positioning can lead to unfavorable hemodynamic patterns, resulting in changes in parietal stress, such as those found in post‐stenotic dilatation region. This research aims to investigate the influence of the prosthetic valve inclination angle in the mechanical stresses acting in the ascending aortic wall. Aortic compliance and blood flow during cardiac cycle were numerically obtained using fluid structure interaction. The aortic model was developed through segmentation of a computed tomography image of a specific patient submitted to TAVI. When compared to standard position (coaxiality match between the prosthesis and the aortic annulus), the inclination of 4° directed to the left main coronary artery decreased the aortic wall area with high values of wall shear stress and pressure. Coaxial positioning optimization of percutaneous aortic prosthesis may decrease the high mechanical stress area. These changes may be important to reduce the aortic remodeling process, vascular calcification or even the prosthesis half‐life. Computational fluid dynamics makes room for personalized medicine, with manufactured prosthesis tailored to each patient.
Complement activation by dialysis membranes and its association with secondary membrane formation and surface charge
Authors: Melchior Pascal , Erlenkötter Ansgar , Zawada Adam M. , Delinski Dirk , Schall Christian , Stauss‐Grabo Manuela , Kennedy James P.
Published: December 2020

Activation of the complement system may occur during blood‐membrane interactions in hemodialysis and contribute to chronic inflammation of patients with end‐stage renal disease. Hydrophilic modification with polyvinylpyrrolidone (PVP) has been suggested to increase the biocompatibility profile of dialysis membranes. In the present study we compared the complement activation of synthetic and cellulose‐based membranes, including the polysulfone membrane with α‐tocopherol‐stabilized PVP‐enriched inner surface of the novel FX CorAL dialyzer, and linked the results to their physical characteristics. Eight synthetic and cellulose‐based dialyzers (FX CorAL, FX CorDiax [Fresenius Medical Care]; Polyflux, THERANOVA [Baxter]; ELISIO, SUREFLUX [Nipro]; xevonta [B. Braun]; FDX [Nikkisio Medical]) were investigated in the present study. Complement activation (C3a, C5a, and sC5b‐9) was evaluated in a 3 hours ex vivo recirculation model with human blood. Albumin sieving coefficients were determined over a 4 hours ex vivo recirculation model with human plasma as a surrogate of secondary membrane formation. Zeta potential was measured as an indicator for the surface charge of the membranes. The FX CorAL dialyzer induced the lowest activation of the three complement factors (C3a: −39.4%; C5a: −57.5%; and sC5b‐9: −58.9% compared to the reference). Highest complement activation was found for the cellulose‐based SUREFLUX (C3a: +154.0%) and the FDX (C5a: +335.0% and sC5b‐9: +287.9%) dialyzers. Moreover, the FX CorAL dialyzer had the nearest‐to‐neutral zeta potential (−2.38 mV) and the lowest albumin sieving coefficient decrease over time. Albumin sieving coefficient decrease was associated with complement activation by the investigated dialyzers. Our present results indicate that the surface modification implemented in the FX CorAL dialyzer reduces the secondary membrane formation and improves the biocompatibility profile. Further clinical studies are needed to investigate whether these observations will result in a lower inflammatory burden of hemodialysis patients.
Systemic counterregulatory response of angiopoietin‐2 after aflibercept therapy for nAMD: a potential escape mechanism
Authors: Angermann Reinhard , Rauchegger Teresa , Nowosielski Yvonne , Seifarth Christof , Egger Stefan , Kralinger Martina T. , Kieselbach Gerhard F. , Zehetner Claus
Published: December 2020

Purpose

To analyse the effect of intravitreal aflibercept injections on systemic angiopoietin‐2 (Ang2) and vascular endothelial growth factor (VEGF)‐A levels in patients with neovascular age‐related macular degeneration (nAMD).

Methods

In a prospective, randomized study, aflibercept (2.0 mg/50 µl) or ranibizumab (0.5 mg/50 µl) was administered intravitreally to 38 treatment‐naive patients. Blood samples were taken before, 7 days after, and 28 days after the first intravitreal therapy. Cytokine levels were measured by enzyme‐linked immunosorbent assay. Twenty‐two age‐ and sex‐matched individuals served as controls.

Results

At baseline, there were no significant differences of systemic Ang2 and VEGF‐A levels among the treatment and control groups. After intravitreal aflibercept administration, median (interquartile range: IQR) systemic Ang2 was significantly upregulated from 1819 pg/ml (1262–3099) to 2123 pg/ml (1441–3769; p = 0.011) 7 days after the drug injection and remained non‐significantly elevated at 1944 pg/ml (1431–2546 pg/ml; p = 0.653) 28 days after the drug injection. Median (IQR) systemic VEGF‐A levels were significantly reduced from 43 pg/ml (30–57) to 8 pg/ml (8–8; p < 0.0001) 7 days and 16 pg/ml (8–26; p = 0.001) 28 days after the injection in the aflibercept group. There were no significant effects on systemic VEGF‐A and Ang2 levels in the ranibizumab group at any time point following the first injection.

Conclusion

In this study, we report significant systemic upregulation of Ang2 after intravitreal aflibercept administration. This counterregulatory response may represent a potential escape mechanism from antiangiogenic therapy.
Retroperitoneal fibrosis and β‐blocking agents: Is there an association?
Authors: Kharagjitsing Hardjit , van Eekeren Rike , van Puijenbroek Eugène P. , van Gelder Teun , van Bommel Eric F. H.
Published: December 2020

Aims

Retroperitoneal fibrosis (RPF) is a rare chronic fibro‐inflammatory disorder that may be secondary to certain drugs, including β‐blocking agents (BBAs). However, their causative role is unclear. We aimed to investigate this association.

Methods

Disproportionality analysis was carried out on cases from 1985 to 4 October 2020 in VigiBase, the World Health Organization pharmacovigilance database. The Bayesian‐based IC025 metric and reporting odds ratio were used in order to assess the adverse event signal. We also analysed all published case reports from the literature regarding BBA‐associated RPF to assess the value of suggested supportive clinical evidence.

Results

In total, 1599 individual case safety reports of RPF were reported to VigiBase, of which 132 (32%) concerned 16 different single BBA. For 12 of these agents (75%), reporting of RPF was disproportionate, indicating a potential safety signal. Line listing analysis of individual case safety reports showed no consistent time interval from start of BBA to RPF diagnosis (range 0.7–264 mo). Dechallenge was negative or unknown in the majority of cases (74%). In 18 published cases from the literature, time from start of BBA to RPF diagnosis varied widely (range 3–156 mo). BBA were discontinued 6 months before (n = 1) or at the time of RPF diagnosis (n = 17). Most patients (84%) also received RPF specific treatment. Follow‐up duration was short (median 5 mo [range 1–24 mo]) and in most cases (83%) relevant follow‐up data were lacking.

Conclusion

Although disproportionality analysis indicated a potential safety signal for RPF associated with BBAs, clinical evidence did not support a cause‐and‐effect relationship.