bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and efficacy of the ChAdOx1 nCoV-19 (AZD1222) Covid-19 vaccine against the B.1.351 variant in South Africa
Authors: Madhi Shabir A. , Baillie Vicky , Cutland Clare L. , Voysey Merryn , Koen Anthonet L. , Fairlie Lee , Padayachee Sherman D. , Dheda Keertan , Barnabas Shaun L. , Bhorat Qasim Ebrahim , Briner Carmen , Kwatra Gaurav ,   NGS-SA,   Wits-VIDA COVID team, Ahmed Khatija , Aley Parvinder , Bhikha Sutika , Bhiman Jinal N. , Bhorat As’ad Ebrahim , Plessis Jeanine du , Esmail Aliasgar , Groenewald Marisa , Horne Elizea , Hwa Shi-Hsia , Jose Aylin , Lambe Teresa , Laubscher Matt , Malahleha Mookho , Masenya Masebole , Masilela Mduduzi , McKenzie Shakeel , Molapo Kgaogelo , Moultrie Andrew , Oelofse Suzette , Patel Faeezah , Pillay Sureshnee , Rhead Sarah , Rodel Hylton , Rossouw Lindie , Taoushanis Carol , Tegally Houriiyah , Thombrayil Asha , Eck Samuel van , Wibmer Constantinos Kurt , Durham Nicholas M. , Kelly Elizabeth J , Villafana Tonya L , Gilbert Sarah , Pollard Andrew J , de Oliveira Tulio , Moore Penny L. , Sigal Alex , Izu Alane
Published: February 2021

Background

Assessing safety and efficacy of Covid-19 vaccines in different populations is essential, as is investigation of efficacy against emerging SARS-CoV-2 variants of concern including the B.1.351 (501Y.V2) variant first identified in South Africa.

Methods

We conducted a randomized multicentre, double blinded controlled trial on safety and efficacy of ChAdOx1-nCoV19 in HIV-uninfected people in South Africa. Participants age 18 to <65 years randomized (1:1) to two doses of vaccine containing 5×1010viral particles or placebo (0.9%NaCl) 21-35 days apart. Post 2nd-dose serum samples (n=25) were tested by pseudotyped (PSVNA) and live virus (LVNA) neutralization assays against the D614G and B.1.351 variants. Primary endpoints were safety and vaccine efficacy (VE) >14 days following second dose against laboratory confirmed symptomatic Covid-19.

Results

2026 HIV-uninfected adults were enrolled between June 24thand Nov 9th, 2020; 1010 and 1011 received at least one dose of placebo or vaccine, respectively. Median age was 31 years. The B.1.351 variant showed increased resistance to vaccinee sera using the PSVNA and LVNA. In the primary endpoint analysis, 23/717 (3.2%) placebo and 19/750 (2.5%) vaccine recipients developed mild-moderate Covid-19; VE 21.9% (95%Confidence Interval: −49.9; 59.8). Of the primary endpoint cases, 39/42 (92.9%) were the B.1.351 variant; against which VE was 10.4% (95%CI: −76.8; 54.8) analyzed as a secondary objective. The incidence of serious adverse events was balanced between the vaccine and placebo groups.

Conclusions

A two-dose regimen of ChAdOx1-nCoV19 did not show protection against mild-moderate Covid-19 due to B.1.351 variant, however, VE against severe Covid-19 is undetermined.

(Funded by The Bill & Melinda Gates Foundation and South African Medical Research Council; ClinicalTrails.gov number,NCT04444674).
A selective sweep in the Spike gene has driven SARS-CoV-2 human adaptation
Authors: Kang Lin , He Guijuan , Sharp Amanda K. , Wang Xiaofeng , Brown Anne M. , Michalak Pawel , Weger-Lucarelli James
Published: February 2021

While SARS-CoV-2 likely has animal origins1, the viral genetic changes necessary to adapt this animal-derived ancestral virus to humans are largely unknown, mostly due to low levels of sequence polymorphism and the notorious difficulties in experimental manipulations of coronavirus genomes. We scanned more than 182,000 SARS-CoV-2 genomes for selective sweep signatures and found that a distinct footprint of positive selection is located around a non-synonymous change (A1114G; T372A) within the Receptor-Binding Domain of the Spike protein, which likely played a critical role in overcoming species barriers and accomplishing interspecies transmission from animals to humans. Structural analysis indicated that the substitution of threonine with an alanine in SARS-CoV-2 concomitantly removes a predicted glycosylation site at N370, resulting in more favorable binding predictions to human ACE2, the cellular receptor. Using a novel bacteria-free cloning system for manipulating RNA virus genomes, we experimentally validated that this SARS-CoV-2-unique substitution significantly increases replication in human cells relative to its putative ancestral variant. Notably, this mutation’s impact on virus replication in human cells was much greater than that of the Spike D614G mutant, which has been widely reported to have been selected for during human-to-human transmission2,3.
The efficacy and safety of Favipiravir in treatment of COVID-19: A systematic review and meta-analysis of clinical trials
Authors: Hassanipour Soheil , Arab-Zozani Morteza , Amani Bahman , Heidarzad Forough , Fathalipour Mohammad , Martinez-de-Hoyo Rudolph
Published: February 2021

The novel coronavirus outbreak began in late December 2019 and rapidly spread worldwide, critically impacting public health systems. A number of already approved and marketed drugs are being tested for repurposing, including Favipiravir. We aim to investigate the efficacy and safety of Favipiravir in treatment of COVID-19 patients through a systematic review and meta-analysis. This systematic review and meta-analysis were reported in accordance with the PRISMA statement. We registered the protocol in the PROSPERO (CRD42020180032). All clinical trials which addressed the safety and efficacy of Favipiravir in comparison to other control groups for treatment of patients with confirmed infection with SARS-CoV2 were included. We searched electronic databases including LitCovid hub/PubMed, Scopus, ISI web of Sciences, Cochrane, and Scientific Information Database up to 31 December 2020. We assessed the risk of bias of the included studies using Cochrane Collaboration criteria. All analyses were performed using the Comprehensive Meta-Analysis software version 2, and the risk ratio index was calculated. Egger and Begg test was used for assessing publication bias. Nine studies were included in our meta-analysis. The results of the meta-analysis revealed a significant clinical improvement in the Favipiravir group versus the control group during seven days after hospitalization (RR=1.24, 95% CI: 1.09-1.41; P=0.001). Viral clearance was more in 14 days after hospitalization in Favipiravir group than control group, but this finding marginally not significant (RR=1.11, 95% CI: 0.98-1.25; P=0.094). Requiring supplemental oxygen therapy in the Favipiravir group was 7% less than the control group, (RR=0.93, 95% CI: 0.67-1.28; P=0.664). Transferred to ICU and adverse events were not statistically different between two groups. The mortality rate in the Favipiravir group was approximately 30% less than the control group, but this finding not statistically significant. Favipiravir possibly exerted no significant beneficial effect in the term of mortality in the general group of patients with mild to moderate COVID-19. We should consider that perhaps the use of antiviral once the patient has symptoms is too late and this would explain their low efficacy in the clinical setting.
Subjective impact of the COVID-19 pandemic on schizotypy and general mental health in Germany and the UK, for independent samples in May and in October 2020
Authors: Daimer Sarah , Mihatsch Lorenz , Ronan Lisa , Murray Graham K. , Knolle Franziska
Published: February 2021

Studies reported a strong impact on mental health during the first wave of the COVID-19 pandemic in March–June, 2020. In this study, we assessed the impact of the pandemic on mental health in general and on schizoptypal traits in two independent general population samples of the UK (May sample N: 239, October sample N: 126; participation at both timepoints: 21) and in two independent general population samples of Germany (May sample N: 543, October sample N: 401; participation at both timepoints: 100) using online surveys. Whereas general psychological symptoms (global symptom index, GSI) and percentage of responders above clinical cut-off for further psychological investigation were higher in the May sample compared to the October sample, schizotypy scores (Schizotypal Personality Questionnaire) were higher in the October sample. We investigated potential associations, using general linear regression models (GLM). For schizotypy scores, we found that loneliness, use of drugs, and financial burden were more strongly corrected with schizotypy in the October compared to the May sample. We identified similar associations for GSI, as for schizotypy scores, in the May and October samples. We furthermore found that living in the UK was related to higher schizotypal scores or GSI. However, individual estimates of the GLM are highly comparable between the two countries. In conclusion, this study shows that while the general psychological impact is lower in the October than the May sample, potentially showing a normative response to an exceptional situation; schizotypy scores are higher at the second timepoint, which may be due to a stronger impact of estimates of loneliness, drug use, and financial burden. The ongoing, exceptional circumstances within this pandemic might increase the risk for developing psychosis in some individuals. The development of general psychological symptoms and schizotypy scores over time requires further attention and investigation.
Interrogating structural inequalities in COVID-19 Mortality in England and Wales
Authors: Griffith Gareth J , Smith George Davey , Manley David , Howe Laura D , Owen Gwilym
Published: February 2021

Background

Numerous observational studies have highlighted structural inequalities in COVID-19 mortality in the UK. Such studies often fail to consider the complex spatial nature of such inequalities in their analysis, leading to the potential for bias and an inability to reach conclusions about the most appropriate structural levels for policy intervention.

Methods

We use publicly available population data on COVID-19 related- and all-cause mortality between March and July 2020 in England and Wales to investigate the spatial scale of such inequalities. We propose a multiscale approach to simultaneously consider four spatial scales at which processes driving inequality may act and apportion inequality between these.

Results

Adjusting for population age structure, number of care homes and residing in the North we find highest regional inequality in March and June/July. We find finer-grained within-region increased steadily from March until July. The importance of spatial context increases over the study period. No analogous pattern is visible for non-COVID mortality. Higher relative deprivation is associated with increased COVID-19 mortality at all stages of the pandemic but does not explain structural inequalities.

Conclusions

Results support initial stochastic viral introduction in the South, with initially high inequality decreasing before the establishment of regional trends by June and July, prior to reported regionality of the “second-wave”. We outline how this framework can help identify structural factors driving such processes, and offer suggestions for a long-term, locally-targeted model of pandemic relief in tandem with regional support to buffer the social context of the area.

Key Messages

Regional inequality in COVID-19 mortality declined from an initial peak in April, before increasing again in June/July.

Within-region inequality increased steadily from March until July.

Strong regional trends are evident in COVID-19 mortality in June/July, prior to wider reporting of regional differences in “second wave”.

Analogous spatial inequalities are not present in non-COVID related mortality over the study period.

These inequalities are not explained by age structure, care homes, or deprivation.
Rapid active-reflection display on dorsal stripes ofAtherinomorus lacunosus
Authors: Iwasaka Masakazu
Published: February 2021

A large number of living creatures are able to use environmental light effectively as a biological display. The biological structural colors are very attractive not only within the coloring species but also to humans. However, the detailed function of bio-reflectors, which constitute the structural color with respect to communication, remains unknown.Atherinomorus lacunosushas alignments of iridophore spots on its dorsal part. Here it is found that a spot with a diameter of approximately 0.1 mm causes a rhythmic blinking of light owing to rapid reflection changes in iridophores existing inside the spot. The iridophores contain reflecting particles which show similar rotational responses to magnetic field under a light exposure. The speed of the intensity change of light at a frequency of approximately 1 Hz is proposed to be controlled by the nervous system ofA. lacunosus. This kind of passive illumination may contribute to the development of a new optical device with low energy consumption.
NECAB2 participates in an endosomal pathway of mitochondrial stress response at striatal synapses
Authors: Bueno Diones , Dey Partha Narayan , Schacht Teresa , Wolf Christina , Wüllner Verena , Morpurgo Elena , Rojas-Charry Liliana , Sessinghaus Lena , Leukel Petra , Sommer Clemens , Radyushkin Konstantin , Schäfer Michael K.E. , Florin Luise , Baumgart Jan , Stamm Paul , Daiber Andreas , Horta Guilherme , Nardi Leonardo , Vasic Verica , Schmeisser Michael J. , Hellwig Andrea , Oskamp Angela , Bauer Andreas , Anand Ruchika , Reichert Andreas S. , Ritz Sandra , Nocera Gianluigi , Jacob Claire , Peper Jonas , Silies Marion , Frauenknecht Katrin B. M. , Methner Axel
Published: February 2021

Synaptic signaling depends on ATP generated by mitochondria. Due to extensive connectivity, the striatum is especially vulnerable to mitochondrial dysfunction and thus requires efficient mitochondrial quality control and repair. We found that global knockout of the neuronal calcium-binding protein 2 (NECAB2) in the mouse causes loss of striatal synapses and behavioral phenotypes related to striatal dysfunction such as reduced motivation and altered sensory gating. Striatal mitochondria fromNecab2knockout mice are more abundant and smaller. They are characterized by increased respiration and superoxide production resulting in oxidative stress. This accumulation of dysfunctional mitochondria is caused by a defective assembly of mitochondria with early endosomes in a pathway that involves the small GTPase Rab5 and its guanine nucleotide exchange factor Alsin/ALS2. NECAB2 therefore participates in an endosomal pathway of mitochondrial stress response and repair important for striatal function.
Nicotine-mediated recruitment of GABAergic neurons to a dopaminergic phenotype attenuates motor deficits in alpha-synuclein Parkinson’s model
Authors: Lai I-Chi , Romoli Benedetto , Keisler Maria , Manfredsson Fredric P. , Powell Susan B. , Dulcis Davide
Published: February 2021

BACKGROUND

Previous work revealed an inverse correlation between smoking and Parkinson’s disease (PD) that is associated with nicotine-induced neuroprotection of dopaminergic (DA) neurons against nigrostriatal damage in PD primates and rodent models. Nicotine, a neuroactive component of tobacco, can directly alter the activity of midbrain DA neurons and induce non-DA neurons in the substantia nigra (SN) to acquire a DA phenotype. We investigated the recruitment mechanism of nigrostriatal GABAergic neurons to express DA phenotypes, such as transcription factor Nurr1 and DA-synthesizing enzyme tyrosine hydroxylase (TH), and the concomitant effects on motor function.

METHODS

Wild-type and α-syn-overexpressing (PD) mice treated with chronic nicotine were assessed by behavioral pattern monitor (BPM) and immunohistochemistry/in-situhybridization to measure behavior and the translational/transcriptional regulation of neurotransmitter phenotype following selective Nurr1 overexpression or DREADD-mediated chemogenetic activation.

RESULTS

Nicotine treatment led to a transcriptional TH and translational Nurr1 upregulation within a pool of SN GABAergic neurons in wild-type animals. In PD mice, nicotine increased Nurr1 expression, reduced the number of α-syn-expressing neurons, and simultaneously rescued motor deficits. Hyperactivation of GABA neurons alone was sufficient to elicitde novotranslational upregulation of Nurr1 in non-DA neurons. Retrograde labeling revealed that a fraction of these GABAergic neurons projects to the dorsal striatum.

CONCLUSIONS

Nicotine exposure initiates neuroprotective mechanisms counteracting the neurodegenerative effects of α-syn accumulation in DA neurons and contributing to Nurr1-mediated therapeutic effects. Revealing the mechanism of nicotine-induced DA plasticity protecting SN neurons against nigrostriatal damage could contribute to developing new strategies for neurotransmitter replacement in PD.
Neural entrainment facilitates duplets: Frequency-tagging differentiates musicians and non-musicians when they tap to the beat
Authors: Celma-Miralles A. , Kleber B.A. , Toro J.M. , Vuust P.
Published: February 2021

Motor coordination to an isochronous beat improves when it is subdivided into equal intervals. Here, we study if this subdivision benefit (i) varies with the kind of subdivision, (ii) is enhanced in individuals with formal musical training, and (iii), is an inherent property of neural oscillations. We recorded electroencephalograms of musicians and non-musicians during: (a) listening to an isochronous beat, (b) listening to one of 4 different subdivisions, (c) listening to the beat again, and (d) listening and tapping the beat with the same subdivisions as in (b). We found that tapping consistency and neural entrainment in condition (d) was enhanced in non-musicians for duplets (1:2) compared to the other types of subdivisions. Musicians showed overall better tapping performance and were equally good at tapping together with duplets, triplets (1:3) and quadruplets (1:4), but not with quintuplets (1:5). This group difference was reflected in enhanced neural responses in the triplet and quadruplet conditions. Importantly, for all participants, the neural entrainment to the beat and its first harmonic (i.e. the duplet frequency) increased after listening to each of the subdivisions (c compared to a). Since these subdivisions are harmonics of the beat frequency, the observed preference of the brain to enhance the simplest subdivision level (duplets) may be an inherent property of neural oscillations. In sum, a tapping advantage for simple binary subdivisions is reflected in neural oscillations to harmonics of the beat, and formal training in music can enhance it.

Highlights

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The neural entrainment to periodic sounds only differs between musicians and non-musicians when they perform a predictive sensorimotor synchronization task.

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After listening to a subdivided beat, the frequencies related to the beat and its first harmonic are enhanced in the EEG, likely stabilizing the perception of the beat.

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There is a natural advantage for binary structures in sensorimotor synchronization, observed in the tapping of duplets by non-musicians, which can be extended to other subdivisions after extensive musical training.
Audiovisual adaptation is expressed in spatial and decisional codes
Authors: Aller Máté , Mihalik Agoston , Noppeney Uta
Published: February 2021

The brain adapts dynamically to the changing sensory statistics of its environment. The neural circuitries and representations that support this cross-sensory plasticity remain unknown. We combined psychophysics and model-based representational fMRI and EEG to characterize how the adult human brain adapts to misaligned audiovisual signals. We show that audiovisual adaptation moulds regional BOLD-responses and fine-scale activity patterns in a widespread network from Heschl’s gyrus to dorsolateral prefrontal cortices. Crucially, audiovisual recalibration relies on distinct spatial and decisional codes that are expressed with opposite gradients and timecourses across the auditory processing hierarchy. Early activity patterns in auditory cortices encode sounds in a continuous space that flexibly adapts to misaligned visual inputs. Later activity patterns in frontoparietal cortices code decisional uncertainty consistent with these spatial transformations. Our findings demonstrate that regions throughout the auditory processing hierarchy multiplex spatial and decisional codes to adapt flexibly to the changing sensory statistics in the environment.
DNA translocase repositions a nucleosome by the lane-switch mechanism
Authors: Nagae Fritz , Brandani Giovanni B. , Takada Shoji , Terakawa Tsuyoshi
Published: February 2021

Translocases such as DNA/RNA polymerases, replicative helicases, and exonucleases are involved in eukaryotic DNA transcription, replication, and repair. Since eukaryotic genomic DNA wraps around histone core complexes and forms nucleosomes, translocases inevitably encounter nucleosomes. Previous studies have shown that a histone core complex repositions upstream (downstream) when SP6RNA or T7 RNA polymerase (bacterial exonuclease, RecBCD) partially unwraps nucleosomal DNA. However, the molecular mechanism of the downstream repositioning remains unclear. In this study, we identify the lane-shift mechanism for downstream nucleosome repositioning via coarse-grained molecular dynamics simulations, which we validated by restriction enzyme digestion assays and deep sequencing assays. In this mechanism, after a translocase unwraps nucleosomal DNA up to the site proximal to the dyad, the remaining wrapped DNA switches its binding region (lane) to that vacated by the unwrapping, and the downstream DNA rewraps, completing downstream repositioning. This mechanism may have crucial implications for transcription through nucleosomes, histone recycling, and nucleosome remodeling.

SIGNIFICANCE

Eukaryotic chromosomes are composed of repeating subunits termed nucleosomes. Thus, proteins that translocate along the chromosome, DNA translocases, inevitably collide with nucleosomes. Previous studies revealed that a translocase repositions a nucleosome upstream or downstream upon their collision. Though the molecular mechanisms of the upstream repositioning have been extensively studied, that of downstream repositioning remains elusive. In this study, we performed coarse-grained molecular dynamics simulations, proposed the lane-shift mechanism for downstream repositioning, and validated this mechanism by restriction enzyme digestion assays and deep sequencing assays. This mechanism has broad implications for how translocases deal with nucleosomes for their functions.
Global detection of DNA repair outcomes induced by CRISPR-Cas9
Authors: Liu Mengzhu , Zhang Weiwei , Xin Changchang , Yin Jianhang , Shang Yafang , Ai Chen , Li Jiaxin , Meng Fei-long , Hu Jiazhi
Published: February 2021

CRISPR-Cas9 generates double-stranded DNA breaks (DSBs) to activate cellular DNA repair pathways for genome editing. The repair of DSBs leads to small insertions or deletions (indels) and other complex byproducts, including large deletions and chromosomal translocations. Indels are well understood to disrupt target genes, while the other deleterious byproducts remain elusive. We developed a newin silicoanalysis pipeline for the previously described primer-extension-mediated sequencing assay to comprehensively characterize CRISPR-Cas9-induced DSB repair outcomes in human or mouse cells. We identified tremendous deleterious DSB repair byproducts of CRISPR-Cas9 editing, including large deletions, plasmid integrations, and chromosomal translocations. We further elucidated the important roles of microhomology, chromosomal interaction, recurrent DSBs, and DSB repair pathways in the generation of these byproducts. Our findings provide an extra dimension for genome editing safety besides off-targets. And caution should be exercised to avoid not only off-target damages but also deleterious DSB repair byproducts during genome editing.
Identification of differentially distributed gene expression and distinct sets of cancer-related genes identified by changes in mean and variability
Authors: Roberts Aedan G. K. , Catchpoole Daniel R. , Kennedy Paul J.
Published: February 2021

There is increasing evidence that changes in the variability or overall distribution of gene expression are important both in normal biology and in diseases, particularly cancer. Genes whose expression differs in variability or distribution without a difference in mean are ignored by traditional differential expression-based analyses. Using a Bayesian hierarchical model that provides tests for both differential variability and differential distribution for bulk RNA-seq data, we report here an investigation into differential variability and distribution in cancer. Analysis of eight paired tumour–normal datasets from The Cancer Genome Atlas confirms that differential variability and distribution are able to identify cancer-related genes. We further demonstrate that differential variability identifies cancer-related genes that are missed by differential expression analysis, and that differential expression and differential variability identify functionally distinct sets of genes. These results suggest that differential variability analysis may provide insights into genetic aspects of cancer that would not be revealed by differential expression, and that differential distribution analysis may allow for more comprehensive identification of cancer-related genes than analyses based on changes in mean or variability alone.
Correlation between structure and function in phosphatidylinositol lipid-dependent Kir2.2 gating
Authors: Zhang Yuxi , Tao Xiao , MacKinnon Roderick
Published: February 2021

Inward rectifier K+(Kir) channels regulate cell membrane potential. Different Kir channels respond to unique ligands, but all are regulated by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). Using planar lipid bilayers we show that Kir2.2 exhibits bursts of openings separated by long quiescent inter-burst periods. Increasing PI(4,5)P2concentration shortens the Kir2.2 inter-burst duration and lengthens the burst duration without affecting dwell times within a burst. From this, we propose that burst and inter-burst durations correspond to the CTD-docked and CTD-undocked conformations observed in the presence and absence of PI(4,5)P2in atomic structures. We also studied the effect of different phosphatidylinositol lipids on Kir2.2 activation and conclude that the 5’ phosphate is essential to Kir2.2 pore opening. Other phosphatidylinositol lipids can compete with PI(4,5)P2but cannot activate Kir2.2 without the 5’ phosphate. PI(4)P, which is directly interconvertible to and from PI(4,5)P2, might thus be a regulator of Kir channels in the plasma membrane.
Monoclonal antibodies targeting the influenza virus N6 neuraminidase
Authors: Strohmeier Shirin , Amanat Fatima , Carreño Juan Manuel , Krammer Florian
Published: February 2021

Influenza A viruses are a diverse species that include 16 hemagglutinin (HA) subtypes and 9 neuraminidase (NA) subtypes. While the antigenicity of many HA subtypes is reasonably well studied, less is known about NA antigenicity, especially when it comes to non-human subtypes that only circulate in animal reservoirs. The N6 NA subtypes are mostly found in viruses infecting birds. However, they have also been identified in viruses that infect mammals, such as swine and seals. More recently, highly pathogenic H5N6 subtype viruses have caused rare infections and mortality in humans. Here, we generated murine mAbs to the N6 NA, characterized their breadth and antiviral propertiesin vitroandin vivoand mapped their epitopes by generating escape mutant viruses. We found that the antibodies had broad reactivity across the American and Eurasian N6 lineages, but relatively little binding and inhibition of the H5N6 NA. Several of the antibodies exhibited strong NA inhibition activity and some also showed activity in the antibody dependent cellular cytotoxicity reporter assay and neutralization assay. In addition, we generated escape mutant viruses for six monoclonal antibodies and found mutations on the lateral ridge of the NA. Lastly, we observed variable protection in H4N6 and H5N6 mouse challenge models when the antibodies were given prophylactically.

Importance

The N6 NA has recently gained prominence due to the emergence of highly pathogenic H5N6 viruses. Currently, there is limited characterization of the antigenicity of avian N6 neuraminidase. Our data is an important first step towards a better understanding of the N6 NA antigenicity.
Use of Convalescent Plasma Therapy among Hospitalized Coronavirus Disease 2019 (COVID-19) Patients: A Single-Center Experience
Authors: Mesina Flordeluna Z. , Mangahas Claudette G. , Gatchalian Ellen M. , Ariola-Ramos Mary Sheila , Torres Rosalio P.
Published: February 2021

COVID-19 Disease has strained our healthcare system. Convalescent plasma has been used to treat emerging infectious diseases -Influenza A/B, SARS-CoV, Ebola virus and now SARS-CoV 2.

OBJECTIVE

This study aims to determine the outcome and clinical course of COVID-19 patients who received convalescent plasma transfusion at Cardinal Santos Medical Center.

METHODS

This is a retrospective cohort analytical study of 75 patients who received convalescent plasma.

RESULTS

Median time from admission to CP transfusion was 3 days. Majority of patients received additional therapies including dexamethasone (100%); Remdesivir (95%); antibiotics (100%), tocilizumab (65%); hemoperfusion (88%) or combination of these. Among the survivors, the median LOS was 15 days while non-survivors have a median LOS of 6 days. One patient (1.33%) had mild transfusion reaction. Four patients (5.33%) developed DVT despite anti-coagulation. There was improvement in the inflammatory markers (LDH pvalue 0.04, CRP pvalue 0.00, Ferritin pvalue 0.0001). There was improvement in the pulmonary parameters -increase in mean PaO2, mean SaO2, and mean PFR; and decrease in mean FiO2 and mean RR post-treatment. Median LOS is 14 days for the CP group vs 11 days for the non-CP group. Mortality rate among the CP group is 25.33% while the non-CP group was 26.67%. LOS and mortality rate did not reach statistical significance.

CONCLUSIONS

There was no significant difference in mortality and length of hospital stay in patients given CP vs controls. CP might have a role in the improvement of inflammatory markers and pulmonary status.
Effectiveness of Influenza Vaccines in the HIVE household cohort over 8 years: is there evidence of indirect protection?
Authors: Malosh Ryan E. , Petrie Joshua G. , Callear Amy , Truscon Rachel , Johnson Emileigh , Evans Richard , Bazzi Latifa , Cheng Caroline , Thompson Mark S. , Martin Emily T. , Monto Arnold S.
Published: February 2021

Background

The evidence that influenza vaccination programs regularly provide protection to unvaccinated individuals (i.e. indirect effects) of a community is lacking. We sought to determine the direct, indirect, and total effects of influenza vaccine in the Household Influenza Vaccine Evaluation (HIVE) cohort.

Methods

Using longitudinal data from the HIVE cohort from 2010-11 through 2017-18, we estimated direct, indirect, and total influenza vaccine effectiveness (VE) and the incidence rate ratio of influenza virus infection using adjusted mixed-effect Poisson regression models. Total effectiveness was determined through comparison of vaccinated members of full or partially vaccinated households to unvaccinated individuals in completely unvaccinated households.

Results

The pooled, direct VE against any influenza was 30.2% (14.0-43.4). Direct VE was higher for influenza A/H1N1 43.9% (3.9 to 63.5) and B 46.7% (17.2 to 57.5) than A/H3N2 31.7% (10.5 to 47.8); and was higher for young children 42.4% (10.1 to 63.0) than adults 18.6% (−6.3 to 37.7). Influenza incidence was highest in completely unvaccinated households (10.6 per 100 person-seasons) and lower at all other levels of household vaccine coverage. We found little evidence of indirect VE after adjusting for potential confounders. Total VET was 56.4% (30.1-72.9) in low coverage, 43.2% (19.5-59.9) in moderate coverage, and 33.0% (12.1 to 49.0) in fully vaccinated households.

Conclusion

Influenza vaccines may have a benefit above and beyond the direct effect but that effect in this study was small. While there may be exceptions, the goal of global vaccine recommendations should remain focused on provision of documented, direct protection to those vaccinated.
kmtricks: Efficient and flexible construction of Bloom filters for large sequencing data collections
Authors: Lemane Téo , Medvedev Paul , Chikhi Rayan , Peterlongo Pierre
Published: February 2021

When indexing large collections of short-read sequencing data, a common operation that has now been implemented in several tools (Sequence Bloom Trees and variants, BIGSI, ..) is to construct a collection of Bloom filters, one per sample. Each Bloom filter is used to represent a set of k-mers which approximates the desired set of all the non-erroneous k-mers present in the sample. However, this approximation is imperfect, especially in the case of metagenomics data. Erroneous but abundant k-mers are wrongly included, and non-erroneous but low-abundant ones are wrongly discarded. We proposekmtricks, a novel approach for generating Bloom filters from terabase-sized collections of sequencing data. Our main contributions are 1/ an efficient method for jointly counting k-mers across multiple samples, including a streamlined Bloom filter construction by directly counting, partitioning and sorting hashes instead of k-mers, which is approximately four times faster than state-of-the-art tools; 2/ a novel technique that takes advantage of joint counting to preserve low-abundant k-mers present in several samples, improving the recovery of non-erroneous k-mers. Our experiments highlight that this technique preserves around 8x more k-mers than the usual yet crude filtering of low-abundance k-mers in a large metagenomics dataset.

Availability

https://github.com/tlemane/kmtricks

Funding

The work was funded by IPL Inria Neuromarkers, ANR Inception (ANR-16-CONV-0005), ANR Prairie (ANR-19-P3IA-0001), ANR SeqDigger (ANR-19-CE45-0008).
N-Terminal finger stabilizes the reversible feline drug GC376 in SARS-CoV-2 Mpro
Authors: Arutyunova Elena , Khan Muhammad Bashir , Fischer Conrad , Lu Jimmy , Lamer Tess , Vuong Wayne , van Belkum Marco J. , McKay Ryan T. , Tyrrell D. Lorne , Vederas John C. , Young Howard S. , Lemieux M. Joanne
Published: February 2021

The main protease (Mpro, also known as 3CL protease) of SARS-CoV-2 is a high priority drug target in the development of antivirals to combat COVID-19 infections. A feline coronavirus antiviral drug, GC376, has been shown to be effective in inhibiting the SARS-CoV-2 main protease and live virus growth. As this drug moves into clinical trials, further characterization of GC376 with the main protease of coronaviruses is required to gain insight into the drug’s properties, such as reversibility and broad specificity. Reversibility is an important factor for therapeutic proteolytic inhibitors to prevent toxicity due to off-target effects. Here we demonstrate that GC376 has nanomolar Kivalues with the Mprofrom both SARS-CoV-2 and SARS-CoV strains. Restoring enzymatic activity after inhibition by GC376 demonstrates reversible binding with both proteases. In addition, the stability and thermodynamic parameters of both proteases were studied to shed light on physical chemical properties of these viral enzymes, revealing higher stability for SARS-CoV-2 Mpro. The comparison of a new X-ray crystal structure of Mprofrom SARS-CoV complexed with GC376 reveals similar molecular mechanism of inhibition compared to SARS-CoV-2 Mpro, and gives insight into the broad specificity properties of this drug. In both structures, we observe domain swapping of the N-termini in the dimer of the Mpro, which facilitates coordination of the drug’s P1 position. These results validate that GC376 is a drug with an off-rate suitable for clinical trials.
Single cell transcriptome mapping identifies a local innate B cell population driving local antibody production and chronic rejection after lung transplantation
Authors: Smirnova Natalia F. , Riemondy Kent , Collins Susan , Patel Kapil N. , Cool Carlyne , Koenigshoff Melanie , Sharma Nirmal S. , Eickelberg Oliver
Published: February 2021

Bronchiolitis obliterans syndrome (BOS) due to chronic rejection is the main reason for poor outcomes after lung transplantation (LTx). We and others have recently identified B cells as major contributors to BOS after LTx. The extent of B cell heterogeneity, however, as well as those B cell populations that determine chronic rejection of the lung, remain entirely unclear. Here, we provide a map of cell population heterogeneity and their gene expression patterns during chronic rejection after orthotopic LTx in mice. Out of a total of 14 major comprehensive cell clusters, corresponding to 11 known major cell subpopulations,Mzb1-expressing plasma cells (PCs) were the most prominently increased cell population in lungs with BOS.Scgb1a1-expressing bronchial epithelial cells were depleted, whileCd14-expressing monocytes andPdgfra-expressing fibroblasts were enriched in BOS grafts. These findings were validated in two different cohorts of human BOS after LTx. MZB1-IgG-double positive PCs infiltrated the airways of patients with BOS, while they were absent from healthy lungs. IgG, but not IgA, IgD, IgE or IgM, were significantly increased in bronchoalveolar lavage from BOS patients, compared with LTx patients who did not develop BOS. Pseudotime and trajectory analysis revealed that aBhlhe41,Cxcr3, Itgb1-triple positive-B cell subset, also expressing classical markers of the innate-like B-1 B cell population, served as the progenitor pool forMzb1+ PCs. This progenitor B cell subset accounted for the increase in IgG2cexpression and production in BOS lung grafts. Importantly,Aicda−/−mice, which lack all isotypes of Ig (except IgM) were protected from the onset of BOS after LTx. In summary, we provide a detailed atlas of cell population changes of chronic rejection after LTx. We have identified IgG-positive PCs and their progenitors – an innate B cell subpopulation characterized by a specific subset of markers - as the major source of local antibody production and a major contributor to both mouse and human BOS after LTx.
Pharmacological inhibition of LSD1 triggers myeloid differentiation by targeting GSE1, a novel oncogene in AML
Authors: Nicosia Luciano , Boffo Francesca Ludovica , Ceccacci Elena , Pallavicini Isabella , Bedin Fabio , Massignani Enrico , Ravasio Roberto , Minucci Saverio , Bonaldi Tiziana
Published: February 2021

The histone de-methylase LSD1 is over-expressed in haematological tumours and has emerged as a promising target for anti-cancer treatment, so that several LSD1 inhibitors are under development and testing, in pre-clinical and clinical settings. However, the complete understanding of their complex mechanism of action is still unreached. Here, we unravelled a novel mode of action of the LSD1 inhibitors MC2580 and DDP-38003, showing that they can induce differentiation of AML cells through the down-regulation of the chromatin protein GSE1. Analysis of the phenotypic effects of GSE1 depletion in NB4 cells showed a strong decrease of cell viabilityin vitroand of tumour growthin vivo. Mechanistically, we found that a set of genes associated with immune response and cytokine signalling pathways are up-regulated by LSD1 inhibitors through GSE1 protein reduction and that LSD1 and GSE1 co-localise at promoters of a subset of these genes at the basal state, enforcing their transcriptional silencing. Moreover, we show that LSD1 inhibitors lead to the reduced binding of GSE1 to these promoters, activating transcriptional programs that trigger myeloid differentiation. Our study offers new insights on GSE1 as a novel therapeutic target for AML.
Gene duplication to the Y chromosome in Trinidadian Guppies
Authors: Lin Yuying , Darolti Iulia , Furman Benjamin L. S. , Almeida Pedro , Sandkam Benjamin A. , Breden Felix , Wright Alison E. , Mank Judith E.
Published: February 2021

Differences in allele frequencies at autosomal genes between males and females in a population can result from two scenarios. Unresolved sexual conflict over survival produces allelic differentiation between the sexes. However, given the substantial mortality costs required to produce allelic differences between males and females at each generation, it remains unclear how many loci within the genome experience significant sexual conflict over survival. Alternatively, recent studies have shown that similarity between autosomal and Y sequence, arising from duplication onto the Y, can create perceived allelic differences, and this represents potentially resolved sexual conflict. However, Y duplications are most likely in species with large non-recombining regions, in part because they simply represent larger targets for duplications. We assessed the genomes of 120 wild-caught guppies, which experience extensive predation- and pathogen-induced mortality and have a relatively small ancestral Y chromosome. We identified seven autosomal genes that show allelic differences between male and female adults. Five of these genes show clear evidence of whole or partial gene duplication to the Y chromosome, suggesting that the male-specific region of the guppy Y chromosome, although relatively small, may nonetheless act as a hotspot for the resolution of sexual conflict. The remaining two genes show evidence of partial homology to the Y. Overall, our findings suggest that the guppy genome experiences a very low level of unresolved sexual conflict over survival, and instead the Y chromosome, despite its small ancestral size and recent origin, acts as a major mechanism of conflict resolution.
Identification of common key genes and pathways between Covid-19 and lung cancer by using protein-protein interaction network analysis
Authors: Nan Kang Soon , Karuppanan Kalimuthu , Kumar Suresh
Published: February 2021

COVID-19 is indeed an infection that is caused by a recently found coronavirus group, a type of virus proven to cause human respiratory diseases. The high mortality rate was observed in patients who had pre-existing health conditions like cancer. However, the molecular mechanism of SARS-CoV-2 infection in lung cancer patients was not discovered yet at the pathway level. This study was about determining the common key genes of COVID-19 and lung cancer through network analysis. The hub genes associated with COVID-19 and lung cancer were identified through Protein-Protein interaction analysis. The hub genes are ALB, CXCL8, FGF2, IL6, INS, MMP2, MMP9, PTGS2, STAT3 and VEGFA. Through gene enrichment, it is identified both COVID-19 and lung cancer have a common pathway in EGFR tyrosine kinase inhibitor resistance, IL-17 signalling pathway, AGE-RAGE signalling pathway in diabetic complications, HIF-1 signalling pathway and pathways in cancer.
N-terminal extensions strengthen hydrophobic inter-subunit interactions between HU’s C-terminal domains to frustrate heterodimer formation
Authors: Arora Kanika , Thakur Bhishem , Mrigwani Arpita , Guptasarma Purnananda
Published: February 2021

HU is a nucleoid-associated protein (NAP) that helps bacterial chromosomal DNA to remain compact.Escherichia colicontains two homologs of HU that are ~ 70 % identical: HU-A and HU-B. The early log phase, late log phase, and stationary phase ofE. coligrowth are reported to be dominated, respectively, by HU-AA homodimers, HU-BB homo-dimers, and HU-AB heterodimers. Here, we show that the formation of HU-AB heterodimers occurs to a much lower degree in HU chains that have a displaced N-terminus, whether through addition of an N-terminal affinity (polyhistidine) tag, or fusion of a fluorescent protein. A combination of mass spectrometry, spectroscopy, chromatography, and electrophoresis (exploring glutaraldehyde crosslinking of subunits) was used to study the mixing, co-expression, unfolding and refolding of HU-AA and HU-BB homodimers. The data suggests that, in HU polypeptides with N-terminal extension, whereas inter-subunit contacts between the alpha helical N-terminal domains (NTDs) undergo facile unfolding and dissociation, inter-subunit contacts between the beta sheet- and IDR-dominated C-terminal domains (CTDs) fail to do so, due to persistence of hydrophobic inter-subunit interactions between two beta sheets. This persistence causes HU to remain nominally dimeric even after substantive unfolding, and frustrates subunit exchange and heterodimer formation.
FRET-based screening in HEK293T identifies p38 MAPK and PKC inhibition as therapeutic targets for α-synuclein aggregation
Authors: Svanbergsson Alexander , Ek Fredrik , Martinsson Isak , Rodo Jordi , Liu Di , Brandi Edoardo , Haikal Caroline , Torres-Garcia Laura , Li Wen , Gouras Gunnar , Olsson Roger , Björklund Tomas , Li Jia-Yi
Published: February 2021

Aggregation of α-synuclein is associated with neurodegeneration and a hallmark pathology in synucleinopathies. These aggregates are thought to function as prion-like particles where the conformation of misfolded α-synuclein determines the induced pathology’s traits similar to prion diseases. Still, little is known about the molecular targets facilitating the conformation-specific biological effects, but their identification could form the basis for new therapeutic intervention. High-throughput screening (HTS) of annotated compound libraries could facilitate mechanistic investigation by identifying targets with impact on α-synuclein aggregation. To this end, we developed a FRET-based cellular reporter in HEK293T cells, with sensitivity down to 6.5 nM α-synuclein seeds. Using this model system, we identified GF109203X, SB202190, and SB203580 as inhibitors capable of preventing induction of α- synuclein aggregation via inhibition of p38 MAPK and PKC, respectively. Our findings highlight the value HTS brings to the mechanistic investigation of α-synuclein aggregation while simultaneously identifying novel therapeutic compounds.
Sucrose synthase activity is not required for cellulose biosynthesis in Arabidopsis
Authors: Wang Wei , Viljamaa Sonja , Hodek Ondrej , Moritz Thomas , Niittylä Totte
Published: February 2021

Biosynthesis of plant cell walls requires UDP-glucose as the substrate for cellulose biosynthesis, and as an intermediate for the synthesis of other matrix polysaccharides. The sucrose cleaving enzyme sucrose synthase (SUS) is thought to have a central role in UDP-glucose biosynthesis, and a long held and much debated hypothesis postulates that SUS is required to supply UDP-glucose to cellulose biosynthesis. To investigate the role of SUS in cellulose biosynthesis ofArabidopsis thalianawe characterized mutants in which four, or all six ArabidopsisSUSgenes were disrupted. Thesesusmutants showed no growth phenotypes, vascular tissue cell wall defects or changes in cellulose content. Moreover, the UDP-glucose content of rosette leaves of the sextuplesusmutants was increased by approximately 20% compared to wild type. It can thus be concluded that cellulose biosynthesis is able to employ alternative UDP-glucose biosynthesis pathway(s), and thereby the model of SUS requirement for cellulose biosynthesis in Arabidopsis can be refuted.