bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinguishing Admissions Specifically for COVID-19 from Incidental
SARS-CoV-2 Admissions: A National EHR Research Consortium Study
Authors: Klann Jeffrey G , Strasser Zachary H , Hutch Meghan R , Kennedy Chris J , Marwaha Jayson S , Morris Michele , Samayamuthu Malarkodi Jebathilagam , Pfaff Ashley C , Estiri Hossein , South Andrew M , Weber Griffin M , Yuan William , Avillach Paul , Wagholikar Kavishwar B , Luo Yuan ,   The Consortium for
                    Clinical Characterization of COVID-19 by EHR (4CE), Omenn Gilbert S , Visweswaran Shyam , Holmes John H , Xia Zongqi , Brat Gabriel A , Murphy Shawn N
Published: February 2022

Admissions are generally classified as COVID-19 hospitalizations if the
patient has a positive SARS-CoV-2 polymerase chain reaction (PCR) test. However,
because 35% of SARS-CoV-2 infections are asymptomatic, patients admitted for
unrelated indications with an incidentally positive test could be misclassified
as a COVID-19 hospitalization. EHR-based studies have been unable to distinguish
between a hospitalization specifically for COVID-19 versus an incidental
SARS-CoV-2 hospitalization. From a retrospective EHR-based cohort in four US
healthcare systems, a random sample of 1,123 SARS-CoV-2 PCR-positive patients
hospitalized between 3/2020–8/2021 was manually chart-reviewed and classified as
admitted-with-COVID-19 (incidental) vs. specifically admitted for COVID-19
(for-COVID-19). EHR-based phenotyped feature sets filtered out incidental
admissions, which occurred in 26%. The top site-specific feature sets had 79-99%
specificity with 62-75% sensitivity, while the best performing across-site
feature set had 71-94% specificity with 69-81% sensitivity. A large proportion
of SARS-CoV-2 PCR-positive admissions were incidental. Straightforward EHR-based
phenotypes differentiated admissions, which is important to assure accurate
public health reporting and research.
LABELLING HUMAN KINEMATICS DATA USING CLASSIFICATION MODELS
Authors: Shi Yuan , Chadderwala Nihir , Ratan Ujjwal
Published: February 2022

The goal of this study is to develop a classification model that can accurately and efficiently label human kinematics data. Kinematics data provides information about the movement of individuals by placing sensors on the human body and tracking their velocity, acceleration and position in three dimensions. These data points are available in C3D format that contains numerical data transformed from 3D data captured from the sensors. The data points can be used to analyse movements of injured patients or patients with physical disorders. To get an accurate view of the movements, the datasets generated by the sensors need to be properly labelled. Due to inconsistencies in the data capture process, there are instances where the markers have missing data or missing labels. The missing labels are a hindrance in motion analysis as it introduces noise and produces incomplete datapoints of sensor’s positioning in 3 dimensional space. Labelling the data manually introduces substantial effort in the analysis process. In this paper, we will describe approaches to pre-process the kinematics data from its raw format and label the data points with missing markers using classification models.
Human Group Size Puzzle: Why It Is Odd That We Live in Large Societies
Authors: David-Barrett Tamas
Published: February 2022

Human groups tend to be much larger than those of non-human primates. This is a puzzle. When ecological factors do not limit primate group size, the problem of coordination creates an upper threshold even when cooperation is guaranteed. This paper offers a simple model of group coordination towards behavioural synchrony to spell out the mechanics of group size limits, and thus show why it is odd that humans live in large societies. The findings suggest that many of our species’ evolved social behaviours and culturally-maintained social technologies emerged as a solution to this problem.
Association of Workload and Practice of Respectful Maternity Care Among the Healthcare Providers, Before and During the COVID-19 Pandemic in South Western Nepal: A Cross-Sectional Study
Authors: Pokharel Alpha , Kiriya Junko , Shibanuma Akira , Silwal Ram , Jimba Masamine
Published: February 2022

Introduction

Respectful maternity care is an approach that involves respecting women’s belief, choices, emotions, and dignity during the childbirth process. As the workload among maternity care workforce affects intrapartum quality care, respectful maternity care might have also been affected, particularly during the pandemic. Thus, this study was conducted to examine the association between workload among healthcare providers and their practice of respectful maternity care, before and during the pandemic.

Methods

A cross-sectional study was conducted in South Western Nepal. A total of 267 healthcare providers from 78 birthing centers were included. Data collection was done through telephone interviews. The exposure variable was workload among the healthcare providers, and the outcome variable was respectful maternity care practice before and during the COVID-19 pandemic. Multilevel mixed-effect linear regression was used to examine the association.

Results

The median client-provider ratio before and during the pandemic was 21.7 and 13.0, respectively. The mean score of respectful maternity care practice was 44.5 (SD 3.8) before the pandemic, which was decreased to 43.6 (SD 4.5) during the pandemic. Client-provider ratio was negatively associated with respectful maternity care practice for both times; before (Coef. −5.16; 95% CI −8.41 to −1.91) and during (Coef. −7.47; 95% CI −12.72 to −2.23) the pandemic.

Conclusions

While a higher client-provider was associated with a lower respectful maternity care practice score both before and during the COVID-19 pandemic, the coefficient was larger during the pandemic. Therefore, workload among the healthcare providers should be considered before the implementation of respectful maternity care, and more attention should be given during the pandemic.
Adaptations for bipedal walking: Musculoskeletal structure and three-dimensional joint mechanics of humans and bipedal chimpanzees (Pan troglodytes)
Authors: O’Neill Matthew C. , Demes Brigitte , Thompson Nathan E. , Larson Susan G. , Stern Jack T. , Umberger Brian R.
Published: February 2022

Humans are unique among apes and other primates in the musculoskeletal design of their lower back, pelvis and lower limbs. Here, we describe the three-dimensional ground reaction forces and lower/hind limb joint mechanics of human and bipedal chimpanzee walking over a full stride and test whether: 1) the estimated limb joint work and power during stance phase, especially the single-support period, is lower in humans than bipedal chimpanzees, 2) the limb joint work and power required for limb swing is lower in humans than in bipedal chimpanzees, and 3) the estimated total mechanical power during walking, accounting for the storage of passive elastic strain energy in humans, is lower in humans than in bipedal chimpanzees. Humans and bipedal chimpanzees were compared at matched dimensionless and dimensional velocities. Our results indicate that humans walk with significantly less work and power output in the first double-support period and the single-support period of stance, but markedly exceed chimpanzees in the second-double support period (i.e., push-off). Humans generate less work and power in limb swing, although the species difference in limb swing power was not statistically significant. We estimated that total mechanical positive ‘muscle fiber’ work and power were 46.9% and 35.8% lower, respectively, in humans than bipedal chimpanzees at matched dimensionless speeds. This is due in part to mechanisms for the storage and release of elastic energy at the ankle and hip in humans. Further, these results indicate distinct heel strike and lateral balance mechanics in humans and bipedal chimpanzees, and suggest a greater dissipation of mechanical energy through soft tissue deformations in humans. Together, our results document important differences between human and bipedal chimpanzee walking mechanics over a full stride, permitting a more comprehensive understanding of the mechanics and energetics of chimpanzee bipedalism and the evolution of hominin walking.
Serological screening in wild ruminants in Germany, 2021/22: No evidence of SARS-CoV-2, bluetongue virus or pestivirus spread but high seroprevalences against Schmallenberg virus
Authors: Wernike Kerstin , Fischer Luisa , Holsteg Mark , Aebischer Andrea , Petrov Anja , Marquart Katharina , Schotte Ulrich , Schön Jacob , Hoffmann Donata , Hechinger Silke , Neubauer-Juric Antonie , Blicke Julia , Mettenleiter Thomas C. , Beer Martin
Published: February 2022

Wildlife animals may be susceptible for multiple infectious agents of public health or veterinary relevance, thereby potentially forming a reservoir that bears the constant risk of re-introduction into the human or livestock population. Here, we serologically investigated 493 wild ruminant samples collected in the 2021/22 hunting season in Germany for the presence of antibodies against the severe acute respiratory coronavirus 2 (SARS-CoV-2) and four viruses pathogenic for domestic ruminants, namely the orthobunyavirus Schmallenberg virus (SBV), the reovirus bluetongue virus (BTV) and ruminant pestiviruses like bovine viral diarrhoea virus or border disease virus. The animal species comprised fallow deer, red deer, roe deer, mouflon and wisent. For coronavirus serology, additional 307 fallow, roe and red deer samples collected between 2017 and 2020 at three military training areas were included. While antibodies against SBV could be detected in about 13.6% of the samples collected in 2021/22, only one fallow deer of unknown age tested positive for anti-BTV antibodies and all samples reacted negative for antibodies against ruminant pestiviruses. In an ELISA based on the receptor-binding domain (RBD) of SARS-CoV-2, 25 out of 493 (5.1%) samples collected in autumn and winter 2021/22 scored positive. This sero-reactivity could not be confirmed by the highly specific virus neutralization test, occurred also in 2017, 2018 and 2019, i.e. prior to the human SARS-CoV-2 pandemic, and was likewise observed against the RBD of the related SARS-CoV-1. Therefore, the SARS-CoV-2-seroreactivity was most likely induced by another, hitherto unknown deer virus belonging to the subgenus Sarbecovirus of betacoronaviruses.
Effect of an amyloidogenic SARS-COV-2 protein fragment on α-synuclein monomers and fibrils
Authors: Jana Asis K. , Lander Chance W. , Chesney Andrew D. , Hansmann Ulrich H. E.
Published: February 2022

Using molecular dynamic simulations we study whether amyloidogenic regions in viral proteins can initiate and modulate formation of α-synuclein aggregates, thought to be the disease-causing agent in Parkinson’s Disease. As an example we choose the nine-residue fragment SFYVYSRVK (SK9), located on the C-terminal of the Envelope protein of SARS-COV-2. We probe how the presence of SK9 affects the conformational ensemble of α-synuclein monomers and the stability of two resolved fibril polymorphs. We find that the viral protein fragment SK9 may alter α-synuclein amyloid formation by shifting the ensemble toward aggregation-prone and preferentially rod-like fibril seeding conformations. However, SK9 has only little effect of the stability of pre-existing or newly-formed fibrils.
Abdominal Imaging Associates Body Composition with COVID-19 Severity
Authors: Basty Nicolas , Sorokin Elena P. , Thanaj Marjola , Srinivasan Ramprakash , Whitcher Brandon , Bell Jimmy D. , Cule Madeleine , Thomas E. Louise
Published: February 2022

The main drivers of COVID-19 disease severity and the impact of COVID-19 on long-term health after recovery are yet to be fully understood. Medical imaging studies investigating COVID-19 to date have mostly been limited to small datasets and post-hoc analyses of severe cases. The UK Biobank recruited recovered SARS-CoV-2 positive individuals (n=967) and matched controls (n=913) who were extensively imaged prior to the pandemic and underwent follow-up scanning. In this study, we investigated longitudinal changes in body composition, as well as the associations of pre-pandemic image-derived phenotypes with COVID-19 severity. Our longitudinal analysis, in a population of mostly mild cases, associated a decrease in lung volume with SARS-CoV-2 positivity. We also observed that increased visceral adipose tissue and liver fat, and reduced muscle volume, prior to COVID-19, were associated with COVID-19 disease severity. Finally, we trained a machine classifier with demographic, anthropometric and imaging traits, and showed that visceral fat, liver fat and muscle volume have prognostic value for COVID-19 disease severity beyond the standard demographic and anthropometric measurements. This combination of image-derived phenotypes from abdominal MRI scans and ensemble learning to predict risk may have future clinical utility in identifying populations at-risk for a severe COVID-19 outcome.
Three-month follow-up of heterologous vs homologous third vaccination in kidney transplant recipients
Authors: Heinzel Andreas , Schretzenmeier Eva , Regele Florina , Hu Karin , Raab Lukas , Eder Michael , Aigner Christof , Jabbour Rhea , Aschauer Constantin , Stefanski Ana-Luisa , Dörner Thomas , Budde Klemens , Reindl-Schwaighofer Roman , Oberbauer Rainer
Published: February 2022

Importance

Response to SARS-CoV-2 vaccines in kidney transplant recipients (KTR) is severely reduced. Heterologous 3rd vaccination combining mRNA and vector vaccines did not increase seroconversion at four weeks after vaccination but evolution of antibody levels beyond the first month remain unknown.

Objective

To assess changes in antibody response following a 3rd vaccination with mRNA or vector vaccine in KTR from month one to month three after vaccination.

Design, Setting and Participants

Three-month follow-up (pre-specified secondary endpoint) of a single-center, single-blinded, 1:1 randomized, controlled trial on 3rd vaccination against SARS-CoV-2 in 201 KTR who did not develop SARS-CoV-2 spike protein antibodies following two doses of an mRNA vaccine.

Intervention(s)

mRNA (BNT162b2 or mRNA-1273) or vector (Ad26COVS1) as 3rd SARS-CoV-2 vaccine

Main Outcomes and Measures

Main outcome was seroconversion at the second follow-up between 60-120 days after the 3rd vaccination. Subsequently, higher cut-off levels associated with neutralizing capacity and protective immunity were applied (i.e. >15, >100, >141 and >264 BAU/mL). In addition, trajectories of antibody levels from month one to month three were analyzed. Finally, SARS-CoV-2 specific CD4 and CD8 T-cells at four weeks were compared among the 18 top responders in both groups.

Results

A total of 169 patients were available for the three-month follow-up. Overall, seroconversion at three months was similar between both groups (45% versus 50% for mRNA and vector group, respectively; OR=1.24, 95%CI=[0.65, 2.37], p=0.539). However, when applying higher cut-off levels, a significantly larger number of individual in the vector group reached antibody levels > 141 and > 264 BAU/mL at the three-month follow-up (141 BAU/mL: 4% vs. 15% OR=4.96, 95%CI=[1.29, 28.21], p=0.009 and 264 BAU/mL: 1% vs. 10% OR=8.75, 95%CI=[1.13, 396.17], p=0.018 for mRNA vs. vector vaccine group, respectively). In line, antibody levels in seroconverted patients further increased from month one to month three in the vector group while remaining unchanged in the mRNA group (median increase: mRNA= 1.35 U/mL and vector = 27.6 U/mL, p = 0.004). Of particular note, there was no difference in the CD4 and CD8 T-cell response between the mRNA and vector vaccine group at month one.

Conclusions and Relevance

Despite a similar overall seroconversion rate at three months following 3rd vaccination in KTR, a heterologous 3rd booster vaccination with Ad26COVS1 resulted in significantly higher antibody levels in responders.

Trial Registration

EurdraCT: 2021-002927-39
Evaluating seasonal variations in human contact patterns and their impact on the transmission of respiratory infectious diseases
Authors: Kummer Allisandra G. , Zhang Juanjuan , Jiang Chenyan , Litvinova Maria , Ventura Paulo C. , Garcia Marc A. , Vespignani Alessandro , Wu Huanyu , Yu Hongjie , Ajelli Marco
Published: February 2022

Considerable uncertainty surrounds the seasonality of respiratory infectious diseases. To which extent the observed seasonality is associated with biological reasons (e.g., virus survival rates, host immune dynamics) or human behavior remains unclear. Here, we investigate the association between temperature and human contact patterns using data collected through a contact diary-based survey between December 24, 2017, and May 30, 2018, in Shanghai, China. We identified a significant inverse relationship between the number of contacts and both the seasonal temperature trend (p=0.003) and daily temperature variation (p=0.009). The average number of contacts increased from 18.9 (95% CI: 14.5-21.6) in December to 20.9 (95% CI: 15.4-26.5) in January before decreasing to 11.6 (95% CI: 8.7-14.8) in May. This seasonal trend in the number of contacts translates into a seasonal trend in the reproduction number – the mean number of secondary cases generated by a typical infector. We developed a compartment model of influenza transmission informed by the derived seasonal trends in the number of contact patterns and validated against A(H1N1)pdm09 influenza data for the focus location and study period. We found that the model shows an excellent agreement with the estimated influenza dynamics providing support to the hypothesis that the seasonality in contact patterns shapes influenza transmission dynamics. Our findings contribute to a deeper understanding of the epidemiology of respiratory infectious diseases and could potentially inform improved preparedness planning.
Gestational SARS-CoV-2 infection is associated with placental expression of immune and trophoblast genes
Authors: Lesseur Corina , Jessel Rebecca H. , Ohrn Sophie , Ma Yula , Li Qian , Dekio Fumiko , Brody Rachel I. , Wetmur James G. , Gigase Frederieke A.J. , Lieber Molly , Lieb Whitney , Lynch Jezelle , Afzal Omara , Ibroci Erona , Rommel Anna-Sophie , Janevic Teresa , Stone Joanne , Howell Elizabeth A. , Galang Romeo R. , Dolan Siobhan M. , Bergink Veerle , De Witte Lotje D. , Chen Jia
Published: February 2022

Introduction

Maternal SARS-CoV-2 infection during pregnancy is associated with adverse pregnancy outcomes and can have effects on the placenta, even in the absence of severe disease or vertical transmission to the fetus. This study aimed to evaluate histopathologic and molecular effects in the placenta after SARS-CoV-2 infection during pregnancy.

Methods

We performed a study of 45 pregnant participants from the Generation C prospective cohort study at the Mount Sinai Health System in New York City. We compared histologic features and the expression of 48 immune and trophoblast genes in placentas delivered from 15 SARS-CoV-2 IgG antibody positive and 30 IgG SARS-CoV-2 antibody negative mothers. Statistical analyses were performed using Fisher’s exact tests, Spearman correlations and linear regression models.

Results

The median gestational age at the time of SARS-CoV-2 IgG serology test was 35 weeks. Two of the IgG positive participants also had a positive RT-PCR nasal swab at delivery. 82.2% of the infants were delivered at term (≥37 weeks), and gestational age at delivery did not differ between the SARS-CoV-2 antibody positive and negative groups. No significant differences were detected between the groups in placental histopathology features. Differential expression analyses revealed decreased expression of two trophoblast genes (PSG3 and CGB3) and increased expression of three immune genes (CXCL10, TLR3 and DDX58) in placentas delivered from SARS-CoV-2 IgG positive participants.

Discussion

SARS-CoV-2 infection during pregnancy is associated with gene expression changes of immune and trophoblast genes in the placenta at birth which could potentially contribute to long-term health effects in the offspring.
Thermodynamic limitations of metabolic strategies for PHB production from formate and fructose in Cupriavidus necator
Authors: Janasch Markus , Crang Nick , Bruch Manuel , Asplund-Samuelsson Johannes , Gynnå Arvid , Jahn Michael , Hudson Elton P.
Published: February 2022

The chemolithotroph Cupriavidus necator H16 is known as a natural producer of the bioplastic-polymer PHB, as well as for its metabolic versatility to utilize different substrates, including formate as the sole carbon and energy source. Depending on the entry point of the substrate, this versatility requires adjustment of the thermodynamic landscape to maintain sufficiently high driving forces for biological processes. Here we employed a model of the core metabolism of C. necator H16 to analyze the thermodynamic driving forces and PHB yields of different metabolic engineering strategies. For this, we enumerated elementary flux modes (EFMs) of the network and evaluated their PHB yields as well as thermodynamics via Max-min driving force (MDF) analysis and random sampling of driving forces. A heterologous ATP:citrate lyase reaction was predicted to increase driving force for producing acetyl-CoA. A heterologous phosphoketolase reaction was predicted to increase maximal PHB yields as well as driving forces. These enzymes were verified experimentally to enhance PHB titers between 60 and 300% in select conditions. The EFM analysis also revealed that metabolic strategies for PHB production from formate may be limited by low driving forces through citrate lyase and aconitase, as well as cofactor balancing, and identified reactions of the core metabolism associated with low and high PHB yield. The findings of this study aid in understanding metabolic adaptation. Furthemore, the outlined approach will be useful in designing metabolic engineering strategies in other non-model bacteria.

Highlights

Elementary flux modes of C. necator for PHB synthesis from fructose and formate.

Metabolite sampling identified common reactions among EFMs with low driving force.

PHB from formate shows low driving forces for aconitase, citrate lyase, NADPH synthesis.

Phosphoketolase and ATP citrate lyase increased driving forces and PHB production.
Efficacy and sex differences in the effects on rat brain microglia of the colony-stimulating factor 1 receptor inhibitor-PLX5622
Authors: Sharon Aviv , Erez Hadas , Spira Micha E.
Published: February 2022

Microglia play pivotal roles in central nervous system development, homeostasis, responses to trauma, neurodegenerative and neuropsychiatric disorders with significant sex-bias in their symptoms and prevalence. The discovery that the survival of microglia in adult brains depends on the expression of the colony-stimulating factor 1 receptor (CSF1R), along with the development of the effective brain permeant CSF1R inhibitors PLX5622, has boosted the investigation of the role of microglia in health, disease and in relations to sex-bias. The effectiveness of PLX5622 in examining the role of microglia has mainly been demonstrated in mice. Surprisingly, despite the critical importance of rat models in brain research, there are only 4 publications in which PLX5622 was used to investigate the roles of microglia in adult rats. This has been attributed to the “impression” that PLX5622 is “ineffective in rats”. In view of the importance and interest in the role of microglia, the indispensability of rats for in vivo electrophysiological brain studies and behavioral research and the high efficacy of PLX5622-chow in eliminating microglia from adult mice brains, we examined the effects of PLX5622-chow on the elimination of the microglia in adult female and male rats. We found significant differences in microglia elimination by ad libitum PLX5622 feeding in male and female rats in different brain regions with significantly greater effectivity in female brains. Our pragmatic study provides practical information on the use and design of PLX5622 in gender-related and rat brain preclinical microglia research.
The structure of insulin granule core determines secretory capacity being reduced in type-2 diabetes
Authors: Barghouth Mohammad , Jiang Xiaoping , Nagao Mototsugu , Chen Ning , Yang Daowei , Ye Yingying , Luan Cheng , Gomez Maria F. , Blom Anna M. , Wollheim Claes B , Eliasson Lena , Renström Erik , Zhang Enming
Published: February 2022

Exocytosis in excitable cells is essential for their physiological functions. Although the exocytotic machinery controlling cellular secretion has been well investigated, the function of the vesicular cargo, i.e. secretory granular content remains obscure. Here we combine dSTORM imaging and single-domain insulin antibody, to dissect the in situ structure of insulin granule cores (IGCs) at nano level. We demonstrate that the size and shape of the IGCs can be regulated by the juxta-granular molecules Nucleobindin-2 and Enolase-1, that further contribute to the stimulated insulin secretion. IGCs located at the plasma membrane are larger than those in the cytosol. The IGCs size is decreased by ∼20% after glucose stimulation due to the release of the peripheral part of IGCs through incomplete granule fusion. Importantly, the reduction of the IGCs size is also observed in non-stimulatory pancreatic β-cells from diabetic db/db mice, Akita (Ins2+/-) mice and human Type-2 diabetic donors, in accordance with impaired secretion. These findings overall highlight the structure of exocytotic insulin cores as a novel modality amenable to targeting in the stimulated exocytosis in β-cells with impaired insulin secretion.
Neural Kernels for Recursive Support Vector Regression as a Model for Episodic Memory
Authors: Leibold Christian
Published: February 2022

Retrieval of episodic memories requires intrinsic reactivation of neuronal activity patterns. The content of the memories are thereby assumed to be stored in synaptic connections. This paper proposes a theory in which these are the synaptic connections that specifically convey the temporal order information contained in the sequences of a neuronal reservoir to the sensory-motor cortical areas that give rise to the subjective impression of retrieval of sensory motor events. The theory is based on a novel recursive version of support vector regression that allows for efficient continuous learning that is only limited by the representational capacity of the reservoir. The paper argues that hippocampal theta sequences are a potential neural substrate underlying this reservoir.The theory is consistent with confabulations and post-hoc alterations of existing memories.
Large haplotypes highlight a complex age structure within the maize pan-genome
Authors: Liu Jianing , Dawe R. Kelly
Published: February 2022

The genomes of maize and other eukaryotes contain stable haplotypes in regions of low recombination. These regions, including centromeres, long heterochromatic blocks and rDNA arrays have been difficult to analyze with respect to their diversity and origin. Greatly improved genome assemblies are now available that enable comparative genomics over these and other non-genic spaces. Using 26 complete maize genomes, we developed methods to align intergenic sequences while excluding genes and regulatory regions. The centromere haplotypes (cenhaps) extend for megabases on either side of the functional centromere regions and appear as evolutionary strata, with haplotype divergence/coalescence times dating as far back as 450 thousand years ago (kya). Application of the same methods to other low recombination regions (heterochromatic knobs and rDNA) and all intergenic spaces revealed that deep coalescence times are ubiquitous across the maize pan-genome. Divergence estimates vary over a broad time scale with peaks at ∼300 kya and 16 kya, reflecting a complex history of gene flow among diverging populations and changes in population size associated with domestication. Cenhaps and other long haplotypes provide vivid displays of this ancient diversity.
Heat Shock Factor 1 (HSF1) specifically potentiates c-MYC-mediated transcription independently of the canonical heat-shock response
Authors: Xu Meng , Lin Ling , Chuang Kun-Han , Ram Babul , Dai Siyuan , Su Kuo-Hui , Tang Zijian , Dai Chengkai
Published: February 2022

Despite its pivotal roles in biology, how the transcriptional activity of c-MYC is attuned quantitatively remain poorly defined. Here, we show that heat shock factor 1 (HSF1), the master transcriptional regulator of the heat-shock, or proteotoxic stress, response, acts as a key modifier of the c-MYC-mediated transcription. HSF1 deficiency diminishes c-MYC DNA binding and dampens its transcriptional activity genome-widely. Mechanistically, c-MYC, MAX, and HSF1 assemble into a transcription factor complex on genomic DNAs and, surprisingly, the DNA binding of HSF1 is dispensable. Instead, HSF1 physically recruits the histone acetyltransferase GCN5, thereby promoting histone acetylation and augmenting c-MYC transcriptional activity. Thus, our studies reveal that HSF1 specifically potentiates the c-MYC-mediated transcription, distinct from its role in the canonical heat-shock response. Importantly, this mechanism of action engenders two distinct c-MYC activation states, primary and advanced, which may be important to accommodate diverse physiological and pathological conditions.
Cerebral Organoids Containing an AUTS2 Missense Variant Model Microcephaly
Authors: Fair Summer R. , Schwind Wesley , Julian Dominic , Biel Alecia , Ramadesikan Swetha , Westfall Jesse , Miller Katherine E. , Kararoudi Meisam Naeimi , Hickey Scott E. , Mosher Theresa Mihalic , McBride Kim L. , Neinast Reid , Fitch James , Lee Dean , White Peter , Wilson Richard K. , Bedrosian Tracy A. , Koboldt Daniel C. , Hester Mark E.
Published: February 2022

Variants in the AUTS2 gene are associated with a broad spectrum of neurological conditions characterized by intellectual disability, microcephaly, and congenital brain malformations. Here, we use a human cerebral organoid (CO) model to investigate the pathophysiology of a heterozygous de novo missense AUTS2 variant identified in a patient with multiple neurological impairments including primary microcephaly and profound intellectual disability. Proband COs exhibit reduced growth, deficits in neural progenitor cell (NPC) proliferation and disrupted NPC polarity within ventricular zone-like regions compared to control COs. We used CRISPR-Cas9-mediated gene editing to correct this variant and demonstrate rescue of impaired organoid growth and NPC proliferative deficits. Single-cell RNA sequencing revealed a marked reduction of G1/S transition gene expression and alterations in WNT-β-Catenin signaling within proband NPCs, uncovering a novel role for AUTS2 in NPCs during human cortical development. Collectively, these results underscore the value of COs to uncover molecular mechanisms underlying AUTS2 syndrome.
Preliminary Evidence of a Link between COVID-19 Vaccines and Otologic Symptoms
Authors: Woodcock Ramsi A. , Bartels Loren J.
Published: February 2022

Abstract

Hypothesis

This study investigates whether U.S. Centers for Disease Control and Prevention Vaccine Adverse Events Reporting System (VAERS) data suggest an association between vertigo, tinnitus, hearing loss, Bell’s palsy and the COVID-19 vaccines administered in the United States.

Background

Published case reports suggest a possible association between various otologic symptoms and the COVID-19 vaccines, but the only published analysis of VAERS data, which did not account for underreporting of late-appearing adverse events, found no association between hearing loss and the vaccines.

Methods

The incidence in VAERS of vertigo, tinnitus, hearing loss, and Bell’s palsy associated with COVID-19 vaccinations administered between December 14, 2020 and June 7, 2021 was compared with published rates for the general population. To account for underreporting of late-appearing adverse events, incidences were calculated using only the initial part of the observation period, during which reported events spike above expected events.

Results

The COVID-19 vaccines were associated with statistically significant increases in the incidence of vertigo, tinnitus, hearing loss, and Bell’s palsy of 1877, 50, 12, and 14 cases per 100,000, respectively. In relation to the mRNA-1273 or BNT162b2 vaccines, the Ad26.COV2.S vaccine was associated with a statistically significant excess incidence of vertigo, tinnitus, and hearing loss of at least 723, 57, and 55 cases per 100,000, respectively.

Conclusion

These results suggest an association between the COVID-19 vaccines and vertigo, tinnitus, hearing loss, and Bell’s palsy. They also suggest that, with respect to vertigo, tinnitus, and hearing loss, the association is relatively strong for the Ad26.COV2.S vaccine.
High nucleotide similarity of three Copia lineage LTR retrotransposons among plant genomes
Authors: Orozco-Arias Simon , Dupeyron Mathilde , Gutiérrez-Duque David , Tabares-Soto Reinel , Guyot Romain
Published: February 2022

Transposable elements (TEs) are mobile genetic elements found in the majority of eukaryotic genomes. Because of their mobility in the host genome, TEs can deeply impact the structure and evolution of chromosomes and can induce mutations affecting coding genes. In response to these potential threats, host genomes use various processes to repress the TE expression, leading to an arm-race between TEs for their persistence and host genomes for their protection. In plants, the major group of TEs is the Long Terminal Repeats retrotransposons (LTR-RT). They are classified into superfamilies (Gypsy, Copia) and sub-classified into lineages according to similarities, structures and presence of coding domains. Among the different ways LTR-RTs can proliferate, horizontal transfer (HT), defined as the nonsexual transmission of nuclear and plastid genetic material between species, is a process allowing LTR-RTs to invade a new genome. Although this phenomenon was considered rare in eukaryotic organisms, recent studies demonstrate numerous potential transfers of LTR-RTs, suggesting that HT may be more frequent than initially estimated.

This study aims to determine which LTR-RT lineages are shared with high similarity among 69 reference genomes that represent the major groups of green plants. We first identified and classified 88,450 LTR-RTs and determined 143 cases of high similarities between pairs of genomes. Most of them involved three Copia lineages (Oryco/Ivana, Retrofit/Ale and Tork/Tar/Ikeros) and very few of them included the Gypsy superfamily. Interestingly, a detailed analysis of three high similarities involving the Tork/Tar/Ikeros group of lineages indicates a patchy distribution of the elements and phylogenetic incongruities, indicating they originated from potential HTs. Overall, our results demonstrate that three specific lineages of Copia share outstanding similarity between very distant species and may probably be involved in horizontal transfer mechanisms.
Microcompartment assembly around multicomponent fluid cargoes
Authors: Tsidilkovski Lev , Mohajerani Farzaneh , Hagan Michael F
Published: February 2022

This article describes dynamical simulations of the assembly of an icosahedral protein shell around a bicomponent fluid cargo. Our simulations are motivated by bacterial microcompartments, which are protein shells found in bacteria that assemble around a complex of enzymes and other components involved in certain metabolic processes. The simulations demonstrate that the relative interaction strengths among the different cargo species play a key role in determining the amount of each species that is encapsulated, their spatial organization, and the nature of the shell assembly pathways. However, the shell protein-shell protein and shell protein-cargo component interactions that help drive assembly and encapsulation also influence cargo composition within certain parameter regimes. These behaviors are governed by a combination of thermodynamic and kinetic effects. In addition to elucidating how natural microcompartments encapsulate multiple components involved within reaction cascades, these results have implications for efforts in synthetic biology to colocalize alternative sets of molecules within microcompartments to accelerate specific reactions. More broadly, the results suggest that coupling between self-assembly and multicomponent liquid-liquid phase separation may play a role in the organization of the cellular cytoplasm.
Dynamics of allosteric regulation of the phospholipase C-γ isozymes upon recruitment to membranes
Authors: Siraliev-Perez Edhriz , Stariha Jordan T.B. , Hoffmann Reece M. , Temple Brenda R. , Zhang Qisheng , Hajicek Nicole , Jenkins Meredith L , Burke John E. , Sondek John
Published: February 2022

Numerous receptor tyrosine kinases and immune receptors activate phospholipase C-gamma (PLC-γ) isozymes at membranes to control diverse cellular processes including phagocytosis, migration, proliferation, and differentiation. The molecular details of this process are not well understood. Using hydrogen-deuterium exchange mass spectrometry (HDX-MS), we show that PLC-γ1 is relatively inert to lipid vesicles that contain its substrate, PIP2, unless first bound to the kinase domain of the fibroblast growth factor receptor (FGFR1). Exchange occurs throughout PLC-γ1 and is exaggerated in PLC-γ1 containing an oncogenic substitution (D1165H) that allosterically activates the lipase. These data support a model whereby initial complex formation shifts the conformational equilibrium of PLC-γ1 to favor activation. This receptor-induced priming of PLC-γ1 also explains the capacity of a kinase-inactive fragment of FGFR1 to modestly enhance the lipase activity of PLC-γ1 operating on lipid vesicles but not a soluble analog of PIP2 and highlights cooperativity between receptor engagement and membrane proximity. Priming is expected to be greatly enhanced for receptors embedded in membranes and nearly universal for the myriad of receptors and co-receptors that bind the PLC-γ isozymes.
Structural basis for RNA-duplex unwinding by the DEAD-box helicase DbpA
Authors: Wurm Jan Philip
Published: February 2022

DEAD-box RNA helicases are implicated in most aspects of RNA biology, where these enzymes unwind short RNA duplexes in an ATP-dependent manner. During the central step of the unwinding cycle, the two domains of the helicase core form a distinct closed conformation that destabilizes the RNA duplex, which ultimately leads to duplex melting. Despite the importance of this step for the unwinding process no high resolution structures of this state are available. Here, we employ nuclear magnetic resonance spectroscopy and X-ray crystallography to determine structures of the DEAD- box helicase DbpA in the closed conformation, complexed with substrate duplexes and single- stranded unwinding product. These structures reveal that DbpA initiates duplex unwinding by interacting with up to three base-paired nucleotides and a 5’ single-stranded RNA duplex overhang. These high-resolution snapshots, together with biochemical assays, rationalize the destabilization of the RNA duplex and are integrated into a conclusive model of the unwinding process.
A novel lipase with dual localisation in Trypanosoma brucei
Authors: Monic S , Lamy A , Thonnus M , Bizarra-Rebelo T , Bringaud F , Smith TK , Figueiredo LM , Rivière L
Published: February 2022

Phospholipases are esterases involved in lipid catabolism. In pathogenic micro-organisms (bacteria, fungi, parasites) they often play a critical role in virulence and pathogenicity. A few phospholipases (PL) have been characterised so far at the gene and protein level in unicellular parasites including African trypanosomes (AT). They could play a role in different processes such as host-pathogen interaction, antigenic variation, intermediary metabolism. By mining the genome database of AT we found putative new phospholipase candidate genes and here we provided biochemical evidence that one of these has lypolytic activity. This protein has a unique non-canonical glycosome targeting signal responsible for its dual localisation in the cytosol and the peroxysomes-related organelles named glycosomes. We also show that this new phospholipase is excreted by these pathogens and that antibodies directed against this protein are generated during an experimental infection with T. brucei gambiense, a subspecies responsible for infection in humans. This feature makes this protein a possible tool for diagnosis.
Early identification of cooperative fragments for protein-protein interaction stabilization
Authors: de Vink Pim J. , Cossar Peter J. , Somsen Bente A. , Ottmann Christian , Brunsveld Luc
Published: February 2022

Modulating protein-protein interactions (PPIs) is an effective approach to drug discovery, with several drugs in the clinic that inhibit PPIs. The orthogonal approach of PPI stabilization has developed slowly, a function of the complicated dynamics of multi-component protein complexes. In contrast to PPI inhibition, where ligand affinity is the driving parameter for efficacy, cooperativity is frequently the directing variable for PPI stabilization. Here we show how STD NMR allows for early-stage detection of cooperativity using the hub protein 14-3-3, a focused library of fragments and several 14-3-3 partner proteins. Further, we validate that the observed enhancement in STD signal is a function of cooperativity of the ternary 14-3-3 complex, using mutagenesis and X-ray crystallography. Additionally, we assess the differential cooperativity of three fragments in a panel of 14-3-3 interaction partners. Finally, we demonstrate how selective 14-3-3 complex formation is a function of cooperativity effects
Using dilution grazing assays to measure size fractionated phytoplankton mortality rates across the freshwater-to-marine continuum
Authors: Barnard Malcolm A. , Paerl Hans W.
Published: February 2022

There is a need for a unified grazing method that can be used across the freshwater-to-marine continuum. To accomplish this, this research utilized dilution grazing assays across the freshwater-to-marine continuum and across the oligotrophic-to-hypereutrophic gradient by measuring size fractions of dilution-based mortality. This was investigated by using 0.7 µm and 0.2 µm prefiltered water and major ion solutions (MIS) as diluent media for use in the Landry-Hassett grazing bioassays run in lake, river, estuarine (riverine and lagoonal), and oceanic shelf systems. Because MIS does not include vitamins that would be in prefiltered natural water, vitamin effects on grazing rate determination were also investigated for the MIS bioassays. Results show that the dilution grazing method can be broadly applied across the freshwater-to-marine continuum and across trophic gradients.
Detection of functional activity in brain white matter using fiber architecture informed synchrony mapping
Authors: Zhao Yu , Gao Yurui , Zu Zhongliang , Li Muwei , Schilling Kurt G. , Anderson Adam W. , Ding Zhaohua , Gore John C.
Published: February 2022

A general linear model is widely used for analyzing fMRI data, in which the blood oxygenation-level dependent (BOLD) signals in gray matter (GM) evoked in response to neural stimulation are modeled by convolving the time course of the expected neural activity with a canonical hemodynamic response function (HRF) obtained a priori. The maps of brain activity produced reflect the magnitude of local BOLD responses. However, detecting BOLD signals in white matter (WM) is more challenging as the BOLD signals are weaker and the HRF is different, and may vary more across the brain. Here we propose a model-free approach to detect changes in BOLD signals in WM by measuring task-evoked increases of BOLD signal synchrony in WM fibers. The proposed approach relies on a simple assumption that, in response to a functional task, BOLD signals in relevant fibers are modulated by stimulus-evoked neural activity and thereby show greater synchrony than when measured in a resting state, even if their magnitudes do not change significantly. This approach is implemented in two technical stages. First, for each voxel a fiber-architecture-informed spatial window is created with orientation distribution functions constructed from diffusion imaging data. This provides the basis for defining neighborhoods in WM that share similar local fiber architectures. Second, a modified principal component analysis (PCA) is used to estimate the synchrony of BOLD signals in each spatial window. The proposed approach is validated using a 3T fMRI dataset from the Human Connectome Project (HCP) at a group level. The results demonstrate that neural activity can be reliably detected as increases in fMRI signal synchrony within WM fibers that are engaged in a task with high sensitivities and reproducibility.
Three membrane fusion pore families determine the pathway to pore dilation
Authors: Su Rui , Wang Shuyuan , McDargh Zachary , O’Shaughnessy Ben
Published: February 2022

During exocytosis secretory vesicles fuse with a target membrane and release neurotransmitters, hormones or other bioactive molecules through a membrane fusion pore. The initially small pore may subsequently dilate for full contents release, as commonly observed in amperometric traces. The size, shape and evolution of the pore is critical to the course of contents release, but exact fusion pore solutions accounting for membrane tension and bending energy constraints have not been available. Here we obtained exact solutions for fusion pores between two membranes. We find three families: a narrow pore, a wide pore and an intermediate tether-like pore. For high tensions these are close to the catenoidal and tether solutions recently reported for freely hinged membrane boundaries. We suggest membrane fusion initially generates a stable narrow pore, and the dilation pathway is a transition to the stable wide pore family. The unstable intermediate pore is the transition state that sets the energy barrier for this dilation pathway. Pore dilation is mechanosensitive, as the energy barrier is lowered by increased membrane tension. Finally, we study fusion pores in nanodiscs, powerful systems for the study of individual pores. We show that nanodiscs stabilize fusion pores by locking them into the narrow pore family.

Significance

During neurotransmission, hormone release and other fundamental processes, secretory vesicles fuse their membranes with target membranes to release contents through an initially small membrane fusion pore that subsequently dilates. Dilation is assisted by proteins such as SNAREs and synaptotagmin. While macroscopic soap film shapes are well characterized, finding exact solutions for microscopic cellular membrane surfaces is made more complex by bending energy constraints. Here, computational analysis revealed three families of fusion pores between two membranes. Our work suggests membrane fusion generates a member of the narrow pore family, and pore dilation is a transition to the wide pore family. The energy barrier that SNAREs or synaptotagmin must surmount to achieve dilation is set by a third unstable intermediate pore family.