bluuebunny/crossref_metadata_2025 huggingface dataset:
Trends of COVID-19 pediatric admissions number during the first 24 weeks of COVID-19 vaccination in Rio de Janeiro, Brazil
Authors: Araujo da Silva André Ricardo , Esteves Mônica del Monaco , de Carvalho Bernardo Rodrigues Rosa , Souza Cristina Vieira , Teixeira Cristiane Henriques
Published: September 2021

Objective

To describe trends of COVID-19 pediatric admissions number during the first 24 weeks of COVID-19 vaccination.

Design

A retrospective study was conducted in children (0-18 years), admitted in two pediatric hospitals of Rio de Janeiro city, between January 17 and July 3, 2021 with confirmed COVID-19 by reverse transcription polymerase chain reaction or serological tests. Trends of COVID-19 pediatric admissions number during the first 24 weeks of COVID-19 vaccination in Rio de Janeiro, Brazil and the pre-vaccine period were measured by linear regression.

Participants

Children admitted in pediatric hospitals in Rio de Janeiro, city, Brazil

Results

The number of total admitted patients (with all diseases) were 5340 during the pre-vaccine period, being 94 (1.8%) of them with confirmed COVID-19, and 4182 children admitted during the vaccine period, with 86 confirmed COVID-19 patients (2.1 %) (p=0.29). Media of cases admitted per/week were 2.02 in pre-vaccine period and 3.6 during the first 24 weeks of COVID vaccination (p=0.009). One death was reported in the pre-vaccine period and four in the vaccine period (p=0.14). Trends of increase in the number of admitted cases were verified both in the pre-vaccine period as in the vaccine period, being more expressive in the last one.

Conclusion

There was trend of increase in number of children admitted with confirmed COVID-19 during the first 24 weeks of COVID-vaccination in Rio de Janeiro, city. Considering that few people were fully vaccinated, reducing of number of admitted children with confirmed COVID-19 was not verified.
Exploration of Alzheimer’s Disease MRI Biomarkers Using APOE4 Carrier Status in the UK Biobank
Authors: Du Jingnan , Liu Zhaowen , Hanford Lindsay C. , Anderson Kevin M. , Feng Jianfeng , Ge Tian , Buckner Randy L.
Published: September 2021

Large-scale datasets enable novel strategies to refine and discover relations among biomarkers of disease. Here 30,863 individuals ages 44-82 from the UK Biobank were analyzed to explore MRI biomarkers associated with Alzheimer’s disease (AD) genetic risk as contrast to general effects of aging. Individuals homozygotic for the E4 variant of apolipoprotein E (APOE4) overlapped non-carriers in their 50s but demonstrated neurodegenerative effects on the hippocampal system beginning in the seventh decade (reduced hippocampal volume, entorhinal thickness, and hippocampal cingulum integrity). Phenome-wide exploration further nominated the posterior thalamic radiation (PTR) as having a strong effect, as well as multiple diffusion MRI (dMRI) and white matter measures consistent with vascular dysfunction. Effects on the hippocampal system and white matter could be dissociated in the homozygotic APOE4 carriers supporting separation between AD and cerebral amyloid angiopathy (CAA) patterns. These results suggest new ways to combine and interrogate measures of neurodegeneration.
Capturing population differences in rates of vascular aging using a deep learning electrocardiogram algorithm: a cross-sectional study
Authors: Benavente Ernest Diez , Lopez-Jimenez Francisco , Iakunchykova Olena , Malyutina Sofia , Kudryavtsev Alexander , Ryabikov Andrew , Friedman Paul A. , Kapa Suraj , Perel Pablo , Wilsgaard Tom , Schirmer Henrik , Clark Taane G. , Attia Zachi I. , Leon David A.
Published: September 2021

Background

Cardiovascular event rates increase with age in all populations. This is thought to be the result of multiple underlying molecular and cellular processes that lead to cumulative vascular damage. Apart from arterial stiffness based on pulse wave velocity there are few other non-invasive measures of this process of vascular aging. We have developed a potential biomarker of vascular aging using deep-learning to predict age from a standard 12-lead electrocardiogram (ECG). The difference between ECG predicted and chronological age (δ-age) can be interpreted as a measure of vascular aging.

Methods

We use data collected in two cross-sectional studies of adults aged 40-69 years in Norway and Russia to test the hypothesis that mean levels of δ-age, derived from a deep-learning model trained on a US population, correspond to the known large differences in cardiovascular mortality between the two countries.

Findings

Substantial differences were found in mean δ-age between populations: Russia-USA (+5·2 years; 0·7, 10 IQR) and Norway-USA (-2·6 years; -7, 2 IQR). These differences were only marginally explained when accounting for differences in established cardiovascular disease risk factors.

Interpretation

δ-age may be an important biomarker of fundamental differences in cardiovascular disease risk between populations as well as between individuals.
Implicit, Intrinsic, Extrinsic (or Environmental), and Host Factors Attributing the Covid-19 Pandemic. Part 2-Implicit Factor Pesticide Use: A Systematic Analysis
Authors: Aggarwal Ananya , Rai Ragini , Joshi Gaurav , Gahtori Prashant
Published: September 2021

Advances in our understanding of complex COVID-19 pandemic would allow us to effectively eliminate and eradicate SARS-COV2 virus. Although tremendous amount of research devoted to the robustness across its biology, diagnostics, vaccines and treatment has exploded in the past two years. However, still science do not have robust answers for causes, for example (i) What are the reasons of non-uniform global distribution of COVID-19? (ii) Why the United States, India, and Brazil, are the first-three most affected nations?, (iii) How did Bhutan, a nation sharing a boundary with China manage nearly 0.34% infections and 3 deaths from COVID-19? Nonetheless, the biomass bistribution of biosphere report suggest more than 1550-fold larger microbial biomass involving bacteria, fungi, archaea, protists and viruses is exist in comparision to all global human population in the biosphere. The rich microbiota act a first line of defence to invade pathogens and affect us both through the environment and microbiome. Unfortunately, a role of pathogen-transmission factors viz. implicit factors (competitive microflora) is still under represented. This study is an attempt from a gold standard correlation methodology using a large pesticide use global data. The non-specific pesticides kill both pests as well as protective microbiota, resulting a loss in rich biodiversity and allow easy pathogen entry to human. Entire predictions were found consistent with the recently observed evidences. These insights enhanced scientific ability to interrogate viral epidemiology and recommended to limit pesticide use for future pandemic prevention.
CHARACTERIZING AND MANAGING AN EPIDEMIC: A FIRST PRINCIPLES MODEL AND A CLOSED FORM SOLUTION TO THE KERMACK AND MCKENDRICK EQUATIONS
Authors: Duclos Ted , Reichert Tom
Published: September 2021

We derived a closed-form solution to the original epidemic equations formulated by Kermack and McKendrick in 1927 (1). The complete solution is validated using independently measured mobility data and accurate predictions of COVID-19 case dynamics in multiple countries. It replicates the observed phenomenology, quantitates pandemic dynamics, and provides simple analytical tools for policy makers. Of particular note, it projects that increased social containment measures shorten an epidemic and reduce the ultimate number of cases and deaths. In contrast, the widely used Susceptible–Infectious–Recovered (SIR) models, based on an approximation to Kermack and McKendrick’s original equations, project that strong containment measures delay the peak in daily infections, causing a longer epidemic. These projections contradict both the complete solution and the observed phenomenology in COVID-19 pandemic data. The closed-form solution elucidates that the two parameters classically used as constants in approximate SIR models cannot, in fact, be reasonably assumed to be constant in real epidemics. This prima facie failure forces the conclusion that the approximate SIR models should not be used to characterize or manage epidemics. As a replacement to the SIR models, the closed-form solution and the expressions derived from the solution form a complete set of analytical tools that can accurately diagnose the state of an epidemic and provide proper guidance for public health decision makers.
Brain white matter after pediatric mild traumatic brain injury: a diffusion tensor and neurite orientation and dispersion imaging study
Authors: Shukla Ayushi , Ware Ashley L. , Guo Sunny , Goodyear Bradley , Beauchamp Miriam H. , Zemek Roger , Craig William , Doan Quynh , Beaulieu Christian , Yeates Keith O. , Lebel Catherine
Published: September 2021

Background

Pediatric mild traumatic brain injury (mTBI) affects millions of children annually. Diffusion tensor imaging (DTI) is sensitive to axonal injuries and white matter microstructure and has been used to characterize the brain changes associated with mild traumatic brain injury (mTBI). Neurite orientation dispersion and density imaging (NODDI) is a diffusion model that can provide additional insight beyond traditional DTI metrics, but has not been examined in pediatric mTBI. The goal of this study was to employ DTI and NODDI to gain added insight into white matter alterations in children with mTBI compared to children with mild orthopedic injury (OI).

Methods

Children (mTBI n=320, OI n=176) aged 8-16.99 years (m12.39 ± 2.32 years) were recruited from emergency departments at five hospitals across Canada and underwent 3T MRI on average 11 days post-injury. DTI and NODDI metrics were calculated for seven major white matter tracts and compared between groups using univariate analysis of covariance controlling for age, sex, and scanner type. False discovery rate (FDR) was used to correct for multiple comparisons.

Results

Univariate analysis revealed no significant group main effects or interactions in DTI or NODDI metrics. Fractional anisotropy and neurite density index in all tracts exhibited a significant positive association with age and mean diffusivity in all tracts exhibited a significant negative association with age in the whole sample.

Conclusions

Overall, there were no differences between mTBI and OI groups in brain white matter microstructure from either DTI or NODDI in the seven tracts. This indicates that mTBI is associated with relatively minor white matter differences, if any, at the post-acute stage. Brain differences may evolve at later stages of injury, so longitudinal studies with long-term follow-up are needed.
Psychological factors associated with instrumental activities of daily living disability in older adults with moderate to severe knee osteoarthritis
Authors: Nanjo Keigo , Ikeda Takashi , Nagashio Naoko , Sakai Tomoko , Jinno Tetsuya
Published: September 2021

BACKGROUND

The population of older adults with knee osteoarthritis (OA)-related disabilities is increasing globally. However, studies regarding instrumental activities of daily living (IADL) in older adults with knee OA are limited.

OBJECTIVE

This study investigated the psychological factors associated with IADL disability in older adults with moderate to severe knee OA.

METHODS

A cross-sectional study was conducted on 179 patients with knee OA aged ≥ 65 years. The six-item short form of the Pain Catastrophizing Scale (PCS-6), the four-item short form of the Pain Self-Efficacy Questionnaire (PSEQ-4), and the fifteen-item Geriatric Depression Scale (GDS-15) were used to assess psychological factors. The participants were divided into IADL-disabled and non-disabled groups. Binary logistic regression analyses were performed with the IADL disability status as the dependent variable. The PCS-6, PSEQ-4, and GDS-15 tools were included as independent variables in the logistic regression model.

RESULTS

Of the total participants, 88 (49.1%) showed disability in conducting IADL. PSEQ-4 (odds ratio =0.90, 95%; confidence interval=0.82–0.99, p=0.02) was a significant independent variable among all psychological factors.

CONCLUSION

Our study showed the importance of assessing self-efficacy using the PSEQ-4 in relation to IADL disability in older adults with moderate to severe knee OA.
Analytical performances of the COVISTIX™ and Panbio™ antigen rapid tests for SARS-CoV-2 detection in an unselected population (all commers)
Authors: Garcia-Cardenas Francisco , Franco Alba , Cortés Ricardo , Bertin Jenny , Valdéz Rafael , Peñaloza Fernando , Frias-Jimenez Emmanuel , Cedro-Tanda Alberto , Mendoza-Vargas Alfredo , Reyes-Grajeda Juan Pablo , Hidalgo-Miranda Alfredo , Herrera Luis A.
Published: September 2021

Importance

A steady increase in acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cases worldwide is causing some regions of the world to withstand a third or even fourth wave of contagion. Swift detection of SARS-CoV-2 infection is paramount for the containment of cases, prevention of sustained contagion; and most importantly, for the reduction of mortality.

Objective

To evaluate the performance and validity of the COVISTIX™ rapid antigen test, for the detection of SARS-CoV-2 in an unselected population and compare it to Panbio™ rapid antigen test and RT-PCR.

Design

This is comparative effectiveness study; samples were collected at two point-of-care facilities in Mexico City between May and August 2021.

Participants

Recruited individuals were probable COVID-19 cases, either symptomatic or asymptomatic persons that were at risk of infection due to close contact to SARS-CoV-2 positive cases.

Diagnostic intervention

RT-PCR was used as gold standard for detection of SARS-CoV-2 in nasal and nasopharyngeal swabs, study subjects were tested in parallel either with the COVISTIX™ or with Panbio™ rapid antigen test.

Main outcome

Diagnostic performance of the COVISTIX™ assay is adequate in all commers since its accuracy parameters were not affected in samples collected after 7 days of symptom onset, and it detected almost 65% of samples with a Ct-value between 30 and 34.

Results

For the population tested with COVISTIX™ (n=783), specificity and sensitivity of the was 96.0% (CI95% 94.0-98.0) and 81% (CI95% 76.0-85.0), as for the Panbio™ (n=2202) population, was 99.0% (CI95%: 0.99-1.00) and 62% (CI%: 58.0-64.0%), respectively.

Conclusions and relevance

The COVISTIX™ rapid antigen test shows a high performance in all comers, thus, this test is also adequate for testing patients who have passed the peak of viral shedding or for asymptomatic patients.
Physiological noise optimizes multiplexed coding of vibrotactile-like signals in somatosensory cortex
Authors: Kamaleddin Mohammad Amin , Shifman Aaron , Sigal Daniel MW , Prescott Steven A
Published: September 2021

Neurons can use different aspects of their spiking to simultaneously represent (multiplex) different features of a stimulus. For example, some pyramidal neurons in primary somatosensory cortex (S1) use the rate and timing of their spikes to respectively encode the intensity and frequency of vibrotactile stimuli. Doing so has several requirements. Because they fire at low rates, pyramidal neurons cannot entrain 1:1 with high-frequency (100-600 Hz) inputs and instead must skip (i.e. not respond to) some stimulus cycles. The proportion of skipped cycles must vary inversely with stimulus intensity for firing rate to encode stimulus intensity. Spikes must phase lock to the stimulus for spike times (intervals) to encode stimulus frequency but, in addition, skipping must occur irregularly to avoid aliasing. Using simulations andin vitroexperiments in which S1 pyramidal neurons were stimulated with inputs emulating those induced by vibrotactile stimuli, we show that fewer cycles are skipped as stimulus intensity increases, as required for rate coding, and that physiological noise induces irregular skipping without disrupting phase locking, as required for temporal coding. This occurs because the reliability and precision of spikes evoked by small- amplitude, fast-onset signals are differentially sensitive to noise. Simulations confirmed that differences in stimulus intensity and frequency can be well discriminated based on differences in spike rate or timing, respectively, but only in the presence of noise. Our results show that multiplexed coding by S1 pyramidal neurons is facilitated rather than degraded by physiological levels of noise. In fact, multiplexing is optimal under physiologically noisy conditions.
NeuroML-DB: Sharing and characterizing data-driven neuroscience models described in NeuroML
Authors: Birgiolas Justas , Haynes Vergil , Gleeson Padraig , Gerkin Richard C. , Dietrich Suzanne W. , Crook Sharon M.
Published: September 2021

As researchers develop computational models of neural systems with increasing sophistication and scale, it is often the case that fullyde novomodel development is impractical and inefficient. Thus arises a critical need to quickly find, evaluate, re-use, and build upon models and model components developed by other researchers. We introduce the NeuroML Database (NeuroML-DB.org), which has been developed to address this need and to complement other model sharing resources. NeuroML-DB stores over 1,500 previously published models of ion channels, cells, and networks that have been translated to the modular NeuroML model description language. The database also provides reciprocal links to other neuroscience model databases (ModelDB, Open Source Brain) as well as access to the original model publications (PubMed). These links along with Neuroscience Information Framework (NIF) search functionality provide deep integration with other neuroscience community modeling resources and greatly facilitate the task of finding suitable models for reuse.

Serving as an intermediate language, NeuroML and its tooling ecosystem enable efficient translation of models to other popular simulator formats. The modular nature also enables efficient analysis of a large number of models and inspection of their properties. Search capabilities of the database, together with web-based, programmable online interfaces, allow the community of researchers to rapidly assess stored model electrophysiology, morphology, and computational complexity properties. We use these capabilities to perform a database-scale analysis of neuron and ion channel models and describe a novel tetrahedral structure formed by cell model clusters in the space of model properties and features.

Author Summary

Computational models of neurons and their circuits are increasingly used by neuroscience researchers as a tool to probe fundamental aspects of brain function. Here we describe a database of computational models of neurons and networks that makes it easier to evaluate and reuse these models. The models in the database are available in a standard format, called NeuroML, that makes it easier to extend and reuse the models in simulation studies using a wide range of simulation software platforms. The use of this standard format also makes it easier to characterize models in an automated way and analyze relationships across the features of simulated data from model simulations.

Striking Image
Interplay between the Genetics of Personality Traits, severe Psychiatric Disorders, and COVID-19 Host Genetics in the Susceptibility to SARS-CoV-2 Infection
Authors: Heilbronner Urs , Streit Fabian , Vogl Thomas , Senner Fanny , Schaupp Sabrina K. , Reich-Erkelenz Daniela , Papiol Sergi , Kohshour Mojtaba Oraki , Klöhn-Saghatolislam Farahnaz , Kalman Janos L. , Heilbronner Maria , Gade Katrin , Comes Ashley L. , Budde Monika , Andlauer Till F. M. , Anderson-Schmidt Heike , Adorjan Kristina , Stürmer Til , Loerbroks Adrian , Amelang Manfred , Poisel Eric , Foo Jerome , Heilmann-Heimbach Stefanie , Forstner Andreas J. , Degenhardt Franziska , Zimmermann Jörg , Wiltfang Jens , von Hagen Martin , Spitzer Carsten , Schmauss Max , Reininghaus Eva , Reimer Jens , Konrad Carsten , Juckel Georg , Lang Fabian U. , Jäger Markus , Figge Christian , Fallgatter Andreas J. , Dietrich Detlef E. , Dannlowski Udo , Baune Bernhardt T. , Arolt Volker , Anghelescu Ion-George , Nöthen Markus M. , Witt Stephanie H. , Andreassen Ole A. , Chen Chi-Hua , Falkai Peter , Rietschel Marcella , Schulze Thomas G. , Schulte Eva C.
Published: September 2021

Background

The SARS-CoV-2 pandemic, with all its impacts on our way of life, is affecting our experiences and mental health. Notably, individuals with mental disorders have been reported to have a higher risk of contracting SARS-CoV-2. Personality traits could represent an important determinant of preventative health behavior and, therefore, the risk of contracting the virus.

Aims

We examined overlapping genetic underpinnings between major psychiatric disorders, personality traits, and susceptibility to SARS-CoV-2 infection.

Methods

Linkage disequilibrium score regression was used to explore the genetic correlations of COVID-19 susceptibility with psychiatric disorders and personality traits based on data from the largest available respective genome-wide association studies (GWAS). In two cohorts (the PsyCourse (n=1346) and the HeiDE (n=3266) study), polygenic risk scores were used to analyze if a genetic association between, psychiatric disorders, personality traits, and COVID-19 susceptibility exists in individual-level data.

Results

We observed no significant genetic correlations of COVID-19 susceptibility with psychiatric disorders. For personality traits, there was a significant genetic correlation for COVID-19 susceptibility with extraversion (p=1.47×10-5; rg=0.284). Yet, this was not reflected in individual-level data from the PsyCourse and HeiDE studies.

Conclusions

We identified no significant correlation between genetic risk factors for severe psychiatric disorders and genetic risk for COVID-19 susceptibility. Among the personality traits, extraversion showed evidence for a positive genetic association with COVID-19 susceptibility, in one but not in another setting. Overall, these findings highlight a complex contribution of genetic and non-genetic components in the interaction between COVID-19 susceptibility and personality traits or mental disorders.
PAOX1expression in mixed-substrate continuous cultures ofKomagataella phaffii(Pichia pastoris) is completely determined by methanol consumption regardless of the secondary carbon source
Authors: Singh Anamika , Narang Atul
Published: September 2021

The expression of recombinant proteins by theAOX1promoter ofKomagataella phaffiiis typically induced by adding methanol to the cultivation medium. Since growth on methanol imposes a high oxygen demand, the medium is often supplemented with an additional secondary carbon source which serves to reduce the consumption of methanol, and hence, oxygen. Early research recommended the use of glycerol as the secondary carbon source, but more recent studies recommend the use of sorbitol because glycerol represses PAOX1expression. To assess the validity of this recommendation, we measured the steady state concentrations of biomass, residual methanol, and LacZ expressed from PAOX1over a wide range of dilution rates (0.02–0.20 h−1) in continuous cultures of the Mut+strain fed with methanol + glycerol (repressing) and methanol + sorbitol (non-repressing). We find that under these conditions, the specific PAOX1expression rate is completely determined by the specific methanol consumption rate regardless of the type (repressing/non-repressing) of the secondary carbon source. In both cultures, the specific PAOX1expression rate is proportional to the specific methanol consumption rate provided that the latter is below 0.15 g/(gdw-h); beyond this threshold consumption rate, the specific PAOX1expression rate of both cultures saturates to the same value. Analysis of the data in the literature shows that the same phenomenon also occurs in continuous cultures ofEscherichia colifed with mixtures of lactose plus repressing/non-repressing carbon sources. The specific Placexpression rate is completely determined by the specific lactose consumption rate regardless of the type of secondary carbon source, glycerol or glucose.

Key points

PAOX1expression rate is completely determined by the methanol consumption rate.

Sorbitol is not necessarily superior secondary carbon source than glycerol.
Layered Feedback Control Overcomes Performance Trade-off in Synthetic Biomolecular Networks
Authors: Hu Chelsea Y. , Murray Richard M.
Published: September 2021

Layered feedback is an optimization strategy in feedback control designs widely used in electrical and mechanical engineering. Layered control theory suggests that the performance of controllers is bound by the universal robustness-efficiency tradeoff limit, which could be overcome by layering two or more feedbacks together. In natural biological networks, genes are often regulated with redundancy and layering to adapt to environmental perturbations. Control theory hypothesizes that this layering architecture is also adopted by nature to overcome this performance trade-off. In this work, we validated this property of layered control with a synthetic network in living E. coli cells. We performed system analysis on a node-based design to confirm the tradeoff properties before proceeding to simulations with an effective mechanistic model, which guided us to the best performing design to engineer in cells. Finally, we interrogated its system dynamics experimentally with eight sets of perturbations on chemical signals, nutrient abundance, and growth temperature. For all cases, we consistently observed that the layered control overcomes the robustness-efficiency trade-off limit. This work experimentally confirmed that layered control could be adopted in synthetic biomolecular networks as a performance optimization strategy. It also provided insights in understanding genetic feedback control architectures in nature.

Abstract Figure
Phase separation of +TIP-networks regulates microtubule dynamics
Authors: Miesch Julie , Wimbish Robert T. , Velluz Marie-Claire , Aumeier Charlotte
Published: September 2021

Regulation of microtubule dynamics is essential for diverse cellular functions, and proteins that bind to dynamic microtubule ends can regulate network dynamics. Here we show that two conserved microtubule end-binding proteins, CLIP-170 and EB3, undergo phase separation and form dense liquid-networks. When CLIP-170 and EB3 act together the multivalency of the network increases, which synergistically increases the amount of protein in the dense phase. In vitro and in cells these liquid networks can condense tubulin. In vitro in the presence of microtubules, EB3/CLIP-170 phase separation can co-condense tubulin all along the microtubule. At this condition microtubule growth speed increases up to two-fold and depolymerization events are strongly reduced, compared to conditions with phase separation deficient networks. Our data show that phase separated EB3/CLIP-170 networks impact microtubule growth dynamics beyond direct protein-microtubule interactions.
Integrated molecular analysis identifies a conserved pericyte gene signature in zebrafish
Authors: Shih Yu-Huan , Portman Daneal , Idrizi Feston , Grosse Ann , Lawson Nathan D.
Published: September 2021

Pericytes reside in capillary beds where they share a basement membrane with endothelial cells and regulate their function. However, little is known about embryonic pericyte development, in part, due to lack of specific molecular markers and genetic tools. Here, we applied single cell RNA-sequencing (scRNA-seq) of platelet derived growth factor beta (pdgfrb)-positive cells to molecularly characterize pericytes in zebrafish larvae. scRNA-seq revealed zebrafish cells expressing mouse pericyte gene orthologs while comparison to bulk RNA-seq from wild type and pdgfrb mutant larvae further refined a pericyte geneset. Subsequent integration with mouse pericyte scRNA-seq profiles revealed a core set of conserved pericyte genes. Using transgenic reporter lines, we validated pericyte expression of two genes identified in our analysis: NDUFA4 mitochondrial complex associated like 2a (ndufa4l2a), and potassium voltage-gated channel, Isk-related family, member 4 (kcne4). Both reporter lines exhibited pericyte expression in multiple anatomical locations, while kcne4 was also detected in a subset of vascular smooth muscle cells. Thus, our integrated molecular analysis revealed a molecular profile for zebrafish pericytes and allowed us to develop new tools to observe these cells in vivo.

SUMMARY STATEMENT

An integrated molecular analysis in zebrafish identifies new molecular markers for pericytes.
Color, activity period, and eye structure in four lineages of ants: pale, nocturnal species have evolved larger eyes and larger facets than their dark, diurnal congeners
Authors: Johnson Robert A. , Rutowski Ronald L.
Published: September 2021

The eyes of insects display an incredible diversity of adaptations to enhance vision across the gamut of light levels that they experience. One commonly studied contrast is the difference in eye structure between nocturnal and diurnal species, with nocturnal species typically having features that enhance eye sensitivity such as larger eyes, larger eye facets, and larger ocelli. In this study, we compared eye structure between workers of closely related nocturnal and diurnal above ground foraging ant species (family Formicidae) in four genera (Myrmecocystus, Aphaenogaster, Temnothorax, Veromessor). In all four genera, nocturnal species tend to have little cuticular pigment (pale), while diurnal species are fully pigmented (dark), hence we could use cuticle coloration as a surrogate for activity pattern. Across three genera (Myrmecocystus, Aphaenogaster, Temnothorax), pale species, as expected for nocturnally active animals had larger eyes, larger facet diameters, and larger visual spans compared to their dark, more day active congeners. This same pattern occurred for one pale species of Veromessor, but not the other. There were no consistent differences between nocturnal and diurnal species in interommatidial angles and eye parameters both within and among genera. Hence, the evolution of eye features that enhance sensitivity in low light levels do not appear to have consistent correlated effects on features related to visual acuity. A survey across several additional ant genera found numerous other pale species with enlarged eyes, suggesting these traits evolved multiple times within and across genera. We also compared size of the anterior ocellus in workers of pale versus dark species of Myrmecocystus. In species with larger workers, the anterior ocellus was smaller in pale than in dark species, but this difference mostly disappeared for species with smaller workers. Presence of the anterior ocellus also was size-dependent in the two largest pale species.
Mitochondrial dynamics regulate genome stability via control of caspase-dependent DNA damage
Authors: Cao Kai , Riley Joel S , Cloix Catherine , Elmasry Yassmin , Ichim Gabriel , Campbell Kirsteen J , Tait Stephen WG
Published: September 2021

Mitochondrial dysfunction is interconnected with cancer. Nevertheless, how defective mitochondria promote cancer is poorly understood. We find that mitochondrial dysfunction promotes DNA damage under conditions of increased apoptotic priming. Underlying this process, we reveal a key role for mitochondrial dynamics in the regulation of DNA damage and genome instability. The ability of mitochondrial dynamics to regulate oncogenic DNA damage centres upon the control of minority MOMP, a process that enables non-lethal caspase activation leading to DNA damage. Mitochondrial fusion suppresses minority MOMP, and its associated DNA damage, by enabling homogenous mitochondrial expression of anti-apoptotic BCL-2 proteins. Finally, we find that mitochondrial dysfunction inhibits pro-apoptotic BAX retrotranslocation, causing BAX mitochondrial localization thereby promoting minority MOMP. Unexpectedly, these data reveal oncogenic effects of mitochondrial dysfunction that are mediated via mitochondrial dynamics and caspase-dependent DNA damage.
Cell-based and cell-free firefly luciferase complementation assay to quantify Human Immunodeficiency Virus type 1 Rev-Rev interaction
Authors: Hansen Tucker , Baris Jodie , Zhao Min , Sutton Richard
Published: September 2021

Rev is an essential regulatory protein of Human Immunodeficiency Virus type 1 (HIV) that is found in the nucleus of infected cells. Rev multimerizes on the Rev-response element (RRE) of HIV RNA to facilitate the export of intron-containing HIV mRNAs from the nucleus to the cytoplasm, and, as such, HIV cannot replicate in the absence of Rev. We have developed cell-intact and cell-free assays based upon a robust firefly split-luciferase complementation system, both of which quantify Rev-Rev interaction. Using the cell-based system we show that additional Crm1 did not impact the interaction whereas excess Rev reduced it. Furthermore, when a series of mutant Revs were tested, there was a strong correlation between the results of the cell-based assay and the results of a functional Rev trans-complementation infectivity assay. Of interest, a camelid nanobody (NB) that was known to inhibit Rev function enhanced Rev-Rev interaction in the cell-based system. We observed a similar increase in Rev-Rev interaction in a cell-free system, when cell lysates expressing NLUC-Rev or CLUC-Rev were simply mixed. In the cell-free system Rev-Rev interaction occurred within minutes and was inhibited by excess Rev. The levels of interaction between the mutant Revs tested varied by mutant type. Treatment of Rev lysates with RNAse minimally reduced the degree of interaction whereas addition of HIV RRE RNA enhanced the interaction. Purified GST-Rev protein inhibited the interaction. The Z-factor (Z’) for the cell-free system was ~0.85 when tested in 96-well format, and anti-Rev NB enhanced the interaction in the cell-free system. Thus, we have developed both cell-intact and cell-free systems that can reliably, rapidly, and reproducibly quantify Rev-Rev interaction. These assays, particularly the cell-free one, may be useful in screening and identifying compounds that inhibit Rev function on a high throughput basis.
Microtubule assembly by soluble tau impairs vesicle endocytosis and excitatory neurotransmission via dynamin sequestration in Alzheimer’s disease synapse model
Authors: Hori Tetsuya , Eguchi Kohgaku , Wang Han-Ying , Miyasaka Tomohiro , Guillaud Laurent , Taoufiq Zacharie , Yamada Hiroshi , Takei Kohji , Takahashi Tomoyuki
Published: September 2021

Elevation of soluble wild-type (WT) tau occurs in synaptic compartments in Alzheimer’s disease. We addressed whether tau elevation affects synaptic transmission at the calyx of Held in brainstem slices. Whole-cell loading of WT human tau (h-tau) in presynaptic terminals at 10-20 µM caused microtubule (MT) assembly and activity-dependent rundown of excitatory neurotransmission. Capacitance measurements revealed that the primary target of WT h-tau is vesicle endocytosis. Blocking MT assembly using nocodazole prevented tau-induced impairments of endocytosis and neurotransmission. Immunofluorescence imaging analyses revealed that MT assembly by WT h-tau loading was associated with an increased bound fraction of the endocytic protein dynamin. A synthetic dodecapeptide corresponding to dynamin-1-pleckstrin-homology domain inhibited MT-dynamin interaction and rescued tau-induced impairments of endocytosis and neurotransmission. We conclude that elevation of presynaptic WT tau induces de novo assembly of MTs, thereby sequestering free dynamins. As a result, endocytosis and subsequent vesicle replenishment are impaired, causing activity-dependent rundown of neurotransmission.

Significance Statement

Wild-type human recombinant tau loaded in rodent presynaptic terminals inhibited vesicle endocytosis, thereby causing activity-dependent rundown of excitatory transmission. This endocytic block is caused by a sequestration of dynamin by excess microtubules newly assembled by tau and can be rescued by a peptide inhibiting the microtubules-dynamin interaction, or by the microtubule disassembler nocodazole. Thus, synaptic dysfunction can be induced by pathological increase of endogenous soluble tau in Alzheimer disease slice model.
CTCF and cohesin promote focal detachment of DNA from the nuclear lamina
Authors: van Schaik Tom , Liu Ning Qing , Manzo Stefano G. , Peric-Hupkes Daan , de Wit Elzo , van Steensel Bas
Published: September 2021

Lamina associated domains (LADs) are large genomic regions that are positioned at the nuclear lamina (NL). It has remained largely unclear what drives the positioning and demarcation of LADs. Because the insulator protein CTCF is enriched at LAD borders, it was postulated that CTCF binding could position a subset of LAD boundaries, possibly through its function in stalling cohesin and hence preventing cohesin to invade into the LAD. To test this, we mapped genome – NL interactions in mouse embryonic stem cells after rapid depletion of CTCF and other perturbations of cohesin dynamics. CTCF and cohesin contribute to a sharp transition in NL interactions at LAD borders, whilst LADs are maintained after depletion of these proteins, also at borders marked by CTCF. CTCF and cohesin may thus reinforce LAD borders, but do not position these. CTCF binding sites within LADs are locally detached from the NL and enriched for accessible DNA and active histone modifications. Remarkably, even though NL positioning is strongly correlated with genome inactivity, this DNA remains accessible after the local detachment is lost following CTCF depletion. At a chromosomal scale, cohesin depletion and cohesin stabilization (depletion of the unloading factor WAPL) quantitatively affect NL interactions, indicative of perturbed chromosomal positioning in the nucleus. Finally, while H3K27me3 is locally enriched at CTCF-marked LAD borders, we find no evidence for an interplay between CTCF and H3K27me3 on NL interactions. Combined, these findings illustrate that CTCF and cohesin do not shape LAD patterns. Rather, these proteins mediate fine-tuning of NL interactions.
Glycosaminoglycans Modulate Long-Range Mechanical Communication Between Cells in Collagen Networks
Authors: Chen Xingyu , Chen Dongning , Ban Ehsan , Janmey Paul A. , Wells Rebecca G. , Shenoy Vivek B.
Published: September 2021

Cells can sense and respond to mechanical forces in fibrous extracellular matrices (ECM) over distances much greater than their size. This phenomenon, termed long-range force transmission, is enabled by the realignment (buckling) of collagen fibers along directions where the forces are tensile (compressive). However, whether other key structural components of the ECM, in particular glycosaminoglycans (GAGs), can affect the efficiency of cellular force transmission remains unclear. Here we developed a theoretical model of force transmission in collagen networks with interpenetrating GAGs, capturing the competition between tension-driven collagen-fiber alignment and the swelling pressure induced by GAGs. Using this model, we show that the swelling pressure provided by GAGs increases the stiffness of the collagen network by stretching the fibers in an isotropic manner. We found that the GAG-induced swelling pressure can help collagen fibers resist buckling as the cells exert contractile forces. This mechanism impedes the alignment of collagen fibers and decreases long-range cellular mechanical communication. We experimentally validated the theoretical predictions by comparing collagen fiber alignment between cellular spheroids cultured on collagen gels versus collagen-GAG co-gels. We found significantly less alignment of collagen in collagen-GAG co-gels, consistent with the prediction that GAGs can prevent collagen fiber alignment. The roles of GAGs in modulating force transmission uncovered in this work can be extended to understand pathological processes such as the formation of fibrotic scars and cancer metastasis, where cells communicate in the presence of abnormally high concentrations of GAGs.

Statement of significance

Glycosaminoglycans (GAGs) are carbohydrates that are expressed ubiquitously in the human body and are among the key macromolecules that influence development, homeostasis, and pathology of native tissues. Abnormal accumulation of GAGs has been observed in metabolic disorders, solid tumors, and fibrotic tissues. Here we theoretically and experimentally show that tissue swelling caused by the highly polar nature of GAGs significantly affects the mechanical interactions between resident cells by altering the organization and alignment of the collagenous extracellular matrix. The roles of GAGs in modulating cellular force transmission revealed here can guide the design of biomaterial scaffolds in regenerative medicine and provides insights on the role of cell-cell communication in tumor progression and fibrosis.
The N terminus of adhesion G protein-coupled receptor GPR126/ADGRG6 as allosteric force integrator
Authors: Mitgau Jakob , Franke Julius , Schinner Camilla , Stephan Gabriele , Berndt Sandra , Placantonakis Dimitris G. , Kalwa Hermann , Spindler Volker , Wilde Caroline , Liebscher Ines
Published: September 2021

The adhesion G protein-coupled receptor (aGPCR) GPR126/ADGRG6 plays an important role in several physiological functions, such as myelination or peripheral nerve repair. This renders the receptor an attractive pharmacological target. GPR126 is a mechano-sensor that translates binding of extracellular matrix (ECM) molecules to its N terminus into a metabotropic intracellular signal. To date, the structural requirements and the character of the forces needed for this ECM-mediated receptor activation are largely unknown.

In this study we provide this information by combining classic second messenger detection with single cell atomic force microscopy. We establish a monoclonal antibody targeting the N terminus to stimulate GPR126 and compare it to the activation through its known ECM ligands collagen IV and laminin 211. As each ligand uses a distinct mode of action, the N terminus can be viewed as an allosteric module that can fine-tune receptor activation in a context-specific manner.
Alpha-Gal Syndrome: Involvement of Amblyomma americanum α-D-galactosidase and α-1,4 Galactosyltransferase enzymes in α-gal metabolism
Authors: Sharma Surendra Raj , Crispell Gary , Mohamed Ahmed , Cox Cameron , Lange Joshua , Choudhary Shailesh , Commins Scott P. , Karim Shahid
Published: September 2021

Alpha-Gal Syndrome (AGS) is an IgE-mediated delayed-type hypersensitivity reaction to the oligosaccharide galactose-⍰-1,3-galactose (α-gal) injected into humans from the lone star tick (Amblyomma americanum) bite. This study aims at the functional characterization of two tick enzymes, α-D-galactosidase (ADGal) and α-1,4 galactosyltransferase (β-1,4GalT) in α-gal metabolism. The ADGal enzyme cleaves terminal α-galactose moieties from glycoproteins and glycolipids, whereas β-1,4GalT transfers α-galactose to a β1,4 terminal linkage acceptor sugars: GlcNAc, Glc, and Xyl in various processes of glycoconjugate synthesis. An RNA interference approach was utilized to silence ADGal and β-1,4GalT in Am. americanum to examine their functional role in α-gal metabolism and AGS onset. Silencing of ADGal led to the significant down regulation of genes involved in galactose metabolism and transport in Am. americanum. Immunoblot and N-glycan analysis of the Am. americanum salivary glands showed a significant reduction in ⍰-gal levels in silenced tissues. However, there was no significant difference in the level of ⍰-gal in β-1,4GalT silenced tick salivary glands. A basophil-activation test showed a decrease in the frequency of activated basophil by ADGal silenced salivary glands. These results provide an insight into the role of α-D galactosidase & β-1,4GalT in tick biology and the probable involvement in the onset of AGS.
PhyloVision: Interactive Software for Integrated Analysis of Single-Cell Transcriptomic and Phylogenetic Data
Authors: Jones Matthew G. , Rosen Yanay , Yosef Nir
Published: September 2021

Recent advances in CRISPR-Cas9 engineering and single-cell assays have enabled the simultaneous measurement of single-cell transcriptomic and phylogenetic profiles. However, there are few computational tools enabling users to integrate and derive insight from a joint analysis of these two modalities. Here, we describe PhyloVision: an open source software for interactively exploring data from both modalities and for identifying and interpreting heritable gene modules whose concerted expression are associated with phylogenetic relationships. PhyloVision provides a feature-rich, interactive, and shareable web-based report for investigating these modules, while also supporting several other data and meta-data exploration capabilities. We demonstrate the utility of PhyloVision using a published dataset of metastatic lung adenocarcinoma cells, whose phylogeny was resolved using a CRISPR/Cas9-based lineage-tracing system. Together, we anticipate that PhyloVision and the methods it implements will be a useful resource for scalable and intuitive data exploration for any assay that simultaneously measures cell state and lineage.
A Statistical Framework for Data Purification with Application to Microbiome Data Analysis
Authors: Sun Zequn , Zhao Jing , Liu Zhaoqian , Ma Qin , Chung Dongjun
Published: September 2021

Identification of disease-associated microbial species is of great biological and clinical interest. However, this investigation still remains challenges due to heterogeneity in microbial composition between individuals, data quality issues, and complex relationships among species. In this paper, we propose a novel data purification algorithm that allows elimination of noise observations, which leads to increased statistical power to detect disease-associated microbial species. We illustrate the proposed algorithm using the metagenomic data generated from colorectal cancer patients.
ProtAnno, an Automated Cell Type Annotation Tool for Single Cell Proteomics Data that integrates information from Multiple Reference Sources
Authors: Deng Wenxuan , Zhu Biqing , Park Seyoung , Sumida Tomokazu S. , Unterman Avraham , Hafler David , Cruz Charles S. Dela , Kaminski Naftali , Lucas Carrie L. , Zhao Hongyu
Published: September 2021

Compared with sequencing-based global genomic profiling, cytometry labels targeted surface markers on millions of cells in parallel either by conjugated rare earth metal particles or Unique Molecular Identifier (UMI) barcodes. Correct annotation of these cells to specific cell types is a key step in the analysis of these data. However, there is no computational tool that automatically annotates single cell proteomics data for cell type inference. In this manuscript, we propose an automated single cellproteomics dataannotation approach calledProtAnnoto facilitate cell type assignments without laborious manual gating. ProtAnno is designed to incorporate information from annotated single cell RNA-seq (scRNA-seq), CITE-seq, and prior data knowledge (which can be imprecise) on biomarkers for different cell types. We have performed extensive simulations to demonstrate the accuracy and robustness of ProtAnno. For several single cell proteomics datasets that have been manually labeled, ProtAnno was able to correctly label most single cells. In summary, ProtAnno offers an accurate and robust tool to automate cell type annotations for large single cell proteomics datasets, and the analysis of such annotated cell types can offer valuable biological insights.