bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinguishing Incubation and Acute Disease Stages of Mild-to-Moderate COVID-19
Authors: Müller Michael , Volzke Johann , Subin Behnam , Schmidt Christian J. , Geerdes-Fenge Hilte , Reisinger Emil C. , Müller-Hilke Brigitte
Published: September 2021

Objective

While numerous studies have already compared the immune responses against SARS-CoV-2 in severely and mild-to-moderately ill COVID-19 patients, longitudinal trajectories are still scarce. We therefore set out to analyze serial blood samples from mild-to-moderately ill patients in order to define the immune landscapes for differently progressed disease stages.

Methods

Twenty-two COVID-19 patients were subjected to consecutive venipuncture within seven days after diagnosis or admittance to hospital. Flow cytometry was performed to analyze peripheral blood immune cell compositions and their activation as were plasma levels of cytokines and SARS-CoV-2 specific immunoglobulins. Healthy donors served as controls.

Results

Integrating the kinetics of plasmablasts and SARS-CoV-2 specific antibodies allowed for the definition of three disease stages of early COVID-19. The incubation phase was characterized by a sharp increase in pro-inflammatory monocytes and terminally differentiated cytotoxic T cells. The latter correlated significantly with elevated concentrations of IP-10. Early acute infection featured a peak in PD-1+ cytotoxic T cells, plasmablasts and increasing titers of virus specific antibodies. During late acute infection, immature neutrophils were enriched whereas all other parameters returned to baseline.

Conclusion

Our findings will help to define landmarks that are indispensable for the refinement of new anti-viral and anti-inflammatory therapeutics, and may also inform clinicians to optimize treatment and prevent fatal outcome.
Vaccinations or Non-Pharmaceutical Interventions: Safe Reopening of Schools in England
Authors: Cuesta-Lazaro Carolina , Quera-Bofarull Arnau , Aylett-Bullock Joseph , Lawrence Bryan N. , Fong Kevin , Icaza-Lizaola Miguel , Sedgewick Aidan , Truong Henry , Vernon Ian , Williams Julian , Pagel Christina , Krauss Frank
Published: September 2021

With high levels of the Delta variant of COVID-19 circulating in England during September 2021, schools are set to reopen with few school-based non-pharmaceutical interventions (NPIs). In this paper, we present simulation results obtained from the individual-based model, June, for English school opening after a prior vaccination campaign using an optimistic set of assumptions about vaccine efficacy and the likelihood of prior-reinfection. We take a scenario-based approach to modelling potential interventions to assess relative changes rather than real-world forecasts. Specifically, we assess the effects of vaccinating those aged 16-17, those aged 12-17, and not vaccinating children at all relative to only vaccinating the adult population, addressing what might have happened had the UK began teenage vaccinations earlier. Vaccinating children in the 12-15 age group would have had a significant impact on the course of the epidemic, saving thousands of lives overall in these simulations. In the absence of such a vaccination campaign our simulations show there could still be a significant positive impact on the epidemic (fewer cases, fewer deaths) by continuing NPI strategies in schools. Our analysis suggests that the best results in terms of lives saved are likely derived from a combination of the now planned vaccination campaign and NPIs in schools.
COVID-19 Outcomes in Patients with Cancer: Findings from the University of California Health System Database
Authors: Kwon D. H. , Cadena Pico J. E. , Nguyen S. , Chan K. H. R. , Soper B. , Gryshuk A. L. , Ray P. , Huang F. W.
Published: September 2021

Background

Patients with cancer are at risk for poor COVID-19 outcomes. We aimed to identify cancer-related risk factors for poor COVID-19 outcomes.

Patients and Methods

We conducted a retrospective cohort study using the University of California Health COVID Research Data Set. This database includes prospectively-collected, electronic health data of patients who underwent testing for SARS-CoV-2 at seventeen California medical centers. We identified adult patients tested for SARS-CoV-2 between February 1, 2020 and December 31, 2020, and selected a cohort of patients with cancer using diagnostic codes. We obtained demographic, comorbidity, laboratory, cancer type, and antineoplastic therapy data. The primary outcome was hospitalization within 30 days after first positive SARS-CoV-2 test. Secondary outcomes were SARS-CoV-2 positivity and composite endpoint for severe COVID-19 (intensive care, mechanical ventilation, or death within 30 days after first positive test). We used multivariable logistic regression to identify cancer-related factors associated with outcomes.

Results

We identified 409,462 patients undergoing SARS-CoV-2 testing. Of 49,918 patients with cancer, 1,781 (3.6%) tested positive. Patients with cancer were less likely to test positive (OR 0.69, 95%CI 0.66-0.73, P<0.001). BCR-ABL-negative myeloproliferative neoplasms (polycythemia vera, essential thrombocythemia, and primary myelofibrosis) (OR 2.51, 95%CI 1.29-4.89, P=0.007); venetoclax (OR 3.63, 95%CI 1.02-12.92, P=0.046); methotrexate (OR 3.65, 95%CI 1.17-11.37, P=0.026); Asian race (OR 1.92, 95%CI 1.23-2.98, P=0.004); and Hispanic/Latino ethnicity (OR 1.96, 95%CI 1.41-2.73, P<0.001) were associated with increased hospitalization risk. Among 388 hospitalized patients with cancer and COVID-19, cancer type and therapy type were not associated with severe COVID-19.

Conclusions

In this large, diverse cohort of Californians, cancer was not a risk factor for SARS-CoV-2 positivity. Patients with BCR/ABL-negative myeloproliferative neoplasm and patients receiving methotrexate or venetoclax may be at an increased risk of hospitalization following SARS-CoV-2 infection. Further mechanistic and comparative studies are needed to explain and confirm our findings.
Increasing triacylglycerol formation and lipid storage by unsaturated lipids protects renal proximal tubules in diabetes
Authors: Pérez-Martí Albert , Ramakrishnan Suresh , Li Jiayi , Dugourd Aurelien , Molenaar Martijn R. , De La Motte Luigi R. , Grand Kelli , Mansouri Anis , Parisot Mélanie , Lienkamp Soeren S. , Saez-Rodriguez Julio , Simons Matias
Published: September 2021

In diabetic patients, dyslipidemia frequently contributes to organ damage such as diabetic kidney disease (DKD). DKD is associated with excessive renal deposition of triacylglycerol (TAG) in lipid droplets (LD). Yet, it is unclear whether LDs play a protective or damaging role and how this might be influenced by dietary patterns. By using a diabetes mouse model, we find here that high fat diet enriched in the unsaturated oleic acid (OA) caused more lipid storage in LDs in renal proximal tubular cells (PTC) but less tubular damage than a corresponding butter diet with the saturated palmitic acid (PA). Mechanistically, we identify endoplasmic reticulum (ER) stress as the main cause of PA-induced PTC injury. ER stress is caused by elevated cellular levels of saturated TAG precursors and to higher membrane order in the ER. The resulting cell death is preceded by a transcriptional rewiring of phospholipid metabolism. Simultaneous addition of OA rescues the cytotoxic effects by normalizing membrane order and by increasing the total TAG amount. The latter also stimulates the formation of LDs that in turn can release unsaturated lipids upon demand by lipolysis. Our study thus clarifies mechanisms underlying PA-induced cell stress in PTCs and emphasizes the importance of olive oil for the prevention of DKD.
State-wide Genomic Epidemiology Investigations of COVID-19 Infections in Healthcare Workers – Insights for Future Pandemic Preparedness
Authors: Watt Anne E. , Sherry Norelle L. , Andersson Patiyan , Lane Courtney R. , Johnson Sandra , Wilmot Mathilda , Horan Kristy , Sait Michelle , Ballard Susan A. , Crachi Christina , Beck Dianne J. , Marshall Caroline , Kainer Marion , Stuart Rhonda , McGrath Christian , Kwong Jason C. , Bass Pauline , Kelley Peter G. , Crowe Amy , Guy Stephen , Macesic Nenad , Smith Karen , Williamson Deborah A. , Seemann Torsten , Howden Benjamin P.
Published: September 2021

Background

COVID-19 has resulted in many infections in healthcare workers (HCWs) globally. We performed state-wide SARS-CoV-2 genomic epidemiological investigations to identify HCW transmission dynamics and provide recommendations to optimise healthcare system preparedness for future outbreaks.

Methods

Genome sequencing was attempted on all COVID-19 cases in Victoria, Australia. We combined genomic and epidemiologic data to investigate the source of HCW infections across multiple healthcare facilities (HCFs) in the state. Phylogenetic analysis and fine-scale hierarchical clustering were performed for the entire Victorian dataset including community and healthcare cases. Facilities provided standardised epidemiological data and putative transmission links.

Findings

Between March and October 2020, approximately 1,240 HCW COVID-19 infection cases were identified; 765 are included here. Genomic sequencing was successful for 612 (80%) cases. Thirty-six investigations were undertaken across 12 HCFs. Genomic analysis revealed that multiple introductions of COVID-19 into facilities (31/36) were more common than single introductions (5/36). Major contributors to HCW acquisitions included mobility of staff and patients between wards and facilities, and characteristics and behaviours of individual patients including super-spreading events. Key limitations at the HCF level were identified.

Interpretation

Genomic epidemiological analyses enhanced understanding of HCW infections, revealing unsuspected clusters and transmission networks. Combined analysis of all HCWs and patients in a HCF should be conducted, supported by high rates of sequencing coverage for all cases in the population. Established systems for integrated genomic epidemiological investigations in healthcare settings will improve HCW safety in future pandemics.

Funding

The Victorian Government, the National Health and Medical Research Council Australia, and the Medical Research Future Fund.
The phenomenology of tics and tic-like behavior in TikTok
Authors: Vera Alonso Zea , Bruce Adrienne , Garris Jordan , Tochen Laura , Bhatia Poonam , Lehman Rebecca K , Lopez Wendi , Wu Steve W. , Gilbert Donald L.
Published: September 2021

Background and Objective

Pediatricians and pediatric subspecialists worldwide have reported a marked increase in functional (conversion) disorders with tic-like behaviors during the COVID-19 pandemic. These patients often report frequent viewing of Tourette Syndrome (TS) TikTok videos, suggesting disease modeling. We aimed to evaluate tic phenomenology in videos posted on TikTok.

Methods

The 100 most-viewed videos under #tourettes in TikTok were randomly assigned to two primary reviewers (n=3; <2 years independent practice), all pediatric neurologists specializing in movement disorders, for extraction and classification of tic phenomenology. Initial disagreements were solved by consensus. If not resolved, a senior reviewer (n=5; >2 years independent pediatric movement-disorder practice) served as tiebreaker. In addition, two primary and one senior reviewer rated each video on a Likert scale from 1= “All the tics are typical of TS” to 5= “None of the tics are typical of TS”. Mean scores and Spearman correlation between primary and senior reviewers were calculated.

Results

Six videos without tic-like behaviors were excluded. Most videos depicted coprophenomena (coprolalia: 53.2%; copropraxia: 20.2%), often with unusual characteristics. Frequently, videos demonstrated atypical phenomenology such as very strong influence by the environment (motor: 54.3%; phonic: 54.3%), aggression (19.1%), throwing objects (22.3%), self-injurious behaviors (27.7%), and long phrases (>3 words; 45.7%). Most videos portrayed atypical, non-tic behaviors (Median [IQR] Likert ratings: Primary 4.5 [4-5]; Senior 5 [3-5]). Primary vs. senior rater scores demonstrated moderate agreement (r = 0.46; p<0.001).

Conclusions

TS symptoms portrayals on highly-viewed TikTok videos are predominantly not representative or typical of TS.

Highlights

Many teenagers with functional tic-like disorder have been reported during the COVID-19 pandemic.

These patients report increased viewing of Tourette Syndrome TikTok videos, a popular social media platform, and present with similar tic-like behaviors.

Current TikTok videos are poorly representative of Tourette syndrome and more consistent with functional tic-like behavior.

We provide a detailed description of the phenomenology tics and tic-like behavior portrayed in TikTok.
OpenClinicalAI: enabling AI to diagnose diseases in real-world clinical settings
Authors: Huang Yunyou , Wang Nana , Tang Suqin , Ma Li , Hao Tianshu , Jiang Zihan , Zhang Fan , Kang Guoxin , Miao Xiuxia , Guan Xianglong , Zhang Ruchang , Zhang Zhifei , Zhan Jianfeng ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: September 2021

This paper quantitatively reveals the state-of-the-art and state-of-the-practice AI systems only achieve acceptable performance on the stringent conditions that all categories of subjects are known, which we call closed clinical settings, but fail to work in real-world clinical settings. Compared to the diagnosis task in the closed setting, real-world clinical settings pose severe challenges, and we must treat them differently. We build a clinical AI benchmark named Clinical AIBench to set up real-world clinical settings to facilitate researches. We propose an open, dynamic machine learning framework and develop an AI system named OpenClinicalAI to diagnose diseases in real-world clinical settings. The first versions of Clinical AIBench and OpenClinicalAI target Alzheimer’s disease. In the real-world clinical setting, OpenClinicalAI significantly out-performs the state-of-the-art AI system. In addition, OpenClinicalAI develops personalized diagnosis strategies to avoid unnecessary testing and seamlessly collaborates with clinicians. It is promising to be embedded in the current medical systems to improve medical services.

One-Sentence Summary

We propose a clinical AI benchmark and an open, dynamic machine learning framework to enable AI diagnosis systems to land in real-world clinical settings.
Wound Complications Following Surgery to the Lymph Nodes: A protocol for a systematic review and meta-analysis
Authors: Nzenwa Ikemsinachi C. , Iqbal Hassan A. , Hardie Claire , Smith George E , Matteucci Paolo L , Totty Joshua P
Published: September 2021

Background

Malignancies that spread to the lymph nodes may be identified through surgical biopsy, and treatment of metastatic disease may be through lymph node dissection. These surgeries, however, may be associated with significant adverse outcomes, particularly wound complications, the true incidence of which remains unknown. Multiple studies have reported their individual rates of complications in isolation. The aim of this study will be to systematically evaluate data that presents the incidence of wound complications in patients undergoing these surgeries.

Methods

We have designed and registered a protocol for a systematic review and meta-analysis of studies presenting incidence data. We will search MEDLINE, EMBASE and CENTRAL for relevant articles published before March 30th, 2021. Meta-analysis will be undertaken to synthesise an overall incidence of surgical site infection, wound dehiscence, haematoma and seroma. Subgroup analyses will investigate the effects of anatomical location, primary malignancy and study design on pooled incidence. Risk of bias will be evaluated for each included study using bespoke tools matched to the study design.

Discussion

The results of this study will provide the incidence of wound complications and secondary complications following lymph node surgery. This will directly impact upon the consent process, and may influence the nature of future research studies aimed at reducing post-operative complications.
Comprehensive analysis of DNA replication timing in genetic diseases and gene knockouts identifies MCM10 as a novel regulator of the replication program
Authors: Caballero Madison , Ge Tiffany , Rebelo Ana Rita , Seo Seungmae , Kim Sean , Brooks Kayla , Zuccaro Michael , Kanagaraj Radhakrishnan , Vershkov Dan , Kim Dongsung , Smogorzewska Agata , Smolka Marcus , Benvenisty Nissim , West Stephen C , Egli Dieter , Mace Emily M , Koren Amnon
Published: September 2021

Cellular proliferation depends on the accurate and timely replication of the genome. Several genetic diseases are caused by mutations in key DNA replication genes; however, it remains unclear whether these genes influence the normal program of DNA replication timing. Similarly, the factors that regulate DNA replication dynamics are poorly understood. To systematically identify trans-acting modulators of replication timing, we profiled replication in 184 cell lines from three cell types, encompassing 60 different gene knockouts or genetic diseases. Through a rigorous approach that considers the background variability of replication timing, we concluded that most samples displayed normal replication timing. However, mutations in two genes showed consistently abnormal replication timing. The first gene was RIF1, a known modulator of replication timing. The second was MCM10, a highly conserved member of the pre-replication complex. MCM10 mutant cells demonstrated replication timing variability comprising 46% of the genome and at different locations than RIF1 knockouts. Replication timing alterations in MCM10-mutant cells was predominantly comprised of replication initiation defects. Taken together, this study demonstrates the remarkable robustness of the human replication timing program and reveals MCM10 as a novel modulator of DNA replication timing.
TAAC - TMS Adaptable Auditory Control: a universal tool to mask TMS click
Authors: Russo S. , Sarasso S. , Puglisi G.E. , Dal Palù D. , Pigorini A. , Casarotto S. , D’Ambrosio S. , Astolfi A. , Massimini M. , Rosanova M. , Fecchio M.
Published: September 2021

Background

Coupling transcranial magnetic stimulation with electroencephalography (TMS-EEG) allows recording the EEG response to a direct, non-invasive cortical perturbation. However, obtaining a genuine TMS-evoked EEG potential requires controlling for several confounds, among which a main source is represented by the auditory evoked potentials (AEPs) associated to the TMS discharge noise (TMS click). This contaminating factor can be in principle prevented by playing a masking noise through earphones.

New method

Here we release TMS Adaptable Auditory Control (TAAC), a highly flexible, open-source, Matlab®-based interface that generates in real-time customized masking noises. TAAC creates noises starting from the stimulator-specific TMS click and tailors them to fit the individual, subject-specific click perception by mixing and manipulating the standard noises in both time and frequency domains.

Results

We showed that TAAC allows us to provide standard as well as customized noises able to effectively and safely mask the TMS click.

Comparison with existing methods

Here, we showcased two customized noises by comparing them to two standard noises previously used in the TMS literature (i.e., a white noise and a noise generated from the stimulator-specific TMS click only). For each, we quantified the Sound Pressure Level (SPL; measured by a Head and Torso Simulator - HATS) required to mask the TMS click in a population of 20 healthy subjects. Both customized noises were effective at safe (according to OSHA and NIOSH safety guidelines), lower SPLs with respect to standard noises.

Conclusions

At odds with previous methods, TAAC allows creating effective and safe masking noises specifically tailored on each TMS device and subject. The combination of TAAC with tools for the real-time visualization of TEPs can help control the influence of auditory confounds also in non-compliant patients. Finally, TAAC is a highly flexible and open-source tool, so it can be further extended to meet different experimental requirements.
APOK3, a pollen killer antidote in Arabidopsis thaliana
Authors: Simon Matthieu , Durand Stéphanie , Ricou Anthony , Vrielynck Nathalie , Mayjonade Baptiste , Gouzy Jérôme , Boyer Roxane , Roux Fabrice , Camilleri Christine , Budar Françoise
Published: September 2021

According to the principles of heredity, each parental allele of hybrids equally participates in the progeny. At some loci, however, it happens that one allele is favored to the expense of the other. Gamete killers are genetic systems where one allele (the killer) triggers the death of the gametes carrying the other (killed) allele. They have been found in many organisms, and are of major interest to understand mechanisms of evolution and speciation. Gamete killers are particularly prevalent in plants, where they can compromise crop breeding. Here, we deciphered a pollen killer in Arabidopsis thaliana by exploiting natural variation, de novo genomic sequencing and mutants, and analyzing segregations in crosses. We found that the killer allele carries an antidote gene flanked by two elements mandatory for the killing activity. We identified the gene encoding the antidote, a chimeric protein addressed to mitochondria. This gene appeared in the species by association of domains recruited from other genes, and it recently underwent duplications within a highly variable locus, particularly in the killer genotypes. Exploring the species diversity, we identified sequence polymorphisms correlated with the antidote activity.
The genetic and social contributions to sex differences in lifespan in Drosophila serrata
Authors: Narayan Vikram P. , Wilson Alastair J. , Chenoweth Stephen F.
Published: September 2021

Sex differences in lifespan remain an intriguing puzzle for evolutionary biologists. A possible explanation for lower lifespan in males is the unconditional expression of recessive deleterious alleles in heterogametic X chromosomes in males (the unguarded X hypothesis). Empirical evidence, however, has yielded controversial results that can be attributed to differences in both genetic and social background. Here, we test the unguarded X hypothesis in Drosophila serrata using a factorial design to quantify the effects of genotype, sex, social environment, and their interactions on phenotypic variation for lifespan. Using an experimental approach, we manipulated two inbred laboratory genotypes and their reciprocal F1s, while controlling for different levels of density and mating status to account for any potential social effects. Our results also show subtle but significant genotype dependent effects for both density and mating, but ultimately find the unguarded X hypothesis insufficient to fully explain sexual dimorphism in D. serrata lifespan.
Comparing Heritability Estimators under Alternative Structures of Linkage Disequilibrium
Authors: Min Alan , Thompson Elizabeth , Basu Saonli
Published: September 2021

SNP heritability of a trait is the proportion of its variance explained by the additive effects of the genome-wide single nucleotide polymorphisms (SNPs). The existing approaches to estimate SNP heritability can be broadly classified into two categories. One set of approaches model the SNP effects as fixed effects and the other treats the SNP effects as random effects. These methods make certain assumptions about the dependency among individuals (familial relationship) as well as the dependency among markers (linkage disequilibrium, LD) to provide consistent estimates of SNP heritability as the number of individuals increases. While various approaches have been proposed to account for such dependencies, it remains unclear which estimates reported in the literature are more robust against various model mis-specifications. Here we investigate the impact of different structures of LD and familial relatedness on heritability estimation. We show that the performance of different methods for heritability estimation depends heavily on the structure of the underlying pattern of LD and the degree of relatedness among sampled individuals. However, contrary to the claim in the current literature, we did not find significant differences in the performance of these fixed-SNP-effects and random-SNP-effects approaches. Moreover, we established the equivalence between the two method-of-moments estimators, one from each of these two lines of approaches.
The genome of the endangeredMacadamia janseniidisplays little diversity but represents an important genetic resource for plant breeding
Authors: Sharma Priyanka , Murigneux Valentine , Haimovitz Jasmine , Nock Catherine J. , Tian Wei , Masouleh Ardashir Kharabian , Topp Bruce , Alam Mobashwer , Furtado Agnelo , Henry Robert J.
Published: September 2021

Macadamia, a recently domesticated expanding nut crop in the tropical and subtropical regions of the world, is one of the most economically important genera in the diverse and widely adapted Proteaceae family. All four species ofMacadamiaare rare in the wild with the most recently discovered,M. jansenii, being endangered. TheM. janseniigenome has been used as a model for testing sequencing methods using a wide range of long read sequencing techniques. Here we report a chromosome level genome assembly, generated using a combination of Pacific Biosciences sequencing and Hi-C, comprising 14 pseudo-molecules, with a N50 of 58 Mb and a total 758 Mb genome assembly size of which 56% is repetitive. Completeness assessment revealed that the assembly covered 96.9% of the conserved single copy genes. Annotation predicted 31,591 protein coding genes and allowed the characterization of genes encoding biosynthesis of cyanogenic glycosides, fatty acid metabolism and anti-microbial proteins. Re-sequencing of seven other genotypes confirmed low diversity and low heterozygosity within this endangered species. Important morphological characteristics of this species such as small tree size and high kernel recovery suggest thatM. janseniiis an important source of these commercial traits for breeding. As a member of a small group of families that are sister to the core eudicots, this high-quality genome also provides a key resource for evolutionary and comparative genomics studies.
Genetic variation in ALDH4A1 predicts muscle health over the lifespan and across species
Authors: Villa Osvaldo , Stuhr Nicole L. , Yen Chia-An , Crimmins Eileen M. , Em Arpawong Thalida , Curran Sean P.
Published: September 2021

Environmental stress can negatively impact organismal aging, however, the long-term impact of endogenously derived reactive oxygen species from normal cellular metabolism remains less clear. Here we define the evolutionarily conserved mitochondrial enzyme ALH-6/ALDH4A1 as a biomarker for age-related changes in muscle health by combining C. elegans genetics and a gene-wide association study (GeneWAS) from aged human participants of the US Health and Retirement Study (HRS)1–4. In a screen for mutations that activate SKN-1-dependent oxidative stress responses in the muscle of C. elegans5–7, we identified 96 independent genetic mutants harboring loss-of-function alleles of alh-6, exclusively. These genetic mutations map across the ALH-6 polypeptide, which lead to age-dependent loss of muscle health. Intriguingly, genetic variants in ALDH4A1 differentially impact age-related muscle function in humans. Taken together, our work uncovers mitochondrial alh-6/ALDH4A1 as a critical component of normal muscle aging across species and a predictive biomarker for muscle health over the lifespan.
Mechanoaccumulation of non-muscle myosin IIB during mitosis requires its translocation activity
Authors: Wang Chao , Ding Jingjing , Wei Qiaodong , Du Shoukang , Gong Xiaobo , Chew Ting Gang
Published: September 2021

Non-muscle myosin II (NMII) is a force-generating mechanosensitive enzyme that responds to mechanical forces exerted on cells. Mechanoresponse of NMIIs confers mechanical adaptability to cells growing and dividing in a physically complex microenvironment. In response to mechanical forces, NMIIs mechanoaccumulate at the cell cortex with applied stress. Much less is known about how NMII mechanoaccumulation is mechanistically regulated. In this study, we subject cells in mitosis to compressive forces and show that mitotic cells promote active RhoA mechanoaccumulation, and via ROCK signaling, activate and stabilize NMIIB at the cell cortex. In line with RhoA in activating the myosin motor activity, we further show that the motor activity driving actin filament translocation, but not just the actin-binding function of NMIIB plays a dominant regulatory role in NMIIB mechanoaccumulation. Thus, the motor activity coordinates structural movement and nucleotide state changes to fine-tune actin-binding affinity optimal for NMIIs to generate and respond to forces.
Pseudomonas aeruginosa synthesizes the autoinducers of its oxylipin-dependent quorum sensing system extracellularly
Authors: Martínez Eriel , Orihuela Carlos J. , Campos-Gomez Javier
Published: September 2021

The oxylipin-dependent quorum sensing system (ODS) of Pseudomonas aeruginosa relies on the production and sensing of two oxylipin autoinducers, 10S-hydroxy-(8E)-octadecenoic acid (10-HOME) and 7S,10S dihydroxy-(8E)-octadecenoic acid (7,10-DiHOME). Here, and contrary to the prevailing notion that bacterial autoinducers are synthesized intracellularly, we show that 10-HOME and 7,10-DiHOME biosynthesis occurs extracellularly, and this requires the secretion of the oxylipin synthases. We implemented a genetic screen of P. aeruginosa strain PAO1, which identified fourteen genes required for the synthesis of oxylipins. Among the identified genes, four encoded components of the ODS system and the other ten were part of the Xcp type II secretion system (T2SS). We created a deletion mutant of xcpQ, which encodes the outer membrane component of Xcp, and found it recapitulated the impaired functionality of the transposon mutants. Upon further examination, the lack of ODS function was demonstrated to be caused by the blocking of the DS enzymes secretion. Notably, the xcpQ mutant activated the ODS system when exposed to 10-HOME and 7,10-DiHOME, indicating that the sensing component of this quorum sensing system remains fully functional. In contrast with the detrimental effect previously described for T2SS in biofilm formation, here we observed that T2SS was required for robust in vitro and in vivo biofilm formation in an ODS dependent manner. To the best of our knowledge, this study is the first to find QS autoinducers that are synthetized in the extracellular space and provides new evidence for the role of the T2SS for biofilm formation in P. aeruginosa.

IMPORTANCE

We previously showed that the ODS quorum sensing system of P. aeruginosa produces and responds to oxylipins derived from host oleic acid by enhancing biofilm formation and virulence. Herein, we developed a genetic screen strategy to explore the molecular basis for oxylipins synthesis and detection. Unexpectedly, we found that the ODS autoinducer synthases cross the outer membrane using the Xcp Type 2 secretion system of P. aeruginosa and thus, the biosynthesis of oxylipins occur extracellularly. Biofilm formation, which was thought to be impaired as result of Xcp activity, was found to be enhanced as result of ODS activation. This is a unique QS system strategy and reveals a new way by which P. aeruginosa interacts with the host environment.
Genome-scale metabolic modeling reveals increased reliance on valine catabolism in clinical isolates of Klebsiella pneumoniae
Authors: Jenior Matthew L , Dickenson Mary E , Papin Jason A
Published: September 2021

Infections due to carbapenem-resistant Enterobacteriaceae have recently emerged as one of the most urgent threats to hospitalized patients within the United States and Europe. By far the most common etiological agent of these infections is Klebsiella pneumoniae, frequently manifesting in hospital-acquired pneumonia with a mortality rate of ∼50% even with antimicrobial intervention. We performed transcriptomic analysis of data collected from in vitro characterization of both laboratory and clinical isolates revealed shifts in expression of multiple master metabolic regulators across isolate types. Metabolism has been previously shown to be an effective target for antibacterial therapy, and GENREs have provided a powerful means to accelerate identification of potential targets in silico. Combining these techniques with the transcriptome meta-analysis, we generated context-specific models of metabolism utilizing a well-curated GENRE of K. pneumoniae (iYL1228) to identify novel therapeutic targets. Functional metabolic analyses revealed that both composition and metabolic activity of clinical isolate-associated context-specific models significantly differs from laboratory isolate-associated models of the bacterium. Additionally, we identified increased consumption of L-valine in clinical isolate-specific growth simulations. Importantly, valine has been shown to augment macrophage phagocytosis, and this result could be indicative of an immunosuppressive strategy Klebsiella pneumoniae evolved for survival during infection. These findings warrant future studies for potential efficacy of valine transaminase inhibition as a target against K. pneumoniae infection.

Importance

Incidences of infection by Klebsiella pneumoniae have grown in frequency to become the leading agents of CRE infection among hospitalized patients in the United States and Europe. Transcriptomic meta-analysis of data collected from both laboratory and clinical isolates indicated significant shifts in expression of key transcription factors related to metabolism. Metabolic network reconstructions have previously proven effective for quickly identifying potential targets in silico, therefore we combined these approaches by integrating the transcriptomic data from each isolate type into a well-curated GENRE of K. pneumoniae to predict emergent metabolic patterns. Leveraging this systems-biology approach we found discordant patterns of active metabolism between clinical and laboratory isolates, with a striking difference in L-valine catabolism. Exogenous valine is known to increase macrophage phagocytosis, and our results may support immunomodulatory activity in K. pneumoniae evolved to avoid host clearance.
Low levels of Fe and Se with high IL-6/IL-10 likely influence nutritional immunity in tuberculosis patients
Authors: Kaushik Sandeep R. , Sahu Sukanya , Guha Hritusree , Saha Sourav , Das Ranjit , Kupa Rukuwe-u , Kapfo Wetetsho , Deka Trinayan , Basumatary Rumi , Thong Asunu , Dasgupta Arunabha , Goswami Bidhan , Pandey Amit Kumar , Saikia Lahari , Khamo Vinotsole , Das Anjan , Nanda Ranjan Kumar
Published: September 2021

Tuberculosis (TB) patients present dysregulated immunity, iron metabolism and anaemia of inflammation. In this study, circulatory cytokines, trace metals, and iron-related proteins (hepcidin, ferroportin, transferrin, DMT1, Nramp1, ferritin, ceruloplasmin, hemojuvelin, aconitase, transferring receptor) were monitored in case (active tuberculosis patients: ATB) and control (non-tuberculosis: NTB and healthy) study populations (n=72, male, 42.94 mean age (16-83)). Using serum elemental and cytokine levels, a partial least square discriminate analysis model (PLS-DA) was built and variables with a VIP score of >0.6 were selected as important markers. A biosignature of IL-13, IL-12(p70), IFN-γ, IL-10, IL-5, IL-18, IL-4, Selenium, and Aluminium clustered ATB away from controls. Interestingly, low iron and selenium levels, while high copper and aluminum levels were observed in ATB subjects. All the important serum cytokines were positively correlated in ATB subjects. A low abundance of transferrin, ferroportin, and hemojuvelin, while higher ferritin and ceruloplasmin levels explained an altered iron metabolism in ATB subjects which partially resolved upon completion of treatment. Further, the identified biosignature in TB patients, that explained anemia of inflammation, along with perturbed iron homeostasis could be useful targets for the development of host-directed adjunct therapeutics.
Professional practice for COVID-19 risk reduction among health care workers: a Cross-Sectional Study with Matched Case-Control Comparison
Authors: Sarah Wilson , Audrey Mouet , Camille Jeanne-Leroyer , France Borgey , Emmanuelle Odinet-Raulin , Xavier Humbert , Simon Le Hello , Pascal Thibon
Published: September 2021

Background

Health care workers (HCWs) are particularly exposed to COVID-19 and therefore it is paramount to study preventive measures in this population.

Aim

To investigate socio-demographic factors and professional practice associated with the risk of COVID-19 among HCWs in health establishments in Normandy, France

Methods

A cross-sectional and 3 case-control studies were conducted in order to explore the possible risk factors that lead to SARS-CoV2 transmission within HCWs, based on an online questionnaire. The case-control studies focused on risk factors associated with care of COVID-19 patients, care of non COVID-19 patients and contacts between colleagues.

Findings

Among 2,058 respondents, respectively 1,363 (66.2%) and 695 (33.8%) in medical and medico-social establishments, 301 (14.6%) reported having been infected by SARS-CoV2. When caring for COVID-19 patients, HCWs who declared wearing respirators, either for all patient care (ORa 0.39; 95% CI: 0.29-0.51) or only when exposed to aerosol-generating procedures (ORa 0.56; 95% CI: 0.43-0.70), had a lower risk of infection compared with HCWs who declared wearing mainly surgical masks. During care of non COVID-19 patients, wearing mainly a respirator was associated with a higher risk of infection (ORa 1.84; 95% CI: 1.06-3.37). An increased risk was also found for HCWs who changed uniform in workplace changing rooms (ORa 1.93; 95% CI: 1.63-2.29).

Conclusion

Correct use of PPE adapted to the situation and risk level is essential in protecting HCWs against infection.
Pre-conceptional maternal vitamin B12 supplementation improves offspring neurodevelopment at 2 years of age: PRIYA trial
Authors: D’souza Naomi , Behere Rishikesh V , Patni Bindu , Deshpande Madhavi , Bhat Dattatray , Bhalerao Aboli , Sonawane Swapnali , Shah Rohan , Ladkat Rasika , Yajnik Pallavi , Kumaran Kalyanaraman , Fall Caroline , Yajnik Chittaranjan S
Published: September 2021

Background

Nutritional interventions during the first 1000 days of life improves lifelong health. Better pre-conceptional maternal nutrition improves the nutrition of the early embryo. Vitamins B12 and folate are important for fetal neural development. Vitamin B12 deficiency is common in India.

Methods

In the Pune Rural Intervention in Young Adolescents (PRIYA) adolescents (N=557, 226 females) were provided with vitamin B12 (2µg/day) with or without multiple micronutrients, or a placebo, from preconception until delivery. All groups received mandatory iron and folic acid. We used the Bayley’s Scale of Infant Development (BSID-III) at 24-42 months of age to investigate effects on offspring neurodevelopment. We examined cord blood concentrations of brain-derived neurotropic factor (BDNF).

Results

Participants in the three groups had similar baseline B12 levels. These improved in the B12 supplemented groups at pre-conceptional and pregnancy (28 weeks gestation) measurements, reflected in higher cord holo-TC levels compared to the placebo. Neurodevelopmental outcomes are available for 74 children. Offspring in the B12 alone group (n=21) performed better than the placebo (n=27) on cognition (p=0.044) and language (p=0.020) domains (adjusted for maternal baseline B12 levels). There were no differences between the B12+MMN (n=26) and placebo group. Cord blood BDNF levels were highest in the B12 alone group (not statistically significant).

Conclusion

Pre-conceptional vitamin B12 supplementation improved maternal B12 status and offspring neurodevelopment at 2 years of age. The usefulness of cord BDNF as a marker of brain development needs further investigation. Our results highlight the importance of intervening in the pre-conceptional period.
Second wave of the Covid-19 pandemic in Delhi, India: high seroprevalence not a deterrent?
Authors: Sharma Nandini , Sharma Pragya , Basu Saurav , Bakshi Ritika , Gupta Ekta , Agarwal Reshu , Dushyant Kumar , Mundeja Nutan , Marak Zeasley , Singh Sanjay , Singh Gautam Kumar , Rustagi Ruchir , Sarin S K
Published: September 2021

Background

We report the findings of a large follow-up community-based serosurvey and correlating it with the COVID-19 test-positivity rate and the case load observed during the peak of the second wave of the Covid-19 pandemic in Delhi, India.

Methods

Individuals of age ≥5 years were recruited from 274 wards of the state (population ∼ 19.6 million) during January 11 to January 22’ 2021. A total of 100 participants each were included from all the wards for a net sample size of ∼28,000. A multi-stage sampling technique was applied for selection of participants for the household serosurvey. Anti SARS CoV-2 IgG antibodies were detected by using the VITROS assay (90% Sn, 100% Sp).

Results

Antibody positivity was observed in 14,298 (50.76%) of the 28,169 samples. The age, sex and district population weighted seroprevalence of the IgG SARS-CoV-2 was 50.52% (95% C.I. 49.94-51.10) and after adjustment for assay characteristics was 56.13% (95% C.I. 55.49-56.77). On adjusted analysis, participants aged ≥50 years, of female gender, housewives, having ever lived in containment zones, urban slum dwellers, and diabetes or hypertensive patients had significantly higher odds of SARS-CoV-2 antibody positivity.

The peak infection rate and the test positivity rate since October 2020 were initially observed in mid-November 2020 with a subsequent steep declining trend, followed by a period of persistently low case burden lasting until the first week of March 2021. This was followed by a steady increase followed by an exponential surge in infections from April 2021 onwards culminating in the second wave of the pandemic.

Conclusions

The presence of infection induced immunity from SARS-CoV-2 even in more than one in two people can be ineffective in protecting the population.
Transcriptomic-based quantification of the epithelial-hybrid-mesenchymal spectrum across biological contexts
Authors: Mandal Susmita , Tejaswi Tanishq , Janivara Rohini , Srikrishnan Syamanthak , Thakur Pradipti , Sahoo Sarthak , Chakraborty Priyanka , Sohal Sukhwinder Singh , Levine Herbert , George Jason T , Jolly Mohit Kumar
Published: September 2021

Epithelial-mesenchymal plasticity (EMP) underlies embryonic development, wound healing, and cancer metastasis and fibrosis. Cancer cells exhibiting EMP often have more aggressive behavior, characterized by drug resistance, and tumor-initiating and immuno-evasive traits. Thus, the EMP status of cancer cells can be a critical indicator of patient prognosis. Here, we compare three distinct transcriptomic-based metrics – each derived using a different gene list and algorithm – that quantify the EMP spectrum. Our results for 96 cancer-related RNA-seq datasets reveal a high degree of concordance among these metrics in quantifying the extent of EMP. Moreover, each metric, despite being trained on cancer expression profiles, recapitulates the expected changes in EMP scores for non-cancer contexts such as lung fibrosis and cellular reprogramming into induced pluripotent stem cells. Thus, we offer a scoring platform to quantify the extent of EMP in vitro and in vivo for diverse biological applications including cancer.
Lipid chaperone LBP-8 coordinates with nuclear factors to promote longevity in Caenorhabditis elegans
Authors: Duffy Jonathon , Zhang Qinghao , Jung Sung Y. , Wang Meng C.
Published: September 2021

Eukaryotic cells are composed of a variety of organelles. Their coordination plays crucial roles in cellular homeostasis and organism longevity and is mediated by proteins with the ability to transport between different organelles. In Caenorhabditis elegans, LBP-8 is a pro-longevity lipid chaperone that can localize to both lysosomes and the nucleus. Here we profiled LBP-8’s binding partners using immunoprecipitation and mass spectrometry. From the 45 identified candidates, we discovered four nuclear factors that are required for the LBP-8-induced longevity. Among them, RPC-2, an RNA Polymerase III core subunit, is also necessary for the nuclear localization of LBP-8. Moreover, we have screened nuclear transport machinery components, and revealed the requirement of the nuclear import, not export, for the LBP-8 longevity effects. Together, these results suggest that the lipid chaperone LBP-8 relies on specific nuclear factors to retain in the nucleus and regulate longevity.
Effective population size for culturally evolving traits
Authors: Deffner Dominik , Kandler Anne , Fogarty Laurel
Published: September 2021

Population size has long been considered an important driver of cultural diversity and complexity. Results from population genetics, however, demonstrate that in populations with complex demographic structure or mode of inheritance, it is not the census population size, N, but the effective size of a population, Ne, that determines important evolutionary parameters. Here, we examine the concept of effective population size for traits that evolve culturally, through processes of innovation and social learning. We use mathematical and computational modeling approaches to investigate how cultural Ne and levels of diversity depend on (1) the way traits are learned, (2) population connectedness, and (3) social network structure. We show that one-to-many and frequency-dependent transmission can temporally or permanently lower effective population size compared to census numbers. We caution that migration and cultural exchange can have counter-intuitive effects on Ne. Network density in random networks leaves Ne unchanged, scale-free networks tend to decrease and small-world networks tend to increase Ne compared to census numbers. For one-to-many transmission and different network structures, effective size and cultural diversity are closely associated. For connectedness, however, even small amounts of migration and cultural exchange result in high diversity independently of Ne. Our results highlight the importance of carefully defining effective population size for cultural systems and show that inferring Ne requires detailed knowledge about underlying cultural and demographic processes.

AUTHOR SUMMARY

Human populations show immense cultural diversity and researchers have regarded population size as an important driver of cultural variation and complexity. Our approach is based on cultural evolutionary theory which applies ideas about evolution to understand how cultural traits change over time. We employ insights from population genetics about the “effective” size of a population (i.e. the size that matters for important evolutionary outcomes) to understand how and when larger populations can be expected to be more culturally diverse. Specifically, we provide a formal derivation for cultural effective population size and use mathematical and computational models to study how effective size and cultural diversity depend on (1) the way culture is transmitted, (2) levels of migration and cultural exchange, as well as (3) social network structure. Our results highlight the importance of effective sizes for cultural evolution and provide heuristics for empirical researchers to decide when census numbers could be used as proxies for the theoretically relevant effective numbers and when they should not.