bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparing the age and sex trajectories of SARS-CoV-2 morbidity with other respiratory pathogens points to potential immune mechanisms
Authors: Metcalf C. Jessica E. , Paireau Juliette , O’Driscoll Megan , Pivette Mathilde , Hubert Bruno , Pontais Isabelle , Cummings Derek , Cauchemez Simon , Salje Henrik
Published: January 2021

Comparing age and sex differences in SARS-CoV-2 hospitalization and mortality with influenza and other health outcomes opens the way to generating hypotheses as to the underlying mechanisms, building on the extraordinary advances in immunology and physiology that have occurred over the last year. Notable departures in health outcomes starting around puberty suggest that burdens associated with influenza and other causes are reduced relative to the two emergent coronaviruses over much of adult life. Two possible hypotheses could explain this: protective adaptive immunity for influenza and other infections, or greater sensitivity to immunosenescence in the coronaviruses. Comparison of sex differences suggest an important role for adaptive immunity; but immunosenescence might also be relevant, if males experience faster immunosenescence. Involvement of the renin-angiotensin-system in SARS-CoV-2 infection might drive high sensitivity to disruptions of homeostasis. Overall, these results highlight the long tail of vulnerability in the age profile relevant to the emergent coronaviruses, which more transmissible variants have the potential to uncover at the younger end of the scale, and aging populations will expose at the other end of the scale.
Computational modelling of EEG and fMRI paradigms reveals a consistent loss of pyramidal cell synaptic gain in schizophrenia
Authors: Adams Rick A , Pinotsis Dimitris , Tsirlis Konstantinos , Unruh Leonhardt , Mahajan Aashna , Horas Ana Montero , Convertino Laura , Summerfelt Ann , Sampath Hemalatha , Du Xiaoming Michael , Kochunov Peter , Ji Jie Lisa , Repovs Grega , Murray John D , Friston Karl J , Hong L Elliot , Anticevic Alan
Published: January 2021

Diminished synaptic gain – the sensitivity of postsynaptic responses to neural inputs – may be a fundamental synaptic pathology in schizophrenia. Evidence for this is indirect, however. Furthermore, it is unclear whether pyramidal cells or interneurons (or both) are affected, or how these deficits relate to symptoms. Participants with schizophrenia (Scz, n=108), their relatives (n=57), and controls (n=107) underwent three electroencephalography paradigms – resting, mismatch negativity, and 40 Hz auditory steady-state response – and resting functional magnetic resonance imaging. Dynamic causal modelling was used to quantify synaptic connectivity in cortical microcircuits. Across all four paradigms, characteristic Scz data features were best explained by models with greater self-inhibition (decreased synaptic gain), in pyramidal cells. Furthermore, disinhibition in auditory areas predicted abnormal auditory perception (and positive symptoms) in Scz, in three paradigms. Thus, psychotic symptoms of Scz may result from a downregulation of inhibitory interneurons that may compensate for diminished postsynaptic gain in pyramidal cells.
Predicting severity of Covid-19 using standard laboratory parameters
Authors: Buchmüller Thimo , Gröning Ingmar , Ihl Ralf
Published: January 2021

Background

More than 1.6 million people have already deceased due to a COVID-19 infection making it a major public health concern. A prediction of severe courses can enhance treatment quality and thus lower fatality and morbidity rates. The use of laboratory parameters has recently been established for a prediction. However, laboratory parameters have rarely been used in combination to predict severe outcomes.

Method

We used a retrospective case-control design to analyze risk factors derived from laboratory parameters. Patients treated for COVID-19 at an hospital in Krefeld, Germany, from March to May 2020 were included (n =42). Patients were classified into two categories based on their outcome (Mild course vs. treatment in intensive care unit). Laboratory parameters were compared across severity categories using non-parametric statistic. Identified laboratory parameters were used in a logistic regression model. The model was replicated using a) clinical standardized parameters b) aggregated factors derived from a factor analysis.

Results

Patients in intensive care unit showed elevated ALT, CRP and LDH levels, a higher leukocyte and neutrophile count, a higher neutrophile ratio and a lowered lymphocyte ratio. We were able to classify 95.1% of all cases correctly (96.6% of mild and 91.7% of severe cases, p<.001).

Conclusion

A number of routinely collected laboratory parameters is associated with a severe outcome of COVID-19. The combination of these parameters provides a powerful tool in predicting severity and can enhance treatment effectiveness.
Persistence of a pandemic in the presence of susceptibility and infectivity distributions in a population: Mathematical model
Authors: Mukherjee Saumyak , Mondal Sayantan , Bagchi Biman
Published: January 2021

The birth and death of a pandemic can be region specific. Pandemic seems to make repeated appearance in some places which is often attributed to human neglect and seasonal change. However, difference could arise from different distributions ofinherent susceptibility(σinh) andexternal infectivity(ιext) from one population to another. These are often ignored in the theoretical treatments of an infectious disease progression. While the former is determined by the immunity of an individual towards a disease, the latter depends on the duration of exposure to the infection. Here we model the spatio-temporal propagation of a pandemic using a generalized SIR (Susceptible-Infected-Removed) model by introducing the susceptibility and infectivity distributions to comprehend their combined effects. These aspects have remained inadequately addressed till date. We consider the coupling betweenσinhandιextthrough a new critical infection parameter (γc). We find that the neglect of these distributions, as in the naive SIR model, results in anoverestimation in the estimate of the herd immunity threshold. That is, the presence of the distributions could dramatically reduce the rate of spread. Additionally, we include the effects of long-range migration by seeding new infections in a region. We solve the resulting master equations by performing Kinetic Monte Carlo Cellular Automata (KMC-CA) simulations. Importantly,our simulations can reproduce the multiple infection peak scenario of a pandemic. The latent interactions between disease migration and the distributions of susceptibility and infectivity can render the progression a character vastly different from the naive SIR model. In particular, inclusion of these additional features renders the problem a character of a living percolating system where the disease cluster can survive by spatial migration.
Analysis of Intervention Effectiveness Using Early Outbreak Transmission Dynamics to Guide Future Pandemic Management and Decision-Making in Kuwait
Authors: Tyshenko Michael G. , Oraby Tamer , Longenecker Joseph , Vainio Harri , Gasana Janvier , Alali Walid Q. , AlSeaidan Mohammad , Elsaadany Susie , Al-Zoughool Mustafa
Published: January 2021

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a World Health Organization designated pandemic that can result in severe symptoms and death that disproportionately affects older patients or those with comorbidities. Kuwait reported its first imported cases of COVID-19 on February 24, 2020. Analysis of data from the first three months of community transmission of the COVID-19 outbreak in Kuwait can provide important guidance for decision-making when dealing with future SARS-CoV-2 epidemic wave management. The analysis of intervention scenarios can help to evaluate the possible impacts of various outbreak control measures going forward which aim to reduce the effective reproduction number during the initial outbreak wave. Herein we use a modified susceptible-exposed-asymptomatic-infectious-removed (SEAIR) transmission model to estimate the outbreak dynamics of SARS-CoV-2 transmission in Kuwait. We fit case data from the first 96 days in the model to estimate the basic reproduction number and used Google mobility data to refine community contact matrices. The SEAIR modelled scenarios allow for the analysis of various interventions to determine their effectiveness. The model can help inform future pandemic wave management, not only in Kuwait but for other countries as well.
Ciliary and extraciliary Gpr161 pools repress hedgehog signaling in a tissue-specific manner
Authors: Hwang Sun-Hee , Somatilaka Bandarigoda N. , White Kevin , Mukhopadhyay Saikat
Published: January 2021

The role of compartmentalized cAMP signaling in primary cilia is not well understood. The cilia-localized G-protein-coupled receptor—Gpr161 represses hedgehog pathway via cAMP signaling. Here, by generating knock-in mutant mouse at endogenousGpr161locus (mut1), we show that ciliary and extraciliary receptor pools repress hedgehog signaling in a tissue-specific manner. Gpr161mut1was competent in generating cAMP but did not transit through cilia. Compared to knockout,Gpr161mut1had delayed embryonic lethality, less upregulation of hedgehog targets and partially down-regulated Gli3-repressor. Ventral-most progenitor expansion in neural tube ofGpr161knockout occurred in a Gli2-activator-dependent manner but was not seen inGpr161mut1. Intermediate-level ventralization occurred from Gpr161 lack specifically in cilia but was restored by increased extraciliary mutant generating Gli3-repressor. Morphogenesis in limb buds and midface that require Gli-repressor manifested hedgehog hyperactivation phenotypes— polydactyly and midfacial widening—inGpr161mut1. Thus, ciliary and extraciliary cAMP signaling establishes tissue-specific Gli-repressor thresholds in dictating morpho-phenotypic outcomes.

Impact statement

Signaling by Cilia

Signaling by cAMP specifically in cilia directs tissue-specific morphogenesis
Silencing and stimulating the medial amygdala impairs ejaculation but not sexual incentive motivation in male rats
Authors: Huijgens Patty T. , Heijkoop Roy , Snoeren Eelke M.S.
Published: January 2021

The medial amygdala (MeA) is a sexually dimorphic brain region that integrates sensory information and hormonal signaling, and is involved in the regulation of social behaviors. Lesion studies have shown a role for the MeA in copulation, most prominently in the promotion of ejaculation. The role of the MeA in sexual motivation, but also in temporal patterning of copulation, has not been extensively studied in rats. Here, we investigated the effect of chemogenetic inhibition and stimulation of the MeA on sexual incentive motivation and copulation in sexually experienced male rats. AAV5-CaMKIIa viral vectors coding for Gi, Gq, or no DREADDs (sham) were bilaterally infused into the MeA. Rats were assessed in the sexual incentive motivation test and copulation test upon systemic CNO or vehicle administration. We report that MeA stimulation and inhibition did not affect sexual incentive motivation. Moreover, both stimulation and inhibition of the MeA decreased the number of ejaculations in a 30 minute copulation test and increased ejaculation latency and the number of mounts and intromissions preceding ejaculation, while leaving the temporal pattern of copulation intact. These results indicate that the MeA may be involved in the processing of sensory feedback required to reach ejaculation threshold. The convergence of the behavioral effects of stimulating as well as inhibiting the MeA may reflect opposing behavioral control of specific neuronal populations within the MeA.
A class I hydrophobin inTrichoderma virensinfluences plant-microbe interactions through enhancement of enzyme activity and MAMP recognition
Authors: Taylor James T. , Krieger Inna , Crutcher Frankie K. , Jamieson Pierce , Horwitz Benjamin A. , Kolomiets Michael V. , Kenerley Charles M.
Published: January 2021

The filamentous fungus,Trichoderma virens, is a well-known mycoparasitic plant symbiont, valued for its biocontrol capabilities.T. virensinitiates a symbiotic relationship with a plant host through the colonization of its roots. To achieve colonization, the fungus must communicate with the host and evade its innate defenses. Hydrophobins fromTrichoderma spp.have previously been demonstrated to be involved in colonization of host roots. In this study, the class I hydrophobin, HFB9A fromT. virenswas characterized for a potential role in root colonization. Δhfb9a gene deletion mutants colonized less than the wild-type strain, were unable to induce systemic resistance againstColletotrichum graminicola, and showed a reduction in the activity of its cell wall degrading enzymes. The purified HFB9A protein was able to complement the enzyme activity of mutant culture filtrates as well as enhance the activity of commercially sourced cellulase. When exogenously applied to Arabidopsis plants, HFB9A protein induced phosphorylation of AtMAPK3/6, suggesting that it functions as a microbe-associated molecular pattern.
Allopatric divergence of cooperators confers cheating resistance and limits the effects of a defector mutation
Authors: Schaal Kaitlin A. , Yu Yuen-Tsu Nicco , Vasse Marie , Velicer Gregory J.
Published: January 2021

Social defectors may meet diverse cooperators. Genotype-by-genotype interactions may constrain the ranges of cooperators upon which particular defectors can cheat, limiting cheater spread. The bacterium Myxococcus xanthus undergoes cooperative multicellular development, but some developmental defectors cheat on cooperators during this process. In this study, interactions between a cheater disrupted at the signaling genecsgAand allopatrically diversified cooperators reveal a very small cheating range. Expectedly, the cheater failed to cheat on all natural-isolate cooperators owing to non-cheater-specific antagonisms. Surprisingly, lab-evolved cooperators that diverged from their cheating-susceptible ancestor by fewer than 20 mutations and without experiencing cheating had already exited thecsgAmutant’s cheating range. Cooperators might also diversify in the potential for a mutation to reduce expression of cooperative trait or generate a cheating phenotype. A newcsgAmutation constructed in several highly diverged cooperators generated diverse sporulation phenotypes, ranging from a complete defect to no defect, indicating that genetic backgrounds can limit the set of genomes in which a mutation creates a defector. Our results suggest that natural populations feature geographic mosaics of cooperators that have diversified in their susceptibility to particular cheaters and in the phenotypes generated by any given cooperation-gene mutation.

Significance statement

Selection on cooperators exploited by obligate cheaters can induce evolution of resistance to cheating. Here we show that cooperators can also rapidly evolve immunity to cheating simply as a byproduct of evolutionary divergence in environments in which cooperation and cheating at the focal trait do not occur because the trait is not expressed. We also find that differences in the genomic context in which a cooperation-gene mutation arises can profoundly alter its phenotypic effect and determine whether the mutation generates a social defect at all - a pre-requisite for obligate cheating. These findings suggest that general divergence of social populations under a broad range of environmental conditions can restrict both the set of mutations that might generate social defectors in the first place and the host range of such defectors once they arise.
Nectar bacteria stimulate pollen germination and bursting to enhance their fitness
Authors: Christensen S. M. , Munkres I. , Vannette R. L.
Published: January 2021

For many flower visitors, pollen is the primary source of non-carbon nutrition, but pollen has physical defenses that make it difficult for consumers to access nutrients. Nectar-dwelling microbes are nearly ubiquitous among flowers and can reach high densities, despite the fact that floral nectar is nitrogen limited, containing only very low concentrations of non-carbon nutrients. Pollen contains trace micronutrients and high protein content but is protected by a recalcitrant outer shell. Here, we report that a common genus of nectar-dwelling bacteria,Acinetobacter, exploits pollen nutrition by inducing pollen germination and bursting. We use time course germination assays to quantify the effect ofAcinetobacterspecies on pollen germination and pollen bursting. Inoculation withAcinetobacterspecies resulted in increased germination rates within 15 minutes, and bursting by 45 minutes, as compared to uninoculated pollen. The pollen germination and bursting phenotype is density-dependent, with lower concentrations of A.pollinisSCC477 resulting in a longer lag time before the spike in germination, which is then closely followed by a spike in bursting. Lastly,A. pollinisgrows to nearly twice the density with germinable pollen vs ungerminable pollen, indicating that their ability to induce and exploit germination plays an important role in rapid growth. To our knowledge, this is the first direct test of non-plant biological induction of pollen germination, as well as the first evidence of induced germination as a method of nutrient procurement, as the microbes appear to hijack the pollen’s normally tightly controlled germination mechanisms for their benefit. Our results suggest that further study of microbe-pollen interactions may inform many aspects of pollination ecology, including microbial ecology in flowers, the mechanisms of pollinator nutrient acquisition from pollen, and cues of pollen germination for plant reproduction.
Is Palmer’s elm leaf goldenrod real? The Angiosperms353 kit provides within-species signal inSolidago ulmifolias.l
Authors: Beck James B. , Markley Morgan L. , Zielke Mackenzie G. , Thomas Justin R. , Hale Haley J. , Williams Lindsay D. , Johnson Matthew G.
Published: January 2021

The genusSolidagorepresents a taxonomically challenging group due to its sheer number of species, putative hybridization, polyploidy, and shallow genetic divergence among species. Here we use a dataset obtained exclusively from herbarium specimens to evaluate the status ofSolidago ulmifoliavar.palmeri,a morphologically subtle taxon potentially confined to Alabama, Arkansas, Mississippi, and Missouri. A multivariate analysis of both discrete and continuous morphological data revealed no clear distinction betweenS. ulmifoliavar.palmeriandSolidago ulmifoliavar.ulmifolia. Solidago ulmifoliavar.palmeri’s status was also assessed with a phylogenomic and SNP clustering analysis of data generated with the “Angiosperms353” probe kit. Neither analysis supportedSolidago ulmifoliavar.palmerias a distinct taxon, and we suggest that this name should be discarded. The status ofSolidago delicatula(formerly known asSolidago ulmifoliavar.microphylla)was also assessed. Both morphological and phylogenic analyses supported the species status ofS. delicatulaand we suggest maintaining this species at its current rank. These results highlight the utility of the Angiosperms353 probe kit, both with herbarium tissue and at lower taxonomic levels. Indeed, this is the first study to utilize this kit to identify genetic groups within a species.
Synthetic Promoter Designs Enabled by a Comprehensive Analysis of Plant Core Promoters
Authors: Jores Tobias , Tonnies Jackson , Wrightsman Travis , Buckler Edward S. , Cuperus Josh T. , Fields Stanley , Queitsch Christine
Published: January 2021

Targeted engineering of plant gene expression holds great promise for ensuring food security and for producing biopharmaceuticals in plants. However, this engineering requires thorough knowledge ofcis-regulatory elements in order to precisely control either endogenous or introduced genes. To generate this knowledge, we used a massively parallel reporter assay to measure the activity of nearly complete sets of promoters from Arabidopsis, maize and sorghum. We demonstrate that core promoter elements – notably the TATA-box – as well as promoter GC content and promoter-proximal transcription factor binding sites influence promoter strength. By performing the experiments in two assay systems, leaves of the dicot tobacco and protoplasts of the monocot maize, we detect species-specific differences in the contributions of GC content and transcription factors to promoter strength. Using these observations, we built computational models to predict promoter strength in both assay systems, allowing us to design highly active promoters comparable in activity to the viral 35S minimal promoter. Our results establish a promising experimental approach to optimize native promoter elements and generate synthetic ones with desirable features.
A role for prefoldins in H2A.Z deposition inArabidopsis
Authors: Marí-Carmona Cristina , Forment Javier , Blázquez Miguel A. , Alabadí David
Published: January 2021

The prefoldin complex (PFDc) participates in cellular proteostasis in eukaryotes by acting as cochaperone of the chaperonin CTT. This role is mainly exerted in the cytoplasm where it contributes to the correct folding of client proteins, thus preventing them to form aggregations and cellular damage. Several reports indicate, however, that they also play a role in transcriptional regulation in the nucleus in several model species. In this work, we have investigated how extended is the role of PFDs in nuclear processes by inspecting their interactome and their coexpression networks in yeast, fly, and humans. The analysis indicates that they may perform extensive, conserved functions in nuclear processes. The construction of the predicted interactome forArabidopsisPFDs, based on the ortholog interactions, has allowed us to identify many putative PFD interactors linking them to unanticipated processes, such as chromatin remodeling. Based on this analysis, we have investigated the role of PFDs in H2A.Z deposition through their interaction with the chromatin remodeling complex SWR1c. Our results show that PFDs have a positive effect on SWR1c, which is reflected in defects in H2A.Z deposition in hundreds of genes in seedlings defective in PFD3 and PFD5 activities.
Identification of hub molecules of FUS-ALS by Bayesian gene regulatory network analysis of iPSC model: iBRN
Authors: Nogami Masahiro , Ishikawa Mitsuru , Doi Atsushi , Sano Osamu , Sone Takefumi , Akiyama Tetsuya , Aoki Masashi , Nakanishi Atsushi , Ogi Kazuhiro , Yano Masato , Okano Hideyuki
Published: January 2021

Fused in sarcoma/translated in liposarcoma (FUS) is a causative gene of amyotrophic lateral sclerosis (ALS). Mutated FUS causes accumulation of DNA damage and cytosolic stress granule (SG) formation, thereby motor neuron (MN) death. However, key molecular aetiology remains unclear. Here, we applied a novel platform technology, iBRN, “Non-biased”Bayesian gene regulatorynetwork analysis based oninduced pluripotent stem cell (iPSC)-derived cell model, to elucidate the molecular aetiology using transcriptome of iPSC-derived MNs harboring FUSH517D. iBRN revealed “hub molecules”, which strongly influenced transcriptome network, such as miR-125b-5p-TIMELESS axis and PRKDC for the molecular aetiology. Next, we confirmed miR-125b-5p-TIMELESS axis in FUSH517DMNs such that miR-125b-5p regulated several DNA repair-related genes including TIMELESS. In addition, we validated both introduction of miR-125b-5p and knocking down of TIMELESS caused DNA damage in the cell culture model. Furthermore, PRKDC was strongly associated with FUS mis-localization into SGs by DNA damage under impaired DNA-PK activity. Collectively, our iBRN strategy provides the first compelling evidence to elucidate molecular aetiology in neurodegenerative diseases.

Highlights

A new platform technology, “iBRN”, Bayesian gene regulatory network analysis based on iPSC cells

iBRN identifies hub molecules to strongly influence the gene network in FUS-ALS

PRKDC specifically acts as a guardian against FUS mis-localization during DNA damage stress

miR-125b-5p-TIMELESS axis regulates DNA repair-related genes in FUS-ALS.
Leishmania donovanimetacyclic promastigotes impair phagosome properties in inflammatory monocytes
Authors: Matte Christine , Duque Guillermo Arango , Descoteaux Albert
Published: January 2021

Leishmaniasis, a debilitating disease with clinical manifestations ranging from self-healing ulcers to life-threatening visceral pathologies, is caused by protozoan parasites of theLeishmaniagenus. These professional vacuolar pathogens are transmitted by infected sand flies to mammalian hosts as metacyclic promastigotes and are rapidly internalized by various phagocyte populations. Classical monocytes are among the first myeloid cells to migrate to infection sites. Recent evidence shows that recruitment of these cells contributes to parasite burden and to the establishment of chronic disease. However, the nature ofLeishmania-inflammatory monocyte interactions during the early stages of host infection has not been well investigated. Here, we aimed to assess the impact ofLeishmania donovanimetacyclic promastigotes on antimicrobial responses within these cells. Our data showed that inflammatory monocytes were readily colonized byL. donovanimetacyclic promastigotes, while infection withEscherichia coliwas efficiently cleared. Upon internalization, metacyclic promastigotes inhibited superoxide production at the parasitophorous vacuole (PV) through a mechanism involving exclusion of NADPH oxidase subunits gp91phoxand p47phoxfrom the PV membrane. Moreover, we observed that unlike phagosomes enclosing zymosan particles, vacuoles containing parasites acidified poorly. Interestingly, whereas the parasite surface coat virulence glycolipid lipophosphoglycan was responsible for the inhibition of PV acidification, impairement of the NADPH oxidase assembly was independent of lipophosphoglycan and of the metalloprotease GP63. Collectively, these observations indicate that permissiveness of inflammatory monocytes toL. donovanimay thus be related to the ability of this parasite to impair the microbicidal properties of phagosomes.
Association of Inflammation with Depression and Anxiety: Evidence for Symptom-Specificity and Potential Causality from UK Biobank and NESDA Cohorts
Authors: Milaneschi Yuri , Kappelmann Nils , Ye Zheng , Lamers Femke , Moser Sylvain , Jones Peter B. , Burgess Stephen , Penninx Brenda W. J. H. , Khandaker Golam M.
Published: January 2021

We examined whether inflammation is uniformly associated with all depressive and anxiety symptoms, and whether these associations are potentially causal. Data was from 147,478 individuals from the UK Biobank (UKB) and 2,905 from the Netherlands Study of Depression and Anxiety (NESDA). Circulating C-reactive protein (CRP) was measured in both cohorts and interleukin-6 (IL-6) in NESDA. Genetic instruments for these proteins were obtained from published GWAS and UKB. Depressive and anxiety symptoms were assessed with self-report questionnaires. In NESDA, neurovegetative (appetite, sleep, psychomotor) symptoms were disaggregated as increased vs. decreased. In joint analyses, circulating CRP was associated with depressive symptoms of depressed mood (OR=1.06, 95%CI=1.05-1.08), altered appetite (OR=1.25, 95%CI=1.23-1.28), sleep problems (OR=1.05, 95%CI=1.04-1.06), and fatigue (OR=1.12, 95%CI=1.11-1.14), and with anxiety symptoms of irritability (OR=1.06, 95%CI=1.05-1.08) and worrying control (OR=1.03, 95%CI=1.02-1.04). Further analyses in NESDA using IL-6 as exposure confirmed associations with depressive symptoms, including anhedonia (OR=1.30, 95%CI=1.12-1.52). Both CRP (OR=1.27, 95%CI=1.13-1.43) and IL-6 (OR=1.26, 95%CI=1.07-1.49) were associated with increased sleep. CRP was associated with increased appetite (OR=1.21, 95%CI=1.08-1.35) while IL-6 with decreased appetite (OR=1.45, 95%CI=1.18-1.79). In Mendelian Randomization analyses, increased risk of fatigue (estimate=0.25, SE=0.08) and sleep problems (estimate=0.19, SE=0.07) were associated with genetically-predicted higher IL-6 activity. Inflammation was associated with core depressive symptoms of low mood and anhedonia and somatic/neurovegetative symptoms of fatigue, altered sleep and appetite changes. Less consistent associations were found for anxiety. The IL-6/IL-6R pathway could be causally linked to depression. Experimental studies are required to further evaluate causality, mechanisms, and usefulness of immunotherapies for depressive symptoms.
Polygenic Risk Scores for Alzheimer’s Disease and Mild Cognitive Impairment in Hispanics/Latinos in the U.S: The Study of Latinos – Investigation of Neurocognitive Aging
Authors: Sofer Tamar , Kurniansyah Nuzulul , Granot-Hershkovitz Einat , Goodman Matthew O. , Tarraf Wassim , Broce Iris , Lipton Richard B. , Daviglus Martha , Lamar Melissa , Wassertheil-Smoller Sylvia , Cai Jianwen , DeCarli Charles S. , Gonzalez Hector M. , Fornage Myriam
Published: January 2021

Introduction

Polygenic Risk Score (PRS) are powerful summaries of genetic risk alleles that can potentially be used to predict disease outcomes and guide treatment decisions. Hispanics/Latinos suffer from higher rates of Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI) compared to non-Hispanic Whites, yet the strongest known genetic risk factor for AD, APOE-ϵ4 allele, has weak association with AD in Hispanics/Latinos. We evaluated PRS constructed based on Genome-Wide Association Studies (GWAS) of AD in predicting MCI in Hispanics/Latinos when accounting for APOE alleles and variants.

Methods

We used summary statistics from four GWAS of AD to construct PRS that predict MCI in 4,189 diverse Hispanics/Latinos (mean age 63 years, 47% males) from the Study of Latinos-Investigation of Neurocognitive Aging. We assessed the PRS associations with MCI in the combined set of people and in groups defined by genetic ancestry and Hispanic/Latino background, and when including and excluding single nucleotide polymorphisms (SNPs) from the APOE gene region.

Results

A PRS constructed based on GWAS of AD in the FINNGEN Biobank was associated with MCI (OR = 1.34, 95% CI [1.15, 1.55]), and its association was mostly driven by 158 APOE region SNPs. A PRS constructed based on a multi-ethnic AD GWAS was associated with MCI (OR=1.22, 95% CI [1.08, 1.37]) without including any APOE region SNPs. APOE-ϵ4 and APOE-ϵ2 alleles were not associated with MCI.

Discussion

A combination of APOE region SNPs is associated with MCI in Hispanics/Latinos despite APOE-ϵ4 and APOE-ϵ2 alleles not being associated with MCI.
Weighted burden analysis in 200,000 exome-sequenced subjects characterises rare variant effects on risk of type 2 diabetes
Authors: Curtis David
Published: January 2021

Type 2 diabetes (T2D) is a disease for which both common genetic variants and environmental factors influence risk. A few genes have been identified in which very rare variants have large effects on risk and here we carry out a weighted burden analysis of rare variants in a sample of over 200,000 exome-sequenced participants in the UK Biobank project, of whom over 13,000 have T2D. Variant weights were allocated based on allele frequency and predicted effect, as informed by a previous analysis of hyperlipidaemia. There was an exome-wide significant increased burden of rare, functional variants in three genes,GCK, HNF4AandGIGYF1. GIGYF1has not previously been identified as a diabetes risk gene but its product is plausibly involved in the modification of insulin signalling. A number of other genes did not attain exome-wide significance but were highly ranked and potentially of interest, includingALAD, PPARG, GYG1andGHRL. Loss of function (LOF) variants were associated with T2D inGCKandGIGYF1whereas nonsynonymous variants annotated as probably damaging were associated inGCKandHNF4A. Overall, fewer than 1% of T2D cases carried one of these variants. In two genes previously implicated in diabetes aetiology,HNF1AandHNF1B, there was an excess of LOF variants among cases but the small numbers of these fell well short of statistical significance, suggesting that even larger datasets will be helpful for more fully elucidating the contribution of rare genetic variants to T2D risk. This research has been conducted using the UK Biobank Resource.
Migration and Outbreaks of Vaccine-Preventable Disease in Europe: A Systematic Review
Authors: Deal Anna , Halliday Rachael , Crawshaw Alison , Hayward Sally , Burnard Amelia , Rustage Kieran , Carter Jessica , Mehrotra Anushka , Knights Felicity , Campos-Matos Ines , Majeed Azeem , Friedland Jon S. , Edelstein Michael , Mounier-Jack Sandra , Hargreaves Sally ,   in collaboration with the ESCMID Study Group for Infections in Travellers and Migrants (ESGITM)
Published: January 2021

Background

Migrant populations (defined as foreign-born) are one of several under-immunised groups in the EU/EEA, yet little is known about how they are affected by outbreaks of vaccine-preventable diseases (VPDs). This information is vital to develop targeted strategies to improve the health of diverse migrant communities and to assess risk factors and correlations with major European peaks in incidence of key VPDs over time.

Methods

We did a systematic review (PROSPERO CRD42019157473; Medline, EMBASE, and Global Health January 2000 to October 2019) adhering to PRISMA guidelines, to identify studies on VPD outbreaks (measles, mumps, rubella, diphtheria, pertussis, polio, hepatitis A,N meningitidis, andH influenzae) in migrants residing in the EU/EEA and Switzerland.

Results

45 studies were included, reporting on 47 distinct VPD outbreaks across 13 countries (26 [55%] were reported between 2010 and 2020, including 16 [34%] since 2015). Most reported outbreaks involving migrants were of measles (n=24; 6578 total cases), followed by varicella (n=11; 596 cases), hepatitis A (n=7; 1510 cases), rubella (n=3; 487 cases) and mumps (n=2; 295 cases). 19 (40%) of outbreaks, predominantly varicella and measles, were reported in temporary camps or shelters for asylum seekers and refugees. Of 11 varicella outbreaks, 82% were associated with adult migrants. Half of measles outbreaks (n=12) were associated with migrants from Eastern European countries, often involving migrants of Roma ethnicity.

Conclusions

Migrants represent one of several under-immunised groups involved in VPD outbreaks in Europe, with adult and child refugees and asylum seekers residing in shelters or temporary camps at particular risk, alongside specific nationality groups. Vulnerability varies by disease, setting, and individual demographics, highlighting the importance of tailoring strategies for implementing catch-up vaccination to specific groups, alongside the strengthening of routine data collection, in order to meet regional and global vaccination targets. Better understanding vaccine uptake and demand issues in migrant groups, and reducing the barriers they face to accessing vaccination services, is urgently needed, with direct implications for COVID-19 vaccine delivery at the current time. Strengthening vaccine delivery to migrant populations will require a greater focus on co-designing vaccine uptake strategies in close collaboration with affected communities.

Funder

NIHR
Heart rate variability predicts decline in sensorimotor rhythm control
Authors: Nann Marius , Haslacher David , Colucci Annalisa , Eskofier Bjoern , von Tscharner Vinzenz , Soekadar Surjo R.
Published: January 2021

Voluntary control of sensorimotor rhythms (SMR, 8-12 Hz) can be used for brain-computer interface (BCI)-based operation of an assistive hand exoskeleton, e.g., in finger paralysis after stroke. To gain SMR control, stroke survivors are usually instructed to engage in motor imagery (MI) or to attempt moving the paralyzed fingers resulting in task- or event-related desynchronization (ERD) of SMR (SMR-ERD). However, as these tasks are cognitively demanding, especially for stroke survivors suffering from cognitive impairments, BCI control performance can deteriorate considerably over time. It would thus be important to identify biomarkers that predict decline in BCI control performance within an ongoing session in order to optimize the man-machine interaction scheme. Here we determine the link between BCI control performance over time and heart rate variability (HRV). Specifically, we investigated whether HRV can be used as a biomarker to predict decline during voluntary control of SMR-ERD across 17 healthy participants using Granger causality. SMR-ERD was visually displayed on a screen. Participants were instructed to engage in MI-based SMR-ERD control over two consecutive runs of 8.5 minutes each. During the second run, task difficulty was gradually increased. While control performance (p= .18) and HRV (p= .16) remained unchanged across participants during the first run, during the second run, both measures declined over time at high correlation (performance: -0.61%/10s,p= 0; HRV: -0.007ms/10s,p< .001). We found that HRV Granger-caused BCI control performance (p< .001) exhibited predictive characteristics of HRV on an individual participant level. These results suggest that HRV can predict decline in BCI performance paving the way for adaptive BCI control paradigms, e.g., to individualize and optimize assistive BCI systems in stroke.
Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses in autoimmune disorders
Authors: Wilmes Stephan , Jeffrey Polly-Anne , Martinez-Fabregas Jonathan , Hafer Maximillian , Fyfe Paul , Pohler Elizabeth , Gaggero Silvia , López-García Martín , Lythe Grant , Guerrier Thomas , Launay David , Suman Mitra , Piehler Jacob , Molina-París Carmen , Moraga Ignacio
Published: January 2021

Cytokines elicit pleiotropic and non-redundant activities despite strong overlap in their usage of receptors, JAKs and STATs molecules. We use IL-6 and IL-27 to ask how two cytokines activating the same signaling pathway have different biological roles. We found that IL-27 induces more sustained STAT1 phosphorylation than IL-6, with the two cytokines inducing comparable levels of STAT3 phosphorylation. Mathematical and statistical modelling of IL-6 and IL-27 signaling identified STAT3 binding to GP130, and STAT1 binding to IL-27Rα, as the main dynamical processes contributing to sustained pSTAT1 by IL-27. Mutation of Tyr613 on IL-27Rα decreased IL-27-induced STAT1 phosphorylation by 80% but had limited effect on STAT3 phosphorylation. Strong receptor/STAT coupling by IL-27 initiated a unique gene expression program, which required sustained STAT1 phosphorylation and IRF1 expression and was enriched in classical Interferon Stimulated Genes. Interestingly, the STAT/receptor coupling exhibited by IL-6/IL-27 was altered in patients with Systemic lupus erythematosus (SLE). IL-6/IL-27 induced a more potent STAT1 activation in SLE patients than in healthy controls, which correlated with higher STAT1 expression in these patients. Partial inhibition of JAK activation by sub-saturating doses of Tofacitinib specifically lowered the levels of STAT1 activation by IL-6. Our data show that receptor and STATs concentrations critically contribute to shape cytokine responses and generate functional pleiotropy in health and disease.
The molecular principles of Piwi-mediated co-transcriptional silencing through the dimeric SFiNX complex
Authors: Schnabl Jakob , Wang Juncheng , Hohmann Ulrich , Gehre Maja , Batki Julia , Andreev Veselin I. , Purkhauser Kim , Fasching Nina , Duchek Peter , Novatchkova Maria , Mechtler Karl , Plaschka Clemens , Patel Dinshaw J. , Brennecke Julius
Published: January 2021

Nuclear Argonaute proteins, guided to nascent target RNAs by their bound small RNAs, elicit co-transcriptional silencing through heterochromatin formation at transposon insertions and repetitive genomic loci. The molecular mechanisms involved in this process are incompletely understood. Here, we propose that the SFiNX complex, a silencing mediator downstream of nuclear Piwi-piRNA complexes inDrosophila, enables co-transcriptional silencing via the formation of molecular condensates. Condensate formation is stimulated by nucleic acid binding and requires SFiNX dimerization, mediated by the dynein light chain protein, LC8/Cutup. LC8’s function within SFiNX can be bypassed with a heterologous dimerization domain, suggesting that dimerization is a constitutive feature of SFiNX. Mutations preventing LC8-mediated SFiNX dimerization result in loss of condensate formationin vitroand inability of Piwi to initiate heterochromatin formation and silence transposonsin vivo. Formation of molecular condensates might be a general mechanism that underlies effective heterochromatin establishment at small RNA target loci in a co-transcriptional manner.
From adverse to beneficial – contrasting dietary effects of freshwater mixotrophs on zooplankton
Authors: Vad Csaba F. , Schneider Claudia , Fischer Robert , Kainz Martin J. , Ptacnik Robert
Published: January 2021

The importance of mixotrophic algae as key bacterivores in microbial food webs is increasingly acknowledged, but their effects on the next trophic level remain poorly understood. Their high stoichiometric food quality is contrasted by anti-grazing strategies.

We tested the quality of freshwater mixotrophs as prey for zooplankton, using four non-colonial chrysophyte species and a cryptophyte as a high quality reference food. We (1) analyzed the stoichiometric and biochemical (fatty acid) composition of the mixotrophs, and (2) quantified their dietary effects onDaphnia longispinasurvival.

Survival ofD. longispinasignificantly depended on the identity of species provided as food, ranging from higher to lower as compared to starvation. This was not reflected in differences in cellular stoichiometry or fatty acid profiles of the mixotrophs. We suggest that toxicity may be the driver for the observed differences.

Generalization of the dietary effects of mixotrophic chrysophytes does not appear straightforward. Besides fundamental species-specific differences, potential toxic effects may vary depending on environmental cues or physiological strategies. Notably in our study,Ochromonas tuberculata, a species previously reported to be deleterious turned out to be a beneficial food source, in terms of enabling high survival ofD. longispina.

We challenge the generality of the assumption that chrysophytes are of low value as food for zooplankton. We recommend that future studies test how environmental conditions and physiological strategies shape the quality of mixotrophs as food for consumers at higher trophic levels, specifically focusing on effects of dietary toxicity.
To denoise or to cluster? That is not the question. Optimizing pipelines for COI metabarcoding and metaphylogeography
Authors: Antich A. , Palacin C. , Wangensteen O.S. , Turon X.
Published: January 2021

The recent blooming of metabarcoding applications to biodiversity studies comes with some relevant methodological debates. One such issue concerns the treatment of reads by denoising or by clustering methods, which have been wrongly presented as alternatives. It has also been suggested that denoised sequence variants should replace clusters as the basic unit of metabarcoding analyses, missing the fact that sequence clusters are a proxy for species-level entities, the basic unit in biodiversity studies. We argue here that methods developed and tested for ribosomal markers have been uncritically applied to highly variable markers such as cytochrome oxidase I (COI) without conceptual or operational (e.g., parameter setting) adjustment. COI has a naturally high intraspecies variability that should be assessed and reported, as it is a source of highly valuable information. We contend that denoising and clustering are not alternatives. Rather, they are complementary and both should be used together in COI metabarcoding pipelines. Using a typical dataset from benthic marine communities, we compared two denoising procedures (based on the UNOISE3 and the DADA2 algorithms), set suitable parameters for denoising and clustering COI datasets, and compared the outcome of applying these processes in different orders. Our results indicate that denoising based on the UNOISE3 algorithm preserves a higher intra-cluster variability. We suggest and test ways to improve this algorithm taking into account the natural variability of each codon position in coding genes. The order of the steps (denoising and clustering) has little influence on the final outcome. We recommend researchers to consider reporting their results in terms of both denoised sequences (a proxy for haplotypes) and clusters formed (a proxy for species), and to avoid collapsing the sequences of the latter into a single representative. This will allow studies at the cluster (ideally equating species-level diversity) and at the intra-cluster level, and will ease additivity and comparability between studies.
Extracellular vimentin as a target against SARS-CoV-2 host cell invasion
Authors: Suprewicz Łukasz , Swoger Maxx , Gupta Sarthak , Piktel Ewelina , Byfield Fitzroy J. , Iwamoto Daniel V. , Germann Danielle , Reszeć Joanna , Marcińczyk Natalia , Carroll Robert J. , Lenart Marzena , Pyrc Krzysztof , Janmey Paul , Schwarz J.M. , Bucki Robert , Patteson Alison
Published: January 2021

Infection of human cells by pathogens, including SARS-CoV-2, typically proceeds by cell surface binding to a crucial receptor. In the case of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) has been identified as a necessary receptor, but not all ACE2-expressing cells are equally infected, suggesting that other extracellular factors are involved in host cell invasion by SARS-CoV-2. Vimentin is an intermediate filament protein that is increasingly recognized as being present on the extracellular surface of a subset of cell types, where it can bind to and facilitate pathogens’ cellular uptake. Here, we present evidence that extracellular vimentin might act as a critical component of the SARS-CoV-2 spike protein-ACE2 complex in mediating SARS-CoV-2 cell entry. We demonstrate direct binding between vimentin and SARS-CoV-2 pseudovirus coated with the SARS-CoV-2 spike protein and show that antibodies against vimentin blockin vitroSARS-CoV-2 pseudovirus infection of ACE2-expressing cells. Our results suggest new therapeutic strategies for preventing and slowing SARS-CoV-2 infection, focusing on targeting cell host surface vimentin.
HBO1-MLL interaction promotes AF4/ENL/P-TEFb-mediated leukemogenesis
Authors: Takahashi Satoshi , Kanai Akinori , Okuda Hiroshi , Miyamoto Ryo , Kawamura Takeshi , Matsui Hirotaka , Inaba Toshiya , Takaori-Kondo Akifumi , Yokoyama Akihiko
Published: January 2021

Leukemic oncoproteins cause uncontrolled self-renewal of hematopoietic progenitors by aberrant gene activation, eventually causing leukemia. However, the molecular mechanism of aberrant gene activation remains elusive. Here, we showed that leukemic MLL fusion proteins associate with the HBO1 histone acetyltransferase (HAT) complex through their TRX2 domain. Among many MLL fusions, MLL-ELL particularly depended on its association with the HBO1 complex for leukemic transformation. The C-terminal portion of ELL provided a binding platform for multiple factors including AF4, EAF1 and p53. MLL-ELL activated gene expression by loading an AF4 /ENL/P-TEFb complex (AEP) onto the target promoters. The HBO1 complex promoted the use of AEP over EAF1 and p53. Moreover, the NUP98-HBO1 fusion protein exerted its oncogenic properties via interaction with MLL but not its intrinsic HAT activity. Thus, the interaction between HBO1 and MLL is an important nexus in leukemic transformation, which may serve as a therapeutic target for drug development.