bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating the policy of closing bars and restaurants in Cataluña and its effects on mobility and COVID19 incidence
Authors: Smith Matthew , Ponce-de-Leon Miguel , Valencia Alfonso
Published: December 2021

The world has gone through unprecedented changes since the global pandemic hit. During the early phase of the pandemic, the absence of known drugs or pharmaceutical treatments forced governments to introduce different policies in order to help reduce contagion rates and manage the economic consequences of the pandemic. This paper analyses the causal impact on mobility and COVID19 incidence from policy makers in Cataluña, Spain. We use annonimized phone-based mobility data together with reported incidence and apply a series of causal impact models frequently used in econometrics and policy evaluation in order to measure the policies impact.. We analyse the case of Cataluña and the public policy decision of closing all bars and restaurants down for a 5 week period between the 2020-16-10 to 2020-23-11. We find that this decision led to a significant reduction in mobility. It not only led to reductions in mobility but from a behavioural economics standpoint we highlight how people responded to the policy decision. Moreover, the policy of closing bars and restaurants slowed the incidence rate of COVID19 after a time lag has been taken into account. These finding are significant since governments worldwide want to restrict movements of people in order to slow down COVID19 incidence without infringing on their rights directly.
Synthesize Heterogeneous Biological Knowledge via Representation Learning for Alzheimer’s Disease Drug Repurposing
Authors: Hsieh Kang-Lin , Plascencia-Villa German , Lin Ko-Hong , Perry George , Jiang Xiaoqian , Kim Yejin
Published: December 2021

Developing drugs for treating Alzheimer’s disease (AD) has been extremely challenging and costly due to limited knowledge on underlying biological mechanisms and therapeutic targets. Repurposing drugs or their combination has shown potential in accelerating drug development due to the reduced drug toxicity while targeting multiple pathologies. To address the challenge in AD drug development, we developed a multi-task deep learning pipeline to integrate a comprehensive knowledge graph on biological/pharmacological interactions and multi-level evidence on drug efficacy, to identify repurposable drugs and their combination candidates. We developed and computationally validated a heterogeneous graph representation model with transfer learning from universal biomedical databases and joint optimization with AD risk genes. Using the drug embedding from the heterogeneous graph representation model, we ranked drug candidates based on evidence from post-treatment transcriptomic patterns, mechanistic efficacy in preclinical models, population-based treatment effect, and Phase II/III clinical trials. We mechanistically validated the top-ranked candidates in neuronal cells, identifying drug combinations with efficacy in reducing oxidative stress and safety in maintaining neuronal viability and morphology. Our neuronal response experiments confirmed several biologically efficacious drug combinations. This pipeline showed that harmonizing heterogeneous and complementary data/knowledge, including human interactome, transcriptome patterns, experimental efficacy, and real-world patient data shed light on the drug development of complex diseases.

One-Sentence Summary

A novel multitask deep learning method that synthesize heterogeneous biological knowledge to identify repurposable drugs for Alzheimer’s Disease.
A novel disease mechanism leading to the expression of a disallowed gene in the pancreatic beta-cell identified by non-coding, regulatory mutations controlling HK1
Authors: Wakeling Matthew N. , Owens Nick D. L. , Hopkinson Jessica R. , Johnson Matthew B. , Houghton Jayne A.L. , Dastamani Antonia , Flaxman Christine S. , Wyatt Rebecca C. , Hewat Thomas I. , Hopkins Jasmin J. , Laver Thomas W. , Van Heugten Rachel , Weedon Michael N. , De Franco Elisa , Patel Kashyap A. , Ellard Sian , Morgan Noel G. , Cheesman Edmund , Banerjee Indraneel , Hattersley Andrew T. , Dunne Mark J. ,   International Congenital Hyperinsulinism Consortium, Richardson Sarah J. , Flanagan Sarah E.
Published: December 2021

Gene expression is tightly regulated with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function. This silencing is largely controlled by non-coding elements and their disruption might cause human disease. We performed gene-agnostic screening of the non-coding regions to discover new molecular causes of congenital hyperinsulinism. This identified 14 non-coding de novo mutations affecting a 42bp conserved region encompassed by a regulatory element in intron 2 of Hexokinase 1 (HK1), a pancreatic beta-cell disallowed gene. We demonstrated that these mutations resulted in expression of HK1 in the pancreatic beta-cells causing inappropriate insulin secretion and congenital hyperinsulinism. These mutations identify a regulatory region critical for cell-specific silencing. Importantly, this has revealed a new disease mechanism for non-coding mutations that cause inappropriate expression of a disallowed gene.
Identification of ATP2B4 regulatory element containing functional genetic variants associated with severe malaria
Authors: Nisar Samia , Torres Magali , Thiam Alassane , Pouvelle Bruno , Rosier Florian , Gallardo Frederic , Ka Oumar , Mbengue Babacar , Diallo Rokhaya Ndiaye , Brosseau Laura , Spicuglia Salvatore , Dieye Alioune , Marquet Sandrine , Rihet Pascal
Published: December 2021

Genome-wide association studies (GWAS) for severe malaria have identified 30 genetic variants that are mostly located in non-coding regions, with only a few associations replicated in independent populations. In this study, we aimed at identifying potential causal genetic variants located in these loci and demonstrate their functional activity. We systematically investigated the regulatory effect of the SNPs in linkage disequilibrium with the tagSNPs associated with severe malaria in several populations. Annotating and prioritizing genetic variants led to the identification of a regulatory region containing 5 ATP2B4 SNPs in linkage disequilibrium with the tagSNP rs10900585. We confirmed the association of rs10900585 and also found significant associations of severe malaria with our candidate SNPs (rs11240734, rs1541252, rs1541253, rs1541254, and rs1541255) in a Senegalese population. Then, we showed that this region had both promoter and enhancer activities and that both individual SNPs and the combination of SNPs had regulatory effects using luciferase reporter assays. Moreover, CRISPR/Cas9-mediated deletion of this region decreased ATP2B4 transcript and protein levels and increased Ca2+ intracellular concentration in the K562 cell line. Taken together, our data show that severe malaria-associated genetic variants alter the activity of a promoter with enhancer function. We showed that this regulatory element controls the expression of ATP2B4 that encodes a plasma membrane calcium-transporting ATPase 4 (PMCA4), which is the major calcium pump on red blood cells. Altering the activity of this regulatory element affects the risk of severe malaria probably through calcium concentration effect on parasitaemia.
The relationship between visually evoked effects and concussion in youth
Authors: Gentile Carlyn Patterson , Aguirre Geoffrey K , Arbogast Kristy B. , Master Christina L.
Published: December 2021

Increased sensitivity to light is common following concussion. Viewing a flickering light can also produce uncomfortable somatic sensations like nausea or headache. Here we examined effects evoked by viewing a patterned, flickering screen in a cohort of 81 uninjured youth athletes and 84 youth with concussion. We used exploratory factor analysis and identified two primary dimensions of variation: the presence or absence of visually evoked effects, and variation in the tendency to manifest effects that localized to the eyes (e.g., eye watering), versus more generalized neurologic symptoms (e.g., headache). Based on these two primary dimensions, we grouped participants into three categories of evoked symptomatology: no effects, eye-predominant effects, and brain-predominant effects. A similar proportion of participants reported eye-predominant effects in the uninjured (33.3%) and concussion (32.1%) groups. By contrast, participants who experienced brain-predominant effects were almost entirely from the concussion group (1.2% of uninjured, 35.7% of concussed). The presence of brain-predominant effects was associated with a higher concussion symptom burden and reduced performance on visio-vestibular tasks. Our findings indicate that the experience of negative constitutional, somatic sensations in response to a dynamic visual stimulus is a salient marker of concussion and is indicative of more severe concussion symptomatology. We speculate that differences in visually evoked effects reflect varying levels of activation of the trigeminal nociceptive system.
Cellular and humoral responses to SARS-CoV-2 vaccination in immunosuppressed patients
Authors: Mohanraj Dinesh , Baldwin Samuel , Singh Satbeer , Gordon Alun , Whitelegg Alison
Published: December 2021

Objective

SARS-CoV-2 vaccinations have demonstrated vaccine immunogenicity in healthy volunteers, however, efficacy in immunosuppressed patients is less well characterised. Subsequently, there is an urgent need to address the impact of immunosuppression on vaccine immunogenicity.

Methods

Serological, T-cell ELISpot, cytokines and immunophenotyping investigations were used to assess vaccine responses (either BNT162b2 mRNA or ChAdOx1 nCoV-19) in double-vaccinated patients receiving immunosuppression for renal transplants or haematological malignancies (n=13). Immunological responses in immunosuppressed patients (VACC-IS) were compared to immunocompetent vaccinated (VACC-IC, n=12), unvaccinated (UNVACC, n=11) and infection-naïve unvaccinated (HC, n=3) cohorts. All participants, except HC, had prior COVID-19 infection.

Results

T-cell responses were identical between VACC-IS and VACC-IC (92%) to spike-peptide (S) stimulation. UNVACC had the highest T-cell non-responders (n=3), whereas VACC-IC and VACC-IS both had one T-cell non-responder. No significant differences in humoral responses were observed between VACC-IC and VACC-IS, with 92% (12/13) of VACC-IS patients demonstrating seropositivity. One VACC-IS failed to seroconvert, however had detectable T-cell responses. All VACC-IC participants were seropositive for anti-spike antibodies. Furthermore, both VACC-IS and VACC-IC participants elicited strong Th1 cytokine response with immunodominance towards S-peptide. Differences in T-cell immunophenotyping were seen between VACC-IS and VACC-IC, with lower CD8+ activation and T-effector memory phenotype observed in VACC-IS.

Conclusion

SARS-CoV-2 vaccines are immunogenic in patients receiving immunosuppressive therapy, with responses comparable to vaccinated immunocompetent participants. Lower humoral responses were seen in patients treated with B-cell depleting therapeutics, but with preserved T-cell responses. We suggest further work to correlate both protective immunity and longevity of these responses in both healthy and immunosuppressed patients.
A multiplex protein panel assay determines disease severity and is prognostic about outcome in COVID-19 patients
Authors: Wang Ziyue , Cryar Adam , Lemke Oliver , Ludwig Daniela , Tober-Lau Pinkus , Helbig Elisa Theresa , Blake Daniel , Lane Catherine S , Sayers Rebekah L , Mueller Christoph , Zeiser Johannes , Townsend StJohn , Demichev Vadim , Mülleder Michael , Kurth Florian , Sirka Ernestas , Hartl Johannes , Ralser Markus
Published: December 2021

Global healthcare systems continue to be challenged by the COVID-19 pandemic, and there is a need for clinical assays that can both help to optimize resource allocation and accelerate the development and evaluation of new therapies. Here, we present a multiplex proteomic panel assay for the assessment of disease severity and outcome prediction in COVID-19. The assay quantifies 50 peptides derived from 30 COVID-19 severity markers in a single measurement using analytical flow rate liquid chromatography and multiple reaction monitoring (LC-MRM), on equipment that is broadly available in routine and regulated analytical laboratories. We demonstrate accurate classification of COVID-19 severity in patients from two cohorts. Furthermore, the assay outperforms established risk assessments such as SOFA and APACHE II in predicting survival in a longitudinal COVID-19 cohort. The prognostic value implies its use for support of clinical decisions in settings with overstrained healthcare resources e.g. to optimally allocate resources to severely ill individuals with high chance of survival. It can furthermore be helpful for monitoring of novel therapies in clinical trials.
Using an electronic frailty index to predict adverse outcomes in geriatric COVID-19 patients: data from the Stockholm GeroCovid study
Authors: Mak Jonathan K. L. , Eriksdotter Maria , Annetorp Martin , Kuja-Halkola Ralf , Kananen Laura , Boström Anne-Marie , Kivipelto Miia , Metzner Carina , Jerlardtz Viktoria Bäck , Engström Malin , Johnson Peter , Lundberg Lars Göran , Åkesson Elisabet , Öberg Carina Sühl , Olsson Maria , Cederholm Tommy , Hägg Sara , Religa Dorota , Jylhävä Juulia
Published: December 2021

Background

The Clinical Frailty Scale (CFS) is a strong predictor for worse outcomes in geriatric COVID-19 patients, but it is less clear whether an electronic frailty index (eFI) constructed from routinely collected electronic health records (EHRs) provides similar predictive value. This study aimed to investigate the predictive ability of an eFI in comparison to other frailty and comorbidity measures, using mortality, readmission, and the length of stay as outcomes in geriatric COVID-19 patients.

Methods

We conducted a retrospective cohort study using EHRs from nine geriatric clinics in Stockholm, Sweden, comprising 3,405 COVID-19 patients (mean age 81.9 years) between 1/3/2020 and 31/10/2021. Frailty was assessed using a 48-item eFI developed for Swedish geriatric patients, the CFS, and Hospital Frailty Risk Score (HFRS). Comorbidity was measured using the Charlson Comorbidity Index (CCI). We analyzed in-hospital mortality and 30-day readmission using logistic regression and area under receiver operating characteristic curve (AUC). 30-day and 6-month mortality were modelled by Cox regression, and the length of stay by linear regression.

Results

Controlling for age and sex, a 10% increase in the eFI was associated with higher risks of in-hospital mortality (odds ratio [OR]=2.84; 95% confidence interval=2.31-3.51), 30-day mortality (hazard ratio [HR]=2.30; 1.99-2.65), 6-month mortality (HR=2.33; 2.07-2.62), 30-day readmission (OR=1.34; 1.06-1.68), and longer length of stay (β=2.28; 1.90-2.66).

The CFS, HFRS and CCI similarly predicted these outcomes, but the eFI had the best predictive accuracy for in-hospital mortality (AUC=0.775).

Conclusions

An eFI based on routinely collected EHRs can be applied in identifying high-risk geriatric COVID-19 patients.
Risk assessment of banknotes as a fomite of SARS-CoV-2 in cash payment transactions
Authors: Schijven Jack , Wind Mark , Todt Daniel , Howes John , Tamele Barbora , Steinmann Eike
Published: December 2021

Background

The COVID 19 pandemic has triggered concerns and assumptions globally about transmission of the SARS-CoV-2 virus via cash transactions.

Objectives

Assess the risk of contracting COVID-19 through exposure to SARS-CoV-2 via cash acting as a fomite in payment transactions.

Methods

A quantitative microbial risk assessment was conducted for a worst-case scenario assuming an infectious person at the onset of symptoms, when virion concentrations in coughed droplets are at their highest. This person then contaminates a banknote by coughing on it and immediately hands it over to another person, who might then be infected by transferring the virions with a finger from the contaminated banknote to a facial mucous membrane. The scenario considered transfer efficiency of virions on the banknote to fingertips when droplets were still wet and after having dried up and subsequently being touched by finger printing or rubbing the object.

Results

Accounting for the likelihood of the worst-case scenario to occur by considering 1) a local prevalence of 100 COVID-19 cases/100,000 persons, 2) a maximum of about 1/5th of infected persons transmit high virus loads and 3) the numbers of cash transactions/person/day, the risk of contracting COVID-19 via person-to-person cash transactions was estimated to be much lower than once per 39,000 days (107 years) for a single person. In the general populace, there will be a maximum of 2.6 expected cases/100,000 persons/day. The risk for a cashier at an average point of sale was estimated to be much less than once per 430 working days (21 months).

Discussion

The worst-case scenario is a rare event, therefore, for a single person, the risk of contracting COVID-19 via person-to-person cash transactions is very low. At a point of sale, the risk to the cashier proportionally increases but it is still low.
Design of an optimal combination therapy with broadly neutralizing antibodies to suppress HIV-1
Authors: LaMont Colin , Otwinowski Jakub , Vanshylla Kanika , Gruell Henning , Klein Florian , Nourmohammad Armita
Published: December 2021

Broadly neutralizing antibodies (bNAbs) are promising targets for vaccination and therapy against HIV. Passive infusions of bNAbs have shown promise in clinical trials as a potential alternative for anti-retroviral therapy. A key challenge for the potential clinical application of bnAbs is the suppression of viral escape, which is more effectively achieved with a combination of bNAbs. However, identifying an optimal bNAb cocktail is combinatorially complex. Here, we propose a computational approach to predict the efficacy of a bNAb therapy trial based on the population genetics of HIV escape, which we parametrize using high-throughput HIV sequence data from a cohort of untreated bNAb-naive patients. By quantifying the mutational target size and the fitness cost of HIV-1 escape from bNAbs, we reliably predict the distribution of rebound times in three clinical trials. Importantly, we show that early rebounds are dominated by the pre-treatment standing variation of HIV-1 populations, rather than spontaneous mutations during treatment. Lastly, we show that a cocktail of three bNAbs is necessary to suppress the chances of viral escape below 1%, and we predict the optimal composition of such a bNAb cocktail. Our results offer a rational design for bNAb therapy against HIV-1, and more generally show how genetic data could be used to predict treatment outcomes and design new approaches to pathogenic control.
A practical guideline of genomics-driven drug discovery in the era of global biobank meta-analysis
Authors: Namba Shinichi , Konuma Takahiro , Wu Kuan-Han , Zhou Wei ,   Global Biobank Meta-analysis Initiative, Okada Yukinori
Published: December 2021

Genomics-driven drug discovery is indispensable for accelerating the development of novel therapeutic targets. However, the drug discovery framework based on evidence from genome-wide association studies (GWAS) has not been established, especially for cross-population GWAS meta-analysis. Here, we introduce a practical guideline for genomics-driven drug discovery for cross-population meta-analysis, as lessons from the Global Biobank Meta-analysis Initiative (GBMI). Our drug discovery framework encompassed three methodologies and was applied to the 13 common diseases targeted by GBMI (Nmean= 1,329,242). First, we evaluated the overlap enrichment between disease risk genes and the drug-target genes of the disease-relevant medication categories. An omnibus approach integrating the four gene prioritization tools yielded twice the enrichment in the disease-relevant medication categories compared with any single tool, and identified drugs with approved indications for asthma, gout, and venous thromboembolism. Second, we performed an endophenotype Mendelian randomization analysis using protein quantitative trait loci as instrumental variables. After the application of quality controls, including a colocalization analysis, significant causal relationships were estimated for 18 protein–disease pairs, including MAP2K inhibitors for heart failure. Third, we conducted anin silicoscreening for negative correlations between genetically determined disease case–control gene expression profiles and compound-regulated ones. Significant negative correlations were observed for 31 compound–disease pairs, including a histone deacetylase inhibitor for asthma. Integration of the three methodologies provided a comprehensive catalog of candidate drugs for repositioning, nominating promising drug candidates targeting the genes involved in the coagulation process for venous thromboembolism. Our study highlighted key factors for successful genomics-driven drug discovery using cross-population meta-analysis.
Safety and immunogenicity of the third booster dose with inactivated, viral vector, and mRNA COVID-19 vaccines in fully immunized healthy adults with inactivated vaccine
Authors: Kanokudom Sitthichai , Assawakosri Suvichada , Suntronwong Nungruthai , Auphimai Chompoonut , Nilyanimit Pornjarim , Vichaiwattana Preeyaporn , Thongmee Thanunrat , Yorsaeng Ritthideach , Srimuan Donchida , Thatsanatorn Thaksaporn , Klinfueng Sirapa , Sudhinaraset Natthinee , Wanlapakorn Nasamon , Honsawek Sittisak , Poovorawan Yong
Published: December 2021

The coronavirus disease-2019 (COVID-19) pandemic has become a severe healthcare problem worldwide since the first outbreak in late December 2019. Currently, the COVID-19 vaccine has been used in many countries, but it is still unable to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection despite patients receiving full vaccination doses. Therefore, we aimed to appraise the booster effect of the different platforms of vaccines, including inactivated vaccine (BBIBP), viral vector vaccine (AZD122), and mRNA vaccine (BNT162b2) in healthy adults who received the full dose of inactivated vaccine (CoronaVac). The booster dose was safe with no serious adverse events. Moreover, the immunogenicity indicated that the booster dose with viral vector and mRNA vaccine achieved a significant proportion of Ig anti-receptor binding domain (RBD), IgG anti-RBD, and IgA anti-S1 booster response. In contrast, inactivated vaccine achieved a lower booster response than others. Consequently, the neutralization activity of vaccinated serum had a high inhibition of over 90% against SARS-CoV-2 wild-type and their variants (B.1.1.7–alpha, B.1.351–beta, and B.1.617.2–delta). In addition, IgG anti-nucleocapsid was observed only among the group that received the BBIBP booster. Our study found a significant increase in levels of interferon gamma-secreting T-cell response after the additional viral vector or mRNA booster vaccination. This study showed that administration with either viral vector (AZD1222) or mRNA (BNT162b2) boosters in individuals with a history of two doses of inactivated vaccine (CoronaVac) obtained great immunogenicity with acceptable adverse events.
Underlying co morbidity reveals unique immune signatures in Type II diabetes patients infected with SARS-CoV2
Authors: Sengupta Soumya , Bhattacharya Gargee , Chatterjee Sanchari , Datey Ankita , Shaw Shubham K , Suranjika Sandhya , Nath Paritosh , Barik Prakash K , Prasad Punit , Chattopadhyay Soma , Swain Rajeeb K , Parida Ajay , Devadas Satish
Published: December 2021

Background

SARS-CoV2 infection in patients with comorbidities, particularly T2DM has been a major challenge globally. Here, we did whole blood immunophenotyping along with plasma cytokine, chemokine, antibody isotyping and viral load determination from oropharyngeal swab to understand the immune pathology in the T2DM patients infected with SARS-CoV2.

Methods

Blood samples from 25 Covid-19 positive patients having T2DM, 10 Covid-19 positive patients not having T2DM and 10 Covid-19 negative, non-diabetic healthy controls were assessed for various immune cells by analyzing for their signature surface proteins in mass cytometry. Circulating cytokines, chemokines and antibody isotypes were determined from plasma. Viral copy number was determined from oropharyngeal swabs. All our representative data corroborated with laboratory findings.

Results

Our observations encompass T2DM patients having elevated levels of both type I and type II cytokines and higher levels of circulating IgA, IgM, IgG1 and IgG2 as compared to NDM and healthy volunteers. They also displayed higher percentages of granulocytes, mDCs, plasmablasts, Th2-like cells, CD4+ EM cells, CD8+ TE cells as compared to healthy volunteers. T2DM patients also displayed lower percentages of pDCs, lymphocytes, CD8+ TE cells, CD4+, CD8+ EM.

Conclusion

Our study demonstrated that patients with T2DM displayed higher inflammatory markers and a dysregulated anti-viral and anti-inflammatory response when compared to NDM and healthy controls.

Contribution to the field

Covid-19 infection in people with comorbidities, particularly T2DM has been a cause of mortality in several nations and they represent an extremely vulnerable population to Covid-19. This study is one of the most comprehensive study from India, to understand the interplay between immune response and viremia occurring in these T2DM patients infected with SARS-CoV2 and will help in designing public health response and vaccination priorities.
Characterization of a novel polyextremotolerant fungus, Exophiala viscosa, with insights into its melanin regulation and ecological niche
Authors: Carr Erin C. , Barton Quin , Grambo Sarah , Sullivan Mitchell , Renfro Cecile M. , Kuo Alan , Pangilinan Jasmyn , Lipzen Anna , Keymanesh Keykhosrow , Savage Emily , Barry Kerrie , Grigoriev Igor V. , Riekhof Wayne R. , Harris Steven D.
Published: December 2021

Black yeasts are polyextremotolerant fungi that contain high amounts of melanin in their cell wall and maintain a primarily yeast form. These fungi grow in xeric, nutrient deplete environments which implies that they require highly flexible metabolisms and have been suggested to contain the ability to form lichen-like mutualisms with nearby algae and bacteria. However, the exact ecological niche and interactions between these fungi and their surrounding community is not well understood. We have isolated two novel black yeasts from the genusExophialathat were recovered from dryland biological soil crusts. Despite notable differences in colony and cellular morphology, both fungi appear to be members of the same species, which has been namedExophiala viscosa (i.e., E. viscosaJF 03-3 Goopyand E. viscosaJF 03-4F Slimy). A combination of whole genome sequencing, phenotypic experiments, and melanin regulation experiments have been performed on these isolates to fully characterize these fungi and help decipher their fundamental niches within the biological soil crust consortium. Our results reveal thatE. viscosais capable of utilizing a wide variety of carbon and nitrogen sources potentially derived from symbiotic microbes, can withstand many forms of abiotic stresses, and excrete melanin that can potentially provide UV resistance to the biological soil crust community. Besides the identification of a novel species within the genusExophiala, our study also provides new insight into the regulation of melanin production in polyextremotolerant fungi.
FcγRIIB regulates (auto)antibody responses by limiting marginal zone B cell activation
Authors: Barlev Ashley N. , Malkiel Susan , Dorjée Annemarie L. , Suurmond Jolien , Diamond Betty
Published: December 2021

FcγRIIB is an inhibitory receptor expressed throughout B cell development. Diminished expression or function is associated with lupus in mice and humans, in particular through an effect on autoantibody production and plasma cell differentiation. Here, we analysed the effect of B cell-intrinsic FcγRIIB expression on B cell activation and plasma cell differentiation.

Loss of FcγRIIB on B cells (Fcgr2b cKO mice) led to a spontaneous increase in autoantibody titers. This increase was most striking for IgG3, suggestive of increased extrafollicular responses. Marginal zone (MZ) and IgG3+ B cells had the highest expression of FcγRIIB and the increase in serum IgG3 was linked to increased MZ B cell signaling and activation in the absence of FcγRIIB. Likewise, human circulating MZ-like B cells had the highest expression of FcγRIIB, and their activation was most strongly inhibited by engaging FcγRIIB. Finally, marked increases in IgG3+ plasma cells and B cells were observed during extrafollicular plasma cell responses with both T-dependent and T-independent antigens in Fcgr2b cKO mice. The increased IgG3 response following immunization of Fcgr2b cKO mice was lost in MZ-deficient Notch2/Fcgr2b cKO mice.

Thus, we present a model where high FcγRIIB expression in MZ B cells prevents their hyperactivation and ensuing autoimmunity.

Graphical abstract
Transposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer
Authors: Lykoskoufis Nikolaos M. R. , Planet Evarist , Ongen Halit , Trono Didier , Dermitzakis Emmanouil T.
Published: December 2021

Transposable elements (TEs) are interspersed repeats that contribute to more than half of the human genome, and TE-embedded regulatory sequences are increasingly recognized as major components of the human regulome. Perturbations of this system can contribute to tumorigenesis, but the impact of TEs on gene expression in cancer cells remains to be fully assessed. Here, we analyzed 275 normal colon and 276 colorectal cancer (CRC) samples from the SYSCOL colorectal cancer cohort and discovered 10,111 and 5,152 TE expression quantitative trait loci (eQTLs) in normal and tumor tissues, respectively. Amongst the latter, 376 were exclusive to CRC, likely driven by changes in methylation patterns. We identified that transcription factors are more enriched in tumor-specific TE-eQTLs than shared TE-eQTLs, indicating that TEs are more specifically regulated in tumor than normal. Using Bayesian Networks to assess the causal relationship between eQTL variants, TEs and genes, we identified that 1,758 TEs are mediators of genetic effect, altering the expression of 1,626 nearby genes significantly more in tumor compared to normal, of which 51 are cancer driver genes. We show that tumor-specific TE-eQTLs trigger the driver capability of TEs subsequently impacting expression of nearby genes. Collectively, our results highlight a global profile of a new class of cancer drivers, thereby enhancing our understanding of tumorigenesis and providing potential new candidate mechanisms for therapeutic target development.
Human IAPP is a contributor to painful diabetic peripheral neuropathy
Authors: Albariqi Mohammed M. H. , Versteeg Sabine , Brakkee Elisabeth M. , Coert J. Henk , Elenbaas Barend O. W. , Prado Judith , Hack C. Erik , Höppener Jo W. M. , Eijkelkamp Niels
Published: December 2021

Peripheral neuropathy is a frequent complication of type 2 diabetes mellitus (T2DM). We investigated whether human islet amyloid polypeptide (hIAPP), which forms pathogenic aggregates that damage pancreatic islet β-cells in T2DM, is involved in T2DM-associated peripheral neuropathy.In vitro, hIAPP incubation with sensory neurons reduced neurite outgrowth and increased levels of mitochondrial reactive oxygen species. Transgenic hIAPP mice that have elevated plasma hIAPP levels without hyperglycemia developed peripheral neuropathy as evidenced by pain-associated behavior and reduced intra-epidermal nerve fiber (IENF) density. Similarly, hIAPP Ob/Ob mice that have hyperglycaemia in combination with elevated plasma hIAPP levels had signs of neuropathy, although more aggravated.

In wild-type mice, intraplantar and intravenous hIAPP injections induced long-lasting allodynia and decreased IENF density. Non-aggregating murine IAPP, mutated hIAPP (Pramlintide), or hIAPP with pharmacologically inhibited aggregation did not induce these effects. T2DM patients had reduced IENF density and more hIAPP oligomers in the skin compared to non-T2DM controls. Thus, we provide evidence that hIAPP aggregation is neurotoxic and mediates peripheral neuropathy in mice. The increased abundance of hIAPP aggregates in the skin of T2DM patients supports the notion that hIAPP is a potential contributor to T2DM neuropathy in humans.

Graphic abstract
Inactivation mechanism and efficacy of grape seed extract for Human Norovirus surrogate
Authors: Oh Chamteut , Chowdhury Ratul , Samineni Laxmicharan , Shisler Joanna L , Kumar Manish , Nguyen Thanh H.
Published: December 2021

Proper disinfection of harvested food and water is critical to minimize infectious disease. Grape seed extract (GSE), a commonly used health supplement, is a mixture of plant-derived polyphenols. Polyphenols possess anti-microbial and -fungal properties, but anti-viral effects are not well-known. Here we show that GSE outperformed chemical disinfectants (e.g., free chlorine and peracetic acids) in inactivating Tulane virus, a human norovirus surrogate. GSE induced virus aggregation, an event that correlated with a decrease in virus titers. This aggregation and disinfection was not reversible. Molecular docking simulations indicate that polyphenols potentially formed hydrogen bonds and strong hydrophobic interactions with specific residues in viral capsid proteins. Together, these data suggest that polyphenols physically associate with viral capsid proteins to aggregate viruses as a means to inhibit virus entry into the host cell. Plant-based polyphenols like GSE are an attractive alternative to chemical disinfectants to remove infectious viruses from water or food.

Importance

Human noroviruses are major food- and water-borne pathogens, causing approximately 20% of all cases of acute gastroenteritis cases in developing and developed countries. Proper sanitation or disinfection are critical strategies to minimize human norovirus-caused disease until a reliable vaccine is created. Grape seed extract (GSE) is a mixture of plant-derived polyphenols that is used as a health supplement. Polyphenols are known for antimicrobial, antifungal, and antibiofilm activities, but antiviral effects are not well-known. In studies here, plant-derived polyphenols outperformed chemical disinfectants (e.g., free chlorine and peracetic acids) in inactivating Tulane virus, a human norovirus surrogate. Based on data from additional molecular assays and molecular docking simulations, the current model is that the polyphenols in GSE bind to the Tulane virus capsid, an event that triggers virion aggregation. It is thought that this aggregation prevents Tulane virus from entering host cells.
Multiplexed high-throughput immune cell imaging reveals molecular health-associated phenotypes
Authors: Severin Yannik , Hale Benjamin D. , Mena Julien , Goslings David , Frey Beat M. , Snijder Berend
Published: December 2021

Phenotypic plasticity is essential to the immune system, yet the factors that shape it are not fully understood. Here, we comprehensively analyze immune cell phenotypes including morphology across human cohorts by single-round multiplexed immunofluorescence, automated microscopy, and deep learning. Using the uncertainty of convolutional neural networks to cluster the phenotypes of 8 distinct immune cell subsets, we find that the resulting maps are influenced by donor age, gender, and blood pressure, revealing distinct polarization and activation-associated phenotypes across immune cell classes. We further associate T-cell morphology to transcriptional state based on their joint donor variability, and validate an inflammation-associated polarized T-cell morphology, and an age-associated loss of mitochondria in CD4+T-cells. Taken together, we show that immune cell phenotypes reflect both molecular and personal health information, opening new perspectives into the deep immune phenotyping of individual people in health and disease.
Cancer tolerance to chromosomal instability is driven by Stat1 inactivation in vivo
Authors: Schubert Michael , Hong Christy , Jilderda Laura J. , Rueda Marta Requesens , Tijhuis Andréa E. , Simon Judith E. , Bakker Petra L. , Cooper Jon L. , Damaskou Aristi , Wardenaar René , Bakker Bjorn , Gupta Sahil , van den Brink Anouk , Ruiz Lorena Andrade , Koster Miriam H. , Youssef Sameh A. , Luinenburg Danielle , Strong Alex , Engleitner Thomas , Ponstingl Hannes , de Haan Gerald , de Bruin Alain , Rad Roland , Nijman Hans W. , Medema René H. , van Vugt Marcel A.T.M. , de Bruyn Marco , Spierings Diana C.J. , Colomé-Tatché Maria , Vassiliou George S. , Foijer Floris
Published: December 2021

Chromosomal instability is a hallmark of cancer, but also an instigator of aneuploidy-induced stress, reducing cellular fitness. To better understand how cells with CIN adjust to aneuploidy and adopt a malignant fate in vivo, we performed a genome-wide mutagenesis screen in mice. We find that specifically aneuploid tumors inactivate Stat1 signaling in combination with increased Myc activity. By contrast, loss of p53 is common, but not enriched in CIN tumors. Validation in another tissue type confirmed that CIN promotes immune cell infiltration, which is alleviated by Stat1 loss combined with Myc activation, but not with p53 inactivation, or Myc activation alone. Importantly, we find that this mechanism is preserved in human aneuploid cancers. We conclude that aneuploid cancers inactivate Stat1 signaling to circumvent immune surveillance.
Permissive aggregative group formation favors coexistence in yeast
Authors: Belpaire Tom E. R. , Pešek Jiří , Lories Bram , Verstrepen Kevin J. , Steenackers Hans P. , Ramon Herman , Smeets Bart
Published: December 2021

In Saccharomyces cerevisiae, the FLO1 gene encodes flocculins that lead to formation of multicellular flocs, that offer protection to the constituent cells. Flo1p was found to preferentially bind to fellow cooperators compared to defectors lacking FLO1 expression, resulting in enrichment of cooperators within the flocs. Given this dual function in cooperation and kin recognition, FLO1 has been termed a ‘green beard gene’. Because of the heterophilic nature of Flo1p binding however, we hypothesize that kin recognition is permissive and depends on the relative stability of FLO1+/flo1− versus FLO1+/FLO1+ bonds, which itself can be dependent on environmental conditions and intrinsic cell properties. We combine single cell measurements of adhesion strengths, individual cell-based simulations of cluster formation and evolution, and in vitro flocculation experiments to study the impact of relative bond stability on defector exclusion as well as benefit and stability of cooperation. We hereto vary the relative bond stability by changing the shear flow rate and the inherent bond strength. We identify a marked trade-off between both aspects of the green beard mechanism, with reduced relative bond stability leading to increased kin recognition, but at the expense of decreased cluster sizes and benefit of cooperation. Most notably, we show that the selection of FLO1 cooperators is negative-frequency dependent, which we directly attribute to the permissive character of the Flo1p bond. Taking into account the costs associated to FLO1 expression, this asymmetric selection results in a broad range of ecological conditions where coexistence between cooperators and defectors is stable. Although the kin recognition aspect of the FLO1 ‘green beard gene’ is thus limited and condition dependent, the negative-frequency dependency of selection can conserve the diversity of flocculent and non-flocculent phenotypes ensuring flexibility towards variable selective pressures.
Pectin self-assembly and its disruption by water: Insights into plant cell wall mechanics
Authors: John Jacob , Ray Debes , Aswal Vinod K. , Deshpande Abhijit P. , Varughese Susy
Published: December 2021

Plant cell walls undergo multiple cycles of dehydration and rehydration during their life. Calcium crosslinked low methoxy pectin is a major constituent of plant cell walls. Understanding the dehydration-rehydration behavior of pectin gels may shed light on the water transport and mechanics of plant cells. In this work, we report the contributions of microstructure to the mechanics of pectin-Ca gels subjected to different extents of dehydration and subsequent rehydration. This is investigated using a pectin gel composition that forms ‘egg-box bundles’, a characteristic feature of the microstructure of low methoxy pectin-Ca gels. Large Amplitude Oscillatory Shear (LAOS) rheology along with Small Angle Neutron Scattering and Near Infrared (NIR) spectroscopy on pectin gels are used to elucidate the mechanical and microstructural changes during dehydration-rehydration cycles. As the extent of dehydration increase, the reswelling ability, strain-stiffening behavior and the yield strain decreases. These effects are more prominent at faster rates of dehydration and are not completely reversible upon rehydration to the initial undried state. Microstructural changes due to the aggregation of egg-box bundles and single chains and the associated changes in the water configurations lead to these irreversible changes.
An accelerometer-derived ballistocardiogram method for detecting heartrates in free-ranging marine mammals
Authors: Czapanskiy Max F. , Ponganis Paul J. , Fahlbusch James A. , Schmitt T. L. , Goldbogen Jeremy A.
Published: December 2021

Physio-logging methods, which use animal-borne devices to record physiological variables, are entering a new era driven by advances in sensor development. However, existing datasets collected with traditional bio-loggers, such as accelerometers, still contain untapped eco-physiological information. Here we present a computational method for extracting heartrate from high-resolution accelerometer data using a ballistocardiogram. We validated our method with simultaneous accelerometer-electrocardiogram tag deployments in a controlled setting on a killer whale (Orcinus orca) and demonstrate the method recovers previously observed cardiovascular patterns in a blue whale (Balaenoptera musculus), including the magnitude of apneic bradycardia and increase in heart rate prior to and during ascent. Our ballistocardiogram method may be applied to mine heart rates from previously collected accelerometery and expand our understanding of comparative cardiovascular physiology.
Energy expenditure deficits drive obesity in a mouse model of Alström syndrome
Authors: Stephenson Erin J , Kinney Clint E , Statyton Amanda S , Han Joan C
Published: December 2021

Alström syndrome (AS) is a rare multi-system disorder for which early-onset childhood obesity is a cardinal feature. Like humans with AS, animal models withAlms1loss-of-function mutations develop obesity, supporting the notion that ALMS1/Alms1 is required for the regulatory control of energy balance across species. This study aimed to determine which component(s) of energy balance are reliant on Alms1. Here, we performed comprehensive energy balance phenotypingAlms1tvrm102mice at both eight- and eighteen-weeks-of-age. We found that adiposity gains occurred early and rapidly inAlms1tvrm102male mice but much later in females. Rapid increases in body fat in males was due to a marked reduction in energy expenditure (EE) during early life and not due to any genotype-specific increases in energy intake under chow conditions. Energy intake did increase in a genotype-specific manner when mice were provided a high-fat-diet, exacerbating the effects of reduced EE on obesity progression. The EE deficit observed in maleAlms1tvrm102mice did not persist as mice aged, suggesting loss of Alms1 either causes a developmental delay in the mechanisms controlling early life EE, or that activation of compensatory mechanisms occurs after obesity is established. Future studies will determine how ALMS1/Alms1 modulates EE and how sex moderates this process.
A Spatial Transcriptomics Study of the Brain-Electrode Interface in Rat Motor Cortex
Authors: Whitsitt Quentin A. , Patel Bella , Hunt Brad , Purcell Erin K.
Published: December 2021

The study of the foreign body reaction to implanted electrodes in the brain is an important area of research for the future development of neuroprostheses and experimental electrophysiology. After electrode implantation in the brain, microglial activation, reactive astrogliosis, and neuronal cell death create an environment immediately surrounding the electrode that is significantly altered from its homeostatic state. To uncover physiological changes potentially affecting device function and longevity, spatial transcriptomics was implemented in this preliminary study to identify changes in gene expression driven by electrode implantation. This RNA-sequencing technique (10x Genomics, Visium) uses spatially coded, RNA-binding oligonucleotides on a microscope slide to spatially identify each sequencing read. For these experiments, sections of rat motor cortex implanted with Michigan-style silicon electrodes were mounted on the Visium slide for processing. Each tissue section was labeled for neurons and astrocytes using immunohistochemistry to provide a spatial reference for mapping each sequencing read relative to the device tract. Results from rat motor cortex at 24 hours, 1 week, and 6 weeks post implantation showed up to 5811 differentially expressed genes between implanted and non-implanted tissue sections. Many of these genes are related to biological mechanisms previously reported in studies of the foreign body response to implanted electrodes, while others are novel to this study. These results will provide a foundation for future work to both improve and measure the effects of gene expression on the long-term stability of recordings from implanted electrodes in the brain. Ongoing work will expand on these initial observations as we gain a better understanding of the dynamic, molecular changes taking place in the brain in response to electrode implantation.
Mechanical stretch regulates macropinocytosis in Hydra vulgaris
Authors: Skokan Taylor D. , Hobmayer Bert , McKinley Kara L. , Vale Ronald D.
Published: December 2021

Cells rely on a diverse array of engulfment processes to sense, exploit, and adapt to their environments. Macropinocytosis is a versatile example of such a process, allowing for the indiscriminate and rapid uptake of large volumes of fluid and membrane. Much of the molecular machinery essential for macropinocytosis has been well established. However, most of these studies relied on tissue culture models, leaving the regulation of this process within the context of organs and organisms unresolved. Here, we report that large-scale macropinocytosis occurs in the outer epithelial layer of the cnidarian Hydra vulgaris. Exploiting Hydra’s relatively simple body plan, we developed approaches to visualize macropinocytosis over extended periods of time in living tissue, revealing constitutive engulfment across the entire body axis. Using pharmacological perturbations, we establish a role for stretch-activated channels, including Piezo, and downstream calcium influx in inhibiting this process. Finally, we show that the direct application of planar stretch leads to calcium influx and a corresponding inhibition of macropinocytosis. Together, our approaches provide a platform for the mechanistic dissection of constitutive macropinocytosis in physiological contexts and reveal a role for macropinocytosis in responding to membrane tension.