bluuebunny/crossref_metadata_2025 huggingface dataset:
Clumpiness: Modeling the Impact of Social Dynamics on COVID-19 Spread
Authors: Goertzel Ben , Pennachin Cassio , Duong Deborah , Iklé Matt , Duncan Michael , Boyd James , Senna André , Durães Ramon
Published: April 2021

We present an agent based simulation model configured for exploring the dynamics of disease spread in the context of agents that group together through homophily, the principle of “like attracts like”. To study the properties of this model, we introduce two novel social network inter-connectivity measures, “clumpiness” and “hoprank,” that are the same basic concept defined at global and local levels, respectively. The measures may be computed from samples of readily available demographic data, and are useful for measuring probabilistic packet transmission through social networks. In three studies we apply clumpiness to measure the effects, on COVID-19 transmission, caused by social networks of both homophilic physical proximity and homophilic information replication. The particular characteristic we are interested in about disease transmission is herd immunity, the percentage of a population that has to be immune in order to prevent infection from spreading to those who are not. Two studies demonstrate innovations measuring herd immunity levels and predicting future outbreak locations, procedures relevant to epidemiological control policy. In the first study, we look at how homophilic physical proximity networks form natural bubbles that act as frictive surfaces that affect the speed of transmission of packets and influence herd immunity levels. In the second study, we test clumpiness in homophilic proximity social networks as a predictor of future infection outbreaks at the level of individual schools, restaurants, and workplaces. Our third study demonstrates that protective social bubbles form naturally from homophilic information replication networks, and enhance the natural bubbles that come from the homophilic physical proximity networks. Accurate description of this information environment lays the foundation for epidemiological messaging policy formation.
Association between physical-activity trajectories and cognitive decline in adults 50 years of age or older
Authors: Cheval Boris , Csajbók Zsófia , Formánek Tomáš , Sieber Stefan , Boisgontier Matthieu P. , Cullati Stéphane , Cermakova Pavla
Published: April 2021

Objectives

To investigate the associations of physical-activity trajectories with the level of cognitive performance and its decline in adults 50 years of age or older.

Methods

We studied 38729 individuals (63 ± 9 years; 57% women) enrolled in the Survey of Health, Ageing and Retirement in Europe (SHARE). Physical activity was self-reported and cognitive performance was assessed based on immediate recall, verbal fluency, and delayed recall. Physical-activity trajectories were estimated using growth mixture modelling and linear mixed effects models were used to investigate the associations between the trajectories and cognitive performance.

Results

The models identified two physical-activity trajectories of physical activity: constantly-high physical activity (N=27634: 71%) and decreasing physical activity (N=11095; 29%). Results showed that participants in the decreasing physical-activity group exhibited a lower level of cognitive performance compared to the high physical-activity group (immediate recall: ß=0.94; 95% confidence interval [CI]=0.92 to 0.95; verbal fluency: ß=0.98; 95% CI=0.97 to 0.98; delayed recall: ß=0.95; 95% CI=0.94 to 0.97). Moreover, compared with participants in the constantly-high physical-activity group, participants in the decreasing physical-activity group showed a steeper decline in all cognitive measures (immediate recall: ß=-0.04; 95% CI=-0.05 to −0.04; verbal fluency: ß=-0.22; 95% CI=-0.24 to −0.21; delayed recall: ß=-0.04; 95% CI=-0.05 to −0.04).

Conclusions

Physical-activity trajectories are associated with the level and evolution of cognitive performance in adults over 50 years. Specifically, our findings suggest that a decline in physical activity over multiple years is associated with a lower level and a steeper decline in cognitive performance.
Treatment of Early Hypertension among Persons Living with HIV in Haiti: protocol for a randomized controlled trial
Authors: Yan Lily D , Rouzier Vanessa , Dade Eliezer , Guiteau Collette , Pierre Jean Lookens , St-Preux Stephano , Metz Miranda , Oparil Suzanne , Pape Jean William , McNairy Margaret
Published: April 2021

Background

People living with HIV (PLWH) are at increased risk of cardiovascular disease (CVD) and death, with greater burdens of both HIV and CVD in lower-middle income countries. Treating prehypertension in PLWH may reduce progression to hypertension, CVD risk and potentially mortality. However, no trial has evaluated earlier blood pressure treatment for PLWH. We propose a randomized controlled trial to assess the feasibility, benefits, and risks of initiating antihypertensive treatment among PLWH with prehypertension, comparing prehypertension treatment to standard of care following current WHO guidelines.

Methods

A total of 250 adults 18-65 years and living with HIV (PLWH) with viral suppression in the past 12 months, who have prehypertension will be randomized to prehypertension treatment versus standard of care. Prehypertension is defined as having a systolic blood pressure (SBP) 120-139 mmHg or diastolic blood pressure (DBP) 80-89 mmHg. In the prehypertension treatment arm, participants will initiate amlodipine 5 mg daily immediately. In the standard of care arm, participants will initiate amlodipine only if they develop hypertension defined as SBP ≥ 140 mmHg or DBP ≥ 90 mmHg. The primary outcome is the difference in mean change of SBP from enrollment to 12 months. Secondary outcomes include feasibility, acceptability, adverse effects, HIV viral suppression, and medication adherence. Qualitative in-depth interviews with providers and participants will explore attitudes about initiating amlodipine, satisfaction, perceived CVD risk, and implementation challenges.

Discussion

PLWH have a higher CVD risk and may benefit from a lower BP threshold for initiation of antihypertensive treatment.

Trial registration

Clinicaltrials.gov registration number NCT04692467, registration date December 15, 2020, protocol ID 20-03021735.
Comorbidity Risk Factors Contributing to COVID-19 Related Deaths in Florida, March 1, 2020-January 16, 2021
Authors: Weiss Ursula K. , Maynard Jason D. , McDaniel Katherine , Cohen Alyssa , Bailey Marie , Rivkees Scott A.
Published: April 2021

Objectives

To assess the association of specific comorbid conditions to COVID-19 deaths in Florida among decedents 16 to 64 years of age.

Methods

This report uses Florida vital statistics death data over the period of March 1, 2020 through January 16, 2021, to estimate the effects of comorbid conditions on COVID-19 mortality for decedents 16 to 64 years of age. All cases of COVID-19 death occurring in Florida, regardless of resident status, were evaluated. The comorbidities, or contributing causes of death, identified in this report include Down syndrome, asthma, diabetes, pulmonary fibrosis, obesity, dementia, immunodeficiency, kidney disease, chronic obstructive pulmonary disease, hypertension, heart disease, and chronic liver disease and cirrhosis. The study uses a binary logistic regression to examine the relationship between COVID-19 and non-COVID-19 death and contributing causes of death based on information in the death record. Odds ratios were calculated as a residual of the logistic regression.

Results

Among COVID-19 deaths, Down syndrome was 15.26 times more likely to be a contributing cause of death compared to non-COVID-19 deaths followed by asthma (OR 7.74), diabetes (OR 6.11), pulmonary fibrosis (OR 5.13), obesity (OR 4.66), dementia (OR 4.51), immunodeficiency (OR 2.49), and kidney disease (OR 2.13). Chronic liver disease and cirrhosis (OR 0.95) and cancer (OR 0.79) had lower odds of being a contributing cause of death.

Conclusions

Heart disease, chronic liver disease and cirrhosis, and cancer were not risk factors for death from COVID-19 among decedents. Additional studies are needed to elucidate associations between race/ethnicity, socioeconomic status, and behavioral factors.
COMplex mental health PAThways (COMPAT) Study: a mixed methods study to inform an evidence-based service delivery model for people with complex needs: Study protocol
Authors: Saini Pooja , Martin Antony , McIntyre Jason , Balmer Anna , Burton Sam , Roks Hana , Sambrook Laura , Shetty Amrith , Nathan Rajan
Published: April 2021

Background

Mental health services for adults, as they are currently configured, have been designed to provide predominantly community-based interventions. It has long been recognised that some patients have such significant clinical and/or risk needs that those needs cannot be adequately met within standard service delivery models, resulting in a pressing need to consider the best models for this group of people. This paper shares a protocol for a mixed methods study that aims to understand: the profile and history of service users described as having complex needs; the decision-making processes by clinicians that lead to complex needs categorisation; service users and carers experience of service use; and, associated economic impact. This protocol describes a comprehensive evaluation that aims to inform an evidence-based service delivery model for people with complex needs.

Methods

We will use a mixed methods design, combining quantitative and qualitative methods using in-depth descriptive and inferential analysis of patient records, written medical notes and in-depth interviews with service users, carers, and clinicians. The study will include five components: (1) a quantitative description and analysis of the demographic clinical characteristics of the patient group; (2) an economic evaluation of alternative patient pathways; (3) semi-structured interviews about service user and carer experiences; (4) using data from components 1-3 to co-produce vignettes jointly with relevant stakeholders involved in the care of service users with complex mental health needs; and, (5) semi-structured interviews about clinical decision-making by clinicians in relation to this patient group, using the vignettes as example case studies.

Discussion

The study’s key outcomes will be to: examine the resource use and cost-impact associated with alternative care pathways to the NHS and other sectors of the economy (including social care); explore patient health and non-health outcomes associated with alternative care pathways; and, gain an understanding of a complex service user group and how treatment decisions are made to inform consistent and person-centred future service delivery.
Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response
Authors: Pagadala Meghana , Wu Victoria H. , Pérez-Guijarro Eva , Kim Hyo , Castro Andrea , Talwar James , Sears Timothy , Gonzalez-Colin Cristian , Cao Steven , Schmiedel Benjamin J. , Goudarzi Shervin , Kirani Divya , Salem Rany M. , Morris Gerald P. , Harismendy Olivier , Patel Sandip Pravin , Mesirov Jill P. , Zanetti Maurizio , Day Chi-Ping , Fan Chun Chieh , Thompson Wesley K. , Merlino Glenn , Gutkind J. Silvio , Vijayanand Pandurangan , Carter Hannah
Published: April 2021

With the continued promise of immunotherapy as an avenue for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Approaches that intersect SNP modifiers of molecular phenotype, such as gene expression, with disease phenotypes have shown promise for implicating causal genetic factors. Here we evaluated 194 literature-curated TIME associations and 890 associations detected with 157 immune phenotype (IP) components found using genotypes from over 8,000 individuals in The Cancer Genome Atlas. Of these 1084, 233 associations comprising 219 unique TIME-SNPs were also cancer relevant, associating with cancer risk, survival, and/or immunotherapy treatment response. Many cancer relevant TIME-SNPS overlapped regions of active transcription, and were associated with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. TIME-SNPs associated with cancer risk and response to immunotherapy implicated genes involved in antigen presentation, especially by antigen presenting cells. The strongest associations with survival were withPD-L1andCTLA-4, suggesting that SNPs modifying the potential for immune evasion could contribute to disease progression. To assess whether our approach could reveal novel cancer immunotherapy targets, we inhibitedCTSS,a gene implicated by cancer risk and immunotherapy response-associated TIME-SNPs; CTSS inhibition resulted in slowed tumor growth and extended survivalin vivo. These results validate the potential of cancer relevant TIME-SNPs to implicate target genes for countering immune suppressive characteristics of the TIME and set the stage for future host genetics analysis integrating germline variation and TIME characteristics.

Significance

A systematic screen for common germline variants associated with the tumor immune microenvironment across > 8000 tumors reveals novel cancer risk factors and targets for immunotherapy.
Dietary, Cultural and Pathogens-related Selective Pressures Shaped Differential Adaptive Evolution Among Native Mexican Populations
Authors: Ojeda-Granados Claudia , Abondio Paolo , Setti Alice , Sarno Stefania , Gnecchi-Ruscone Guido Alberto , González-Orozco Eduardo , De Fanti Sara , Jiménez-Kaufmann Andres , Rangel-Villalobos Héctor , Moreno-Estrada Andrés , Sazzini Marco
Published: April 2021

Native American genetic ancestry has been remarkably implicated with increased risk of diverse health issues in several Mexican populations, especially in relation to the dramatic changes in environmental, dietary and cultural settings they have recently undergone. In particular, the effects of these ecological transitions and Westernization of lifestyles have been investigated so far predominantly on Admixed individuals. Nevertheless, indigenous groups, rather than admixed Mexicans, have plausibly retained the highest proportions of genetic components shaped by natural selection in response to the ancient milieu experienced by Mexican ancestors during their pre-Columbian evolutionary history. These formerly adaptive alleles/haplotypes have the potential to represent the genetic determinants of some biological traits peculiar to the Mexican people and a reservoir of loci with potential biomedical relevance. To test such a hypothesis, we used high-resolution genomic data to infer the unique adaptive evolution of 15 Native Mexican groups selected as reasonable descendants of the main pre-Columbian Mexican civilizations. A combination of haplotype-based and gene-network analyses enabled us to detect genomic signatures ascribable to polygenic adaptive traits evolved by the main genetic clusters of indigenous Mexican populations to cope with local environmental and/or cultural conditions. Some of them were also found to play a role in modulating the susceptibility/resistance of these groups to certain pathological conditions, thus providing new evidence for diverse selective pressures having contributed to shape current biological and disease-risk patterns in present-day Native and Mestizo Mexican populations.
The transcription factor reservoir and chromatin landscape in activated plasmacytoid dendritic cells
Authors: Mann-Nüttel Ritu , Ali Shafaqat , Petzsch Patrick , Köhrer Karl , Alferink Judith , Scheu Stefanie
Published: April 2021

Transcription factors (TFs) control gene expression by direct binding to regulatory regions of target genes but also by impacting chromatin landscapes and thereby modulating DNA accessibility for other TFs. To date, the global TF reservoir in plasmacytoid dendritic cells (pDCs), a cell type with the unique capacity to produce unmatched amounts of type I interferons, has not been fully characterized. To fill this gap, we have performed a comprehensive analysis in naïve and TLR9-activated pDCs in a time course study covering early timepoints after stimulation (2h, 6h, 12h) integrating gene expression (RNA-Seq), chromatin landscape (ATAC-Seq) and Gene Ontology studies. We found that 70% of all described TFs are expressed in pDCs for at least one stimulation time point and that activation predominantly “turned on” the chromatin regions associated with TF genes. We hereby define the complete set of TLR9-regulated TFs in pDCs. Further, this study identifies the AP-1 family of TFs as potentially important but so far less well characterized regulators of pDC function.
BioNetComp: a Python package for biological network development and comparison
Authors: Carvalho Lucas M.
Published: April 2021

Due to the large generation of omics data on a large scale in the last few years, the extraction of information from biological data has become more complex and its integration or comparison as well. One of the ways to represent interactions of biological data is through networks, which summarize information on interactions between their nodes through edges. The comparison of two biological networks using network metrics, biological enrichment, and visualization consists of data that allows us to understand differences in the interactomes of contrasting conditions. We describe BioNetComp, a python package to compare two different interactomes through different metrics and data visualization without the need for a web platform or software, just by command-line. As a result, we present a comparison made between the interactomes generated from the differentially expressed genes at two different points during a typical bioethanol fermentation. BioNetComp is available at github.com/lmigueel/BioNetComp.
Profiling the Human Phosphoproteome to Estimate the True Extent of Protein Phosphorylation
Authors: Kalyuzhnyy Anton , Eyers Patrick A. , Eyers Claire E. , Sun Zhi , Deutsch Eric W. , Jones Andrew R.
Published: April 2021

Mass spectrometry-based phosphoproteomics allows large-scale generation of phosphorylation site data. However, analytical pipelines need to be carefully designed and optimised to minimise incorrect identification of phosphopeptide sequences or wrong localisation of phosphorylation sites within those peptides. Public databases such as PhosphoSitePlus (PSP) and PeptideAtlas (PA) compile results from published papers or openly available MS data, but to our knowledge, there is no database-level control for false discovery of sites, subsequently leading to the likely overestimation of true phosphosites. It is therefore difficult for researchers to assess which phosphosites are “real” and which are likely to be artefacts of data processing. By profiling the human phosphoproteome, we aimed to estimate the false discovery rate (FDR) of phosphosites based on available evidence in PSP and/or PA and predict a more realistic count of true phosphosites. We ranked sites into phosphorylation likelihood sets based on layers of accumulated evidence and then analysed them in terms of amino acid conservation across 100 species, sequence properties and functional annotations of associated proteins. We demonstrated significant differences between the sets and developed a method for independent phosphosite FDR estimation. Remarkably, we estimated a false discovery rate of 86.1%, 95.4% and 82.2% within sets of described phosphoserine (pSer), phosphothreonine (pThr) and phosphotyrosine (pTyr) sites respectively for which only a single piece of identification evidence is available (the vast majority of sites in PSP). Overall, we estimate that ∼56,000 Ser, 10,000 Thr and 12,000 Tyr phosphosites in the human proteome have truly been identified to date, based on evidence in PSP and/or PA, which is lower than most published estimates. Furthermore, our analysis estimated ∼91,000 Ser, 49,000 Thr and 26,000 Tyr sites that are likely to represent false-positive phosphosite identifications. We conclude that researchers should be aware of the significant potential for false positive sites to be present in public databases and should evaluate the evidence behind the phosphosites used in their research.
Development of a rapid LC-MS/MS method for the simultaneous quantification of various flavonoids and phytohormones extracted fromMedicago Truncatulaleaves
Authors: Bisht Neema , Gupta Arunima , Awasthi Pallavi , Goel Atul , Chandran Divya , Sharma Neha , Singh Nirpendra
Published: April 2021

Flavonoids are small metabolites of plants, which are involved in the regulation of plant development as well as defence against pathogens. Quantitation of these flavonoids in plant samples is highly important and essential in the food and herbal industry. Hence, robust, reliable and sensitive methods are required for the analysis of these compounds in plant samples. In the present study, a high performance liquid chromatographic-tandem mass spectrometric (HPLC– ESI-MS/MS) method was developed and validated for the determination of nine flavonoids, including Liquiritigenin, Naringenin, Genistein, Daidzein, Formononetin, Biochanin A, 2’-hydroxy formononetin, 2’-methoxyformononetin, Medicarpin, and two phytohormones, Salicylic acid and Jasmonic acid, inMedicago truncatula. The analytes were separated by means of C-18, reversed-phase chromatography and detected using QTRAP mass spectrometer. Molecules were quantified using different transitions in positive and negative ion modes simultaneously in 12 minutes. The on-column limit of detection of all the analytes was as low as 0.03 pg, whereas the limit of quantification of all the compounds was observed upto 0.1 pg levels. Further the method was also validated in terms of specificity, linearity (r2> 0.99), average recovery (90.6 – 110.3%), accuracy (RE% ≤ 3%) and precision (RSD% ≤ 3%). As a proof of concept, the developed method was successfully used for the quantitation of these flavonoids and phytohormones from leaf extract ofMedicago truncatula.
Angiopoietin 1 and integrin beta 1b are vital for zebrafish brain development
Authors: Chen Yu-Chia , Martins Tomás A. , Marchica Valentina , Panula Pertti
Published: April 2021

This study aimed at identifying the role of angiopoietin 1 (angpt1) in brain development, the mode of action of angpt1, and the main targets in the zebrafish brain. We investigated embryonic brain angiogenesis and neural development in theangpt1sa14264,itgb1bmi371,tekhu1667mutant fish, and the effects of transgenic overexpression ofangpt1in the larval brain. Lack ofangpt1was associated with downregulation oftekand upregulation ofitgb1b. We found deficiencies in the patterning of proliferation, the vascular network and reticulospinal neurons in the hindbrain, and selective deficiencies in specific neurotransmitter systems. In theangpt1sa14264anditgb1bmi371larval brains, using microangiography, retrograde labeling, and immunostaining, we demonstrated that the targeted destruction ofangpt1sa14264anditgb1bmi371mutant fish caused severe irregular cerebrovascular development, aberrant hindbrain patterning, downregulation of neural proliferation, expansion of the radial glial progenitors, deficiencies of dopaminergic, histaminergic, and GABAergic populations in the larval brain. In contrast, thetekhu1667mutants regularly grew with no such apparent phenotypes. Neurally overexpressedangpt1promoted opposite effects by increasing the vascular branching, increasing cell proliferation, and neuronal progenitors. Notably, zebrafishangpt1showed neurogenic activity independent of its typical receptortek, indicating the novel role of a dual regulation byangpt1in embryonic neurogenesis and angiogenesis in zebrafish. The results show that angpt1 and its interaction with itgb1b are crucial in zebrafish brain neuronal and vascular development and suggest that angpt1 through itgb1b can act as a neurogenic factor in the neural proliferation fate in the developing brain.
Phylogeny Reveals Novel HipA-Homologous Kinase Families and Toxin – Antitoxin Gene Organizations
Authors: Gerdes Kenn , Bærentsen Rene , Brodersen Ditlev E.
Published: April 2021

Toxin – Antitoxin modules function in the genetic stability of mobile genetic elements, bacteriophage defense, and antibiotic tolerance. A gain-of-function mutation of the Escherichia coli K-12 hipBA module can induce antibiotic tolerance in a subpopulation of bacterial cells, a phenomenon known as persistence. HipA is a Ser/Thr kinase that phosphorylates and inactivates glutamyl tRNA synthetase, inhibiting cellular translation and inducing the stringent response. Additional characterized HipA homologues include HipT from pathogenic E. coli O127 and YjjJ of E. coli K-12, which are encoded by tri-cistronic hipBST and monocistronic operons, respectively. The apparent diversity of HipA homologues in bacterial genomes inspired us to investigate overall phylogeny. Here we present a comprehensive phylogenetic analysis of the Hip kinases in bacteria and archaea that expands on this diversity by revealing seven novel kinase families. Kinases of one family, encoded by monocistronic operons, consist of an N-terminal core kinase domain, a HipS-like domain and a HIRAN (HIP116 Rad5p N-terminal) domain. HIRAN domains bind single or double-stranded DNA ends. Moreover, five types of bicistronic kinase operons encode putative antitoxins with HipS-HIRAN, HipS, γδ-resolvase or Stl repressor-like domains. Finally, our analysis indicates that reversion of hipBA gene-order happened independently several times during evolution.

Importance

Bacterial multidrug tolerance and persistence are problems of increasing scientific and medical significance. The first gene discovered to confer persistence was hipA, encoding the kinase toxin of the hipBA toxin-antitoxin (TA) module of E. coli. HipA-homologous kinases phosphorylate and thereby inactivate specific tRNA synthetases, thus inhibiting protein translation and cell proliferation. Here, we present a comprehensive phylogenetic analysis of bacterial Hip kinases and discover seven new families with novel operon structures and domains. Overall, Hip kinases are encoded by TA modules with at least 10 different genetic organizations, seven of which have not been described before. These results open up exciting avenues for the experimental analysis of the superfamily of Hip kinases.
Multiplex Fragment Analysis Identifies SARS-CoV-2 Variants
Authors: Clark A.E. , Wang Z. , Cantarel B. , Kanchwala M. , Xing C. , Chen L. , Irwin P. , Xu Y. , Oliver D. , Lee F. , Gagan J.R. , Filkins L. , Muthukumar A. , Park J.Y. , Sarode R. , SoRelle J.A.
Published: April 2021

The rapid spread of SARS-CoV-2 Variants of Concern (VOC) necessitates systematic efforts for epidemiological surveillance. The current method for identifying variants is viral whole genome sequencing (WGS). Broad clinical adoption of sequencing is limited by costly equipment, bioinformatics support, technical expertise, and time for implementation. Here we describe a scalable, multiplex, non-sequencing-based capillary electrophoresis assay to affordably screen for SARS-CoV-2 VOC.
More than a year after the onset of the CoVid-19 pandemic in the UK: lessons learned from a minimalistic model capturing essential features including social awareness and policy making
Authors: Durán-Olivencia Miguel A. , Kalliadasis Serafim
Published: April 2021

The number of new daily SARS-CoV-2 infections experienced an abrupt increase during the last quarter of 2020 in almost every European country. The phenomenological explanation offered was a new mutation of the virus, first identified in the UK. We use publicly available data in combination with a time-delayed controlled SIR model, which captures the effects of preventive measures and concomitant social response on the spreading of the virus. The model, which has a unique transmission rate, enables us to reproduce the waves of infection occurred in the UK. This suggests that the new SARS-CoV-2 UK variant is as transmissible as previous strains. Our findings reveal that the sudden surge in cases was in fact related to the relaxation of preventive measures and social awareness. We also simulate the combined effects of restrictions and vaccination campaigns in 2021, demonstrating that lockdown policies are not fully effective to flatten the curve; fully effective mitigation can only be achieved via a vigorous vaccination campaign. As a matter of fact, incorporating recent data about vaccine efficacy, our simulations advocate that the UK might have overcome the worse of the CoVid-19 pandemic, provided that the vaccination campaign maintains a rate of approximately 140k jabs per day.
Patterns and Changes in Expectation of Life at Birth in India: 1998-2017
Authors: Chaurasia Aalok Ranjan
Published: April 2021

This paper analyses patterns and changes in the expectation of life at birth in India and decomposes the increase in the expectation of life at birth between 1998-2002 and 2013-2017. The analysis reveals considerable volatility in the increase in the expectation of life at birth in the country and in its different population groups and states. In recent years, there is considerable deceleration in the increase in the expectation of life at birth in the country because of the deceleration in the increase in female expectation of life at birth. The decomposition exercise reveals that most of the increase in the expectation of life at birth is attributed to the improvement in the survival probability in the first five years of life. The analysis also suggests that the recent deceleration in the increase in female expectation of life at birth may be attributed to the decrease in the person-years lived in the age group 40-65 years.
SARS-CoV-2-associated ssRNAs activate inflammation and immunity via TLR7/8
Authors: Salvi Valentina , Nguyen Hoang Oanh , Sozio Francesca , Schioppa Tiziana , Laffranchi Mattia , Scapini Patrizia , Passari Mauro , Barbazza Ilaria , Tiberio Laura , Tamassia Nicola , Garlanda Cecilia , Del Prete Annalisa , Cassatella Marco A. , Mantovani Alberto , Sozzani Silvano , Bosisio Daniela
Published: April 2021

The inflammatory and IFN pathways of innate immunity play a key role in both resistance and pathogenesis of Coronavirus Disease 2019 (COVID-19). Innate sensors and SARS-CoV-2-Associated Molecular Patterns (SAMPs) remain to be completely defined. Here we identify single-stranded RNA (ssRNA) fragments from SARS-CoV-2 genome as direct activators of endosomal TLR7/8 and MyD88 pathway. The same sequences induced human DC activation in terms of phenotype and functions, such as IFN and cytokine production and Th1 polarization. A bioinformatic scan of the viral genome identified several hundreds of fragments potentially activating TLR7/8, suggesting that products of virus endosomal processing potently activate the IFN and inflammatory responses downstream these receptors. In vivo, SAMPs induced MyD88-dependent lung inflammation characterized by accumulation of proinflammatory and cytotoxic mediators and immune cell infiltration, as well as splenic DC phenotypical maturation. These results identify TLR7/8 as crucial cellular sensors of ssRNAs encoded by SARS-CoV-2 involved in host resistance and disease pathogenesis of COVID-19.
A suite of activity-based probes to dissect the KLK activome in drug-resistant prostate cancer
Authors: Lovell Scott , Zhang Leran , Kryza Thomas , Neodo Anna , Bock Nathalie , Williams Elizabeth D. , Engelsberger Elisabeth , Xu Congyi , Bakker Alexander T. , De Vita Elena , Maneiro Maria , Tanaka Reiko J. , Bevan Charlotte L. , Clements Judith A. , Tate Edward W.
Published: April 2021

Kallikrein-related peptidases (KLKs) are a family of secreted serine proteases, which form a network – the KLK activome – with an important role in proteolysis and signaling. In prostate cancer (PCa), increased KLK activity promotes tumor growth and metastasis through multiple biochemical pathways, and specific quantification and tracking of changes in the KLK activome could contribute to validation of KLKs as potential drug targets. Herein we report a technology platform based on novel activity-based probes (ABPs) and inhibitors with unprecedented potency and selectivity enabling simultaneous orthogonal analysis of KLK2, KLK3 and KLK14 activity in hormone-responsive PCa cell lines and tumor homogenates. Using selective inhibitors and multiplexed fluorescent activity-based protein profiling (ABPP) we dissect the KLK activome in PCa cells and show that increased KLK14 activity leads to a migratory phenotype. Furthermore, using biotinylated ABPs we show that active KLK molecules are secreted into the bone microenvironment by PCa cells following stimulation by osteoblasts suggesting KLK-mediated signaling mechanisms could contribute to PCa metastasis to bone. Together our findings show that ABPP is a powerful approach to dissect dysregulation of the KLK activome as a promising and previously underappreciated therapeutic target in advanced PCa.
XBP1s-Mediated ER Proteostasis Network Enhancement Can Selectively Improve the Folding and Secretion of an Osteogenesis Imperfecta-Causing Collagen-I Variant
Authors: DiChiara Andrew S. , Doan Ngoc-Duc , Bikovtseva Agata A. , Rowley Lynn , Butty Vincent L. , Weis MaryAnn E. , Eyre David R. , Lamandé Shireen R. , Bateman John F. , Shoulders Matthew D.
Published: April 2021

Osteogenesis imperfecta (OI) is typically caused by autosomal dominant mutations in genes encoding collagen type-I, most commonly resulting in Gly→Ser triple-helical domain substitutions that disrupt collagen folding and/or stability. Here, we test the hypothesis that upregulating the endoplasmic reticulum (ER) proteo-stasis network via the unfolded protein response (UPR) can improve the folding and secretion of the clinically severe, prototypical OI-causingCOL1A1p.G425S collagen-α1(I) variant. We first show that small molecules that activate the entire UPR by causing global ER protein misfolding stress severely ablate collagen-I secretion from both G425S Colα1(I)- and wild-type (WT) Colα1(I)-expressing primary fibroblasts. In contrast, stress-independent, specific induction of just the UPR’s XBP1s transcriptional response can enhance collagen-I secretion from G425S Colα1(I) patient primary fibroblasts up to ~300% of basal levels. Notably, the effect is selective – collagen-I secretion from WT Colα1(I)-expressing healthy donor primary fibroblasts is unaltered by XBP1s. XBP1s pathway activation appears to post-translationally enhance the folding/assembly and secretion of G425S Colα1(I), as only modest impacts on collagen-I transcription or synthesis are observed. Consistent with this notion, we find that the stable, triple-helical collagen-I secreted by XBP1s-activated G425S α1(I) patient fibroblasts includes a higher proportion of the mutant α1(I) polypeptide than the collagen-I secreted under basal ER proteostasis conditions. We note that consistent reproducibility of these results is dependent on as yet unascertained experimental variables. Still, these promising observations suggest the potential for ER proteo-stasis network modulation to improve mutant collagen proteostasis in the collagenopathies, motivating further investigation of the effect’s generality, underlying mechanism, and potential therapeutic benefits.
Multi-modal engineering ofBstDNA polymerase for thermostability in ultra-fast LAMP reactions
Authors: Paik Inyup , Ngo Phuoc H. T. , Shroff Raghav , Maranhao Andre C. , Walker David J.F. , Bhadra Sanchita , Ellington Andrew D.
Published: April 2021

DNA polymerase fromGeobacillus stearothermophilus, BstDNA polymerase (BstDNAP), is a versatile enzyme with robust strand-displacing activity that enables loop-mediated isothermal amplification (LAMP). Despite its exclusive usage in LAMP assay, its properties remain open to improvement. Here, we describe logical redesign ofBstDNAP by using multimodal application of several independent and orthogonal rational engineering methods such as domain addition, supercharging, and machine learning predictions of amino acid substitutions. The resulting Br512g3 enzyme is not only thermostable and extremely robust but it also displays improved reverse transcription activity and the ability to carry out ultrafast LAMP at 74 °C. Our study illustrates a new enzyme engineering strategy as well as contributes a novel engineered strand displacing DNA polymerase of high value to diagnostics and other fields.
Physiological Substrates and Ontogeny-Specific Expression of the Ubiquitin Ligases MARCH1 and MARCH8
Authors: Schriek Patrick , Liu Haiyin , Ching Alan C. , Huang Pauline , Gupta Nishma , Wilson Kayla R. , Tsai MinHsuang , Yan Yuting , Macri Christophe F. , Dagley Laura F. , Infusini Giuseppe , Webb Andrew I. , McWilliam Hamish , Ishido Satoshi , Mintern Justine D. , Villadangos Jose A.
Published: April 2021

MARCH1 and MARCH8 are ubiquitin ligases that control the expression and trafficking of critical immunoreceptors. Understanding of their function is hampered by three major knowledge gaps: (i) it is unclear which cell types utilize these ligases; (ii) their level of redundancy is unknown; and (iii) most of their putative substrates have been described in cell lines, often overexpressing MARCH1 or MARCH8, and it is unclear which substrates are regulated by either ligasein vivo. Here we address these questions by systematically analyzing the immune cell repertoire of MARCH1- or MARCH8-deficient mice, and applying unbiased proteomic profiling of the plasma membrane of primary cells to identify MARCH1 and MARCH8 substrates. Only CD86 and MHC II were unequivocally identified as immunoreceptors regulated by MARCH1 and MARCH8, but each ligase carried out its function in different tissues. MARCH1 regulated MHC II and CD86 in professional and “atypical” antigen presenting cells of hematopoietic origin, whereas MARCH8 only operated in non-hematopoietic cells. Our results reveal that the range of cells constitutively endowed with antigen-presentation capacity is wider than generally appreciated. They also establish MARCH1 and MARCH8 as specialized regulators of CD4+ T cell immunity in two ontogenically distinct cellular compartments.
Excitatory-inhibitory balance modulates the formation and dynamics of neuronal assemblies in cortical networks
Authors: Sadeh Sadra , Clopath Claudia
Published: April 2021

Repetitive activation of subpopulation of neurons in cortical networks leads to the formation of neuronal assemblies, which can guide learning and behavior. Recent technological advances have made the artificial induction of such assemblies feasible, yet how various patterns of activation can shape their emergence in different operating regimes is not clear. Here we studied this question in large-scale cortical networks composed of excitatory (E) and inhibitory (I) neurons. We found that the dynamics of the network in which neuronal assemblies are embedded is important for their induction. In networks with strong E-E coupling at the border of E-I balance, increasing the number of perturbed neurons enhanced the potentiation of ensembles. This was, however, accompanied by off-target potentiation of connections from unperturbed neurons. When strong E-E connectivity was combined with dominant E-I interactions, formation of ensembles became specific. Counter-intuitively, increasing the number of perturbed neurons in this regime decreased the average potentiation of individual synapses, leading to an optimal assembly formation at intermediate sizes. This was due to potent lateral inhibition in this regime, which also slowed down the formation of neuronal assemblies, resulting in a speed-accuracy trade-off in the performance of the networks in pattern completion and behavioral discrimination. Our results therefore suggest that the two regimes might be suited for different cognitive tasks, with fast regimes enabling crude detections and slow but specific regimes favoring finer discriminations. Functional connectivity inferred from recent experiments in mouse cortical networks seems to be consistent with the latter regime, but we show that recurrent and top-down mechanisms can dynamically modulate the networks to switch between different states. Our work provides a framework to study how neuronal perturbations can lead to network-wide plasticity under biologically realistic conditions, and sheds light on the design of future experiments to optimally induce behaviorally relevant neuronal assemblies.
North America Insect Invades the World: the Case of the Flood Mosquito,Aedes vexans(Diptera: Culicidae), from Mitochondrial DNA
Authors: Vargas-Espinosa José Heriberto , Aguirre-Obando Oscar Alexander
Published: April 2021

The flood mosquito,Aedes vexans(Diptera: Culicidae), native of Canada, and currently present in all continents, has a vector competence for 30 arboviruses, being responsible for transmitting diseases, like West Nile fever, Rift Valley fever, Saint Louis Encephalitis and Eastern Equine Encephalitis. Hence, knowing the structure and gene flow ofA. vexansis important to develop adequate vector control strategies for this species. For this, from partial sequences of the mitochondrial COI gene available in Bold and GenBank, it was possible to determine the Haplotypic (Hd) and nucleotide (π) gene diversity, genetic structuring and gene flow at global, continental, and country levels. In total, 1184 sequences were recovered, distributed between America (88.60%), Europe (7.35%), Asia (3.89%), and Africa (0.17%). From these, 395 haplotypes (H) were detected without presence of pseudogenes (NUMTs), with H1 being the most frequent (24.58%) and between H12 - H395 the least frequent varying between 0.93% (H12) and 0.08% (H395). Phylogenetically, the haplotypes were grouped into six clades. Clade I grouped haplotypes from countries in America and Europe, while clades II and III presented haplotypes exclusively from Asia and Europe; clade IV grouped only one haplotype from Africa and the last ultimo clade V grouped haplotypes from America and Africa. The globalHdand π was 0.92 and 0.01, respectively. In addition, evidence was obtained of genetic structuring among continents (7.07%), countries (1.62%), and within countries (91.30%; FST= 0.08, p < 0.05) and no isolation by distance was detected (r = 0.003, p > 0.05). These results suggest that the mosquito populations that invaded other continents originate directly from the American continent, where possibly transcontinental commercial routes favored their long-distance dispersion.
Echocardiographic mitral valve association with morphometric measurements in Cavalier King Charles Spaniels via Inverse Probability Weighting analysis
Authors: Bagardi Mara , Ghilardi Sara , Locatelli Chiara , Bionda Arianna , Polli Michele , Bussadori Claudio M. , Colombo Fabio M. , Pazzagli Laura , Brambilla Paola G.
Published: April 2021

Development and progression of myxomatous mitral valve disease (MMVD) in Cavalier King Charles Spaniels (CKCS) are difficult to predict. Identification at a young age of dogs with a morphotype associated with more severe mitral disease is desirable. The aims of this study were to: 1) describe the physical, morphometric, and echocardiographic features of MMVD affected Cavalier King Charles Spaniels (CKCS) in American College of Veterinary Internal Medicine (ACVIM) class B1; 2) evaluate the influence of morphometric physical measurements on murmur intensity, mitral valve prolapse (MVP), regurgitant jet size and indexed mitral valve and annulus measurements. Fifty-two MMVD affected CKCS in ACVIM class B1 were included. This is a prospective clinical cross-sectional study. Morphometric measurements, which included body, thorax, and the head sizing of each dog, have been investigated to establish the association with heart murmur intensity, valvular and annular echocardiographic measurements, MVP and regurgitant jet size using inverse probability weighting (IPW) analyses to adjust for confounding. The IPW analyses showed that when head length and nose length decreased, dogs had more severe regurgitant jet size. Furthermore, subjects with more pronounced head stop angle had thicker anterior mitral valve leaflets. A brachycephalic morphotype, with dogs more similar to King Charles Spaniel breed in cephalic morphology, is associated with a more severe regurgitant jet size and with valvular characteristics related to worse forms of MMVD.
Time-series trend of pandemic SARS-CoV-2 variants visualized using batch-learning self-organizing map for oligonucleotide compositions
Authors: Abe Takashi , Furukawa Ryuki , Iwasaki Yuki , Ikemura Toshimichi
Published: April 2021

To confront the global threat of coronavirus disease 2019, a massive number of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome sequences have been decoded, with the results promptly released through the GISAID database. Based on variant types, eight clades have already been defined in GISAID, but the diversity can be far greater. Owing to the explosive increase in available sequences, it is important to develop new technologies that can easily grasp the whole picture of the big-sequence data and support efficient knowledge discovery. An ability to efficiently clarify the detailed time-series changes in genome-wide mutation patterns will enable us to promptly identify and characterize dangerous variants that rapidly increase their population frequency. Here, we collectively analyzed over 150,000 SARS-CoV-2 genomes to understand their overall features and time-dependent changes using a batch-learning self-organizing map (BLSOM) for oligonucleotide composition, which is an unsupervised machine learning method. BLSOM can separate clades defined by GISAID with high precision, and each clade is subdivided into clusters, which shows a differential increase/decrease pattern based on geographic region and time. This allowed us to identify prevalent strains in each region and to show the commonality and diversity of the prevalent strains. Comprehensive characterization of the oligonucleotide composition of SARS-CoV-2 and elucidation of time-series trends of the population frequency of variants can clarify the viral adaptation processes after invasion into the human population and the time-dependent trend of prevalent epidemic strains across various regions, such as continents.
Glycine attenuates impairments of stimulus-evoked gamma oscillation in the ketamine model of schizophrenia
Authors: Haaf Moritz , Curic Stjepan , Steinmann Saskia , Rauh Jonas , Leicht Gregor , Mulert Christoph
Published: April 2021

Although a substantial number of studies suggests some clinical benefit concerning negative symptoms in schizophrenia through the modulation of NMDA-receptor function, none of these approaches achieved clinical approval. Given the large body of evidence concerning glutamatergic dysfunction in a subgroup of patients, biomarkers to identify those with a relevant clinical benefit through glutamatergic modulation are urgently needed. A similar reduction of the early auditory evoked gamma-band response (aeGBR) as found in schizophrenia patients can be observed in healthy subjects in the ketamine-model, which addresses the putative excitation / inhibition (E/I) imbalance of the diseases. Moreover, this change in gamma-band oscillations can be related to the emergence of negative symptoms. Accordingly, this study investigated whether glycine-related increases of the aeGBR accompany an improvement concerning negative symptoms in the ketamine-model. The impact of subanesthetic ketamine doses and the pretreatment with glycine was examined in twenty-four healthy male participants while performing a cognitively demanding aeGBR paradigm with 64-channel electroencephalography. Negative Symptoms were assessed through the Positive and Negative Syndrome Scale (PANSS). Ketamine alone caused a reduction of the aeGBR amplitude associated with more pronounced negative symptoms compared to placebo. Pretreatment with glycine attenuated both, the ketamine-induced alterations of the aeGBR amplitude and the increased PANSS negative scores in glycine-responders, classified based on relative aeGBR increase. Thus, we propose that the aeGBR represents a possible biomarker for negative symptoms in schizophrenia related to insufficient glutamatergic neurotransmission. This would allow to identify patients with negative symptoms, who might benefit from glutamatergic treatment.