bluuebunny/crossref_metadata_2025 huggingface dataset:
A scalable analytical approach from bacterial genomes to epidemiology
Authors: Didelot Xavier , Parkhill Julian
Published: August 2022

Recent years have seen a remarkable increase in the practicality of sequencing whole genomes from large numbers of bacterial isolates. The availability of this data has huge potential to deliver new insights into the evolution and epidemiology of bacterial pathogens, but the scalability of the analytical methodology has been lagging behind that of the sequencing technology. Here we present a step-by-step approach for such large-scale genomic epidemiology analyses, from bacterial genomes to epidemiological interpretations. A central component of this approach is the dated phylogeny, which is a phylogenetic tree with branch lengths measured in units of time. The construction of dated phylogenies from bacterial genomic data needs to account for the disruptive effect of recombination on phylogenetic relationships, and we describe how this can be achieved. Dated phylogenies can then be used to perform fine-scale or large-scale epidemiological analyses, depending on the proportion of cases for which genomes are available. A key feature of this approach is computational scalability and in particular the ability to process hundreds or thousands of genomes within a matter of hours. This is a clear advantage of the step-by-step approach described here. We discuss other advantages and disadvantages of the approach, as well as potential improvements and avenues for future research.

This article is part of a discussion meeting issue ‘Genomic population structures of microbial pathogens’.
Fetoscopic Endoluminal Tracheal Occlusion with Smart-TO balloon: efficacy of removal and safety
Authors: Sananès Nicolas , Basurto David , Cordier Anne-Gaël , Elie Caroline , Russo Francesca , Benachi Alexandra , Deprest Jan
Published: August 2022

Introduction

One of the drawbacks of fetoscopic endoluminal tracheal occlusion (FETO) for congenital diaphragmatic hernia is the need for a second invasive intervention to reestablish airway patency. The “Smart-TO” (Strasbourg University-BSMTI, France) is a new balloon for FETO, which spontaneously deflates when positioned near a strong magnetic field, e.g., generated by a magnetic resonance image (MRI) scanner. Translational experiments have demonstrated its efficacy and safety. We will now use the Smart-TO balloon for the first time in humans. Our main objective is the efficacy of prenatal deflation of the balloon by the magnetic field generated by an MRI scanner.

Material and methods

This is a phase-I study conducted in the fetal medicine units of Antoine–Béclère Hospital, France, and UZ Leuven, Belgium. Conceived in parallel, protocols were amended by the local Ethics Committees, resulting in some minor differences. This trial is a single-arm interventional feasibility study. Twenty (France) and 25 (Belgium) participants will have FETO with the Smart-TO balloon. Balloon deflation will be scheduled at 34 weeks or earlier if clinically required. The primary endpoint is the successful deflation of the Smart-TO balloon after exposure to the magnetic field of an MRI, assessed through ultrasound immediately after MRI-exposure. The secondary objective is to report on the safety of the balloon. The percentage of fetuses in whom the balloon is deflated after exposure will be calculated with its 95% confidence interval. Safety will be evaluated by reporting the nature, number, and percentage of serious unexpected or adverse reactions.

Conclusion

This phase-I study may provide the first evidence of the potential to reverse the occlusion by Smart-TO and free the airways non-invasively, as well a safety data.
Combining cash transfers and cognitive behavioral therapy to reduce antisocial behavior in young men: A mediation analysis of a randomized controlled trial in Liberia
Authors: Carpena Marina Xavier , Paula Cristiane Silvestre , Loret de Mola Christian , Hessel Philipp , Avendano Mauricio , Evans-Lacko Sara , Matijasevich Alicia
Published: August 2022

Background

Interventions that combine cognitive behavioral therapy (CBT) with unconditional cash transfers (UCT) reduce the risk of antisocial behavior (ASB), but the underlying mechanisms are unclear. In this paper, we test the role of psychological and cognitive mechanisms in explaining this effect. We assessed the mediating role of executive function, self-control, and time preferences.

Methods

We used data from the Sustainable Transformation of Youth in Liberia, a community-based randomized controlled trial of criminally engaged men. The men were randomized into: Group-1: control (n=237); and Group-2: CBT+UCT (n=207). ASB was measured 12-13 months after the interventions were completed, and the following mediators were assessed 2-5 weeks later: (i) self-control, (ii) time preferences and (iii) executive functions. We estimated the natural direct effect (NDE) and the natural indirect effect (NIE) of the intervention over ASB.

Results

Self-control, time preferences and a weighted index of all three mediators were associated with ASB scores, but the intervention had an effect on time preferences only [B= 0.09 95%CI (0.03; 0.15)]. There was no evidence that the effect of the intervention on ASB was mediated by self-control [BNIE= 0.007 95%CI (-0.01; 0.02)], time preferences [BNIE= -0.02 95%CI (-0.05; 0.01)], executive functions [BNIE= 0.002 95%CI (-0.002; 0.006)] or the weighted index of the mediators [BNIE= -0.0005 95%CI (-0.03; 0.02)].

Conclusions

UCT and CBT lead to improvements in ASB, even in the absence of mediation via psychological and cognitive functions. Findings suggest that the causal mechanisms may involve non-psychological pathways.
Subjective Cognitive Decline is a Better Marker for Future Cognitive Decline in Females than in Males
Authors: Oliver Michael D. , Morrison Cassandra , Kamal Farooq , Graham Jillian , Dadar Mahsa
Published: August 2022

Background

The identification of biomarkers and other mechanisms for early detection of Alzheimer’s disease is critical to the development and further advancement of therapies and interventions targeted at managing symptoms and tracking the pathophysiology of disease. The endorsement of subjective cognitive decline (SCD) has emerged as a potential indicator of early change in cognitive status that may be predictive of future impairment at a time when measurable declines in neuropsychological performance cannot be detected. While there are numerous findings revealing sex differences in the prevalence of Alzheimer’s disease, there is a paucity of research examining sex differences in SCD. Therefore, the goal of this project is to determine if the relationship between the endorsement of SCD and future cognitive changes differ as a function of biological sex.

Methods

A sample of 3019 male and female healthy older adults (2188 without SCD, 831 with SCD), with a mean follow-up time of 5.7 years, were included from the Rush Alzheimer’s Disease Center Research Sharing Hub. Linear regressions were performed to determine group differences in baseline cognitive scores, while linear mixed effects models were computed to determine group differences in the rate of cognitive change over time.

Results

Individuals endorsing SCD had significantly lower baseline cognitive scores and increased rates of decline in all cognitive domains compared to those without SCD. Males exhibited significantly lower scores in baseline performance in global cognition, episodic memory, semantic memory, and perceptual speed regardless of SCD classification. Females with SCD were found to decline at significantly faster rates than both males with SCD and males and females without SCD in all cognitive domains over 15-year follow-up.

Conclusions

SCD is related to lower baseline cognitive performance and faster cognitive decline compared to those who do not endorse SCD. Females with SCD have the fastest rate of decline suggesting that SCD may be more predictive of future decline in females than in males. Therapeutic interventions targeting SCD in females may aid in the mitigation of sex disparities in AD prevalence.
Pre-symptomatic reduction of individuality in the AppNL-F knock-in model of Alzheimer’s disease
Authors: Ehret Fanny , Pelz Meike S. , Senko Anna N. , Soto Karla E. G. , Liu Hang , Kempermann Gerd
Published: August 2022

While one third of the risk for Alzheimer’s disease (AD) is explained by environment and lifestyle, AD pathology also affects individual lifestyle, possibly long before clinical manifestation of dementia. To study this hidden disease effect with its potentially large impact on coping with AD, we examined in mice how the AppNL-F/NL-F (NL-F) knock-in mutation affects the pre-symptomatic response to environmental enrichment (ENR). We assessed the emergence of inter-individual phenotypic variation while both genetic background and the shared environment were held constant, thereby isolating the contribution of individual behavior (‘non-shared environment’). After 4 months of ENR, in NL-F both mean and variability of plasma ApoE were increased, suggesting a pre-symptomatic variation in pathogenic processes. Roaming entropy (RE) as a measure of behavioral activity was continuously assessed with radiofrequency identification (RFID) technology and revealed reduced habituation and variance in NL-F compared to controls. Intra-individual variation decreased but behavioral predictability and stability were reduced in NL-F. Seven months after discontinuation of ENR we found no difference in plaque size and number, but ENR increased variance in hippocampal plaque counts in NL-F. A reactive increase in adult hippocampal neurogenesis in NL-F, known from other models, was normalized by ENR. Our data suggest that, while NL-F has early effects on individual behavioral patterns in response to ENR, there are lasting effects at the level of cellular plasticity even after discontinuation of ENR. Hence, early behavior matters for maintaining individual behavioral trajectories and brain plasticity even under maximally constraint conditions.
How to optimally sample a sequence for rapid analysis
Authors: Frith Martin C. , Shaw Jim , Spouge John L.
Published: August 2022

We face an increasing flood of genetic sequence data, from diverse sources, requiring rapid computational analysis. Rapid analysis can be achieved by sampling a subset of positions in each sequence. Previous sequence-sampling methods, such as minimizers, syncmers, and minimally-overlapping words, were developed by heuristic intuition, and are not optimal.

We present a sequence-sampling approach that provably optimizes sensitivity for a whole class of sequence comparison methods, for randomly-evolving sequences. It it likely near-optimal for a wide range of alignmentbased and alignment-free analyses. For real biological DNA, it increases specificity by avoiding simple repeats. Our approach generalizes universal hitting sets (which guarantee to sample a sequence at least once), and polar sets (which guarantee to sample a sequence at most once). This helps us understand how to do rapid sequence analysis as accurately as possible.
Estimating bone marrow adiposity from head MRI and identifying its genetic architecture
Authors: Kaufmann Tobias , Bjørnstad Pål Marius , Falck Martin , Nerland Stener , O’Connell Kevin , Frei Oleksandr , Andreassen Ole A. , Westlye Lars T. , Djurovic Srdjan , Hughes Timothy
Published: August 2022

Bone marrow adiposity changes radically through the lifespan, but this phenomenon is poorly characterised and understood in humans. Large datasets of magnetic resonance imaging (MRI) scans of the head have been collected to study the human brain, but also contain unexploited information about other organs. We developed an artificial neural network that localises calvarial bone marrow in T1-weighted MRI head scans, enabling us to study its composition in several large MRI datasets, and to model sex-dimorphic age trajectories, including the effect of menopause. We revealed high heritability in single-nucleotide polymorphism and twin data, and identified 41 genetic loci significantly associated with the trait, including six sex-specific loci. Integrating mapped genes with existing bone marrow single-cell RNA-sequencing data revealed patterns of adipogenic lineage differentiation and lipid loading. Finally, we identified significant genetic correlations with several human traits, including cognitive ability and Parkinson’s disease, which is intriguing in light of the recently discovered channels that link calvarial bone marrow to the meninges.
Upper-room germicidal ultraviolet light reduced respiratory-related absenteeism among pre-school students: an analysis of newly discovered historical data
Authors: Ryan Christopher W.
Published: August 2022

Objectives

To assess the effect of upper-room germicidal ultraviolet light systems (GUV) on child absenteeism from a preschool.

Methods

I fit a generalized linear model for interventional time series to a newly-discovered historical dataset of attendance records from a preschool from 1941 to 1949, where GUV was installed in December 1945.

Results

In all but peak summer months, the presence of GUV was associated with a sizable reduction in child absenteeism due to respiratory illnesses of any cause. Odds ratios for the effect ranged from 0.49 to 0.77, depending on season. In all but high summer, model-predicted absenteeism rates with GUV were a third to a half what they were without it.

Conclusions

Installation of upper-room germicidal light in a preschool in December 1945 was associated with a signficant and operationally meaningful reduction in absenteeism due to respiratory illness of any cause. While today’s overall epidemiological environment may be different from that of the 1940s, COVID-19 has shown us that the human species remains vulnerable to pandemics of novel respiratory pathogens, to say nothing of annual influenza outbreaks. Thus air disinfection in congregate indoor settings remains a critical issue. Wider use of upper-room germicidal UV systems in schools and preschools may be worthwhile to reduce absenteeism due to illness, and the educational, social, and economic consequences that ensue.
Enhancing global preparedness during an ongoing pandemic from partial and noisy data
Authors: Klamser Pascal , d’Andrea Valeria , Di Lauro Francesco , Zachariae Adrian , Bontorin Sebastiano , di Nardo Antonello , Hall Matthew , Maier Benjamin F. , Ferretti Luca , Brockmann Dirk , De Domenico Manlio
Published: August 2022

Abstract

As the coronavirus disease 2019 (COVID-19) spread globally, emerging variants such as B.1.1.529 quickly became dominant worldwide. Sustained community transmission favors the proliferation of mutated sub-lineages with pandemic potential, due to cross-national mobility flows, which are responsible for consecutive cases surge worldwide. We show that, in the early stages of an emerging variant, integrating data from national genomic surveillance and global human mobility with large-scale epidemic modeling allows to quantify its pandemic potential, providing quantifiable indicators for pro-active policy interventions. We validate our framework on worldwide spreading variants and gain insights about the pandemic potential of BA.5, BA.2.75 and other sub- and lineages. We combine the different sources of information in a simple estimate of the pandemic delay and show that only in combination, the pandemic potentials of the lineages are correctly assessed relative to each other. Country-level epidemic intelligence is not enough to contrast the pandemic of respiratory pathogens such as SARS-CoV-2 and a scalable integrated approach, i.e. pandemic intelligence, is required to enhance global preparedness.
From genome to phenome via the proteome: broad capture, antibody-based proteomics to explore disease mechanisms
Authors: Koprulu Mine , Carrasco-Zanini Julia , Wheeler Eleanor , Lockhart Sam , Kerrison Nicola D. , Wareham Nicholas J. , Pietzner Maik , Langenberg Claudia
Published: August 2022

Studying the plasma proteome as the intermediate layer between the genome and the phenome has the potential to identify disease causing genes and proteins and to improve our understanding of the underlying mechanisms. Here, we conducted acis-focused proteogenomic analysis of 2,923 plasma proteins measured in 1,180 individuals using novel antibody-based assays (Olink® Explore 1536 and Explore Expansion) to identify disease causing genes and proteins across the human phenome. We describe 1,553 distinct credible sets of protein quantitative trait loci (pQTL), of which 256 contained cis-pQTLs not previously reported. We identify 224 cis-pQTLs shared with 578 unique health outcomes using statistical colocalization, including, gastrin releasing peptide (GRP) as a potential therapeutic target for type 2 diabetes. We observed convergence of phenotypic consequences of cis-pQTLs and rare loss-of-function gene burden for twelve protein coding genes (e.g.,TIMD4and low-density lipoprotein metabolism), highlighting the complementary nature of both approaches for drug target prioritization. Proteogenomic evidence also improved causal gene assignment at 40% (n=192) of overlapping GWAS loci, includingDKKL1as the candidate causal gene for multiple sclerosis.

Our findings demonstrate the ability of broad capture, high-throughput proteomic technologies to robustly identify new gene-protein-disease links, provide mechanistic insight, and add value to existing GWASs by enabling and refining causal gene assignment.
Prevalence, Pattern and Risk Factors for Work-Related Musculoskeletal Disorders among Nigerian Plumbers
Authors: Mbada Chidozie E. , Abegunrin Aanuoluwa Feyisike , Egwu Michael Ogbonnia , Fatoye Clara Toyin , Moda Haruna , Falade Olatomiwa , Fatoye Francis
Published: August 2022

Plumbing work is more manually driven in low-and-middle income countries (LMICs), and the prevalence of work-related musculoskeletal disorders (WMSDs) among workers who engage in plumbing in LMICs may be worse than earlier reports from developed countries. This study aimed to assess the prevalence, pattern and risk factors for work-related musculoskeletal disorders (WMSDs) among Nigerian plumbers.

A total of 130 consenting plumber participated in this cross-sectional study. The Nordic Musculoskeletal questionnaire and the Job Factor Questionnaire were used to assess information on prevalence and pattern of WMSDs; and perceptions regarding work-related risks factors for WMSDs. Descriptive (mean, frequency, range, percentage and standard deviation) and inferential (Chi-square) statistics were used to analyze data. Alpha level was set at p<0.05.

The mean age of the respondents is 36.56 + 10.418 years. The mean years of experience and working hours per day are 14.15 + 9.161 years and 8.28 + 2.512 hours. Job characteristics were mostly installation of pipes and fixtures (99.2%), equipment and fixtures prior to installation (96.9%), and testing of plumbing system for leaks (88.5%). 12-month and 7-day prevalence of WMSDS were 84.6% and 50.8%. Low-back (63.8%), neck (55.4%) and knee (50%) were the most affected body sites. Having WMSDs limits normal activities involving the low-back (32.3%), knee (25.4%) and neck (23.8%). There was significant association between 12-month prevalence of WMSDs and use of saws and pipe cutters (χ2 = 4.483; p = 0.034), while sites of affectation had significant association with 12-month and 7-day prevalence of WMSDs (p<0.05) respectively.

Nigerian plumbers have a high prevalence of WMSDs affecting most commonly the low back, neck and knee. Plumbing job factors pose mild to moderate risk to developing WMSDs, and use of saws and pipe cutters significantly influence WMSDs.
Improving visual attention following right hemisphere stroke: A preliminary study
Authors: Edwards Grace , Buxbaum Laurel J. , Chen Gang , Edwards Dylan , Battelli Lorella
Published: August 2022

Left inattention is common in individuals following right cerebrovascular accident (RCVA). In neurotypical adults, we have previously found prolonged rightward visual attention resulted in a subsequent increase in leftward attention. Here we applied the same method in neurological patients with RCVA and found improved post-intervention attention both to the left and right of visual fixation in participants with mild to no leftward inattention in comparison to a control. No such benefit was detected in participants with more pronounced leftward inattention. Given the feasibility of the intervention which leverages performance in the right unaffected visual space, future studies should examine the longevity and generalizability of such an intervention to other attention demanding tasks.
Thermotaxis in an apolar, non-neuronal animal
Authors: Zhong Grace , Kroo Laurel , Prakash Manu
Published: August 2022

Neuronal circuits are hallmarks of complex decision making processes in the animal world. How animals without neurons process information and respond to environmental cues promises a new window into studying precursors of neuronal control and origin of the nervous system as we know it today. Robust decision making in animals, such as in chemotaxis or thermotaxis, often requires internal symmetry breaking (such as A-P axis) provided naturally by a given body plan of an animal. Here we report the discovery of robust thermotaxis behavior in Trichoplax adhaerens, an early-divergent, enigmatic animal with no anterior-posterior symmetry breaking (apolar), and no known neurons or muscles. We present the first quantitative and robust behavioral response assay in placozoan, which present an apolar flat geometry. By exposing T. adhaerens to a thermal gradient under a long-term imaging setup, we observe robust thermotaxis that occurs over timescale of hours, independent of any circadian rhythms. We quantify that T. adhaerens can detect thermal gradients of at least 0.1 °C/cm. Positive thermotaxis is observed for a range of baseline temperatures from 17-22.5 °C with motility trajectories to be well-described by a Lévy distribution. Interestingly, the organism does not maintain a fixed orientation while performing thermotaxis. Utilizing natural diversity in size of adult organisms (100um to a few mm), we also demonstrate a critical animal size above which thermotaxis behavior is hindered. Several TRP family homologs have been previously reported to be conserved in metazoans, including in T. adhaerens. We discover naringenin, a known TRPM3 antagonist, inhibits thermotaxis in T. adhaerens. The discovery of robust thermotaxis in T. adhaerens provides a tractable handle to interrogate information processing in a brainless animal. Understanding how divergent marine animals process thermal cues is also critical due to rapid temperature rise in our oceans.
Texture coding in higher order somatosensory cortices of primates
Authors: Long Katie H. , Greenspon Charles M. , van Driesche Ashley , Lieber Justin D. , Bensmaia Sliman J.
Published: August 2022

Abstract

Our sense of touch confers to us the ability to perceive textural features over a broad range of spatial scales and material properties, giving rise to a complex sensory experience. To understand the neural basis of texture perception requires that the responses of somatosensory neurons be probed with stimuli that tile the space of spatial scales and material properties experienced during everyday interactions with objects. We have previously shown that neurons in early stages of somatosensory processing – the nerves and somatosensory cortex (S1) – are highly sensitive to texture and carry a representation of texture that is highly informative about the surface but also predicts the evoked sensory experience. In contrast, the texture signals in higher order areas – secondary somatosensory cortex (S2) and the parietal ventral area (PV) – have never been investigated with a rich and naturalistic textural set. To fill this gap, we recorded single-unit activity in S2/PV of macaques while they performed a texture discrimination task. We then characterized the neural responses to texture and compared these to their counterparts in somatosensory cortex (S1). We found that the representation of texture in S2/PV differs markedly from its counterpart in S1. In particular, S2/PV neurons carry a much sparser representation of texture identity and also information about task variables, including the animal’s eventual perceptual decision. S2/PV thus seems to carry a labile representation of texture that reflects task demands rather than faithfully encoding the stimulus.
Annotation of biologically relevant ligands in UniProtKB using ChEBI
Authors: Coudert Elisabeth , Gehant Sebastien , de Castro Edouard , Pozzato Monica , Baratin Delphine , Neto Teresa Batista , Sigrist Christian J.A. , Redaschi Nicole , Bridge Alan ,   The UniProt Consortium
Published: August 2022

Motivation

To provide high quality, computationally tractable annotation of binding sites for biologically relevant (cognate) ligands in UniProtKB using the chemical ontology ChEBI (Chemical Entities of Biological Interest), to better support efforts to study and predict functionally relevant interactions between proteins and small molecule ligands.

Results

We structured the data model for cognate ligand binding site annotations in UniProtKB and performed a complete reannotation of all cognate ligand binding sites using stable unique identifiers from ChEBI, which we now use as the reference vocabulary for all such annotations. We developed improved search and query facilities for cognate ligands in the UniProt website, REST API and SPARQL endpoint that leverage the chemical structure data, nomenclature, and classification that ChEBI provides.

Availability

Binding site annotations for cognate ligands described using ChEBI are available for UniProtKB protein sequence records in several formats (text, XML, and RDF), and are freely available to query and download through the UniProt website (www.uniprot.org), REST API (www.uniprot.org/help/api), SPARQL endpoint (sparql.uniprot.org/), and FTP site (https://ftp.uniprot.org/pub/databases/uniprot/).

Contact

alan.bridge@sib.swiss

Supplementary information

Supplementary Table 1.
3-D structure based prediction of SUMOylation sites
Authors: Ramtirtha Yogendra , Madhusudhan M. S.
Published: August 2022

SUMOylation is a posttranslational modification that involves lysine residues from eukaryotic proteins. Misregulation of the modification has been linked to neuro-degenrative diseases and cancer. All the presently available tools to predict SUMOylation sites are sequence based. Here, we propose a novel structure based prediction tool to discriminate between SUMOylated and non-SUMOylated lysines. We demonstrate the method by carrying out a proof-of-concept study. The method achieved an accuracy of 81% and a Matthews’ Correlation Coefficient of 0.4.
Mechanical and Heat Hyperalgesia upon Withdrawal from Chronic Intermittent Ethanol Vapor depends on Sex, Exposure Duration and Blood Alcohol Concentration in Mice
Authors: Brandner AJ , Baratta AM , Rathod RS , Ferguson C , Taylor BK , Farris SP
Published: August 2022

Approximately half of patients with alcohol use disorder (AUD) report pain and this can be severe during withdrawal. However, many questions remain regarding the importance of sex, blood alcohol concentration (BAC), time course, and pain modality. To examine the impact of sex and BAC on the time course of the development of mechanical and heat hyperalgesia, we characterized a mouse model of Chronic Alcohol Withdrawal Induced Pain (CAWIP) in the presence or absence the alcohol dehydrogenase inhibitor, pyrazole. Male and female C57BL/6J mice underwent chronic intermittent ethanol vapor (CIEV) ± pyrazole exposure for 4 weeks, 4 days/week to induce ethanol dependence. Hind paw sensitivity to the plantar application of mechanical (von Frey filaments) and radiant heat stimuli were measured during weekly observations at 1, 3, 5, 7, 24, and 48 hr after cessation of ethanol exposure. In the presence of pyrazole, males developed mechanical hyperalgesia after the first week of CIEV exposure, peaking at 48 hours after cessation of ethanol. By contrast, females did not develop mechanical hyperalgesia until the fourth week; this also required pyrazole and did not peak until 48 hours. Heat hyperalgesia was consistently observed only in females exposed to ethanol and pyrazole; this developed after the first weekly session and peaked at 1 hour. We conclude that CAWIP develops in a sex –, time –, and BAC – dependent manner in C57BL/6J mice.
Exposure to a hypercaloric diet produces long lasting changes in motivation1
Authors: Zepeda-Ruiz Wendy Andrea , Abonza Paez Héctor Alan , Cerbon Marco , Velazquez Martinez David N.
Published: August 2022

Changes in motivation have been observed following induction of diet-induced obesity. However, to date, results have been contradictory, some authors reporting an increase in motivation to obtain palatable food, but others observing a decrease. Observed differences might be associated with the length of both the evaluation period and exposure to the diet. Therefore, the aim of this study was to evaluate changes in motivation during 20 weeks of exposure to a hypercaloric diet. Performance of the subjects in a progressive ratio schedule was evaluated before and during the exposure to a high-fat, high-sugar choice diet (HFHSc). A decrease in motivation was observed after 2 weeks of diet exposure, low levels of motivation remained throughout 20 weeks. A comparable decrease in motivation took longer (3 weeks) to develop using chow diet in the control group. Overall, our results suggest that, when changes in motivation are being evaluated, long periods of diet exposure made no further contribution, once motivation decreased, it remained low up to 18 weeks. Exposure to a HFHSc diet is a useful animal model of obesity, since it replicates some pathophysiological and psychological features of human obesity such as an increase in fasting glucose levels, body weight and the weight of adipose tissue.
Uncovering personalised glucose responses and circadian rhythms from multiple wearable biosensors with Bayesian dynamical modelling
Authors: Phillips Nicholas E. , Collet Tinh-Hai , Naef Felix
Published: August 2022

Motivation

Wearable biosensors measure physiological variables with high temporal resolution over multiple days and are increasingly employed in clinical settings, such as continuous glucose monitoring in diabetes care. Such datasets bring new opportunities and challenges, and patients, clinicians and researchers are today faced with a common challenge: how to best capture and summarise relevant information from multimodal wearable time series? Here, we aim to provide insights into individual blood glucose dynamics and their relationships with food and drink ingestion, time of day, and coupling with other physiological states such as physical and heart activity. To this end, we generate and analyse multiple wearable device data through the lens of a parsimonious mathematical model with interpretable components and parameters. A key innovation of our method is that the models are learnt on a personalised level for each participant within a Bayesian framework, which enables the characterisation of inter-individual heterogeneity in features such as the glucose response time following meals or underlying circadian rhythms. This framework may prove useful in other populations at risk of cardiometabolic diseases.

Wearable biosensors and smartphone applications can measure physiological variables over multiple days in free-living conditions. We measure food and drink ingestion, glucose dynamics, physical activity, heart rate (HR) and heart rate variability (HRV) in 25 healthy participants over 14 days. We develop a Bayesian framework to learn personal parameters that quantify circadian rhythms and physiological responses to external stressors. Modelling the effects of ingestion events on glucose levels reveals that slower glucose decay kinetics elicit larger postprandial glucose spikes, and we uncover a circadian baseline rhythm of glucose with high amplitudes in some individuals. Physical activity and circadian rhythms explain as much as 40-65% of the HR variance, whereas the variance explained for HRV is more heterogeneous across individuals (20-80%). A more complex model incorporating activity, HR and HRV explains up to 15% additional glucose variability, highlighting the relevance of integrating multiple biosensors to better predict glucose dynamics.
Transdiagnostic Clinical Features Delineate Trajectories of Serious Mental Illness
Authors: De la Hoz Juan F. , Arias Alejandro , Service Susan K. , Castaño Mauricio , Diaz-Zuluaga Ana M. , Song Janet , Gallego Cristian , Ruiz-Sánchez Sergio , Escobar Javier I , Bui Alex A. T. , Bearden Carrie E. , Reus Victor , Lopez-Jaramillo Carlos , Freimer Nelson B. , Olde Loohuis Loes M.
Published: August 2022

Background

Electronic health record (EHR) databases, increasingly available in low- and middle-income countries (LMIC), provide an opportunity to study transdiagnostic features of serious mental illness (SMI) and delineate illness trajectories using clinical data.

Aims

Characterize transdiagnostic features and diagnostic trajectories of SMI using structured and unstructured data from an EHR database in an LMIC institution.

Methods

We conducted a retrospective cohort study using EHR data from 2005-2022 at Clínica San Juan de Dios Manizales, a specialized mental health facility in Caldas, Colombia. We included 22,447 patients treated for schizophrenia (SCZ), bipolar disorder (BD), severe or recurrent major depressive disorder (MDD). We extracted diagnostic codes, clinical notes, and healthcare use data from the EHR database. Using natural language processing, we analyzed the frequency of suicidality and psychosis across SMI diagnoses. Using the diagnostic trajectories, we studied patterns of diagnostic switching and accumulation of comorbidities. Mixed-effect logistic regression was used to assess factors influencing diagnostic stability.

Results

High frequencies of suicidality and psychosis were observed across diagnoses of SCZ, BD, and MDD. Most SMI patients (64%) received multiple diagnoses over time, including switches between primary SMI diagnoses (19%), diagnostic comorbidities (30%), or both (15%). Predictors of diagnostic switching included mentions of delusions in clinical notes (OR=1.50, p=2e-18), prior diagnostic switching (OR=4.02, p=3e-250), and time in treatment, independent of age (log of visit number; OR=0.56, p=5e-66). Over 80% of patients reached diagnostic stability within six years of their first record.

Conclusions

This study demonstrates that integrating structured and unstructured EHR data can reveal clinically relevant, transdiagnostic patterns in SMI, including early predictors of disease trajectories. Our findings underscore the potential of EHR-based tools to aid etiological research and the development of personalized treatment strategies, particularly in LMIC.
Clinical profile of scrub typhus patients during COVID pandemic: A sub-Himalayan single center experience
Authors: Singh Moirangthem Bikram , Bahurupi Yogesh A. , Panda Prasan Kumar , Kalita Deepjyoti
Published: August 2022

Introduction

Scrub typhus is tropical zoonotic disease, commonly presented with multi organ dysfunction and high mortality rate in untreated patients. This study was done to identify clinical features commonly associated with scrub typhus during COVID pandemics, parameters associated with severe scrub typhus and mortality.

Methods

This retrospective study was done in a tertiary care hospital with a total of 52 admitted scrub typhus positive patients in October 2020 to February 2022. Diagnosis was established by scrub IgM ELISA or Rapid antigen test. The clinical and laboratory data, duration of hospital stay and outcomes were collected. Common clinical and laboratory findings were of descriptive analysis. Factors associated with mortality were analysed using Chi-square test.

Results

Fever was the most common presenting symptoms on admission (94.2%) followed by respiratory abnormalities (38.46%). Acute kidney injury was the most common organ failure on admission (67.3%), followed by acute liver injury (46.2%) and thrombocytopenia (32.7%). MODS was seen in 46.15%. Of the total, 30.8% were admitted in ICU. Mortality was seen in 7.7% of all patients. On Chi-square analysis, altered mental status and coagulopathy were associated with significant mortality with p value <0.05.

Conclusion

Scrub typhus can manifest with potentially life-threatening complications such as acute kidney injury, acute liver injury, thrombocytopenia and MODS. The overall case-fatality rate was 7.7%, and presence of altered mental status and coagulopathy were associated with higher mortality. As per literature, COVID has changed few clinical profiles of scrub typhus compared to same center experience before.
Somatic mosaic chromosomal alterations and death of cardiovascular disease causes among cancer survivors: an analysis of the UK Biobank
Authors: Sun Maxine , Cyr Marie-Christyne , Sandoval Johanna , Perreault Louis-Philippe Lemieux , Busque Lambert , Tardif Jean-Claude , Dubé Marie-Pierre
Published: August 2022

Cancer survivors are at an increased risk of cardiovascular disease (CVD) compared to the general population. Here, we evaluated the impact of somatic mosaic chromosomal alterations (mCAs) on death of CVD causes, coronary artery disease (CAD) causes, from cancer, and of any cause in patients with a cancer diagnosis within the UK Biobank (n=48 919). mCAs were derived from DNA genotyping array intensity data and long-range chromosomal phase inference from participants. Overall, 10 070 individuals (20.6%) carried ≥1 mCA clone. In adjusted analyses, mCA was associated with an increased risk of death of CAD causes (hazard ratio [HR]: 1.37, 95% confidence interval [CI]: 1.09-1.71, P=0.006), from cancer (HR: 1.06, 95% CI: 1.00-1.11, P=0.041), and death of any cause (HR: 1.07, 95% CI: 1.02-1.12, P=0.005). Among cancer survivors, carriers of any mCA are at an increased risk of death of CAD causes and of any cause as compared to non-carriers.
Clinical Study to Evaluate the Possible Efficacy and Safety of Antibodies Combination (casirivimab and imdevimab) versus standard antiviral therapy as antiviral agent against Corona virus 2 infection in hospitalized COVID-19 patients
Authors: Hassan Ahmed H. , Hegazy Sahar K. , Radwan Samar T.
Published: August 2022

Introduction

Corona Virus-induced disease – 2019 (COVID-19) pandemic stimulates research works to find a solution to this crisis from starting 2020 year up to now. With ending of the 2021 year, various advances in pharmacotherapy against COVID-19 have emerged.

Regarding antiviral therapy, Casirivimab and imdevimab antibody combination is a type of new immunotherapy against COVID-19. Standard antiviral therapy against COVID-19 includes Remdesivir and Favipravir.

Aim of Study

To compare the efficacy and safety of antibodies cocktail (casirivimab and imdevimab), Remdesivir, and Favipravir in the COVID-19 patients

Patients and Population

265 hospitalized COVID-19 patients were used to represent the COVID-19 population and were assigned into three groups in a ratio of (1:2:2) respectively, Group (A) received REGN3048-3051(Antibodies cocktail (casirivimab and imdevimab), group (B) received remdesivir, and group (C) received favipravir.

Methods

The study design is a single-blind non-Randomized Controlled Trial (non-RCT). The drugs of the study are owned by Mansoura University Hospital (MUH) and prescribed by chest diseases lectures of the faculty of medicine-Mansoura University. The duration of the study is about 6 months after ethical approval.

Results and discussion

Casirivimab and imdevimab achieve less 28-day mortality rate, less mortality at hospital discharge, more negative swab cases, less need for O2 therapy and IMV, less duration of this need, less hospital and ICU stay, less case progression as presented by lower World Health Organization (WHO) scale and better multi-organ functions as presented by lower Sequential Organ Function Assessment (SOFA) score than Remdesivir and Favipravir.

Conclusion

From all of these results, it is concluded that Group A (Casirivimab & imdevimab) has more favorable clinical outcomes than B (remdesivir) & C (favipravir) intervention groups.

Clinical Trial Registration:NCT05502081, 16/08/2022,Clinicaltrials.gov, retrospectively registered
#ChronicPain: Automatic establishment of a chronic pain cohort from social media using machine learning for studying opioid-alternative therapies
Authors: Lakamana Sahithi , Guo Yuting , Ge Yao , Leslie Abimbola , Okunromade Omolola , Yang Yuan-Chi , Gonzalez-Polledo Elena , Perrone Jeanmarie , McKenzie-Brown Anne , Sarker Abeed
Published: August 2022

Due to the high economic and public health burden of chronic pain, and the risk of public health consequences of opioid-based treatments, there is a need to identify effective alternative therapies. The evidence basis for many alternative therapies is weak or nonexistent. Social media presents a unique opportunity to gather large-scale knowledge about such therapies self-reported by sufferers themselves. We attempted to (i) verify the presence of largescale chronic pain-related chatter on Twitter, (ii) develop natural language processing (NLP) and machine learning for automatically detecting chronic pain sufferers, and (iii) identify the types of chronic pain-related information reported by them. We collected data from Twitter using chronic pain-related hashtags and keywords. We manually performed binary annotation of a sample of 4998 posts to indicate if they were self-reports of chronic pain experiences or not, and obtained inter-annotator agreement of 0.82 (Cohen’s kappa). We trained and evaluated several state-of-the-art transformer-based text classification models using the annotated data. The RoBERTa model outperformed all others (F1 score = 0.84; 95% CI: 0.80-0.89), and we used this model to classify a large number of unlabeled posts. We identified 22,795 self-reported chronic pain sufferers and collected their past posted data. Via manual and NLP-driven analyses, we found information about but not limited to alternative treatments, sufferers’ sentiments about treatments, side effects, and self-management strategies. Our social media-based approach will result in an automatically growing massive cohort over time, and the data can be leveraged to identify self-reported effective alternative therapies for diverse chronic pain types.
Model for FRET sensors of allosteric switchable modulator proteins for the determination of allosteric parameters
Authors: Babel Heiko
Published: August 2022

FRET-sensors are a well-established method to investigate protein-protein interactions. To determine how FRET-sensor can be employed for the study of switchable allosteric modulator proteins (SAMPs) I extend a previously established model for enzymatic SAMPs to include a FRET-sensor system. Using this model, I determine the prerequisites for using FRET to investigate modulator-regulator interaction. The model shows, that under saturating stimulus conditions only a trimolecular complex contributes to the measured FRET value. How the signal is relayed by the modulator can be investigated by comparing FRET values of unstimulated and signal-saturated sensor systems. Finally, to determine the allosteric mode of signal transduction the natural logarithm of the ratio of stimulated and unstimulated FRET efficiencies is a useful metric.
Dynamic Disulfide Bond Topologies in von-Willebrand-Factor’s C4-Domain Undermine Platelet Binding
Authors: Kutzki Fabian , Butera Diego , Lay Angelina J. , Maag Denis , Chiu Joyce , Woon Heng-Giap , Kubař Tomáš , Elstner Marcus , Aponte-Santamaría Camilo , Hogg Philip J. , Gräter Frauke
Published: August 2022

Background

The von Willebrand Factor (vWF) is a key player in regulating hemostasis through adhesion of platelets to sites of vascular injury. It is a large multi-domain mechano-sensitive protein stabilized by a net of disulfide bridges. Binding to platelet integrin is achieved by the vWF-C4 domain which exhibits a fixed fold, even under conditions of severe mechanical stress, but only if critical internal disulfide bonds are closed.

Objective

To quantitatively determine C4’s disulfide topologies and their implication in vWF’s platelet-binding function via integrin.

Methods

We employed a combination of classical Molecular Dynamics and quantum mechanical simulations, mass spectrometry, site-directed mutagenesis, and platelet binding assays.

Results

We quantitatively show that two disulfide bonds in the vWF-C4 domain, namely the two major force-bearing ones, are partially reduced in human blood. Reduction leads to pronounced conformational changes within C4 that considerably affect the accessibility of the RGD-integrin binding motif, and thereby impair integrin-mediated platelet binding. Our combined approach also reveals that reduced species in the C4 domain undergo specific thiol/disulfide exchanges with the remaining disulfide bridges, in a process in which mechanical force may increase the proximity of specific reactant cysteines, further trapping C4 in a state of low integrin-binding propensity. We identify a multitude of redox states in all six vWF-C domains, suggesting disulfide bond reduction and swapping to be a general theme.

Conclusion

Overall, our data put forward a mechanism in which disulfide bonds dynamically swap cysteine partners and control the interaction of vWF with integrin and potentially other partners, thereby critically influencing its hemostatic function.

Essentials

Platelet integrins interact with the disulfide-bonded C4 domain of von Willebrand Factor

The redox state of vWF-C4’s disulfide bonds is studied by molecular simulations and experiments

Two bonds are reduced causing C4 unfolding and disulfide swapping

Opening of disulfide bonds impairs integrin-mediated platelet binding
An automation workflow for high-throughput manufacturing and analysis of scaffold-supported 3D tissue arrays
Authors: Cao Ruonan , Li Nancy T , Cadavid Jose L , Latour Simon , Tan Cassidy M , McGuigan Alison P
Published: August 2022

The success rate of bringing novel cancer therapies to the clinic remains extremely low due to the lack of relevant pre-clinical culture models that capture the complexity of human tumours. Patient-derived organoids have emerged as a useful tool to model patient and tumour heterogeneity to begin addressing this need. Scaling these complex culture models while enabling stratified analysis of different cellular sub-populations remains a challenge, however. One strategy to enable higher throughput organoid cultures that also enables easy image-based analysis is the Scaffold-supported Platform for Organoid-based Tissues (SPOT) platform. SPOT allows the generation of flat, thin and dimensionally-defined microtissues in both 96- and 384-well plate footprints and is compatible with tumour organoid culture and downstream image-based readouts. SPOT manufacturing is currently a manual process however, limiting the use of SPOT to perform larger-scale screening. In this study, we integrate and optimize an automation approach to generate tumour-mimetic 3D engineered microtissues in SPOT using a liquid handler, and show comparable within-sample and between-sample variation as the standard manual manufacturing process. Furthermore, we develop a liquid handler-supported whole-cell extraction protocol and as a proof-of-value demonstration, we generate 3D complex tissues containing different proportions of tumour and stromal cells and perform single-cell-based end-point analysis to demonstrate the impact of co-culture on the tumour cell population specifically. We also demonstrate we can incorporate primary patient-derived organoids into the pipeline to capture patient-level tumour heterogeneity. We envision that this automated workflow integrated with 96/384-SPOT and multiple cell types and patient-derived organoid models will provide opportunities for future applications in high-throughput screening for novel personalized therapeutic targets. This pipeline also allows the user to assess dynamic cell responses using high-content longitudinal imaging or downstream single-cell-based analyses.