bluuebunny/crossref_metadata_2025 huggingface dataset:
Vital signs as a source of racial bias
Authors: Velichkovska Bojana , Gjoreski Hristijan , Denkovski Daniel , Kalendar Marija , Mamandipoor Behrooz , Celi Leo Anthony , Osmani Venet
Published: February 2022

Abstract

Background

racial bias has been shown to be present in clinical data, affecting patients unfairly based on their race, ethnicity and socio-economic status. This problem has the potential to be significantly exacerbated in the light of Artificial Intelligence-aided clinical decision making. We sought to investigate whether bias can be introduced from sources that are considered neutral with respect to ethnicity and race and consequently routinely used in modelling, specifically vital signs.

Methods

to perform our analysis, we extracted vital signs from 49,610 admissions from a cohort of adult patients during the first 24 hours after the admission to the Intensive Care Units (ICU), derived from multi-centre eICU-CRD database and single-centre MIMIC-III database, spanning over 208 hospitals and 335 ICUs. Using heart rate, SaO2, respiratory rate, systolic, diastolic, and mean blood pressure, we develop machine learning models based on Logistic Regression and eXtreme Gradient Boosting and investigate their performance in predicting patients’ self-reported race. To balance the dataset between the three ethno-races considered in our study, we use a matching cohort based on age, gender, and admission diagnosis.

Findings

standard machine learning models, derived solely on six vital signs can be used to predict patients’ self-reported race with AUC of 75%. Our findings hold under diverse patient populations, derived from multiple hospitals and intensive care units. We also show that oxygen saturation is a highly predictive variable, even when measured through methods other than pulse oximetry, namely arterial blood gas analysis, suggesting that addressing bias in routinely collected clinical variables will be challenging.

Interpretation

our finding that machine learning models can predict self-reported race using solely vital signs creates a significant risk in clinical decision making, further exacerbating racial inequalities, with highly challenging mitigation measures.

Funding

The funders had no role in the design of this study.
Chronic fatigue associated with post-COVID syndrome versus transient fatigue caused by high intensity exercise: are they comparable in terms of vascular effects?
Authors: Chudzik Michal , Cender Anna , Mordaka Robert , Zielinski Jacek , Katarzynska Joanna , Marcinek Andrzej , Gebicki Jerzy
Published: February 2022

Purpose

The pathophysiology of chronic fatigue associated with post-COVID syndrome is not well recognized. It is assumed that this condition is partly due to vascular dysfunction developed during an acute phase of infection. There is great demand for a diagnostic tool that is able to clinically assess post-COVID syndrome and monitor the rehabilitation process.

Patients and Methods

The Flow Mediated Skin Fluorescence (FMSF) technique appears uniquely suitable for the analysis of basal microcirculatory oscillations and reactive hyperemia induced by transient ischemia. The FMSF was used to measure vascular circulation in 45 patients with post-COVID syndrome. The results were compared with those for a group of 26 amateur runners before and after high intensity exercise, as well as for a control group of 32 healthy age-matched individuals.

Results

Based on the NOI and RHR parameters measured with the FMSF technique, it was found that chronic fatigue associated with post-COVID syndrome is comparable with transient fatigue caused by high-intensity exercise in terms of vascular effects. Both chronic fatigue associated with post-COVID syndrome and transient fatigue caused by high-intensity exercise are associated with vascular stress in the macrocirculation and microcirculation.

Conclusion

The NOI and RHR parameters measured with the FMSF technique can be used for non-invasive clinical assessment of post-COVID syndrome, as well as for monitoring the rehabilitation process.
Determinants of Thyroid Dysfunction among Type 2 Diabetes Patients Attending Private Hospitals in Dire Dawa, Eastern Ethiopia
Authors: Tekalign Alemayehu Molla , Habte Fitsum Berhane , Yimer Robel Mekonnen
Published: February 2022

Purpose

The purpose of this study is to capture the determinants of thyroid dysfunction in type 2 diabetes mellitus at private hospitals in Dire-Dawa, Eastern Ethiopia. Various studies found that thyroid dysfunction is common in type 2 diabetes and it is associated with poor blood glucose control and chronic diabetic complications responsible for morbidity and mortality. However, only limited studies have assessed determinants of thyroid dysfunctions among type 2 diabetes in Ethiopia.

Methods

Unmatched case-control study conducted in two private hospitals found in Dire Dawa town, between May - November 2021. A total of 92 type 2 diabetic patients with thyroid dysfunction as Cases and 183 type 2 diabetes patients with normal thyroid function as controls selected by purposive and systematic random sampling, respectively. Data collected by interview and using checklist, entered into SPSS version 22, and analyzed. Bivariate and multivariate logistic regression analysis employed to identify determinants of thyroid dysfunction with AOR and 95%CI. Independent t-test computed to observe significant mean difference of continuous variables. Variables with P-value < 0.05 declared as significant.

Result

Female gender predominate 65.9% of participants (p= 0.02). The mean glycated hemoglobin level among cases was 10.32 (± 2.4 SD) and 9.249 (± 2.3 SD) among controls, with significant difference (p=0.001). Similarly, the mean LDL cholesterol among cases 116.92 ±45.9 SD and control 102.34 ±43.97SD showed significant difference (p=0.016). Diabetic retinopathy and neuropathy, and ACEI/ARB also significantly associated with thyroid dysfunction (p< 0.05).

Conclusion

Female gender, lower educational level, and duration of diabetes associated with thyroid dysfunction. Most patients in both groups had unacceptably elevated HgA1c which need to be addressed. Thus, screening for thyroid dysfunction, especially the female gender, needs to be done.
Measles incidence in South Africa: a six-year review, 2015 - 2020
Authors: Yousif Mukhlid , Hong Heather , Malfeld Susan , Smit Sheilagh , Makhathini Lillian , Motsamai Tshepo , Tselana Dipolelo , Manamela Morubula , Kamupira Mercy , Maseti Elizabeth , Otwombe Kennedy , McCarthy Kerrigan , Suchard Melinda
Published: February 2022

In 2012 the World Health Organization (WHO) aimed to eliminate measles in five regions by 2020. This retrospective descriptive study reviewed measles surveillance data in South Africa for the period 2015 - 2020 to document the epidemiology of measles and the progress made towards meeting the 2020 measles elimination goal.

A total of 22,578 specimens were tested over the period 2015 - 2020 yielding 401 (1.8%) confirmed measles cases, 321 (1.4%) compatible and 21,856 (96.8%) discarded cases. The most affected age group was 0-4 year olds. At the provincial level, South Africa achieved adequate surveillance, defined as more than two cases of febrile rash notified annually per 100 000 popoulation, except for KwaZulu-Natal and Limpopo in 2020, probably due to COVID-19 lockdown restrictions. Of confirmed cases, only 26% were vaccinated, 3% were too young to receive vaccines, 5% were not vaccinated, and 65% had vaccination status unknown. Measles vaccine effectiveness amongst 1-4 year olds was 80%. Using the standard case definition, South Africa achieved the measles elimination target of less than one case per one million nationally in years 2015, 2016 and 2020. The years 2017 to 2019 had incidence rates exceeded one per million nationally. Using a narrow case definition, that excluded positive rubella cases, improved the indicators with only the year 2017 having an incidence rate of more than one per million.

South Africa displays intermittent measles outbreaks approximately six-yearly interspersed by inter-epidemic periods in which the country meets measles elimination targets. Intense effort is needed to increase the vaccine coverage to avoid periodic outbreaks. Enhanced molecular testing of each case will be required as measles incidence declines regionally.
A longitudinal investigation of blood neurofilament light chain levels in chronic cocaine users
Authors: Bavato F. , Kexel A.K. , Kluwe-Schiavon B. , Maceski A. , Baumgartner M.R , Seifritz E. , Kuhle J. , Quednow B.B.
Published: February 2022

Objectives

To explore the hypothesis that plasma levels of neurofilament light chain (NfL), a marker of neuroaxonal pathology, are elevated in chronic cocaine users (CU) and longitudinally associated with changes in cocaine use.

Methods

As part of the Social Stress Cocaine Study (SSCP), we assessed 35 CU and 35 stimulant-naïve healthy controls (HC) at baseline and at a 4-month follow-up. Plasma NfL levels were determined from blood samples using single molecule array (SIMOA) technology. Substance use was subjectively assessed with an extensive interview and objectively measured via toxicological analysis of urine and 4-month hair samples.

Results

In a generalized linear model corrected for sex, age, and body mass index, NfL plasma levels were elevated in CU compared to HC (p<0.05). A moderate positive correlation between cocaine hair concentration and NfL levels was also found in CU (r(s)=0.36, p=0.03). Changes in cocaine hair concentration (group analysis of increasers vs. decreasers) over the 4-month interval predicted NfL levels at follow-up (p=0.002), indicating a rise in NfL with increased cocaine use and a reduction with decreased use. No associations between use or change of use of other substances (including the cocaine adulterant levamisole) and NfL levels were found (r(s)≤±0.27, p>0.05).

Conclusions

Our findings demonstrate that NfL is a sensitive marker for assessing cocaine-related brain pathology, supporting the utility of blood NfL analysis in addiction research. The results also suggest that cocaine use should be considered a potential confounder in diagnostic applications and clinical studies using NfL.
SurvMaximin: Robust Federated Approach to Transporting Survival Risk Prediction Models
Authors: Wang Xuan , Zhang Harrison G , Xiong Xin , Hong Chuan , Weber Griffin M , Brat Gabriel A , Bonzel Clara-Lea , Luo Yuan , Duan Rui , Palmer Nathan P , Hutch Meghan R , Gutiérrez-Sacristán Alba , Bellazzi Riccardo , Chiovato Luca , Cho Kelly , Dagliati Arianna , Estiri Hossein , García-Barrio Noelia , Griffier Romain , Hanauer David A , Ho Yuk-Lam , Holmes John H , Keller Mark S , Klann Jeffrey G , L’Yi Sehi , Lozano-Zahonero Sara , Maidlow Sarah E , Makoudjou Adeline , Malovini Alberto , Moal Bertrand , Moore Jason H , Morris Michele , Mowery Danielle L , Murphy Shawn N , Neuraz Antoine , Ngiam Kee Yuan , Omenn Gilbert S , Patel Lav P , Pedrera-Jiménez Miguel , Prunotto Andrea , Samayamuthu Malarkodi Jebathilagam , Sanz Vidorreta Fernando J , Schriver Emily R , Schubert Petra , Serrano-Balazote Pablo , South Andrew M , Tan Amelia LM , Tan Byorn W.L. , Tibollo Valentina , Tippmann Patric , Visweswaran Shyam , Xia Zongqi , Yuan William , Zöller Daniela , Kohane Isaac S ,   The Consortium for Clinical Characterization of COVID-19 by EHR (4CE), Avillach Paul , Guo Zijian , Cai Tianxi
Published: February 2022

Objective

For multi-center heterogeneous Real-World Data (RWD) with time-to-event outcomes and high-dimensional features, we propose the SurvMaximin algorithm to estimate Cox model feature coefficients for a target population by borrowing summary information from a set of health care centers without sharing patient-level information.

Materials and Methods

For each of the centers from which we want to borrow information to improve the prediction performance for the target population, a penalized Cox model is fitted to estimate feature coefficients for the center. Using estimated feature coefficients and the covariance matrix of the target population, we then obtain a SurvMaximin estimated set of feature coefficients for the target population. The target population can be an entire cohort comprised of all centers, corresponding to federated learning, or can be a single center, corresponding to transfer learning.

Results

Simulation studies and a real-world international electronic health records application study, with 15 participating health care centers across three countries (France, Germany, and the U.S.), show that the proposed SurvMaximin algorithm achieves comparable or higher accuracy compared with the estimator using only the information of the target site and other existing methods. The SurvMaximin estimator is robust to variations in sample sizes and estimated feature coefficients between centers, which amounts to significantly improved estimates for target sites with fewer observations.

Conclusions

The SurvMaximin method is well suited for both federated and transfer learning in the high-dimensional survival analysis setting. SurvMaximin only requires a one-time summary information exchange from participating centers. Estimated regression vectors can be very heterogeneous. SurvMaximin provides robust Cox feature coefficient estimates without outcome information in the target population and is privacy-preserving.
Express yourself: Quantitative real-time PCR assays for rapid chromosomal antimicrobial resistance detection in Pseudomonas aeruginosa
Authors: Madden Danielle E. , Olagoke Olusola , Baird Timothy , Neill Jane , Ramsay Kay A. , Fraser Tamieka A. , Bell Scott C. , Sarovich Derek S. , Price Erin P.
Published: February 2022

The rise of antimicrobial-resistant (AMR) bacteria is a global health emergency. One critical facet in tackling this epidemic is more rapid AMR diagnosis in serious multi-drug resistant pathogens like Pseudomonas aeruginosa. Here, we designed and then validated two multiplex quantitative real-time PCR (qPCR) assays to simultaneously detect differential expression of the resistance-nodulation-division efflux pumps MexAB-OprM, MexCD-OprJ, MexEF-OprN, MexXY-OprM, the AmpC β-lactamase, and the porin OprD, which are commonly associated with chromosomally-encoded AMR. Next, qPCRs were tested on 15 sputa from 11 participants with P. aeruginosa respiratory infections to determine AMR profiles in vivo. We confirm multiplex qPCR testing feasibility directly on sputa, representing a key advancement in in vivo AMR diagnosis. Notably, comparison of sputa with their derived isolates grown in Luria-Bertani broth (±2.5% NaCl) or a 5-antibiotic cocktail showed marked expression differences, illustrating the difficulty in replicating in vivo expression profiles in vitro. Cystic fibrosis sputa showed significantly reduced mexE and mexY expression when compared with chronic obstructive pulmonary disease sputa, despite harbouring fluoroquinolone- and aminoglycoside-resistant strains, indicating that these loci are not contributing to AMR in vivo. oprD was also significantly downregulated in cystic fibrosis sputa, even in the absence of contemporaneous carbapenem use, suggesting a common adaptive trait in chronic infections that may affect carbapenem efficacy. Sputum ampC expression was highest in participants receiving carbapenems (6.7-15x), some of whom were simultaneously receiving cephalosporins, the latter of which would be rendered ineffective by the upregulated ampC. Our qPCR assays provide valuable insights into the P. aeruginosa resistome, and their use on clinical specimens will permit timely treatment alterations that will improve patient outcomes and antimicrobial stewardship measures.
Genetic population structure across Brittany and the downstream Loire basin provides new insights on the demographic history of Western Europe
Authors: Alves Isabel , Giemza Joanna , Blum Michael , Bernhardsson Carolina , Chatel Stéphanie , Karakachoff Matilde , Pierre Aude Saint , Herzig Anthony F. , Olaso Robert , Monteil Martial , Gallien Véronique , Cabot Elodie , Svensson Emma , Bacq-Daian Delphine , Baron Estelle , Berthelier Charlotte , Besse Céline , Blanché Hélène , Bocher Ozvan , Boland Anne , Bonnaud Stéphanie , Charpentier Eric , Dandine-Roulland Claire , Férec Claude , Fruchet Christine , Lecointe Simon , Floch Edith Le , Ludwig Thomas , Marenne Gaëlle , Meyer Vincent , Quellery Elisabeth , Racimo Fernando , Rouault Karen , Sandron Florian , Schott Jean-Jacques , Suarez Lourdes Velo , Violleau Jade , Willerslev Eske , Coativy Yves , Jézéquel Mael , Bris Daniel Le , Nicolas Clément , Pailler Yvan , Goldberg Marcel , Zins Marie , Marec Hervé Le , Jakobsson Mattias , Darlu Pierre , Génin Emmanuelle , Deleuze Jean-François , Redon Richard , Dina Christian
Published: February 2022

European genetic ancestry originates from three main ancestral populations - Western hunter-gatherers, early European farmers and Yamnaya Eurasian herders - whose edges geographically met in present-day France. Despite its central role to our understanding of how the ancestral populations interacted and gave rise to modern population structure, the population history of France has remained largely understudied. Here, we analysed the high-coverage whole-genome sequences and genome-wide genotype profiles of respectively 856 and 3,234 present-day individuals from the northern half of France, and merged them with publicly available present-day and ancient Europe-wide genotype datasets. We also explored, for the first time, the whole-genome sequences of six mediaeval individuals (300-1100 CE) from Western France to gain insights into the genetic impact of what is commonly known as the Migration Period in Europe. We found extensive fine-scale population structure across Brittany and the downstream Loire basin, emphasising the need for investigating local populations to better understand the distribution of rare and putatively deleterious variants across space. Overall, we observed an increased population differentiation between the northern and southern sides of the river Loire, which are characterised by different proportions of steppe vs. Neolithic-related ancestry. Samples from Western Brittany carry the largest levels of steppe ancestry and show high levels of allele sharing with individuals associated with the Bell Beaker complex, levels that are only comparable with those found in populations lying on the northwestern edges of Europe. Together, our results imply that present-day individuals from Western Brittany retain substantial legacy of the genetic changes that occurred in Northwestern Europe following the arrival of the Bell Beaker people c. 2500 BCE. Such genetic legacy may explain the sharing of disease-related alleles with other present-day populations from Western Britain and Ireland.
ACME: an Affinity-based Cas9 Mediated Enrichment method for targeted nanopore sequencing
Authors: Iyer Shruti V , Kramer Melissa , Goodwin Sara , McCombie W. Richard
Published: February 2022

Targeted sequencing significantly improves accuracy and coverage and aids in providing the depth necessary to detect rare alleles in a heterogenous population of cells. Until the introduction of nanopore Cas9 Targeted-Sequencing (nCATS), a lack of efficient long-read compatible targeting techniques made it difficult to study specific regions of interest on long-read platforms. Existing nCATS-based strategies are currently limited by the per molecule target lengths capturable (<30kb), requiring several Cas9 guides to tile across larger regions of interest, ultimately reducing the number of targets that can be surveyed per reaction. Also, longer read lengths help reduce mapping errors, making it more likely that complex structural rearrangements can be resolved. Absence of a background reduction step in nCATS also increases the competition between non-target and target fragments in the sequencing pool for pore occupancy, decreasing the overall percentage of on-target reads. To address this, we introduce ACME - an Affinity-based Cas9-Mediated Enrichment method - that helps reduce background reads, increasing on-target coverage and size of target regions that can be spanned with single reads to 100kb.

ACME uses a HisTag-based isolation and pulldown of Cas-9 bound non-target reads, reducing the background noise in sequencing. We designed a panel of guide RNAs targeting 10 genes to enrich for specific regions of the cancer genome and tested them in two breast cell lines – MCF 10A and SK-BR-3. These gene targets spanned different size ranges (10kb to 150kb) allowing us to identify the largest target sizes that could be optimally captured by single molecules spanning the entire region. When compared with using just nCATS, the ACME method for background reduction increased the overall coverage across the entire length of all targets by 2-fold to 25-fold. By using ACME to eliminate smaller competing non-targets from the sequencing library, we saw a 3- to 7-fold increase in the number of reads spanning 100% of the gene targets when compared to nCATS. For one of our larger targets, BRCA2, we observed >60-fold target enrichment, close to 70x coverage, and 3-20 reads spanning the entire 95kb target. We observed an increase in enrichment, depth, and number of whole gene spanning reads for other genes on the panel as well across both cell lines, with enrichment as high as 4000-fold for some genes. Furthermore, ACME identified all SVs previously called within our targets by ONT and PacBio whole genome sequencing and performed on par with these platforms for SNP detection when compared with Illumina short-read whole genome sequencing.
Interference of Neuronal TrkB Signaling by the Cannabis-Derived Flavonoids Cannflavins A and B
Authors: Holborn Jennifer , Walczyk-Mooradally Alicyia , Perrin Colby , Alural Begüm , Aitchison Cara , Borenstein Adina , Khokar Jibran Y. , Akhtar Tariq A. , Lalonde Jasmin
Published: February 2022

Cannflavins A and B are flavonoids that accumulate in the Cannabis sativa plant. These specialized metabolites are uniquely prenylated and highly lipophilic, which, a priori, may permit their interaction with membrane-bound enzymes and receptors. Although previous studies found that cannflavins can produce anti-inflammatory responses by inhibiting the biosynthesis of pro- inflammatory mediators, the full extent of their cellular influence remains to be understood. Here, we studied these flavonoids in relation to the Tropomyosin receptor kinase B (TrkB), a receptor tyrosine kinase that is activated by the growth factor brain-derived neurotrophic factor (BDNF). Using mouse primary cortical neurons, we first collected evidence that cannflavins prevent the accumulation of Activity-regulated cytoskeleton-associated (Arc, also known as Arg3.1) protein upon TrkB stimulation by exogenous BDNF in these cells. Consistent with this effect, we also observed a reduced activation of TrkB and downstream signaling effectors that mediate Arc mRNA transcription when BDNF was co-applied with the cannflavins. Of note, we also performed a high-throughput screen that demonstrated a lack of agonist action of cannflavins towards 320 different G protein-coupled receptors, a result that specifically limit the possibility of a TrkB transinactivation scenario via G protein signaling to explain our results with dissociated neurons. Finally, we used Neuro2a cells overexpressing TrkB to show that cannflavins can block the growth of neurites and increased survival rate produced by the higher abundance of the receptor in this model. Taken together, our study offers a new path to understand the reported effects of cannflavins and other closely related compounds in different cellular contexts.
Systematic lncRNA mapping to genome-wide co-essential pathways uncovers cancer dependency on uncharacterized lncRNAs
Authors: Mitra Ramkrishna , Adams Clare M. , Eischen Christine M.
Published: February 2022

Quantification of gene dependency across hundreds of cell lines using genome-scale CRISPR screens have revealed co-essential pathways/modules and critical functions of uncharacterized genes. In contrast to protein-coding genes, robust CRISPR-based loss-of-function screens are lacking for long non-coding RNAs (lncRNAs), which are key regulators of many cellular process, leaving many essential lncRNAs unidentified and uninvestigated. Integrating copy- number, epigenetic, and transcriptomic data of >800 cancer cell lines with CRISPR-derived co-essential pathways, our method recapitulates known essential lncRNAs and predicts proliferation/growth dependency of 289 poorly characterized lncRNAs. Analyzing lncRNA dependencies across ten cancer types and their expression alteration by diverse growth- inhibitors across cell types, we prioritize 30 high-confidence pan-cancer proliferation/growth- regulating lncRNAs. Further evaluating two previously uncharacterized top proliferation-suppressive lncRNAs (PSLR-1, PSLR-2) showed they are transcriptionally regulated by p53, induced by multiple cancer treatments, and significantly correlate to increased cancer patient survival. These lncRNAs modulate G2 cell cycle-regulating genes within the FOXM1 transcriptional network, inducing a G2 arrest and inhibiting proliferation and colony formation. Collectively, our results serve as a powerful resource for exploring lncRNA-mediated regulation of cellular fitness in cancer, circumventing current limitations in lncRNA research.
Hindbrain catecholaminergic inputs to the paraventricular thalamus scale feeding and metabolic efficiency in stress-related contexts
Authors: Dumont Clarisse , Li Guangping , Castel Julien , Luquet Serge , Gangarossa Giuseppe
Published: February 2022

The regulation of food intake and energy balance relies on the dynamic integration of exteroceptive and interoceptive signals monitoring nutritional, metabolic, cognitive and emotional states. The paraventricular thalamus (PVT) is a central hub that, by integrating sensory, metabolic and emotional states, may contribute to the regulation of feeding and homeostatic/allostatic processes. However, the underlying PVT circuits remain still elusive. Here, we aimed at unraveling the role of catecholaminergic (CA) inputs to the PVT in scaling feeding and metabolic efficiency. First, using region-specific retrograde disruption of CA projections, we show that PVT CA inputs mainly arise from the hindbrain, notably the locus coeruleus (LC) and the nucleus tractus solitarius (NTS). Second, taking advantage of integrative calorimetric measurements of metabolic efficiency, we reveal that CA inputs to the PVT scale adaptive feeding and metabolic responses in environmental, behavioral, physiological and metabolic stress-like contexts. Third, we show that hindbrainTH→PVT inputs contribute in modulating the activity of PVT as well as lateral (LH) and dorsomedial (DMH) hypothalamic neurons.

In conclusion, this study, by assessing the key role of CA inputs to the PVT in scaling homeostatic/allostatic regulations of feeding patterns, reveals the integrative and converging hindbrainTH→PVT paths that contribute to whole-body metabolic adaptations in stress-like contexts.

Key points

The paraventricular thalamus (PVT) is known to receive projections from the hindbrain. Here, we confirm and further extend current knowledge on the existence of hindbrainTH→PVT catecholaminergic (CA) inputs, notably from the locus coeruleus (LC) and the nucleus tractus solitarius (NTS), with the NTS representing the main source.

Disruption of hindbrainTH→PVT inputs contribute to the modulation of PVT-neurons activity.

HindbrainTH→PVT inputs scale feeding strategies in environmental, behavioral, physiological and metabolic stress-like contexts.

HindbrainTH→PVT inputs participate in regulating metabolic efficiency and nutrient partitioning in stress-like contexts.

HindbrainTH→PVT, directly and/or indirectly, contribute in modulating the downstream activity of lateral (LH) and dorsomedial (DMH) hypothalamic neurons.
Lung epithelial cell-derived C3 protects against pneumonia-induced lung injury
Authors: Ozantürk Ayşe N. , Sahu Sanjaya K. , Kulkarni Devesha H. , Ma Lina , Barve Ruteja A , McPhatter Ja’Nia , Garnica Lorena , Dannull Linus , Kunen Jeremy , Wu Xiaobo , Brody Steven L. , Atkinson John P. , Kulkarni Hrishikesh S.
Published: February 2022

The complement component C3 is a fundamental plasma protein for host defense. However, recent work has demonstrated the critical importance of local C3 expression in cell survival. Here we analyzed the effects of local versus peripheral sources of C3 expression in a model of bacterial pneumonia. While mice with global C3 deficiency had severe pneumonia-induced lung injury, those deficient in liver-deficient C3 remain protected, comparable to wildtype mice.

Human lung transcriptome analysis showed secretory epithelial cells are a major source of C3. Mice with a C3 gene ablation from lung epithelial cells had worse pulmonary injury compared to wild type, despite maintaining normal circulating C3 levels. Finally, in human cellular and mouse pneumonia models, we show that C3 reduces epithelial cell death mediated through the alternative pathway component Factor B. Thus, our findings suggest that a locally-derived C3-Factor B pathway protects the lung mucosal barrier.

One Sentence Summary

Lung-derived C3 mitigates severe bacterial pneumonia suggesting a novel cytoprotective role at mucosal barrier surfaces independent of circulating C3.
Interdisciplinary analyses of Bronze Age communities from Western Hungary reveal complex population histories
Authors: Gerber Dániel , Szeifert Bea , Székely Orsolya , Egyed Balázs , Gyuris Balázs , Giblin Julia I. , Horváth Anikó , Köhler Kitti , Kulcsár Gabriella , Kustár Ágnes , Major István , Molnár Mihály , Palcsu László , Szeverényi Vajk , Fábián Szilvia , Mende Balázs Gusztáv , Bondár Mária , Ari Eszter , Kiss Viktória , Szécsényi-Nagy Anna
Published: February 2022

In this study we report 21 ancient shotgun genomes from present-day Western Hungary, from previously understudied Late Copper Age Baden, and Bronze Age Somogyvár-Vinkovci, Kisapostag, and Encrusted Pottery archaeological cultures (3530 – 1620 cal BCE). Our results indicate the presence of high steppe ancestry in the Somogyvár-Vinkovci culture. They were then replaced by the Kisapostag group, who exhibit an outstandingly high (up to ∼47%) Mesolithic hunter-gatherer ancestry, despite this component being thought to be highly diluted by the time of the Early Bronze Age. The Kisapostag population contributed the genetic basis for the succeeding community of the Encrusted pottery culture. We also found an elevated hunter-gatherer component in a local Baden culture associated individual, but no connections were proven to the Bronze Age individuals. The hunter-gatherer ancestry in Kisapostag is likely derived from two main sources, one from a Funnelbeaker or Globular Amphora culture related population and one from a previously unrecognised source in Eastern Europe. We show that this ancestry not only appeared in various groups in Bronze Age Central Europe, but also made contributions to Baltic populations. The social structure of Kisapostag and Encrusted pottery cultures is patrilocal, similarly to most contemporaneous groups. Furthermore, we developed new methods and method standards for computational analyses of ancient DNA, implemented to our newly developed and freely available bioinformatic package. By analysing clinical traits, we found carriers of aneuploidy and inheritable genetic diseases. Finally, based on genetic and anthropological data, we present here the first female facial reconstruction from the Bronze Age Carpathian Basin.
Musical expertise shapes visual-melodic memory integration
Authors: Hoffmann Martina , Schmidt Alexander , Ploner Christoph J.
Published: February 2022

Music can act as a powerful mnemonic device that can elicit vivid episodic memories. However, how musical information is integrated with non-musical information is largely unknown. Here, we investigated whether and how musical expertise modulates binding of melodies and visual information into integrated memory representations. We reasoned that the significant mnemonic demands of musicianship might alter the underlying integration process and reveal mechanisms by which music promotes retrieval of non-musical memories. Professional musicians and musical laypersons learned overlapping pairs of everyday objects and melodies (AB- and BC-pairs, object-melody and melody-object pairs). Participants were then tested for memory of studied pairs (direct trials) and for inferential AC-decisions (indirect trials). Although musicians showed a higher overall performance than non-musicians, both groups performed well above chance level in both trial types. Non-musicians reacted faster in indirect compared to direct trials, whereas the reverse pattern was found in musicians. Differential correlations of trial type performance between groups further suggested that non-musicians efficiently formed integrated ABC-triplets already during the encoding phase of the task, while musicians separately memorized AB- and BC-pairs and recombined them at retrieval for AC-decisions. Our results suggest that integrative encoding is a default mechanism for integration of musical and non-musical stimuli that works with great efficacy even in musically untrained subjects and may contribute to the everyday experience of music-evoked episodic memories. By contrast, recombination at retrieval seems to be an advanced strategy for memory integration that critically depends on an expert ability to maintain and discriminate musical stimuli across extended memory delays.
Testing the Efficacy of Transungual Drug Delivery System (Nail Lacquer) Containing Terbinafine AgainstAspergillus brasiliensisfor the Topical Treatment of Onychomycosis
Authors: Rao Shivani. H. , Bhalekar Mangesh. R. , Kelkar Samruddhi. H. , Godbole Shivani. S. , Kharche Riddhesh. A.
Published: February 2022

According to a survey of 42 epidemiological studies, the cases of Non-dermatophyte mould onychomycosis (NDMO) caused by Aspergillus species have been found to increase. The number ranges from <1 to 35% of all cases of onychomycosis in the general population and the number is higher in the diabetic population. Around7.7-100% of cases of NDMO are caused by Aspergillus species. Hence the attempt of investigation to test the efficacy of the drug by transungual drug permeation has been made. The antifungal agent ‘Terbinafine’ was incorporated in a topical dosage form (Nail lacquer). The formulation is optimized by a drug design matrix of 23type using Design-Expert®software, version 11 (DX11). The antifungal assay was performed using the Kirby Bauer disk diffusion method and other evaluation parameters like Drying time, Viscosity are evaluated. Optimized formulation with the highest desirability was selected out of all the possible formulations which showed the best results with good physicochemical properties and antifungal activity. Thus, it can be concluded that medicated nail lacquers containing Terbinafine can be used as a successful method to treat non-dermatophyte mould onychomycosis (NDMO) caused by Aspergillus species.
An approachable, flexible, and practical machine learning workshop for biologists
Authors: Magnano Chris S , Mu Fangzhou , Russ Rosemary S , Cvetkovic Milica , Treu Debora , Gitter Anthony
Published: February 2022

The increasing prevalence and importance of machine learning in biological research has created a need for machine learning training resources tailored towards biological researchers. However, existing resources are often inaccessible, infeasible, or inappropriate for biologists because they require significant computational and mathematical knowledge, demand an unrealistic time-investment, or teach skills primarily for computational researchers. We created the Machine Learning for Biologists (ML4Bio) workshop, a short, intensive workshop that empowers biological researchers to comprehend machine learning applications and pursue machine learning collaborations in their own research. The ML4Bio workshop focuses on classification and was designed around 3 principles: (a) focusing on preparedness over fluency or expertise, (b) necessitating minimal coding and mathematical background, and (c) requiring low time investment. It incorporates active learning methods and custom open source software that allows participants to explore machine learning workflows. After multiple sessions to improve workshop design, we performed a study on 3 workshop sessions. Despite some confusion around identifying subtle methodological flaws in machine learning workflows, participants generally reported that the workshop met their goals, provided them with valuable skills and knowledge, and greatly increased their beliefs that they could engage in research that uses machine learning. ML4Bio is an educational tool for biological researchers, and its creation and evaluation provides valuable insight into tailoring educational resources for active researchers in different domains. The workshop materials are available from https://carpentries-incubator.github.io/ml4bio-workshop/ and the ml4bio software is available from https://github.com/gitter-lab/ml4bio.
Mast Cell Derived Histamine Negatively Regulates Hematopoiesis
Authors: Klein Bailey R. , Smith Julianne N.P. , Katabathula Ramachandra , Chaudhary Rahul , Gao Zhenxiang , Cordova Brittany A. , Petroze Frederick , Tiwari Riya , Gerson Stanton L. , Xu Rong , Markowitz Sanford D. , Desai Amar B.
Published: February 2022

Hematopoietic stem cells (HSCs) are essential for generating all blood cell types and maintaining immune function and oxygen transport. This requires tight regulation of self-renewal, differentiation, and quiescence, driven by intrinsic and extrinsic signals. While the influence of many HSC progeny on HSC decisions are recognized, the role of mast cells (MCs) remain understudied. MCs are known for their immunomodulatory functions through the secretion of factors such as histamine and could offer new insights into HSC regulation. In this study, we describe a novel role for MC-derived histamine in modulating HSC behavior. We observed that genetically MC-deficient “SASH” mice exhibit increased hematopoietic output and bone marrow (BM) HSCs, characterized by an enhanced quiescent signature that increases resistance to myeloablative chemotherapy. The SASH microenvironment also contained increased frequencies of HSC-supportive cell types and expression of genes conducive to HSC maintenance, which together accelerated HSC engraftment when wild-type BM was transplanted into SASH recipients. Moreover, we found lower serum histamine levels in SASH mice, and that the enhanced hematopoietic phenotype observed in these mice could be reversed by administering exogenous histamine. Subsequent experiments with FDA-approved antihistamines in wild-type mice revealed that cetirizine, an H1R inverse agonist, notably increased HSC frequency in the BM. Overall, our findings implicate MCs are negative regulators of HSC function. This lays the groundwork for future studies to elucidate the underlying mechanisms and explore the therapeutic potential of modulating histamine signaling to promote hematopoiesis.
Science in motion: A qualitative analysis of journalists’ use and perception of preprints
Authors: Fleerackers Alice , Moorhead Laura , Maggio Lauren A. , Fagan Kaylee , Alperin Juan Pablo
Published: February 2022

This qualitative study explores how and why journalists use preprints — unreviewed research papers — in their reporting. Through thematic analysis of interviews conducted with 19 health and science journalists in the second year of the COVID-19 pandemic, it applies a theoretical framework that conceptualizes COVID-19 preprint research as a form ofpost-normal science, characterized by high scientific uncertainty and societal relevance, urgent need for political decision-making, and value-related policy considerations. Findings suggest that journalists approach the decision to cover preprints as a careful calculation, in which the potential public benefits and the ease of access preprints provided were weighed against risks of spreading misinformation. Journalists described viewing unreviewed studies with extra skepticism and relied on diverse strategies to find, vet, and report on them. Some of these strategies represent standard science journalism, while others, such as labeling unreviewed studies as preprints, mark a departure from the norm. However, journalists also reported barriers to covering preprints, as many felt they lacked the expertise or the time required to fully understand or vet the research. The findings suggest that coverage of preprints is likely to continue post-pandemic, with important implications for scientists, journalists, and the publics who read their work.
Ventral pallidum GABA neurons bidirectionally control opioid relapse across rat behavioral models
Authors: Farrell Mitchell R. , Ye Qiying , Xie Yiyan , Esteban Jeanine Sandra D. , Mahler Stephen V.
Published: February 2022

Opioid addiction is a chronic, relapsing disorder. Whether addicted individuals are forced to abstain or they decide themselves to quit using drugs, relapse rates are high—especially upon encountering contexts and stimuli associated with prior opioid use. Rodents similarly show context- and cue-induced reinstatement of drug seeking following abstinence, and intriguingly, the neural circuits underlying these relapse-like behaviors differ when abstinence is involuntarily imposed, versus when animals decide themselves to cease taking drug. Here, we employ two complementary rat behavioral models of relapse-like behavior for the highly reinforcing opioid drug remifentanil, and asked whether GABAergic neurons in the ventral pallidum (VPGABA) control opioid seeking under these behavioral conditions. Specifically, we asked how chemogenetically stimulating VPGABA neurons with clozapine-N-oxide (CNO) influences the ability of contextual or discrete remifentanil-paired cues to reinstate drug seeking following either voluntary (punishment-induced; GroupPunish), or experimenter-imposed (extinction training; GroupExt) abstinence. In GroupPunish rats, we also chemogenetically inhibited VPGABA neurons, and examined spontaneous VP activity (Fos) during cued-reinstatement. In both GroupPunish and GroupExt rats, stimulating Gq-signaling in VPGABA neurons augmented remifentanil reinstatement in a cue- and context-dependent manner. Conversely, engaging inhibitory Gi-signaling in VPGABA neurons in GroupPunish suppressed cue-induced reinstatement, and additionally cue-triggered seeking was correlated with Fos in rostral, but not caudal VP. In contrast, neither stimulating nor inhibiting VPGABA neurons influenced unpunished remifentanil self-administration. We conclude that VPGABA neurons bidirectionally control opioid seeking regardless of the specific relapse model employed, highlighting their fundamental role in opioid relapse-like behavior across behavioral models, and potentially across species.

Highlights

We acutely inhibit or stimulate VP GABA neurons during opioid seeking

VP GABA neurons mediate relapse-like behavior across behavioral models

Behavioral context impacts DREADD stimulation of behavior, not VP activity

Rostral, not caudal VP Fos correlates with opioid reinstatement
Analysis of altered pre-mRNA splicing patterns caused by a mutation in the RNA binding protein hnRNPA1 linked to amyotrophic lateral sclerosis
Authors: Lee Yeon J. , Rio Donald C.
Published: February 2022

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by loss of motor neurons. Human genetic studies have linked mutations in RNA binding proteins as causative for this disease. The hnRNPA1 protein, a known pre-mRNA splicing factor, is mutated in a number of ALS patients. Here, we generate two cell models to investigate how a mutation in the C-terminal low complexity domain of hnRNPA1 affects global pre-mRNA splicing patterns and RNA binding. We show that a single amino acid change in the C-terminal low complexity domain (D262V) leads to changes in splicing of thousands of transcripts whose genes are linked to the DNA damage response, cilia organization and translation. We also show that there are changes in RNA binding of the mutant hnRNPA1 protein to transcripts whose splicing patterns change. Finally, we show that cells expressing the hnRNPA1 D262V mutation exhibit an aggregation phenotype, markedly reduced growth rates and changes in stress granules. This study shows that global changes in pre-mRNA splicing patterns caused by a single mutation in the hnRNPA1 protein lead to phenotypes related to ALS and that specific cellular pathways are affected.
Towards Effective and Generalizable Fine-tuning for Pre-trained Molecular Graph Models
Authors: Xia Jun , Zheng Jiangbin , Tan Cheng , Wang Ge , Li Stan Z.
Published: February 2022

Graph Neural Networks (GNNs) and Transformer have emerged as dominant tools for AI-driven drug discovery. Many state-of-the-art methods first pre-train GNNs or the hybrid of GNNs and Transformer on a large molecular database and then fine-tune on downstream tasks. However, different from other domains such as computer vision (CV) or natural language processing (NLP), getting labels for molecular data of downstream tasks often requires resource-intensive wet-lab experiments. Besides, the pre-trained models are often of extremely high complexity with huge parameters. These often cause the fine-tuned model to over-fit the training data of downstream tasks and significantly deteriorate the performance. To alleviate these critical yet under-explored issues, we propose two straightforward yet effective strategies to attain better generalization performance: 1. MolAug, which enriches the molecular datasets of down-stream tasks with chemical homologies and enantiomers; 2. WordReg, which controls the complexity of the pre-trained models with a smoothness-inducing regularization built on dropout. Extensive experiments demonstrate that our proposed strategies achieve notable and consistent improvements over vanilla fine-tuning and yield multiple state-of-the-art results. Also, these strategies are model-agnostic and readily pluggable into fine-tuning of various pre-trained molecular graph models. We will release the code and the fine-tuned models.
CDMAP/CDVIS: Context-dependent Mutation Analysis Package and Visualization Software
Authors: Patton David L. , Cardenas Thomas , Mele Perrin , Navarro Jon , Sung Way
Published: February 2022

The Context-dependent Mutation Analysis Package and Visualization Software (CDMAP/CDVIS) is an automated, modular toolkit used for analysis and visualization of context-dependent mutation patterns (site-specific variation in mutation rate from neighboring-nucleotide effects). The CDMAP algorithm calculates context-dependent mutation rates in chromosomes or replichores, and can generate high-resolution figures to analyze variation in mutation rate across spatiotemporal scales. Output from CDMAP can be integrated into CDVIS, an interactive database for visualizing mutation patterns across multiple taxa simultaneously.
Circulatory exosomes from COVID-19 patients trigger NLRP3 inflammasome in endothelial cells
Authors: Sur Subhayan , Steele Robert , Isbell T. Scott , Ray Ranjit , Ray Ratna B.
Published: February 2022

SARS-CoV-2 infection induces inflammatory response, cytokine storm, venous thromboembolism, coagulopathy, and multiple organ damage. Resting endothelial cells prevent coagulation, control blood flow and inhibit inflammation. However, it remains unknown how SARS-CoV-2 induces strong molecular signals in distant cells for immunopathogenesis. In this study, we examined the consequence of human endothelial cells (microvascular endothelial cells (HMEC-1) and liver endothelial cells (TMNK-1)) to exosomes from plasma of severe COVID-19 patients. We observed a significant induction of NLRP3, caspase-1 and IL-1β mRNA expression in the endothelial cells following exposure to exosomes from plasma of COVID-19 patients as compared to that of healthy donors. Activation of caspase-1 was noted in the endothelial cell culture medium following exposure to the COVID-19 exosomes. Further, COVID-19 exosomes significantly induced mature IL-1β secretion in the endothelial cell culture medium. Thus, our results demonstrated for the first time that exosomes from COVID-19 plasma trigger NLRP3 inflammasome in endothelial cells of distant organs.