bluuebunny/crossref_metadata_2025 huggingface dataset:
Highly conserved brain vascular receptor ALPL mediates transport of engineered viral vectors across the blood-brain barrier
Authors: Moyer Tyler C. , Hoffman Brett A. , Chen Weitong , Shah Ishan , Ren Xiao-Qin , Knox Tatiana , Liu Jiachen , Wang Wei , Li Jiangyu , Khalid Hamza , Kulkarni Anupriya S. , Egbuchulam Munachiso , Clement Joseph , Bloedel Alexis , Child Matthew , Kaur Rupinderjit , Rouse Emily , Graham Kristin , Maura Damien , Thorpe Zachary , Sayed-Zahid Ambreen , Chung Charlotte Hiu-Yan , Kutchin Alexander , Johnson Amy , Yao Johnny , Thompson Jeffrey , Pande Nilesh , Nonnenmacher Mathieu E.
Published: March 2024

Delivery of systemically administered therapeutics to the central nervous system (CNS) is restricted by the blood-brain barrier (BBB). Bioengineered Adeno-Associated Virus (AAV) capsids have been shown to penetrate the BBB with great efficacy in mouse and non-human primate models, but their translational potential is often limited by species selectivity and undefined mechanisms of action. Here, we apply our RNA-guided TRACER AAV capsid evolution platform to generate VCAP-102, an AAV9 variant with markedly increased brain tropism following intravenous delivery in both rodents and primates. VCAP-102 demonstrates a similar CNS tropism in cynomolgus macaque, african green monkey, marmoset and mouse, showing 20- to 400-fold increased transgene expression across multiple brain regions relative to AAV9. We demonstrate that the enhanced CNS tropism of VCAP-102 results from direct interaction with alkaline phosphatase (ALPL), a highly conserved membrane-associated protein expressed on the brain vasculature. VCAP-102 interacts with human, primate and murine ALPL isoforms, and ectopic expression of ALPL is sufficient to initiate receptor-mediated transcytosis of VCAP-102 in an in vitro transwell model. Our work identifies VCAP-102 as a cross-species CNS gene delivery vector with a strong potential for clinical translation and establishes ALPL as a brain delivery shuttle capable of efficient BBB transport to maximize CNS delivery of biotherapeutics.
Forecasting Dengue Fever in Brazil Using Multimodal Data, Including Climate Data
Authors: Danko David C. , Vörösmarty Charles , Cak Anthony , Corsi Fabio , Patel Suraj , Papciak John , Wells Heather , Albanese Anthony , Mason Christopher E. , Maciel-de-Freitas Rafael , Nagy-Szakal Dorottya , O’Hara Niamh B.
Published: March 2024

Dengue fever is a major tropical disease transmitted byAedesmosquitoes. Dengue affects more than 120 countries with highly variable year to year infection rates. Despite high variability, dengue has a clear relationship to climate factors and human demography. Global trends to higher temperatures and greater disorderly urban development are increasing the scale and scope of dengue risk. Dengue has complex human immunity with 4 known serotypes that make multiple infections possible. Accurate forecasting of dengue fever would allow for appropriate interventions and improved public health outcomes. We demonstrate,GeoSeeq Dengue, a forecasting model for dengue fever in Brazil. GeoSeeq Dengue predicts dengue outbreaks monthly in 5,570 Brazilian municipalities at 1, 3, and 6 months ahead of the outbreak. Model accuracy compares favorably to a historical baseline model, making it a promising model for informing public health response. We evaluate how different types of input variables effect model accuracy and explore how this model could be adapted to other countries. This model could inform public health responses to dengue including targeting vector control programs, public health education messaging, and the newly launched dengue vaccine rollout.
Pan-UK Biobank GWAS improves discovery, analysis of genetic architecture, and resolution into ancestry-enriched effects
Authors: Karczewski Konrad J. , Gupta Rahul , Kanai Masahiro , Lu Wenhan , Tsuo Kristin , Wang Ying , Walters Raymond K. , Turley Patrick , Callier Shawneequa , Shah Nirav N. , Baya Nikolas , Palmer Duncan S. , Goldstein Jacqueline I. , Sarma Gopal , Solomonson Matthew , Cheng Nathan , Bryant Sam , Churchhouse Claire , Cusick Caroline M. , Poterba Timothy , Compitello John , King Daniel , Zhou Wei , Seed Cotton , Finucane Hilary K. , Daly Mark J. , Neale Benjamin M. , Atkinson Elizabeth G. , Martin Alicia R.
Published: March 2024

Large biobanks, such as the UK Biobank (UKB), enable massive phenome by genome-wide association studies that elucidate genetic etiology of complex traits. However, individuals from diverse genetic ancestry groups are often excluded from association analyses due to concerns about population structure introducing false positive associations. Here, we generate mixed model associations and meta-analyses across genetic ancestry groups, inclusive of a larger fraction of the UKB than previous efforts, to produce freely-available summary statistics for 7,266 traits. We build a quality control and analysis framework informed by genetic architecture. Overall, we identify 14,676 significant loci (p < 5 x 10-8) in the meta-analysis that were not found in the EUR genetic ancestry group alone, including novel associations for example betweenCAMK2Dand triglycerides. We also highlight associations from ancestry-enriched variation, including a known pleiotropic missense variant inG6PDassociated with several biomarker traits. We release these results publicly alongside FAQs that describe caveats for interpretation of results, enhancing available resources for interpretation of risk variants across diverse populations.
Enrichment of Rare Variants of Hemophagocytic Lymphohistiocytosis Genes in Systemic Juvenile Idiopathic Arthritis
Authors: Marques Mariana Correia , Rubin Danielle , Shuldiner Emily , Datta Mallika , Schmitz Elizabeth , Cruz Gustavo Gutierrez , Patt Andrew , Bennett Elizabeth , Grom Alexei , Foell Dirk , Gattorno Marco , Bohnsack John , Yeung Rae S. M. , Prahalad Sampath , Mellins Elizabeth , Anton Jordi , Len Claudio Arnaldo , Oliveira Sheila , Woo Patricia , Ozen Seza ,   INCHARGE Consortium, Deng Zuoming , Ombrello Michael J.
Published: March 2024

Objective

To evaluate whether there is an enrichment of rare variants in familial hemophagocytic lymphohistiocytosis (HLH) genes and systemic juvenile idiopathic arthritis (sJIA) with or without macrophage activation syndrome (MAS).

Methods

Targeted sequencing of HLH genes (LYST, PRF1, RAB27A, STX11, STXBP2, UNC13D) was performed in sJIA subjects from an established cohort. Sequence data from control subjects were obtainedin silico(dbGaP:phs000280.v8.p2). Rare variant association testing (RVT) was performed with sequence kernel association test (SKAT) package. Significance was defined as p<0.05 after 100,000 permutations.

Results

Sequencing data from 524 sJIA cases were jointly called and harmonized with exome-derived target data from 3000 controls. Quality control operations produced a set of 481 cases and 2924 ancestrally-matched control subjects. RVT of sJIA cases and controls revealed a significant association with rare protein-altering variants (minor allele frequency [MAF]<0.01) ofSTXBP2(p=0.020), and ultra-rare variants (MAF<0.001) ofSTXBP2(p=0.007) andUNC13D(p=0.045). A subanalysis of 32 cases with known MAS and 90 without revealed significant association of rareUNC13Dvariants (p=0.0047). Additionally, sJIA patients more often carried ≥2 HLH variants than did controls (p=0.007), driven largely by digenic combinations involvingLYST.

Conclusion

We identified an enrichment of rare HLH variants in sJIA patients compared with healthy controls, driven bySTXBP2andUNC13D. Biallelic variation in HLH genes was associated with sJIA, driven byLYST. OnlyUNC13Ddisplayed enrichment in patients with MAS. This suggests that HLH variants may contribute to the pathophysiology of sJIA, even without MAS.
Sorting out assortativity: when can we assess the contributions of different population groups to epidemic transmission?
Authors: Geismar Cyril , White Peter J , Cori Anne , Jombart Thibaut
Published: March 2024

Characterising the transmission dynamics between various population groups is critical for implementing effective outbreak control measures whilst minimising financial costs and societal disruption. Traditionally, mathematical models have primarily relied on assumptions of contact patterns to characterise transmission between groups. Thanks to technological and methodological advances, transmission chain data is increasingly available, providing information about individual-level transmission. However, it remains unclear how effectively and under what conditions such data can inform on transmission patterns between groups. In this paper, we introduce a novel metric that leverages transmission chain data to estimate group transmission assortativity; this quantifies the extent to which individuals transmit within their own group compared to others. Through extensive simulations, we assessed the conditions under which our estimator performs effectively and established guidelines for minimal data requirements. Notably, we demonstrate that detecting and quantifying transmission assortativity is most reliable when groups have reached their epidemic peaks, consist of at least 30 cases each, and represent at least 10% of the total population each.
The status quo on existing routine health information management systems that have incorporated key population unique identifier codes in Sub-Saharan Africa: Protocol for systematic review
Authors: Rampilo Mashudu , Phalane Edith , Phaswana-Mafuya Refilwe Nancy
Published: March 2024

Introduction: Despite having the world's largest HIV epidemic, Sub-Saharan Africa (SSA) including South Africa (SA) has not yet achieved the 95-95-95 targets. To meet these targets, accurate and reliable key populations (KPs) disaggregated data is critical for guiding the HIV response. The inclusion of KPs Unique Identifier Code (UIC) on country routine health information management systems (RHIMS) can improve targeted resource allocation, reporting, and accountability. There is a gap in comprehensive review on how countries that implemented the unique identifier code went about in doing so. Methods and analysis A three-step search strategy will be utilized to get both published and unpublished documents. First, an initial search of MEDLINE identified keywords and MeSH terms. Second, a systematic search of electronic bibliographic databases including MEDLINE, PubMed, Scopus, PLOS ONE and Google Scholar, and thirdly, searching the reference list of all included reviews (hand-searching journals and reference tracking). Studies that meet the following PICO (Population, Intervention, Comparison, Outcome) criteria will be included: P: Published and unpublished materials reporting on key populations, namely men who have sex with men (MSM), sex workers (SW), people who inject/use drugs (PWI/UD), and transgender (TG); I: biometric fingerprint, alphanumeric code and any KPs UIC system; C: no unique identifier system; and O: KPs-specific 95-95-95 HIV cascade, KPs knowing HIV status, KPs on ART, ART adherence and Viral load suppression. This protocol was prepared using the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). References will be managed through ENDNOTE version 21 software. Two authors will screen the studies using Covidence software version 2.0 for inclusion according to the prescribed eligibility criteria. Differences will be addressed by consensus and with the assistance of an experienced third reviewer. Ethics and dissemination: This review will summarize findings from published studies containing non-identifiable data. The results will be disseminated via preprints, open-access peer-reviewed journals, and conference presentations. PROSPERO registration number: CRD42023440656
Menopausal symptom burden as a predictor of mid- to late-life cognitive function and mild behavioral impairment symptoms: A CAN-PROTECT study
Authors: Crockford Jasper F.E. , Guan Dylan X , Einstein Gillian , Ballard Clive , Creese Bryon , Corbett Anne , Pickering Ellie , Bloomfield Adam , Roach Pamela , Smith Eric E , Ismail Zahinoor
Published: March 2024

Background

Recent evidence suggests the experience of menopausal symptoms (i.e., perimenopausal symptoms) may be associated with cognitive and behavioural changes. We investigated these two relationships in a sample of post-menopausal females.

Design

Cross-sectional observational study.

Setting

Participant data was collected from the Canadian Platform for Research Online to Investigate Health, Quality of Life, Cognition, Behaviour, Function, and Caregiving in Aging (CAN-PROTECT) study.

Participants

896 post-menopausal female participants.

Methods

Menopausal symptom burden was operationalized by summing the total number of recalled perimenopausal symptoms experienced. Cognitive function was measured using the Everyday Cognition (ECog-II) Scale, with higher scores reflecting greater severity. Mild Behavioral Impairment (MBI) was measured using the Mild Behavioral Impairment Checklist (MBI-C), with higher scores reflecting greater severity. A negative-binomial regression model examined the relationship between menopausal symptom burden and cognitive function, while a zero-inflated negative binomial regression model examined the relationship between menopausal symptom burden and MBI symptoms. Models adjusted for age, years of education, age of menopausal onset, type of menopause, and hormone therapy (HT). Age of menopausal onset and use of HT in the two associations were investigated with moderation analyses.

Results

Greater menopausal symptom burden was associated with higher ECog-II total scores (b [95% confidence interval (CI)] = 5.37 [2.85, 7.97]) and higher MBI-C total scores (b [95% CI] = 6.09 [2.50, 9.80]). Use of HT did not significantly associate with ECog-II total scores (b [95% CI] = -10.98 [-25.33, 6.35]), however, HT was significantly associated with lower MBI-C total scores (b [95% CI] = -26.90 [-43.35, -5.67]).

Conclusions

Menopausal symptom burden is associated with poorer cognitive function and more MBI symptoms in mid- to late life. HT may help mitigate symptoms of MBI. These findings suggest the experience of menopause may indicate susceptibility to cognitive and behavioural changes, both markers of dementia.
Quantifying Oxygen Demand by Patients Hospitalized with COVID-19 at a Large Safety-Net Hospital Using Multiple Methodologies
Authors: Vanderburg Sky , Law Tyler , Shete Priya B. , Riviello Elisabeth D. , Hendrickson Carolyn M. , Burns Gregory D. , Jain Vivek , Lipnick Michael S.
Published: March 2024

Background

During the COVID-19 pandemic, many facilities worldwide struggled to forecast oxygen demand, which often exceeded oxygen supply to the detriment of patient care. Accurate estimates of oxygen demand by patients with COVID-19 are scarce, and proposed estimation methods have not been fully evaluated or implemented. To address this knowledge gap, oxygen demand by COVID-19 patients was calculated at a large safety-net hospital in the United States using patient consumption (demand) data, oxygen procurement (supply) data, and modeled data with a novel calculator tool.

Methods

Data were extracted from electronic medical records of patients admitted with COVID-19 to Zuckerberg San Francisco General Hospital (ZSFG) from March 2020 to March 2022, including every recorded peripheral oxygen saturation (SpO2) measurement as well as oxygen delivery device(s) and settings. Total patient oxygen consumption was calculated as the sum of oxygen delivery amounts for each recorded time interval during hospitalization. Oxygen delivery amounts were calculated using delivery device-specific formulas. Patient and treatment-specific factors which may impact oxygen demand were also reported. For comparison, oxygen procurement logs from the study period were reviewed to estimate supply consumed, and theOxygencalculator.comtool was used to model oxygen demand using an experimental patient population of the same size.

Results

In total, 282,095 time points from 1,076 patients were analyzed. Two-thirds of patients received oxygen, of which 24.3% received high-flow oxygen (HFO) therapy and 16.0% received invasive mechanical ventilation (IMV) at some point. In-hospital mortality was 7.5% overall, 10.8% for patients who received oxygen, and 28.3% for patients who received IMV. The median (IQR) duration of oxygen therapy was 3.1 (0.8-8.9) days, mean (SD) oxygen flow was 5.6 (5.0) liters per minute (LPM), and mean (SD) total volume of oxygen delivered was 180,115 (510,330) liters (L) per hospitalization. Both the supply- and model-based methods overestimated oxygen consumption compared to demand estimated from patient data.

Conclusions

This study represents one of the largest cohorts of patients with COVID-19 for which oxygen demand has been calculated, including patient clinical characteristics which may help explain variations in oxygen demand. Moreover, oxygen demand was quantified using a methodology that could be applied in any setting.
Discovery of knock-down resistance in the major African malaria vectorAnopheles funestus
Authors: Odero Joel O. , Dennis Tristan P. W. , Polo Brian , Nwezeobi Joachim , Boddé Marilou , Nagi Sanjay C. , Hernandez-Koutoucheva Anastasia , Nambunga Ismail H. , Bwanary Hamis , Mkandawile Gustav , Govella Nicodem J , Kaindoa Emmanuel W. , Ferguson Heather M. , Ochomo Eric , Clarkson Chris S. , Miles Alistair , Lawniczak Mara K. N. , Weetman David , Baldini Francesco , Okumu Fredros O.
Published: March 2024

A major mechanism of insecticide resistance in insect pests is knock-down resistance (kdr) caused by mutations in the voltage-gated sodium channel (Vgsc) gene. Despite being common in most malariaAnophelesvector species,kdrmutations have never been observed inAnopheles funestus, the principal malaria vector in Eastern and Southern Africa. While monitoring 10 populations ofAn. funestusin Tanzania, we unexpectedly found resistance to DDT, a banned insecticide, in one location. Through whole-genome sequencing of 333An. funestussamples from these populations, we found 8 novel amino acid substitutions in theVgscgene, including thekdrvariant, L976F (L1014F inAn. gambiae), in tight linkage disequilibrium with another (P1842S). The mutants were found only at high frequency in one region, with a significant decline between 2017 and 2023. Notably,kdrL976F was strongly associated with survivorship to the exposure to DDT insecticide, while no clear association was noted with a pyrethroid insecticide (deltamethrin). Further study is necessary to identify the origin and spread ofkdrinAn. funestus, and the potential threat to current insecticide-based vector control in Africa.

Significance

Knock-down resistance (kdr) mutations confer resistance to malaria vector control insecticides and pose a grave threat to malaria control. Here, we report the first discovery of kdr inAn. funestus, the principal malaria vector in East and Southern Africa. Kdr inAn. funestusconferred resistance to DDT but not deltamethrin. Based on extensive DDT contamination and unofficial usage in Tanzania, it is possible that kdr emerged because of widespread organic pollution as opposed to through public health efforts. Regardless of origin, the discovery of kdr inAn. funestusis an alarming development that warrants immediate, extensive follow-up and close surveillance to establish the origin, and extent to which it may threaten malaria control inAn. funestus.
Spaceflight causes strain dependent gene expression changes associated with lipid and extracellular matrix dysregulation in the mouse kidney in vivo
Authors: Finch Rebecca H. , Vitry Geraldine , Siew Keith , Walsh Stephen B. , Behesti Afshin , Hardiman Gary , da Silveira Willian A.
Published: March 2024

To explore new worlds we must ensure humans can survive and thrive in the space environment. Incidence of kidney stones in astronauts is a major risk factor associated with long term missions, caused by increased blood calcium levels due to bone demineralisation triggered by microgravity and space radiation. Transcriptomic changes have been observed in other tissues during spaceflight, including the kidney. We analysed kidney transcriptome patterns in two different strains of mice flown on the International Space Station, C57BL/6J and BALB/c. Here we show a link between spaceflight and transcriptome patterns associated with dysregulation of lipid and extracellular matrix metabolism and altered transforming growth factor-beta signalling. A stronger response was seen in C57BL/6J mice than BALB/c. Genetic differences in hyaluronan metabolism between strains may confer protection against extracellular matrix remodelling through downregulation of epithelial-mesenchymal transition. We intend for our findings to contribute to development of new countermeasures against kidney disease in astronauts and people here on Earth.
An unsupervised deep learning framework encodes super-resolved image features to decode bacterial cell cycle
Authors: Griffié Juliette , Zhang Chen , Denereaz Julien , Pham Thanh-An , Weissbart Gauthier , Sieben Christian , Lambert Ambroise , Veening Jan-Willem , Manley Suliana
Published: March 2024

Super-resolution microscopy can resolve cellular features at the nanoscale. However, increased spatial resolution comes with increased phototoxicity, and reduced temporal resolution. As a result, studies that require the highest spatial resolutions often rely on static or fixed images, lacking dynamic information. This is particularly true of bacteria, whose lateral dimensions approach the scale of the diffraction limit. In this work, we present Enso, a method based on unsupervised machine learning to recover bacterial cell cycle and cell type information from static single molecule localization microscopy (SMLM) images, whilst retaining nanoscale spatial resolution. Enso uses single-cell images as input, and orders cells according to their spatial pattern progression, ultimately linked to the cell cycle. Our method requires noa prioriknowledge or categories, and is validated on both simulated and user-annotated experimental data.
BinDash 2.0: New MinHash Scheme Allows Ultra-fast and Accurate Genome Search and Comparisons
Authors: Zhao Jianshu , Zhao Xiaofei , Pierre-Both Jean , Konstantinidis Konstantinos T.
Published: March 2024

Motivation

Comparing large number of genomes in term of their genomic distance is becoming more and more challenging because there is an increasing number of microbial genomes deposited in public databases. Nowadays, we may need to estimate pairwise distances between millions or even billions of genomes. Few softwares can perform such comparisons efficiently.

Results

Here we update the multi-threaded software BinDash by implementing several new MinHash algorithms and computational optimization (e.g. Simple Instruction Multiple Data, SIMD) for ultra-fast and accurate genome search and comparisons at trillion scale. That is, we implemented b-bit one-permutation rolling MinHash with optimal/faster densification with SIMD. Now with BinDash 2, we can perform 0.1 trillion (or ∼10^11) pairs of genome comparisons in about 1.8 hours on a descent computer cluster or several hours on personal laptops, a ∼50% or more improvement over original version. The ANI (average nucleotide identity) estimated by BinDash is well correlated with other accurate but much slower ANI estimators such as FastANI or alignment-based ANI. In line with the findings from comparing 90K genomes (∼10^9 comparisons) via FastANI, the 85% ∼ 95% ANI gap is consistent in our study of ∼10^11 prokaryotic genome comparisons via BinDash2, which indicates fundamental ecological and evolutionary forces keeping species-like unit (e.g., > 95% ANI) together.

Availability and implementation

BinDash is released under the Apache 2.0 license at:https://github.com/zhaoxiaofei/bindash

Contact

kostas.konstantinidis@gatech.edu

Supplementary information

Supplementary data are available at Bioinformatics online.
Pseudogenisation of NK3 Homeobox 2 (Nkx3.2) in Monotremes Provides Insight into Unique Gastric Anatomy and Physiology
Authors: Dann Jackson , Qu Zhipeng , Shearwin-Whyatt Linda , van der Ploeg Rachel , Grützner Frank
Published: March 2024

Development of the vertebrate antral stomach and pyloric sphincter (antropyloric region) – involved in enzymatic breakdown and thoroughfare of food - is underpinned by a highly conserved developmental pathway involving the hedgehog, bone morphogenetic protein (BMP) and Wingless/Int-1 (Wnt) protein families. Monotremes are a unique lineage where acid-based digestion has been lost, and this correlates with a lack of genes for gastric acid and enzymes in the genomes of the platypus (Ornithorhynchus anatinus) and short-beaked echidna (Tachyglossus aculeatus). Furthermore, these species feature unique gastric phenotypes, both with truncated and aglandular antral stomachs and the platypus with no pylorus. Here, we explore the genetic underpinning of monotreme gastric phenotypes, investigating genes important in antropyloric development using the newest monotreme genome sequences (mOrnAna1.pri.v4 and mTacAcu1) together with RNA-seq data. We found that the pathway is generally conserved but, NK3 homeobox 2 (Nkx3.2) was pseudogenised in both platypus and echidna. We speculate that pyloric-like restriction in the echidna may correlate with independent evolution ofGrem1andBmp4sequences, and that the convergent loss of gastric acid and stomach size genotypes and phenotypes in teleost and monotreme lineages may be a result of eco-evolutionary dynamics. These findings reflect the effects of gene loss on phenotypic evolution and further elucidate the genetic control of monotreme stomach anatomy and physiology.
Does Intermittent Nutrition Enterally Normalise hormonal and metabolic responses to feeding in critically ill adults? A protocol for the DINE-Normal proof-of-concept randomised parallel group study
Authors: Beattie Clodagh E , Thomas Matt , Borislavova Borislava , Smith Harry A , Ambler Michael , White Paul , Hayes Kati , Milne Danielle , Ramesh Aravind V , Gonzalez Javier T , Betts James A , Pickering Anthony E
Published: March 2024

Introduction

Over half of patients who spend >48 hours in the intensive care unit (ICU) are fed via a nasogastric (NG) tube. Current guidance recommends continuous delivery of feed throughout the day and night. Emerging evidence from healthy human studies shows that NG feeding in an intermittent pattern (rather than continuous) promotes phasic hormonal, digestive and metabolic responses that are important for effective nutrition. It is not yet known whether this will translate to the critically ill population. Here we present the protocol for a proof-of-concept study comparing diurnal intermittent versus continuous feeding for patients in the intensive care unit.

Methods and Analysis

The study is a single-centre, prospective, randomised, open-label trial comparing intermittent enteral nutrition with the current standard practice of continuous enteral feeding. It aims to recruit participants (n=30) needing enteral nutrition via an NG tube for >24 hours who will be randomised to a diurnal intermittent or a continuous feeding regime with equivalent nutritional value. The primary outcome is peak plasma insulin / c-peptide within 3 hours of delivering the morning bolus feed on the second study day, compared to that seen in the continuous feed delivery group at the same timepoint. Secondary outcomes include feasibility, tolerability, efficacy and metabolic / hormonal profiles.

Ethics and Dissemination

This trial has been registered prospectively with the Clinical Trials Registry (clinicaltrials.govNCT06115044). We obtained ethical approval from the Wales Research Ethics Committee 3 prior to data collection (reference 23/WA/0297). We will publish the results of this study in an open-access peer-reviewed journal.

Strengths and Limitations of this Study

Having studied metabolic consequences of intermittent versus continuous nasogastric feed delivery in healthy volunteers, our trial team is well positioned to explore the direct ‘bench-to-bedside’ exploration of the interaction between critical illness and the mode of feed delivery through detailed profiling of metabolic hormones.

The intermittent feeding intervention in this study has been carefully considered to replicate diurnal rhythms, with sufficient fasting between feeding cycles, to allow us to capture a difference in response to continuous feeding if one exists.

The findings of this study will inform the feasibility and design of a trial of the effectiveness of intermittent diurnal nutrition in critically ill adults.

This is an open-label, single-centre study, which may bias the interpretation and limit the generalisability of the results.
Increasing intra- and inter-subtype HIV diversity despite declining HIV incidence in Uganda
Authors: Kim Seungwon , Kigozi Godfrey , Martin Michael A. , Galiwango Ronald M. , Quinn Thomas C. , Redd Andrew D. , Ssekubugu Robert , Bonsall David , Ssemwanga Deogratius , Rambaut Andrew , Herbeck Joshua T. , Reynolds Steven J. , Foley Brian , Abeler-Dörner Lucie , Fraser Christophe , Ratmann Oliver , Kagaayi Joseph , Laeyendecker Oliver , Grabowski M. Kate
Published: March 2024

HIV incidence has been declining in Africa with scale-up of HIV interventions. However, there is limited data on HIV evolutionary trends in African populations with waning epidemics. We evaluated changes in HIV viral diversity and genetic divergence in southern Uganda over a twenty-five-year period spanning the introduction and scale-up of HIV prevention and treatment programs using HIV sequence and survey data from the Rakai Community Cohort Study, an open longitudinal population-based HIV surveillance cohort.Gag(p24) andenv(gp41) HIV data were generated from persons living with HIV (PLHIV) in 31 inland semi-urban trading and agrarian communities (1994 to 2018) and four hyperendemic Lake Victoria fishing communities (2011 to 2018) under continuous surveillance. HIV subtype was assigned using the Recombination Identification Program with phylogenetic confirmation. Inter-subtype diversity was estimated using the Shannon diversity index and intra-subtype diversity with the nucleotide diversity and pairwise TN93 genetic distance. Genetic divergence was measured using root-to-tip distance and pairwise TN93 genetic distance analyses. Evolutionary dynamics were assessed among demographic and behavioral sub-groups, including by migration status. 9,931 HIV sequences were available from 4,999 PLHIV, including 3,060 and 1,939 persons residing in inland and fishing communities, respectively. In inland communities, subtype A1 viruses proportionately increased from 14.3% in 1995 to 25.9% in 2017 (p<0.001), while those of subtype D declined from 73.2% in 1995 to 28.2% in 2017 (p<0.001). The proportion of viruses classified as recombinants significantly increased by more than four-fold. Inter-subtype HIV diversity has generally increased. While p24 intra-subtype genetic diversity and divergence leveled off after 2014, diversity and divergence of gp41 increased through 2017. Inter- and intra-subtype viral diversity increased across all population sub-groups, including among individuals with no recent migration history or extra-community sexual partners. This study provides insights into population-level HIV evolutionary dynamics in declining African HIV epidemics following the scale-up of HIV prevention and treatment programs. Continued molecular surveillance may provide a better understanding of the dynamics driving population HIV evolution and yield important insights for epidemic control and vaccine development.
Refining the scope of genetic influences on alcohol misuse through environmental stratification and gene-environment interaction
Authors: Savage Jeanne E. , de Leeuw Christiaan A. , Werme Josefin ,   Spit for Science Working Group, Dick Danielle M. , Posthuma Danielle , van der Sluis Sophie
Published: March 2024

Background

Gene-environment interaction (G×E) is likely an important influence shaping individual differences in alcohol misuse (AM), yet it has not been extensively studied in molecular genetic research. In this study, we utilize a series of genome-wide gene-environment interaction (GWEIS) andin silicoannotation methods with the aim of improving gene identification and biological understanding of AM.

Methods

We carried out GWEIS for four AM phenotypes in the large UK Biobank sample (N= 360,314), with trauma exposure and socioeconomic status (SES) as moderators of the genetic effects. Exploratory analyses compared stratified GWAS and GWEIS modelling approaches. We applied functional annotation, gene- and gene-set enrichment, and polygenic score analyses to interpret the GWEIS results.

Results

GWEIS models showed few genetic variants with significant interaction effects across all gene-environment pairs. Enrichment analyses identified moderation by SES of the genesNOXA1,DLGAP1, andUBE2L3,on drinking quantity and the geneIFIT1Bon drinking frequency. Except forDLGAP1, these genes have not previously been linked to AM. The most robust results (GWEIS interactionp= 4.59e-09) were seen for SES moderating the effects of variants linked to immune-related genes on a pattern of drinking with versus without meals.

Conclusions

Even in large samples, G×E effects are difficult to detect at the molecular level. Our results highlight several genes and a potential mechanism of immune system functioning behind the moderating effect of SES on the genetic influences on AM. While GWEIS seems to be a preferred approach over stratified GWAS, modelling molecular G×E effects remains a challenge that will require larger consortia and more in-depth phenotypic measurement.
Forecasting the spatial spread of an Ebola epidemic in real-time: comparing predictions of mathematical models and experts
Authors: Munday James D , Rosello Alicia , Edmunds W. John , Funk Sebastian
Published: March 2024

Ebola virus disease outbreaks can often be controlled, but require rapid response efforts frequently with profound operational complexities. Mathematical models can be used to support response planning, but it is unclear if models improve the prior understanding of experts.

We performed repeated surveys of Ebola response experts during an outbreak. From each expert we elicited the probability of cases exceeding four thresholds between two and 20 cases in a set of small geographical areas in the following calendar month. We compared the predictive performance of these forecasts to those of two mathematical models with different spatial interaction components.

An ensemble combining the forecasts of all experts performed similarly to the two models. Experts showed stronger bias than models forecasting two-case threshold exceedance. Experts and models both performed better when predicting exceedance of higher thresholds. The models also tended to be better at risk-ranking areas than experts.

Our results support the use of models in outbreak contexts, offering a convenient and scalable route to a quantified situational awareness, which can provide confidence in or to call into question existing advice of experts. There could be value in combining expert opinion and modelled forecasts to support the response to future outbreaks.
The Impact of Alcohol Misuse in Trauma Patients: A Scoping Review Protocol
Authors: Garland Chantae , Abdulla Nhayan , Lee Donghyun , Spiwak Rae , Logsetty Sarvesh , Nantais Jordan
Published: March 2024

Background

Alcohol use is a contributing factor in many cases of traumatic injury. There is conflicting evidence on the impact of alcohol use at the time of physical trauma on severity of injury and hospital course. Similarly, the significance of alcohol use disorder on outcomes in hospitalized trauma patients is unclear. This scoping review aims to provide a concise overview of the current literature surrounding peri-trauma alcohol use and alcohol use disorder on injury severity, in-hospital complications, patient outcomes, and long-term health impact of alcohol use in trauma. We will also explore the associated healthcare costs of this patient population.

Methods

A systematic search of the following databases MEDLINE, EMBASE, and Cochrane Library will be completed to extract all studies that meet our inclusion criteria from January 2000 onwards. Case reports will be excluded. Two reviewers will screen all citations, abstracts, and full text articles. A third reviewer will act as tiebreaker at each stage of the screening process. A narrative synthesis without meta-analysis will be conducted and assessed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines.

Discussion

This review will contribute to the literature by providing a concise overview of the current data on the impact of alcohol on outcomes following trauma. We will explore the overall themes in the literature, limitations, and future directions to focus forthcoming research in this patient population.

Scoping review registration

Open Science Framework (https://doi.org/10.17605/OSF.IO/Z84WK)

Support

There were no funders or sponsors involved in the development of this protocol
WGBS of Differentiating Adipocytes Reveals Variations in DMRs and Context-Dependent Gene Expression
Authors: Yadav Binduma , Singh Dalwinder , Mantri Shrikant , Rishi Vikas
Published: March 2024

Obesity, characterised by the accumulation of excess fat, is a complex condition resulting from the combination of genetic and epigenetic factors. Recent studies have found correspondence between DNA methylation and cell differentiation, suggesting a role of the former in cell fate determination. There is a lack of comprehensive understanding concerning the underpinnings of preadipocyte differentiation, specifically when cells are undergoing terminal differentiation (TD). To gain insight into dynamic genome-wide methylation, 3T3 L1 preadipocyte cells were differentiated by a hormone cocktail. The genomic DNA was isolated from undifferentiated cells and 4 hrs (4H), 2 days (2D) post-differentiated cells, and 15 days (15D) TD cells. We employed whole-genome bisulfite sequencing (WGBS) to ascertain global genomic DNA methylation alterations at single base resolution as preadipocyte cells differentiate. The genome-wide distribution of DNA methylation showed similar overall patterns in pre- and post- and terminally differentiated adipocytes, according to WGBS analysis. DNA methylation decreases at 4H after differentiation initiation, followed by methylation gain as cells approach TD. Studies revealed novel differentially methylated regions (DMRs) associated with adipogenesis. DMR analysis suggested that though DNA methylation is global, noticeable changes are observed at specific sites known as ‘hotspots.’ Hotspots are genomic regions rich in transcription factor (TF) binding sites and exhibit methylation-dependent TF binding. Subsequent analysis indicated hotspots as part of DMRs. The gene expression profile of key adipogenic genes in differentiating adipocytes is context-dependent, as we found a direct and inverse relationship between promoter DNA methylation and gene expression.
Effective Gene Therapy for Metachromatic Leukodystrophy Achieved with Minimal Lentiviral Genomic Integrations
Authors: Tricoli Lucas , Sase Sunetra , Hacker Julia , Pham Vi , Smith Sidney , Chappell Maxwell , Breda Laura , Hurwitz Stephanie , Tanaka Naoto , Castracani Carlo Castruccio , Guerra Amaliris , Hou Zhongqi , Schlotawa Lars , Radhakrishnan Karthikeyan , Kurre Peter , Ahrens-Nicklas Rebecca , Adang Laura , Vanderver Adeline , Rivella Stefano
Published: March 2024

Metachromatic leukodystrophy (MLD) is a fatal lysosomal storage disease (LSD) characterized by the deficient enzymatic activity of arylsulfatase A (ARSA). Combined autologous hematopoietic stem cell transplant (HSCT) with lentiviral (LV) based gene therapy has great potential to treat MLD. However, if enzyme production is inadequate, this could result in continued loss of motor function, implying a high vector copy number (VCN) requirement for optimal enzymatic output. This may place children at increased risk for genomic toxicity due to higher VCN. We increased the expression of ARSA cDNA at single integration by generating novel LVs, optimizing ARSA expression, and enhancing safety. In addition, our vectors achieved optimal transduction in mouse and human HSC with minimal multiplicity of infection (MOI). Our top-performing vector (EA1) showed at least 4X more ARSA activity than the currently EU-approved vector and a superior ability to secrete vesicle-associated ARSA, a critical modality to transfer functional enzymes from microglia to oligodendrocytes. Three-month-oldArsa-KO MLD mice transplanted withArsa-KO BM cells transduced with 0.6 VCN of EA1 demonstrated behavior and CNS histology matching WT mice. Our novel vector boosts efficacy while improving safety as a robust approach for treating early symptomatic MLD patients.
Convergence of inputs from the basal ganglia with layer 5 of motor cortex and cerebellum in mouse motor thalamus
Authors: Koster Kevin P. , Sherman S. Murray
Published: March 2024

A key to motor control is the motor thalamus, where several inputs converge. One excitatory input originates from layer 5 of primary motor cortex (M1L5), while another arises from the deep cerebellar nuclei (Cb). M1L5terminals distribute throughout the motor thalamus and overlap with GABAergic inputs from the basal ganglia output nuclei, the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata (SNr). In contrast, it is thought that Cb and basal ganglia inputs are segregated. Therefore, we hypothesized that one potential function of the GABAergic inputs from basal ganglia is to selectively inhibit, or gate, excitatory signals from M1L5in the motor thalamus. Here, we tested this possibility and determined the circuit organization of mouse (both sexes) motor thalamus using an optogenetic strategy in acute slices. First, we demonstrated the presence of a feedforward transthalamic pathway from M1L5through motor thalamus. Importantly, we discovered that GABAergic inputs from the GPi and SNr converge onto single motor thalamic cells with excitatory synapses from M1L5and, unexpectedly, Cb as well. We interpret these results to indicate that a role of the basal ganglia is to gate the thalamic transmission of M1L5and Cb information to cortex.

Significance Statement

In this study, we extend the common conception of the basal ganglia as an information loop: flowing from cortex to basal ganglia, to thalamus, and back to cortex. We used tricolor viral labeling and an optogenetic approach to reveal that projections from the output nuclei of the basal ganglia converge with inputs from both layer 5 of primary motor cortex and the deep cerebellar nuclei onto individual thalamic relay cells. Not only do these findings add nuance to the notion that cerebellar and basal ganglia circuits through motor thalamus are independent, but also highlight a novel intersection between basal ganglia and cortex that countervails long-held conceptions of how the brain handles motor commands.
PEACOC - Detecting and classifying a wide range of epileptiform activity patterns in rodents
Authors: Heining Katharina , Kilias Antje , Janz Philipp , Haas Carola A , Egert Ulrich
Published: March 2024

Epileptiform activity (EA) manifests in diverse patterns of hypersynchronous network activity. Fundamental research mostly addresses two extreme patterns, individual epileptiform spikes and seizures. We developed PEACOC to detect and classify a wide range of EA patterns in local field potentials. PEACOC delimits EA patterns as bursts of epileptiform spikes, and classifies these bursts according to spike load. In EA from kainate-injected mice, burst patterns displayed a continuum of spike loads. With PEACOC, we partitioned this continuum into bursts of high, medium and low spike load. High-load bursts resembled electrographic seizures. The EA patterns automatically retrieved by PEACOC were reproducible and comparable across animals and laboratories. PEACOC has been employed to diagnose the overall burden of EA in individual mice, and to describe epileptic dynamics at multiple time-scales. We here further report that the rate of high-load bursts was anti-correlated to granule cell dispersion in the dentate gyrus.
Experimentally evolvingDrosophila erectapopulations may fail to establish an effective piRNA-based host defense against invadingP-elements
Authors: Selvaraju Divya , Wierzbicki Filip , Kofler Robert
Published: March 2024

To prevent the spread of transposable elements (TEs), hosts have developed sophisticated defense mechanisms. In mammals and invertebrates, a major defense mechanism operates through PIWI-interacting RNAs (piRNAs). To investigate the establishment of the host defense, we introduced theP-element, one of the most widely studied eukaryotic transposons, into naive lines ofDrosophila erecta. We monitored the invasion in three replicates for more than 50 generations by sequencing the genomic DNA (using short and long reads), the small RNAs, and the transcriptome at regular intervals. A piRNA-based host defense was rapidly established in two replicates (R1, R4) but not in a third (R2), in whichP-element copy numbers kept increasing for over 50 generations. We found that the ping-pong cycle could not be activated in R2, although the ping-pong cycle is fully functional against other TEs. Furthermore, R2 had both insertions in piRNA clusters and siRNAs, suggesting that neither of them is sufficient to trigger the host defense. Our work shows that control of an invading TE requires activation of the ping-pong cycle and that this activation is a stochastic event that may fail in some populations, leading to a proliferation of TEs that ultimately threaten the integrity of the host genome.
Generation of heralded vector-polarized single photons in remotely controlled topological classes
Authors: Corona-Aquino Samuel , Ibarra-Borja Zeferino , Calderón-Losada Omar , Piccirillo Bruno , Vicuña-Hernández Verónica , Moctezuma-Quistian Tonatiuh , Cruz-Ramírez Hector , Lopez-Mago Dorilian , U’Ren Alfred B.
Published: March 2024

We demonstrate an experimental protocol for the preparation and control of heralded single photons in inhomogeneously polarized states, such as vector vortex and full Poincaré beam states. A laser beam is shaped by a voltage-controlled spin-to-orbital angular momentum converter q-plate device, which eliminates the need for an interferometer for the robust preparation of high-quality inhomogeneously polarized beams. Such a beam is then used as a pump in a spontaneous parametric down-conversion (SPDC) photon-pair source. We demonstrate the full pump to heralded single-photon transfer of the intensity and phase distributions, as well as of the vector polarization structure. Additionally, we show that by controlling the polarization to which the heralding idler photon is projected before detection, we can toggle between the direct and basis-switched pump-single-photon transfer. We show that this nonlocal control of the heralded single photon pertains also to the topological class of the resulting heralded single photon. We believe that our work will lead to opportunities in photon-based quantum information processing science.

Published by the American Physical Society
2024