bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Impact of Digital Technology in Care Homes on Unplanned Secondary Care Usage and Associated Costs
Authors: Garner Alex , Lewis Jen , Dixon Simon , Preston Nancy Jean , Caiado Camila C.C.S , Hanratty Barbara , Jones Monica , Knight Jo , Mason Suzanne M 
Published: June 2023

AbstractBackgroundA substantial number of emergency department (ED) attendances from care homes could be classed as avoidable. HealthCall is a technology that aims to streamline residents’ care by recording their observations electronically. Observations are fed to remote clinical staff to triage referrals. This study assessed the effectiveness of the HealthCall technology to safely reduce unplanned secondary care usage and associated costs.MethodsThe study involved 118 care homes across the North East from 2018-2021. Routinely collected NHS secondary care data from County Durham and Darlington NHS Foundation Trust was linked with data from the HealthCall technology App. Four outcomes were modelled monthly using Generalised Linear Mixed Models: counts of emergency attendances, emergency admissions, emergency readmissions (28-days), and length of stay of emergency admissions. A similar approach was taken for costs. The impact ofHealthCall was tested on each outcome using the models.FindingsData from 8,702 residents was used in the analysis. Results show HealthCall reduces the number of emergency attendances by 11%[6%-15%], emergency admissions by 25% 20%-39%], readmissions reduced by 29%[24%-33%] and length of stay by 11%[3%-18%] (with an additional month-by-month decrease of 28%[24%-34%]). The cost analysis found a cost reduction of £57 per resident in 2018, increasing to £113 in 2021.InterpretationThe introduction of a digital technology, such as HealthCall, significantly reduces contacts with and costs resulting from unplanned secondary care usage by care home residents.FundingThis work was funded by Health Data Research UK, CFC0124.
Heterogeneity in Early Postpartum Metabolic Profiles Among Women with GDM Who Progressed to Type 2 Diabetes During 10-Year Follow-Up: The SWIFT Study
Authors: Khan Saifur R , Rost Hannes , Cox Brian , Razani Babak , Alexeeff Stacey , Wheeler Michael B. , Gunderson Erica P. 
Published: June 2023

ABSTRACTGDM is a strong risk factor for progression to T2D after pregnancy. Although both GDM and T2D exhibit heterogeneity, the link between the distinct heterogeneity of GDM and incident T2D has not been established. Herein, we evaluate early postpartum profiles of women with recent GDM who later developed incident T2D using a soft clustering method, followed by the integration of both clinical phenotypic variables and metabolomics to characterize these heterogeneous clusters/groups clinically and their molecular mechanisms. We identified three clusters based on two indices of glucose homeostasis at 6-9 weeks postpartum – HOMA-IR and HOMA-B among women who developed incident T2D during the 12-year follow-up. The clusters were classified as follows: pancreatic beta-cell dysfunction group (cluster-1), insulin resistant group (cluster-3), and a combination of both phenomena (cluster-2) comprising the majority of T2D. We also identified postnatal blood test parameters to distinguish the three clusters for clinical testing. Moreover, we compared these three clusters in their metabolomics profiles at the early stage of the disease to identify the mechanistic insights. A significantly higher concentration of a metabolite at the early stage of a T2D cluster than other clusters indicates its essentiality for the particular disease character. As such, the early-stage characters of T2D cluster-1 pathology include a higher concentration of sphingolipids, acyl-alkyl phosphatidylcholines, lysophosphatidylcholines, and glycine, indicating their essentiality for pancreatic beta-cell function. In contrast, the early-stage characteristics of T2D cluster-3 pathology include a higher concentration of diacyl phosphatidylcholines, acyl-carnitines, isoleucine, and glutamate, indicating their essentiality for insulin actions. Notably, all these biomolecules are found in the T2D cluster-2 with mediocre concentrations, indicating a true nature of a mixed group. In conclusion, we have deconstructed incident T2D heterogeneity and identified three clusters with their clinical testing procedures and molecular mechanisms. This information will aid in adopting proper interventions using a precision medicine approach.
Patterns of retention in care during clients’ first 12 months after HIV treatment initiation in South Africa: a retrospective cohort analysis using routinely collected data
Authors: Maskew Mhairi , Benade Mariet , Huber Amy , Pascoe Sophie , Sande Linda , Rosen Sydney 
Published: June 2023

AbstractBackgroundRetention in HIV care during the early treatment period is one of the most serious challenges facing HIV programs, but the timing and patterns of early disengagement from care remain poorly understood. We describe patterns of engagement in HIV care during the first and second 6-month periods after initiation.MethodsWe analysed retrospective datasets of routinely collected EMR data from ≥18-year-old clients who initiated ART at public sector clinics in South Africa after 01/01/2018 and had ≥14 months potential follow up. Using scheduled visit dates, we classified observed visits into “as planned” or “late” and characterized engagement in care as continuous (all scheduled visits attended ≤28 days late), cyclical (at least one visit >28 days late with a return visit observed) or disengaged (visit not attended and no return visit to the same facility observed).Results33,821 client records were included (65% female, median age 33). By six months after ART initiation, 57% had remained continuously in care, 14% had engaged cyclically, 11% had transferred to another facility, 1% had died and 16% had disengaged from care at the initiating facility. Among disengagers in the first 6 months, 58% did not return after their initiation visit, 10% disengaged within the first three months, and the remaining 32% disengaged between 3-6 months. By 12 months after initiation, the overall proportion disengaged was 23%, and only 38% of the cohort had maintained continuous engagement for the full 12 -month period.. Patterns of engagement that were established during the first 6 months on ART demonstrated little change in months 7-12, with participants who were cyclically engaged in months 0-6 were nearly twice as likely to disengage in months 7-12 as continuous engagers in months 0-6 (relative risk 1.8, 95% CI: 1.70-1.99).ConclusionsAs recently as 2018, fewer than 60% and 45% of clients starting ART in South Africa were continuously engaged in care (no interruptions >28 days) at 6 and 12 months, respectively, at their initiating facilities. The needs of continuous and cyclical engagers and disengagers during the first 6 months after initiation may differ and require different interventions or models of care.
The respiratory enzyme complex Rnf is vital for metabolic adaptation and virulence inFusobacterium nucleatum
Authors: Britton Timmie A. , Wu Chenggang , Chen Yi-Wei , Franklin Dana , Chen Yimin , Camacho Martha I. , Luong Truc T. , Das Asis , Ton-That Hung 
Published: June 2023

ABSTRACTA prominent oral commensal and opportunistic pathogen,Fusobacterium nucleatumcan traverse to extra-oral sites such as placenta and colon, promoting adverse pregnancy outcomes and colorectal cancer, respectively. How this anaerobe sustains many metabolically changing environments enabling its virulence potential remains unclear. Informed by our genome-wide transposon mutagenesis, we report here that the highly conserved Rnf complex, encoded by thernfCDGEABgene cluster, is key to fusobacterial metabolic adaptation and virulence. Genetic disruption of the Rnf complex via non-polar, in-frame deletion ofrnfC(ΔrnfC) abrogates polymicrobial interaction (or coaggregation) associated with adhesin RadD and biofilm formation. The defect in coaggregation is not due to reduced cell surface of RadD, but rather an increased level of extracellular lysine, which binds RadD and inhibits coaggregation. Indeed, removal of extracellular lysine via washing ΔrnfCcells restores coaggregation, while addition of lysine inhibits this process. These phenotypes mirror that of a mutant (ΔkamA) that fails to metabolize extracellular lysine. Strikingly, the ΔrnfCmutant is defective in ATP production, cell growth, cell morphology, and expression of the enzyme MegL that produces hydrogen sulfide from cysteine. Targeted metabolic profiling demonstrated that catabolism of many amino acids, including histidine and lysine, is altered in ΔrnfCcells, thereby reducing production of ATP and metabolites including H2S and butyrate. Most importantly, we show that the ΔrnfCmutant is severely attenuated in a mouse model of preterm birth. The indispensable function of Rnf complex in fusobacterial pathogenesis via modulation of bacterial metabolism makes it an attractive target for developing therapeutic intervention.IMPORTANCEAlthough viewed as an oral commensal, the Gram-negativeF. nucleatumis an opportunistic pathogen that can spread to extra-oral sites such as placenta and colon, promoting adverse pregnancy outcomes and colorectal cancer, respectively. How this anaerobe sustains various metabolically changing environments enabling its virulence potential remains unclear. We demonstrate here that the highly conserved Rnf complex is key to fusobacterial metabolic adaptation and virulence. Genetic disruption of this Rnf complex causes global defects in polymicrobial interaction, biofilm formation, cell growth and morphology, H2S production, and ATP synthesis. Targeted metabolomic profiling demonstrates that the loss of this respiratory enzyme significantly diminishes catabolism of numerous amino acids, which negatively impacts fusobacterial virulence as tested in a preterm birth model in mice.
Directed evolution of nanosensors for the detection of mycotoxins
Authors: Lambert Benjamin P. , Taheri Afsaneh , Wu Shang-Jung , Gillen Alice J. , Kashaninejad Mahdi , Boghossian Ardemis A. 
Published: June 2023

AbstractIn this study, we develop and apply a directed evolution approach to engineer the optical sensing properties of DNA-wrapped single-walled carbon nanotubes (DNA-SWCNTs) towards mycotoxins, a class of molecules critical to detect in the food industry. We successfully demonstrate the creation of sensors for the detection of both the aflatoxin B1 (AFB1) and fumonisin B1 (FB1) mycotoxins based on the specific response of the (9,4) and (7,5) SWCNT chirality fluorescence peaks, respectively. The resulting chirality-specific responsivity was used to demonstrate the multimodal detection of both mycotoxins at different wavelengths of light in the presence of complex food medium. Moreover, we show that directed evolution can be used not only to improve the chiral-dependent selectivity of our sensors to the mycotoxins, but also the sensor sensitivity and fluorescence intensity through multiple rounds of evolution. The approach demonstrated in this study is versatile and could be generalized to other SWCNT sensors as well as other nanosensors comprising a biological element.
H3.3-G34R Mutation-Mediated Epigenetic Reprogramming Leads to Enhanced Efficacy of Immune Stimulatory Gene Therapy in Diffuse Hemispheric Gliomas
Authors: Garcia-Fabiani Maria B. , Haase Santiago , Banerjee Kaushik , Zhu Ziwen , McClellan Brandon L. , Mujeeb Anzar A. , Li Yingxiang , Tronrud Claire E. , Varela Maria L. , West Molly E.J. , Yu Jin , Kadiyala Padma , Taher Ayman W. , Núñez Felipe J. , Alghamri Mahmoud S. , Comba Andrea , Mendez Flor M. , Nicola Candia Alejandro J. , Salazar Brittany , Nunez Fernando M. , Edwards Marta B. , Qin Tingting , Cartaxo Rodrigo T. , Niculcea Michael , Koschmann Carl , Venneti Sriram , Puigdelloses Vallcorba Montserrat , Nasajpour Emon , Pericoli Giulia , Vinci Maria , Kleinman Claudia L. , Jabado Nada , Chandler James P. , Sonabend Adam M. , DeCuypere Michael , Hambardzumyan Dolores , Prolo Laura M. , Mahaney Kelly B. , Grant Gerald A. , Petritsch Claudia K , Welch Joshua D. , Sartor Maureen A. , Lowenstein Pedro R. , Castro Maria G. 
Published: June 2023

ABSTRACTDiffuse hemispheric glioma (DHG), H3 G34-mutant, representing 9-15% of cases, are aggressive Central Nervous System (CNS) tumors with poor prognosis. This study examines the role of epigenetic reprogramming of the immune microenvironment and the response to immune-mediated therapies in G34-mutant DHG. To this end, we utilized human G34-mutant DHG biopsies, primary G34-mutant DHG cultures, and genetically engineered G34-mutant mouse models (GEMMs). Our findings show that the G34 mutation alters histone marks’ deposition at promoter and enhancer regions, leading to the activation of the JAK/STAT pathway, which in turn results in an immune-permissive tumor microenvironment. The implementation of Ad-TK/Ad-Flt3L immunostimulatory gene therapy significantly improved median survival, and lead to over 50% long term survivors. Upon tumor rechallenge in the contralateral hemisphere without any additional treatment, the long-term survivors exhibited robust anti-tumor immunity and immunological memory. These results indicate that immune-mediated therapies hold significant potential for clinical translation in treating patients harboring H3.3-G34 mutant DHGs, offering a promising strategy for improving outcomes in this challenging cancer subtype affecting adolescents and young adults (AYA).STATEMENT OF SIGNIFICANCEThis study uncovers the role of the H3.3-G34 mutation in reprogramming the tumor immune microenvironment in diffuse hemispheric gliomas. Our findings support the implementation of precision medicine informed immunotherapies, aiming at improving enhanced therapeutic outcomes in adolescents and young adults harboring H3.3-G34 mutant DHGs.
Dynamic 1D Search and Processive Nucleosome Translocations by RSC and ISW2 Chromatin Remodelers
Authors: Kim Jee Min , Carcamo Claudia C. , Jazani Sina , Xie Zepei , Feng Xinyu A. , Yamadi Maryam , Poyton Matthew , Holland Katie L. , Grimm Jonathan B. , Lavis Luke D. , Ha Taekjip , Wu Carl 
Published: June 2023

SummaryEukaryotic gene expression is linked to chromatin structure and nucleosome positioning by ATP-dependent chromatin remodelers that establish and maintain nucleosome-depleted regions (NDRs) near transcription start-sites. Conserved yeast RSC and ISW2 remodelers exert antagonistic effects on nucleosomes flanking NDRs, but the temporal dynamics of remodeler search, engagement and directional nucleosome mobilization for promoter accessibility are unknown. Using optical tweezers and 2-color single-particle imaging, we investigated the Brownian diffusion of RSC and ISW2 on free DNA and sparse nucleosome arrays. RSC and ISW2 rapidly scan DNA by one-dimensional hopping and sliding respectively, with dynamic collisions between remodelers followed by recoil or apparent co-diffusion. Static nucleosomes block remodeler diffusion resulting in remodeler recoil or sequestration. Remarkably, both RSC and ISW2 use ATP hydrolysis to translocate mono-nucleosomes processively at ∼30 bp/sec on extended linear DNA under tension. Processivity and opposing push-pull directionalities of nucleosome translocation shown by RSC and ISW2 shape the distinctive landscape of promoter chromatin.
Scrutinizing the protein hydration shell from molecular dynamics simulations against consensus small-angle scattering data
Authors: Linse Johanna-Barbara , Hub Jochen S. 
Published: June 2023

AbstractBiological macromolecules in solution are surrounded by a hydration shell, whose structure differs from the structure of bulk solvent. In crowded cellular environments, hydration shells constitute a large fraction of the overall solvent. While the importance of the hydration shell for numerous biological functions such as molecular recognition or enzymatic activity is widely acknowledged, it is poorly understood how the hydration shell is regulated by macromolecular shape and surface composition, mostly because a quantitative readout of the overall hydration shell structure has been missing. We show that small-angle scattering (SAS) in solution using X-rays (SAXS) or neutrons (SANS) provide a protein-specific footprint of the protein hydration shell that enables quantitative comparison with molecular dynamics (MD) simulations. By means of explicit-solvent SAS predictions, we derived the effect of the hydration shell contrast relative to bulk on the radii of gyrationRgof five proteins using 18 combinations of protein force field and water model. By comparing computedRgvalues from SAXS relative to SANS in D2O with consensus experimental data from a worldwide round-robin study, we found that several but not all force fields yield a hydration shell contrast in remarkable agreement with experimental data. The hydration shell contrast, as captured byRgvalues, strongly depends on the protein charge and geometric shape, thus providing a protein-specific footprint of protein–water interactions and a novel observable for scrutinizing atomistic hydration shell models against experimental data.
Maximizing Heterologous Expression of Engineered Type I Polyketide Synthases: Investigating Codon Optimization Strategies
Authors: Schmidt Matthias , Lee Namil , Zhan Chunjun , Roberts Jacob B. , Nava Alberto A. , Keiser Leah , Vilchez Aaron , Chen Yan , Petzold Christopher J. , Haushalter Robert W. , Blank Lars M. , Keasling Jay D. 
Published: June 2023

ABSTRACTType I polyketide synthases (T1PKSs) hold an enormous potential as a rational production platform for the biosynthesis of specialty chemicals. However, despite the great progress in this field, the heterologous expression of PKSs remains a major challenge. One of the first measures to improve heterologous gene expression can be codon optimization. Although controversial, choosing the wrong codon optimization strategy can have detrimental effects on protein and product levels. In this study, we analyzed 11 different codon variants of an engineered T1PKS and investigated in a systematic approach their influence on heterologous expression inCorynebacterium glutamicum,Escherichia coli, andPseudomonas putida. Our best performing codon variants exhibited a minimum 50-fold increase in PKS protein levels, which also enables the production of an unnatural polyketide in each of the hosts. Furthermore, we developed a free online tool (https://basebuddy.lbl.gov) that offers transparent and highly customizable codon optimization with up-to-date codon usage tables.Here, we not only highlight the significance of codon optimization but also establish the groundwork for high-throughput assembly and characterization of PKS pathways in alternative hosts.
Sex disparities in age-related neuromuscular decline: unveiling female susceptibility from early to late elderly
Authors: Guo Yuxiao , Jones Eleanor J. , Smart Thomas F. , Altheyab Abdulmajeed , Gamage Nishadi , Stashuk Daniel W. , Piasecki Jessica , Phillips Bethan E. , Atherton Philip J. , Piasecki Mathew 
Published: June 2023

AbstractBackgroundFemales typically have a longer lifespan than males which is not matched by an improved healthspan, with older females having higher rates of frailty, characteristic of a sex specific degradation of the neuromuscular system. Several motor unit (MU) characteristics show sex-specific behaviour during mid-level contractions in healthy younger people, highlighting a potential influence of hormonal differences that may be augmented in older age. The purpose of this study was to investigate sex differences in physical performance and MU features of the aged human vastus lateralis (VL) from early to late elderly.MethodsThis study included 21 healthy older males (mean ± SD, range: 67.2 ± 7.6, 56 – 81 yrs) and 17 healthy older females (69.5 ± 5.2, 60 – 78 yrs). Intramuscular electromyography data were collected from VL during standardised submaximal sustained contractions. Muscle size and physical performance characteristics were also measured. Multiple mixed-effects linear regression models with age considered were conducted and statistical significance was accepted when p<0.05.ResultsWhen compared to males, early to late elderly females had smaller cross-sectional area of VL (p<0.001), lower knee extensor torque (p<0.001) and poorer force steadiness (p=0.036), as well as higher MU firing rate (FR) (p=0.025) and greater MU FR variability (p=0.031). With progression from early to late elderly, both sexes showed decreased functional capacity at a similar rate.ConclusionFunctional deterioration occurs to a similar extent in both sexes from early to late elderly. However, throughout the majority of the elderly period males demonstrate a greater muscle size, strength, and functional performance. Older females have greater MUFR variability and worse force steadiness than older males. These findings help to address the lack of MU data in older females, and suggest earlier interventions are needed in older females to prevent functional deterioration and reduce the health-sex paradox within ageing humans.
A large-scale study on the nocturnal behavior of African ungulates in zoos and its influencing factor
Authors: Gübert Jennifer , Hahn-Klimroth Max , Dierkes Paul W. 
Published: June 2023

AbstractThis study analyzed the nocturnal behavior of 196 individuals of 19 ungulate species in 20 zoos in Germany and the Netherlands. To the best of our knowledge, this is the first description of nocturnal behavior for some of the species. The importance of a wide range of possible factors influencing nocturnal behavior is discussed. Specifically, the behavioral states of standing and lying were analyzed, evaluating the proportion and number of phases in each behavior. The underlying data consists of 101,629 hours of video material from 9,239 nights. BOVIDS, a deep learning-based software package, was used to analyze the recordings. The analysis of the influencing factors was based on a random forest regression and a SHAP analysis. The results indicate that age, body size and feeding type are the most important factors influencing nocturnal behavior across all species. There are strong differences between the zebra species and the observed Cetartiodactyla as well as White Rhinos. The main difference is that zebras spend significantly less time in a lying position than Cetartiodactyla.