bluuebunny/crossref_metadata_2025_split huggingface dataset:
Field performance and cost-effectiveness of a point-of-care triage test for HIV virological failure in Southern Africa
Authors: Saura-Lázaro Anna , Bock Peter , van den Bogaart Erika , van Vliet Jessie , Granés Laura , Nel Kerry , Naidoo Vikesh , Scheepers Michelle , Saunders Yvonne , Leal Núria , Ramponi Francesco , Paulussen René , de Wit Tobias Rinke , Naniche Denise , López-Varela Elisa 
Published: September 2023

AbstractIntroductionAntiretroviral therapy (ART) monitoring using viral load (VL) testing is challenging in high-burden, limited-resources settings. Chemokine IP-10 (interferon gamma-induced protein 10) strongly correlates with human immunodeficiency virus (HIV) VL. Its determination could serve to predict virological failure (VF) and to triage patients requiring VL testing. We assessed the field performance of a semi-quantitative IP-10 lateral flow assay (LFA) for VF screening in South Africa, and the cost-effectiveness of its implementation in Mozambique.MethodsA cross-sectional study was conducted between June and December 2021 in three primary health clinics in the Western Cape. Finger prick capillary blood was collected from adults on ART for ≥1 year for direct application onto the IP-10 LFA (index test) and compared with a plasma VL result ≤1 month prior (reference test). We estimated the area under the receiver operating characteristic curves (AUC), sensitivity and specificity, to evaluate IP-10 LFA prediction of VF (VL>1,000 copies/mL). A decision tree model was used to investigate the cost-effectiveness of integrating IP-10 LFA combined with VL testing into the current Mozambican ART monitoring strategy. Averted disability-adjusted life years (DALYs) and HIV infections, and incremental cost-effectiveness ratios were estimated.ResultsAmong 209 participants (median age 38 years and 84% female), 18% had VF. Median IP-10 LFA values were higher among individuals with VF compared to those without (24.0 vs. 14.6; p<0.001). The IP-10 LFA predicted VF with an AUC=0.76 (95% confidence interval (CI) 0.67–0.85), 91.9% sensitivity (95%CI 78.1%–98.3%) and 35.1% specificity (95%CI 28.0%– 42.7%). Integrating the IP-10 LFA in a setting with 20% VF prevalence and 61% VL testing coverage could save 13.0% of costs and avert 14.9% of DALYs and 55.7% new HIV infections. Furthermore, its introduction was estimated to reduce the total number of routine VL tests required for ART monitoring by up to 68%.ConclusionsThe IP-10 LFA is an effective VF triage test for routine ART monitoring. Combining a highly sensitive, low-cost IP-10 LFA-based screening with targeted VL confirmatory testing could result in significant healthcare quality improvements and cost savings in settings with limited access to VL testing.
Improved Detection of Decreased Glucose Handling Capacities via Novel Continuous Glucose Monitoring-Derived Indices: AC_Mean and AC_Var
Authors: Sugimoto Hikaru , Hironaka Ken-ichi , Nakamura Tomoaki , Yamada Tomoko , Miura Hiroshi , Otowa-Suematsu Natsu , Fujii Masashi , Hirota Yushi , Sakaguchi Kazuhiko , Ogawa Wataru , Kuroda Shinya 
Published: September 2023

ABSTRACTBackgroundEfficiently detecting impaired glucose control abilities is a pivotal challenge in public health. This study assessed the utility of relatively easy-to-measure continuous glucose monitoring (CGM)-derived indices in estimating glucose handling capacities calculated from resource-intensive clamp tests.MethodsWe conducted a prospective, single-center, observational cohort study of 64 individuals without prior diabetes diagnosis. The study utilized CGM, oral glucose tolerance test, and hyperglycemic and hyperinsulinemic-euglycemic clamp tests. We validated CGM-derived indices characteristics using an independent dataset and mathematical model with simulated data.FindingsA novel CGM-derived index, AC_Var, was significantly correlated with insulin sensitivity (r = –0.31; 95% CI: –0.52 to –0.06), insulin clearance (r = –0.31; 95% CI: –0.54 to –0.06), and disposition index (DI) (r = –0.31; 95% CI: –0.52 to –0.07) calculated from clamp tests.AC_Var was also significantly correlated with insulin resistance (r = 0.48; 95% CI: 0.23 to 0.68) in an independent dataset. Multivariate analyses indicated AC_Var’s contribution to predicting reduced blood glucose control abilities independent from conventional CGM-derived indices. The prediction model’s accuracy utilizing CGM-measured glucose standard deviation and AC_Var as input variables, with clamp-derived DI as the outcome, closely matched that of predicting clamp- from OGTT-derived DI. Mathematical simulations also underscored AC_Var’s association with insulin clearance and DI.InterpretationCGM-derived indices, including AC_Var, can be useful for screening decreased blood glucose control ability. We developed a web application that calculates these indices (https://cgm-ac-mean-std.streamlit.app/).FundingThe Japan Society for the Promotion of Science KAKENHI, CREST, Japan Science and Technology Agency, and Uehara Memorial Foundation.
Southern Ethiopian skilled birth attendant variations and maternal mortality: a multilevel study of a population-based cross-sectional household survey
Authors: Kea Aschenaki Zerihun , Lindtjorn Bernt , Tekle Achamyelesh Gebretsadik , Hinderaker Sven Gudmund 
Published: September 2023

AbstractIntroductionStudies examining skilled birth attendants (SBA) use and its correlation with maternal mortality at lower administrative levels are scarce. This study assessed the coverage and variations of SBA, the physical accessibility of health facilities for SBA, and the association of SBA with maternal mortality.Materials and methodsA cross-sectional study using a population-based household survey was conducted in six Sidama National Regional State, southern Ethiopia districts, from July 2019 to May 2020. Women who had given birth in the past two years prior to the study were included. Stata 15 and ArcGIS 10.4.1 were used for data analysis. A multilevel logistic regression analysis was conducted to assess the effect of the sampling units and identify factors independently associated with SBA. The association between SBA and maternal mortality was examined using data from a maternal mortality household survey.ResultsA total of 3191 women were interviewed. The coverage of SBA was 46.7%, with high variations in the districts. Thirty percent of SBA use was accounted for by the differences among the districts. One-third of the women travel more than two hours to access the nearest hospital. Districts with low coverage of SBA and located far away from the regional referral centre had high maternal mortality. Education of the mother, occupation of the husband, pregnancy-related complications, use of antenatal care, parity, and distance to the nearest hospital and health centre were associated with the use of SBA.ConclusionsThe coverage of SBA in the Sidama Region was low, with high variations in the districts. Low SBA use was associated with high maternal mortality. Due attention should be given to districts with low coverage of SBA and those located far away from the referral centre. Access to hospitals has to improve. All women should be encouraged to get antenatal care services.
NeuroMechFly v2, simulating embodied sensorimotor control in adultDrosophila
Authors: Wang-Chen Sibo , Stimpfling Victor Alfred , Lam Thomas Ka Chung , Özdil Pembe Gizem , Genoud Louise , Hurtak Femke , Ramdya Pavan 
Published: September 2023

AbstractDiscovering principles underlying the control of animal behavior requires a tight dialogue between experiments and neuromechanical models. Until now, such models, including NeuroMechFly for the adult fly,Drosophila melanogaster, have primarily been used to investigate motor control. Far less studied with realistic body models is how the brain and motor systems work together to perform hierarchical sensorimotor control. Here we present NeuroMechFly v2, a framework that expandsDrosophilaneuromechanical modeling by enabling visual and olfactory sensing, ascending motor feedback, and complex terrains that can be navigated using leg adhesion. We illustrate its capabilities by first constructing biologically inspired locomotor controllers that use ascending motor feedback to perform path integration and head stabilization. Then, we add visual and olfactory sensing to this controller and train it using reinforcement learning to perform a multimodal navigation task in closed loop. Finally, we illustrate more biorealistic modeling in two ways: our model navigates a complex odor plume using aDrosophilaodor taxis strategy, and it uses a connectome-constrained visual system network to follow another simulated fly. With this framework, NeuroMechFly can be used to accelerate the discovery of explanatory models of the nervous system and to develop machine learning-based controllers for autonomous artificial agents and robots.
The sterol transporter STARD3 transports sphingosine at ER-lysosome contact sites
Authors: Hempelmann Pia , Lolicato Fabio , Graziadei Andrea , Brown Ryan D. R. , Spiegel Sarah , Rappsilber Juri , Nickel Walter , Höglinger Doris , Jamecna Denisa 
Published: September 2023

SummarySphingolipids are important structural components of membranes. Additionally, simple sphingolipids such as sphingosine are highly bioactive and participate in complex subcellular signaling. Sphingolipid deregulation is associated with many severe diseases including diabetes, Parkinson’s and cancer. Here, we focus on how sphingosine, generated from sphingolipid catabolism in late endosomes/lysosomes, is reintegrated into the biosynthetic machinery at the endoplasmic reticulum (ER). We characterized the sterol transporter STARD3 as a sphingosine transporter acting at lysosome-ER contact sites. Experiments featuring crosslinkable sphingosine probes, supported by unbiased molecular dynamics simulations, exposed how sphingosine binds to the lipid-binding domain of STARD3. Following the metabolic fate of pre-localized lysosomal sphingosine showed the importance of STARD3 and its actions at contact sites for the integration of sphingosine into ceramide in a cellular context. Our findings provide the first example of inter-organellar sphingosine transfer and pave the way for a better understanding of sphingolipid – sterol co-regulation.
Reconstructing creative thoughts: Hopfield Neural Networks
Authors: Checiu Denisa , Bode Mathias , Khalil Radwa 
Published: September 2023

AbstractFrom a brain processing perspective, the perception of creative thinking is rooted in the underlying cognitive process, which facilitates exploring and cultivating novel avenues and problem-solving strategies. However, it is challenging to emulate the intricate complexity of how the human brain presents a novel way to uncover unique solutions. One potential approach to mitigate this complexity is incorporating creative cognition within the evolving artificial intelligence systems and associated neural models. Hopfield Neural Networks (HNN) are commonly acknowledged as a simplified neural model, renowned for their biological plausibility to store and retrieve information, specifically patterns of neurons. Therefore, we propose for the first time using HNN to generate a potential model that emulates specific cognitive processes of creative thinking based on generating meaningful links between seemingly disparate concepts.
Kappa opioid receptor activation induces epigenetic silencing of brain-derived neurotropic factor via HDAC5 in depression
Authors: Yadav Anubhav , Dogra Shalini , Kumar Boda Arun , Kumari Poonam , Kumar Ajeet , Dash Manish K , Yadav Prem N 
Published: September 2023

AbstractTreatment-resistant depression (TRD) occurs in almost 50% of depressed patients. Central kappa opioid receptor (KOR) agonism has been demonstrated to induce depression and anxiety, while KOR antagonism alleviate depression like symptoms in rodent models and TRD in clinical studies. Previously, we have shown that sustained KOR activation leads to TRD-like phenotype in mice, and modulation of brain-derived neurotrophic factor (BDNF) expression in the prefrontal cortex (PFC) appears to be one of the molecular determinants of the antidepressant response. In the present study, we observed that sustained KOR activation by a selective agonist, U50488, selectively reduced theBdnftranscriptsII, IV, andBdnf CDS(protein-codingExon IX) in the PFC and cultured primary cortical neurons, which was blocked by selective KOR antagonist, norbinaltorphimine. Considering the crucial role of epigenetic pathways inBDNFexpression, we further investigated the role of various epigenetic markers in KOR induced BDNF downregulation in mice. We observed that treatment with U50488 resulted in selective and specific downregulation of acetylation at the 9th lysine residue of the histone H3 protein (H3K9ac) and upregulation of HDAC5 expression in the PFC. Further, using anti-H3K9ac and anti-HDAC5 antibodies in chromatin immune precipitation assay, we detected decreased enrichment of H3K9ac and increased HDAC5 binding atBdnf IIandIVtranscripts after U50488 treatment, which were blocked by a selective KOR antagonist, norbinaltorphimine. Further mechanistic studies using HDAC5 selective inhibitor, LMK235, in primary cortical neurons, and adeno-associated viral shRNA mediated HDAC5-knockdown in the PFC of mice, we demonstrated an essential role of HDAC5 in KOR-mediated reduction ofBdnfexpression in the PFC and depression-like symptoms in mice. These results suggest that KOR engages multiple pathways to induce depression-like symptoms in mice, and provide novel insights into the mechanisms by which activation of KOR regulates major depressive disorders.
A low-input high resolution sequential chromatin immunoprecipitation method captures genome-wide dynamics of bivalent chromatin
Authors: Ho William , Seneviratne Janith A. , Glancy Eleanor , Eckersley-Maslin Melanie A. 
Published: September 2023

AbstractBackgroundBivalent chromatin is an exemplar of epigenetic plasticity. This co-occurrence of active-associated H3K4me3 and inactive-associated H3K27me3 histone modifications on opposite tails of the same nucleosome occurs predominantly at promoters where it poises them for future transcriptional upregulation or terminal silencing. We know little of the dynamics, resolution, and regulation of this chromatin state outside of embryonic stem cells where it was first described. This is partly due to the technical challenges distinguishing bone-fide bivalent chromatin, where both marks are on the same nucleosome, from allelic or sample heterogeneity where there is a mix of H3K4me3-only and H3K27me3-only mononucleosomes.ResultsHere, we present a robust and sensitive method to accurately map genome-wide bivalent chromatin along with all necessary controls from as little as 2 million cells. We optimised and refined the sequential ChIP protocol which uses two sequential overnight immunoprecipitation reactions to robustly purify nucleosomes that are truly bivalent and contain both H3K4me3 and H3K27me3 modifications. Our method generates high quality genome-wide maps with strong peak enrichment and low background which can be analysed using standard bioinformatic packages. Using this method, we detect twice as many bivalent regions in mouse embryonic stem cells as previously identified, bringing the total number of bivalently marked gene promoters to 8,373. Furthermore, profiling Dppa2/4 knockout mouse embryonic stem cells which lose both H3K4me3 and H3K27me3 at approximately 10% of bivalent promoters, demonstrated the ability of our method to capture bivalent chromatin dynamics.ConclusionsOur optimised sequential reChIP method enables high-resolution genome-wide assessment of bivalent chromatin together with all required controls in as little as 2 million cells. We share a detailed protocol and guidelines that will enable bivalent chromatin landscapes to be generated in a range of cellular contexts, greatly enhancing our understanding of bivalent chromatin and epigenetic plasticity beyond embryonic stem cells.
ESR1fusion proteins invoke breast cancer subtype-dependent enrichment of ligand independent pro-oncogenic signatures and phenotypes
Authors: Yates Megan E. , Li Zheqi , Li Yiting , Guzolik Hannah , Wang Xiaosong , Liu Tiantong , Hooda Jagmohan , Atkinson Jennifer M. , Lee Adrian V. , Oesterreich Steffi 
Published: September 2023

AbstractBreast cancer is a leading cause of female mortality and despite advancements in diagnostics and personalized therapeutics, metastatic disease largely remains incurable due to drug resistance. Fortunately, identification of mechanisms of therapeutic resistance have rapidly transformed our understanding of cancer evasion and is enabling targeted treatment regimens. When the druggable estrogen receptor (ER,ESR1), expressed in two-thirds of all breast cancer, is exposed to endocrine therapy, there is risk of somatic mutation development in approximately 30% of cases and subsequent treatment resistance. A more recently discovered mechanism of ER mediated endocrine resistance is the expression of ER fusion proteins. ER fusions, which retain the protein’s DNA binding domain, harborESR1exons 1-6 fused to an in-frame gene partner resulting in loss of the 3’ ER ligand binding domain (LBD). In this report we demonstrate that in no-special type (NST) and invasive lobular carcinoma (ILC) cell line models, ER fusion proteins exhibit robust hyperactivation of canonical ER signaling pathways independent of the ligand estradiol or anti-endocrine therapies such as Fulvestrant and Tamoxifen. We employ cell line models stably overexpressing ER fusion proteins with concurrent endogenous ER knockdown to minimize the influence of endogenous wildtype ER. Cell lines exhibited shared transcriptomic enrichment in pathways known to be drivers of metastatic disease, notably the MYC pathway. The heterogeneous 3’ fusion partners, particularly transcription factorsSOX9andYAP1, evoked varying degrees of transcriptomic and cistromic activity that translated into unique phenotypic readouts. Herein we report that cell line activity is subtype-, fusion-, and assay-specific suggesting that the loss of the LBD, the 3’ fusion partner, and the cellular landscape all influence fusion activity. Therefore, it will be critical to generate additional data on frequency of the ER fusions, in the context of the clinicopathological features of the tumor.SignificanceER fusion proteins exhibit diverse mechanisms of endocrine resistance in breast cancer cell lines representing the no special type (NST) and invasive lobular cancer (ILC) subtypes. Our emphasize upon both the shared and unique cellular adaptations imparted by ER fusions offers the foundation for further translational research and clinical decision making.
Community coalescence altered the potential of horizontal gene transfers within the native soil microbiome
Authors: Liu Xipeng , Hackl Thomas , Salles Joana Falcão 
Published: September 2023

AbstractMicrobial community coalescence, which refers to the mixing of microbial communities, frequently shapes the assemblage of soil microbiomes in natural ecosystems. It can exert selective pressure on the coalescent taxa, leading to ecological changes in microbial community structure or microbial evolutionary changes via horizontal gene transfer (HGT). However, the influence of community coalescence on the potential of HGTs within native communities, particularly in soil ecosystems, remains poorly understood. Here, we experimentally quantified the potential evolutionary consequences of soil coalescence. We achieved that by subjecting microcosms containing natural soil to invasion by several microbial communities and profiling mobile genetic elements (MGEs) and adaptive genes of microbial communities up to 60 days after coalescence. Our findings revealed both specific and common responses of MGEs to coalescences over time. Specific effects differed across invasive communities and were particularly pronounced in the early stages. Common effects were associated with an increased abundance of insertion sequences (ISs) across different treatments, suggesting that ISs played a crucial role in promoting diversification at the community level. In summary, we showed that changing MGE profiles are an intrinsic response of the soil microbial community to coalescence-imposed pressure. Our study provides new insights into the modulation of adaptability in soil microbial communities by utilizing community coalescences to address global challenges.
Parallel evolution of local adaptation inLittorina saxatilisinferred with whole-genome pool-seq data
Authors: Carvalho João , Faria Rui , Butlin Roger K. , Sousa Vítor C. 
Published: September 2023

ABSTRACTParallel evolution of phenotypic divergence offers compelling evidence supporting the influence of natural selection on the divergence process. However, the existence of ecotypes adapted to different habitats in separate locations is not a definitive proof of parallel evolution. Here, we leverage a large pool-seq dataset of the rocky-shore gastropod,Littorina saxatilisto compare and contrast two explicit scenarios of ecotype formation. Populations of this species inhabit contrasting habitats, where the main selective pressure is either wave action or crab predation. Using approximate Bayesian computation to jointly infer demographic parameters and account for pool-seq specific sources of uncertainty, our analysis reveals that ecotype formation at a large geographical scale has occurred in parallel. Parameter estimates provide strong support for a demographic history marked by the spatial separation of the ancestral populations that later gave rise to parallel evolution of ecotypes in Spain and Sweden. Additionally, ecotype formation occurred in the face of continuous gene flow between the diverging ecotypes. These results shed new light on a important model of speciation driven by ecological factors and emphasize the effectiveness of combining pool-seq with ABC for studying parallel evolution across diverse geographical regions.
Heterologous naringenin production in the filamentous fungusPenicillium rubens
Authors: Peng Bo , Dai Lin , Iacovelli Riccardo , Driessen Arnold J. M. , Haslinger Kristina 
Published: September 2023

AbstractNaringenin is a natural product with several reported bioactivities and is the key intermediate for the entire class of plant flavonoids. The translation of flavonoids into modern medicine as pure compounds is often hampered by their low abundance in nature and difficult chemical synthesis. Here, we investigated new avenues toward producing high levels of naringenin in microbial hosts.Penicillium rubensis a well characterized and highly engineered traditional “workhorse” for the production of β-lactam antibiotics and cholesterol-lowering statins. We explored a secondary metabolite deficientP. rubensstrain,P. rubens4xKO, that was derived from an earlier industrial production strain as a promising microbial host for a recombinant flavonoid pathway. By integrating two plant genes encoding for enzymes in the naringenin biosynthesis pathway into the genome of this strain, we achieved a high naringenin titer in flask fermentations 36 h after feeding the precursorp-coumaric acid. Along with the rapid product accumulation of up to an 88% molar yield, we also observed rapid degradation of naringenin. Based on high-resolution mass spectrometric analysis, we identified the degradation products and proposed a naringenin degradation pathway inP. rubens4xKO, which is distinct from other flavonoid-converting pathways reported in fungi. Our approach combines fundamental research with application-oriented microbial engineering, and our findings will pave the way to the more sustainable and economically feasible production of flavonoids for pharmaceutical and nutraceutical applications.