bluuebunny/crossref_metadata_2025_split huggingface dataset:
Point-of-care prognostication in moderate Covid-19: analytical validation and diagnostic accuracy of a soluble urokinase plasminogen activator receptor (suPAR) rapid test
Authors: Chandna Arjun , Mahajan Raman , Gautam Priyanka , Mwandigha Lazaro , Dittrich Sabine , Kumar Vikash , Osborn Jennifer , Kumar Pragya , Koshiaris Constantinos , Varghese George M , Lubell Yoel , Burza Sakib 
Published: November 2022

ABSTRACTThe soluble urokinase plasminogen activator receptor (suPAR) has been proposed as a biomarker for the risk stratification of patients presenting with acute infections. However, most studies evaluating suPAR have used platform-based assays, the diagnostic accuracy of which may differ from point-of-care tests capable of informing timely patient triage in settings without established laboratory capacity.Using samples and data collected during a prospective cohort study of 425 patients presenting with moderate Covid-19 to two hospitals in India, we evaluated the analytical performance and diagnostic accuracy of a commercially-available rapid diagnostic test (RDT) for suPAR, using an enzyme-linked immunoassay (ELISA) as the reference standard. Although agreement between the two tests was limited (bias = −2.46 ng/mL [95% CI = −2.65 to −2.27 ng/mL]), diagnostic accuracy to predict progression to supplemental oxygen requirement was comparable, whether suPAR was used alone (area under the receiver operating characteristic curve [AUC] of RDT = 0.73 [95% CI = 0.68 to 0.79] vs. AUC of ELISA = 0.70 [95% CI = 0.63 to 0.76]; p = 0.12) or as part of a previously published multivariable clinical prediction model (AUC of RDT-based model = 0.74 [95% CI = 0.66 to 0.83] vs. AUC of ELISA-based model = 0.72 [95% CI = 0.64 to 0.81]; p = 0.78).Lack of agreement between the suPAR RDT and ELISA in our cohort warrants further investigation and highlights the importance of assessing candidate point-of-care tests to ensure management algorithms reflect the assay that will ultimately be used to inform patient care. The availability of a quantitative point-of-care test for suPAR opens the door to suPAR-guided risk stratification of patients with Covid-19 and other acute infections in settings with limited laboratory capacity.
Exploring the feasibility of integrating health, nutrition and stimulation interventions for children under three years in Nepal’s health system: a qualitative study
Authors: Dulal Sophiya , Saville Naomi M. , Merom Dafna , Giri Kalpana , Prost Audrey 
Published: November 2022

AbstractCommunity-based primary care settings are a potential entry point for delivering Early Childhood Development (ECD) interventions in Nepal. Past studies have suggested that integrating stimulation with nutrition interventions is an effective way to deliver multiple benefits for children, but there is limited knowledge of how to do this in Nepal. We conducted a qualitative study in Nepal’s Dhanusha district to explore how stimulation interventions for early learning could be integrated into existing health and nutrition programmes within the public health system. Between March and April 2021, we completed semi-structured interviews with caregivers (n=18), health service providers (n=4), district (n=1) and national stakeholders (n=4), as well as policymakers (n=3). We also carried out focus group discussions with Female Community Health Volunteers (FCHVs) (n=2) and health facility operation and management committee members (n=2). We analysed data using the framework method. Respondents were positive about introducing stimulation interventions into maternal and child health and nutrition services. They thought that using health system structures would help in the implementation of integrated interventions. Respondents also highlighted that local governments play a lead role in decision-making but must be supported by provincial and national governments and external agencies. Key factors impeding the integration of stimulation into national programmes included a lack of intersectoral collaboration, poor health worker competency, increased workload for FCHVs, financial constraints, a lack of prioritisation of ECD and inadequate capacity in local governments. Key barriers influencing the uptake of intervention by community members included lack of knowledge about stimulation, caregivers’ limited time, lack of paternal engagement, poverty, religious or caste discrimination, and social restrictions for newlywed women and young mothers. There is an urgent need for an effective coordination mechanism between ministries and within all three tiers of government to support the integration and implementation of scalable ECD interventions in rural Nepal.
Investigating opportunities to prevent Type 2 Diabetes Mellitus after Gestational Diabetes Mellitus: the DIVINE-NSW study
Authors: Lee Vivian YJ , Beech Amanda , Makris Angela , Arnott Clare , Shanthosh Janani , Donges Katherine , Patel Anushka , Henry Amanda 
Published: November 2022

AbstractBackgroundGestational Diabetes Mellitus (GDM), once thought to be fully reversed after pregnancy, is now a firmly established independent risk factor for the subsequent development of Type 2 Diabetes Mellitus (T2DM), cardiovascular disease and other chronic conditions. This provides a strong rationale to identify preventive strategies in women with prior GDM, including intervention soon after childbirth. Currently, preventive strategies are mostly focused on modifying lifestyle, with an emphasis on diet and physical activity. However, evidence for the effectiveness of implementing and sustaining changes in behaviour through lifestyle programs is limited, and only a small proportion of women in Australia are thought to engage in lifestyle modification programs. Consideration of additional approaches, including pharmacotherapy, is therefore warranted. The current study aims to 1) measure the prevalence and identify the predictors (up to 4 years post-partum) of persisting dysglycaemia among a diverse population of urban Australian women with recent GDM, 2) understand women’s views and views of their healthcare providers on long-term risks of T2DM and barriers and facilitators to engaging in screening and preventive strategies (including pharmacotherapy) to mitigate these risks, and 3) examine the feasibility of a randomised controlled trial of preventive drug therapies in this population.MethodsThis is a retrospective cohort study with a qualitative sub-study. We will identify GDM-affected women who gave birth between January 2018 and December 2021 in at least three Sydney Hospitals (Liverpool Hospital, Royal Hospital for Women and St George Hospital) and invite them to participate in the study. Eligible participants will complete an online questionnaire and an oral glucose tolerance test to assess their current glycaemic status if they have not done so within 12 months of consent and are not currently pregnant. A subset of participants will be invited to participate in an interview to understand their perspectives of GDM, long-term risks and willingness to take preventive medications (including willingness to participate in trials of preventive medicines). Interviews with healthcare providers will also be conducted to understand their views of long-term diabetes risk, screening, and preventive strategies for women following GDM.DiscussionThis study will help understand post-GDM care gaps and outcomes currently in Australia, as well as inform the design and conduct of future trials of preventive drug therapies in this population.ANZCT RegistrationACTRN12621001618842
Buoyant-Antigen-Magnetic (BAM) ImmunoSeparation, isolation, and detection of Specific Pathogenic Bacterial Cells
Authors: McNaughton Brandon H. , Anker Jeffrey N. , Kinnunen Päivö K. 
Published: November 2022

ABSTRACTSeparating, collecting, and detecting specific cells and molecules from complex and heterogeneous samples is key for many biomedical, environmental, and food safety applications. Antibodies are widely used to specifically bind cells and molecules to a solid support such as a column or suspended bead to separate, wash, and concentrate them. However, nonspecific binding of non-target cells and molecules to the support limits the specificity and resulting purity of traditional separation methods. Herein we describe a buoyant-antigen-magnetic (BAM) separation approach to increase specificity using two distinct separation processes with “AND” logic. Buoyant silica microbubbles and magnetic microbeads, each with their own antibody, bind to the target cell forming a BAM sandwich complex which can be separated from non-targeted cells (which are neither magnetic nor buoyant), as well as from cells bound to only single buoyant or magnetic microparticles but not both.Escherichia coliO157:H7, a pathogenic bacteria that can contaminate food products, was used as a model organism to establish a nearly 100-fold reduction in the non-specific carryover of non-targetEscherichia colibacteria in comparison to simple magnetic separation. Beads with no attached analyte were also removed. Furthermore, the BAM complexes could be visualized by eye (or camera) providing a rapid and sensitive method for pathogenic bacterial detection. Bacterial concentrations as low as 5 × 104CFU/ml were evident by eye and could easily be distinguished from non-targetS. aureusbacteria even at much higher concentrations (5x107cfu/mL). This approach enabled simple user-friendly measurement for on-site detection and isolation without expensive equipment.HIGHLIGHTS
Optical measurement of glutamate release robustly reports short-term plasticity at a fast central synapse
Authors: Hain Paul Jakob Habakuk , Moser Tobias 
Published: November 2022

AbstractRecently developed fluorescent neurotransmitter indicators have enabled direct measurements of neurotransmitter in the synaptic cleft. Precise optical measurements of neurotransmitter release may be used to make inferences about presynaptic function independent of electrophysiological measurement techniques. Here, we express iGluSnFR, a genetically encoded glutamate reporter in mouse spiral ganglion neurons to compare electrophysiological and optical readouts of presynaptic function and short-term synaptic plasticity at the endbulb of Held synapse. We conclude that iGluSnFR robustly and approximately linearly reports glutamate release from the endbulb of Held during synaptic transmission and allows assessment of short-term plasticity during high-frequency train stimuli. Furthermore, we show that iGluSnFR expression slightly alters the time course of spontaneous postsynaptic currents, but is unlikely to impact measurements of evoked synchronous release of many synaptic vesicles.
A 3D genome atlas of genetic variants and their pathological effects
Authors: Tang Li , Hill Matthew C. , He Mingxing , Chen Junhao , Ellinor Patrick T. , Li Min 
Published: November 2022

AbstractThe spatial architecture of the genome can be categorized into distinct layers. Each layer plays a critical role in transcriptional regulation and/or genomic integrity. Alterations at any level of the 3D genome can lead to an unwanted cascade of molecular events, which may ultimately drive the manifestation of disease. However, a comprehensive atlas of the mutations and structural genetic defects that affect genome organization has yet to be compiled. Moreover, we lack a centralized resource for interpretating the pathological effects of such genetic mutations. Therefore, we curated from the literature all the pathological alterations from the chromosome level on down to single nucleotide polymorphisms (SNPs) in order to investigate these diverse genetic mutations. Using a two-phase scoring algorithm, 3DFunc, we scored the transcriptomic causality of all variants in the context of 3D genome architecture from 20 cancer and 15 normal tissues. Further, 3DFunc can identify pathological variant-gene pairs in non-oncological diseases. Finally, we constructed a web-based database, 3DGeOD (https://www.csuligroup.com/3DGeOD/home), to provide all the curated variants, genomic disruptions, as well as the scoring results derived from 3DFunc. In summary, our study constructed a 3D genome atlas of genetic variants and will serve as a valuable resource for mining the putative pathological effects of any genetic mutation.
Automated decoding the mouse body postures in a whisker nuisance test
Authors: Chelini Gabriele , Fortunato-Asquini Tommaso , Ollari Ottavia , Pecchia Tommaso , Bozzi Yuri 
Published: November 2022

AbstractAbnormal response to sensory stimuli characterizes multiple neuropsychiatric conditions. However, not many tools are currently available to assess somatosensory abnormalities in rodent models of brain disorders, limiting the possibilities to study cellular and molecular correlates of this phenotypic trait. To this goal, previous studies relied on the whisker nuisance test (WNt), in which freely moving mice are constantly stimulated on their whiskers using a wood stick for a set time. The whisker-guided response is then deconstructed in behavioral categories indicative of either anxiety or curiosity. Thus far, WNt was shown to be a valuable tool to investigate sensory-driven abnormalities in mouse models of autism spectrum disorders (ASD), demonstrating a solid translational validity. Nevertheless, assessment of behavioral response in the WNt is currently limited by the lack of an objective quantification method. To overcome this limitation, we developed WNt3R (Whisker Nuisance Test in 3D for Rodents), a MATLAB toolbox that uses the output of the open-source software DeepLabCut to determine discrete body postures associated with multiple ethologically-relevant behaviors. Our results show that behavioral modules identified using WNt3R reliably decode mouse body postures, outperforming the manual user, thus offering a novel and unbiased approach to study altered somatosensory function in rodents.
Assortative mating and mate-choice contributes to a developmental dimorphism inStreblospio benedicti
Authors: Ruskie Erika L. , Zakas Christina 
Published: November 2022

AbstractAssortative mating, where individuals non-randomly mate with respect to phenotype or genotype, can occur when preferences between potential mates have evolved. When such mate preferences occur in a population it can drive evolutionary and phenotypic divergence. But the extent to which assortative mating, mate preference, and development are evolutionarily linked remains unclear. Here we useStreblospio benedicti, a marine annelid with a rare developmental dimorphism, to investigate if mate-choice could contribute to developmental evolution. ForS. benedictitwo types of ecologically and phenotypically similar adults persist in natural populations, but they give rise to distinctly different offspring with alternative lifehistories. This dimorphism persists despite the absence of post-zygotic reproductive barriers, where crosses between the developmental types can produce phenotypically intermediate offspring. How this life-history strategy evolved remains unknown, but assortative mating is a typical first step in evolutionary divergence. Here we investigate if female mate-choice is occurring in this species. We find that mate preferences could be contributing to the maintenance of alternative developmental and life-history strategies.
PTPN1 deficiency modulates BMPR2 signaling and induces endothelial dysfunction in Pulmonary Arterial Hypertension
Authors: Ali Md Khadem , Tian Xuefei , Zhao Lan , Schimmel Katharina , Rhodes Christopher J. , Wilkins Martin R. , Nicolls Mark R. , Spiekerkoetter Edda F. 
Published: November 2022

AbstractBone morphogenic protein receptor 2 (BMPR2) expression and signaling are impaired in pulmonary arterial hypertension (PAH). How BMPR2 signaling is decreased in PAH is poorly understood. Protein tyrosine phosphatases (PTPs) play important roles in vascular remodeling in PAH. To identify whether PTPs modify BMPR2 signaling we used a siRNA-mediated high throughput screening of 22,124 murine genes in mouse myoblastoma reporter cells using ID1 expression as read-out for BMPR2 signaling. We further experimentally validated the top hit, PTPN1 (PTP1B), in human healthy pulmonary arterial endothelial cells (PAECs) either silenced by siRNA or exposed to hypoxia and confirmed its relevance to PAH by measuring PTPN1 levels in blood and PAECs collected from PAH patients. We identified PTPN1 as a novel regulator of BMPR2 signaling in PAECs, which is downregulated in the blood of PAH patients and documented that downregulation of PTPN1 is linked to endothelial dysfunction in PAECs. These findings point to a potential involvement for PTPN1 in PAH and will aid in our understanding of the molecular mechanisms involved in the disease.
Intravital imaging-based genetic screen reveals the transcriptional network governingCandida albicansfilamentation during mammalian infection
Authors: Wakade Rohan S. , Ristow Laurie C. , Wellington Melanie , Krysan Damian J. 
Published: November 2022

AbstractCandida albicansis one of the most common human fungal pathogens.C. albicanspathogenesis is tightly linked to its ability to under a morphogenetic transition from typically budding yeast to filamentous forms of hyphae and pseudohyphae. Filamentous morphogenesis is the most intensively studiedC. albicansvirulence traits; however, nearly all of these studies have been based on in vitro induction of filamentation. Using an intravital imaging assay of filamentation during mammalian infection, we have screened a library of transcription factor mutants to identify those that modulate both the initiation and maintenance of filamentation in vivo. We coupled this initial screen with genetic interaction analysis and in vivo transcription profiling to characterize the transcription factor network governing filamentation in infected mammalian tissue. Three core positive (Efg1, Brg1, and Rob1) and two core negative regulators (Nrg1 and Tup1) of filament initiation were identified. No previous systematic analysis of genes affecting the elongation step has been reported and we found that large set of transcription factors affect filament elongation in vivo including four (Hms1, Lys14, War1, Dal81) with no effect on in vitro elongation. We also show that the gene targets of initiation and elongation regulators are distinct. Genetic interaction analysis of the core positive and negative regulators revealed that the master regulator Efg1 primarily functions to mediate relief of Nrg1 repression and is dispensable for expression of hypha-associated genes in vitro and in vivo. Thus, our analysis not only provide the first characterization of the transcriptional network governingC. albicansfilamentation in vivo but also revealed a fundamentally new mode of function for Efg1, one of the most widely studiedC. albicanstranscription factors.
Astrocyte MCT1 expression does not contribute to the axonal degenerative phenotype observed with ubiquitous MCT1 depletion
Authors: Philips Thomas , Thompson Emily G. , Vijayakumar Balaji G. , Kent Erica R. , Miller Sean J. , Vidensky Svetlana , Farah Mohamed Hassan , Rothstein Jeffrey D. 
Published: November 2022

AbstractWe recently reported that loss of oligodendrocyte metabolic support through the lactate and pyruvate transporter Monocarboxylate Transporter 1 (MCT1) is well tolerated into adulthood. Only with advanced aging did we observe axonal degeneration and hypomyelination due to loss of MCT1 from oligodendroglia lineage cells. MCT1 is also expressed by other glial subtypes, such as astrocytes and endothelial cells where it has been suggested to be essential for learning and memory tasks. However, the importance of MCT1 in these cell types for long-term axonal metabolic support is still unknown. We therefore addressed whether conditional loss of MCT1 from either of these cell types would lead to widespread axonal degeneration with aging. Using a conditional null approach, similar to what was used for oligodendrocyte MCT1 depletion, we observed that conditional knockout of MCT1 from either astrocytes or endothelial cells did not cause neuronal injury. On the other hand, inducible ubiquitous depletion of MCT1 causes late-onset axonal degeneration, comparable with what was observed in our previous study using the oligodendrocyte lineage MCT1 null mice. In summary, we conclude that unlike oligodendrocyte MCT1, astrocyte MCT1 is not an essential driver of astrocyte mediated axonal energy homeostasis with aging.
β-Lapachone Regulates Mammalian Inositol Pyrophosphate Levels in an NQO1- and Oxygen-dependent Manner
Authors: Eisenbeis Verena B. , Qiu Danye , Strotmann Lisa , Liu Guizhen , Prucker Isabel , Ritter Kevin , Loenarz Christoph , Saiardi Adolfo , Jessen Henning J. 
Published: November 2022

1AbstractInositol pyrophosphates (PP-InsPs) are energetic signalling molecules with important functions in mammals. As their biosynthesis depends on ATP concentration, PP-InsPs are tightly connected to cellular energy homeostasis. Consequently, an increasing number of studies involves PP-InsPs in metabolic disorders, such as type 2 diabetes, aspects of tumorigenesis, and hyperphosphatemia. Research conducted in yeast suggests that the PP-InsP pathway is activated in response to reactive oxygen species (ROS). However, the precise modulation of PP-InsPs during cellular ROS signalling is unknown. Here, we report how mammalian PP-InsP levels are changing during exposure to exogenous (H2O2) and endogenous ROS. Using capillary electrophoresis electrospray ionization mass spectrometry (CE-ESI-MS), we found that PP-InsP levels decrease upon exposure to oxidative stressors in HCT116 cells. Application of quinone drugs, particularly β-lapachone (β-lap), under normoxic and hypoxic conditions enabled us to produce ROSin celluloand to show that β-lap treatment caused PP-InsP changes that are oxygen dependent. Experiments in MDA-MB-231 breast cancer cells deficient of NAD(P)H:quinone oxidoreductase-1 (NQO1) demonstrated that β-lap requires NQO1-bioactivation to regulate the cellular metabolism of PP-InsPs. Critically, significant reductions in cellular ATP concentrations were not directly mirrored in reduced PP-InsP levels as shown in NQO1-deficient MDA-MB-231 cells treated with β-lap. The data presented here unveil new aspects of β-lap pharmacology and its impact on PP-InsP levels. Our identification of different quinone drugs as modulators of PP-InsP synthesis will allow to better appreciate their overall impact on cellular function.2Significance StatementInositol pyrophosphates (PP-InsPs) are messenger molecules regulating various functions in mammals. They are associated with the oxidative stress response, but the underlying mechanism is unclear. We investigate PP-InsP signalling in mammalian cells subjected to reactive oxygen species (ROS). Applying the quinone β-lapachone (β-lap) generated intracellular ROS resulting in decreased PP-InsP levels. This indicates a key role of PP-InsPs in cellular signalling under oxidative stress. Moreover, β-lap mediated PP-InsP signalling required oxygen and the enzyme NAD(P)H:quinone oxidoreductase-1 (NQO1). Since quinone drugs are cytotoxic, our data provide a basis for further investigations into the role of PP-InsPs during quinone-dependent chemotherapies. This is of special relevance since a phase II clinical trial demonstrated β-lap efficacy in a combination chemotherapy against pancreatic cancer.