bluuebunny/crossref_metadata_2025 huggingface dataset:
The Impact of an Overactive Bladder Care Pathway on Longitudinal Patient Management
Authors: Selle Jessica M. , Hanson Kristine T. , Habermann Elizabeth B. , Gebhart John B. , Trabuco Emanuel C. , Occhino John A. , Young Alexis D. , Linder Brian J.
Published: March 2024

Importance

Implementation of an overactive bladder (OAB) care pathway may affect treatment patterns and progression.

Objectives

This study aimed to assess the effect of OAB care pathway implementation on treatment patterns for women with OAB.

Study Design

This retrospective cohort study evaluated women with OAB, before (January 1, 2015–December 31, 2017) and after (January 1, 2019–December 31, 2021) care pathway initiation. Care pathway use included standardized counseling, early introduction of therapy, and close follow-up. Primary outcomes included OAB medication use, follow-up visits, third-line therapy, and time to third-line therapy.

Results

A total of 1,349 women were included: 1,194 before care pathway implementation and 155 after. Patients after implementation were more likely to have diabetes mellitus (P= 0.04) and less likely to smoke (P= 0.01). Those managed via a care pathway were more likely to use any medication or third-line therapy within 1 year after consultation (61.3% vs 25.0%;P< 0.001). This included higher proportions receiving a medication (50.3% [95% confidence interval (CI), 41.8%–57.6%] vs 23.3% [95% CI, 20.9%–25.7%];P< 0.001) and progressing to third-line therapy (22.6% [95% CI, 15.7%–28.9%] vs 2.9% [95% CI, 2%–3.9%];P< 0.001). Among those who underwent third-line treatment, care pathway use was associated with shorter time to third-line therapy (median, 10 days [interquartile range, 1–56 days] vs 29 days [interquartile range, 7–191 days];P= 0.013). Those managed via a care pathway were less likely to have additional clinic visits for OAB within 1 year after initial consultation (12.3% vs 23.9%;P< 0.001).

Conclusions

Use of an OAB care pathway was associated with higher rates of oral medication and third-line therapy yet decreased follow-up office visits. Use of an OAB care pathway may promote consistent and efficient care for women with OAB.
Predictors of Care-Seeking Behavior for Treatment of Urinary Incontinence in Women
Authors: LaPier Zoe , Jericevic Dora , Lang Diane , Gregg Steven , Brucker Benjamin , Escobar Christina
Published: March 2024

Importance

Urinary incontinence (UI) is a common and treatable medical condition among women, but only approximately one third of women seek care.

Objective

The objective of this study was to determine factors associated with care-seeking behavior in women with UI.

Study Design

This was a cross-sectional study using patient-reported survey data collected by the National Association for Continence from November 2018 to January 2019. This survey included 60 questions and was conducted using SurveyMonkey. Descriptive statistics were used for baseline characteristics, the χ2 test was used for categorical variables, and multivariate logistic regression was used to determine predictors of care-seeking behavior.

Results

Four hundred eighty-five women completed the survey, 30.7% were not care seeking, and 69.3% were care seeking for UI. Most women were 55 years or older and had UI for more than 4 years. Care-seeking women had more overactive bladder symptoms. Women who sought care were more likely to report feelings of anger, depression, hopelessness, isolation, and report greater social effects from UI than non–care-seeking women. Less than 10% of women who sought care were asked about their UI by a medical professional. In the multivariate logistic regression expenditure of $5 or more on monthly incontinence maintenance, daily UI and older age were associated with seeking care.

Conclusions

Most women in our study population sought care for UI. Factors associated with seeking care were expenditure greater than $5 per month on incontinence, daily UI, and age. This information demonstrates the need for effective implementation of screening interventions to increase treatment access.
Integration of medical legal services into a hospital-based violence intervention program: A survey and interview-based provider needs assessment
Authors: Sonnenberg Jake , Metchick Ariana , Schille Caitlin , Bhatnagar Prashasti , Kessler Lisa , Perry Deborah , Girard Vicki , Taylor Belinda , Hall Erin
Published: March 2024

BACKGROUND

Violent injury among trauma surgery patients is strongly associated with exposure to harmful social determinants of health and negative long-term health outcomes. Medical-legal partnerships in other settings successfully provide patients with legal services to address similar health-harming legal needs and may offer a promising model for the care of violently injured patients.

STUDY DESIGN

An electronic survey tool was distributed to clinicians and staff affiliated with the hospital-based violence intervention program at a single urban level one trauma center. Semistructured follow-up interviews were conducted with participants, and interviews were coded using thematic analysis and grounded theory.

RESULTS

Participants reported many health-harming legal needs among their violently injured patients. The most commonly identified needs were: health insurance denials (62.5%); difficulty accessing crime victims compensation funds (56.3%); trouble accessing official documents (50%); and problems with non-SSDI public benefits (50%). Participants reported inconsistent methods for learning about and responding to patients' health-harming legal needs. The most common barriers to addressing these needs included the following: lack of awareness that a lawyer could help with the issue (68.8%); prioritization of other needs (68.8%); previous negative legal experiences (62.5%); and cost (62.5%). Identified needs encompass issues traditionally addressed by MLPs as well as more novel challenges faced by violent injury survivors.

CONCLUSION

This survey and interview-based study identifies complex health-harming legal needs present among violently injured trauma surgery patients. Medical-legal partnerships specially designed for the setting of violent injury appear well-suited to meet these needs, potentially reducing risk of violent reinjury, long-term negative health outcomes, and health care system costs.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level IV.
Medically relevant tandem repeats in nanopore sequencing of control cohorts
Authors: De Coster Wouter , Höijer Ida , Bruggeman Inge , D'Hert Svenn , Melin Malin , Ameur Adam , Rademakers Rosa
Published: March 2024

Research and diagnostics for medically relevant tandem repeats and repeat expansions are hampered by the lack of population-scale databases. We attempt to fill this gap using our pathSTR web tool, which leverages long-read sequencing of large cohorts to determine repeat length and sequence composition in the general population. The current version includes 878 individuals of the 1000 Genomes Project cohort sequenced on the Oxford Nanopore Technologies PromethION. A comprehensive set of medically relevant tandem repeats were genotyped using STRdust to determine the tandem repeat length and sequence composition. PathSTR provides rich visualizations of this dataset, as well as the feature to upload one’s own data for comparison along the control cohort. We demonstrate the implementation of this application using data from targeted nanopore sequencing of a patient with Myotonic Dystrophy type 1. This resource will empower the genetics community to get a more complete overview of normal variation in tandem repeat length and sequence composition, and enable a better assessment of the pathogenic impact of tandem repeats observed in patients. PathSTR is available athttps://pathstr.bioinf.be
The Burden of Cardiovascular Events According to Cardiovascular Risk Profile in Adults from High-, Middle- and Low-Income Countries
Authors: Leong Darryl ,   PURE Investigators, Yusuf Rita , Iqbal Romaina , Avezum Àlvaro , Yusufali Afzalhussein , Rosengren Annika , Chifamba Jephat , Lanas Fernando , Díaz María Luz , Miranda J. Jaime , Davletov Kairat , Mirrakhimov Erkin M , Yeates Karen , Khatib Rasha , AlHabib Khalid , Gulec Sadi , Paucar Maria , Lopez-Jaramillo Patricio , Yusuf Salim
Published: March 2024

Background Current strategies to prevent adverse cardiovascular outcomes focus on secondary prevention and primary prevention in high-risk groups. The proportion of events occurring in lower-risk groups globally is unknown. Methods We prospectively documented fatal or non-fatal myocardial infarction, stroke, heart failure, or any other fatal cardiovascular event stratified by history of cardiovascular disease (CVD), and by the INTERHEART and the Framingham risk score in those without prior CVD, in 189,097 adults from 26 high-, middle- and low-income countries. Results Participants mean±SD age was 51±10 years and 59% were women. We observed 14,829 outcome events affecting 8% of the cohort during a median 12.4 years follow-up. Overall, 44% of outcome events occurred in CVD-naive participants at low or intermediate INTERHEART risk and 56% occurred in in CVD-naive participants at non-high Framingham risk. The proportion of adverse cardiovascular outcomes occurring in these lower risk groups was inversely related to country income level and was higher in women (55%) than in men (35%). Conclusions To achieve a substantial population-level reduction in CVD, preventive strategies for CVD are essential in those considered low- or intermediate-risk.
Mapping under-five mortality in Malawi: towards achieving sustainable development goals
Authors: Vellemu Ruth , Sakala Melody , Chisope Evetta Kuwala , Chirombo James
Published: March 2024

As many low- and middle-income countries continue making gains towards attaining sustainable development goals in under-five mortality, surveillance of mortality outcomes and indicators at the sub-district level will become important as national- and district-level estimates may mask areas with a high burden. Spatial statistical modelling techniques such as geostatistical prevalence mapping can play a role in identifying hotspots of relatively high under-five mortality. To achieve this objective, it is necessary to combine data from multiple sources with different spatial resolutions to produce maps that reveal these hotspot clusters. We pooled DHS, high-resolution census data, economic vulnerability, and malaria risk data to estimate under-five mortality at a sub-district level in Malawi. Using a Bayesian hierarchical modelling approach, we fitted a binomial generalized linear geostatistical model with local area effects to generate estimates of under-five mortality at a sub-district level in Malawi. Results, in general, showed low mortality rates across the country with pockets of locations mostly in northern Malawi showing elevated risk. Rural locations were associated with higher odds of under-five mortality compared to urban locations. Our study provides a better understanding of progress made after the Millennium Development Goals in 2015 and can help improve surveillance through the application of targeted interventions which can lead to the attainment of sustainable development goals by 2030.
Synthesis of geometrically realistic and watertight neuronal ultrastructure manifolds forin silicomodeling
Authors: Abdellah Marwan , Foni Alessandro , Cantero Juan José García , Guerrero Nadir Román , Boci Elvis , Fleury Adrien , Coggan Jay S. , Keller Daniel , Planas Judit , Courcol Jean-Denis , Khazen Georges
Published: March 2024

Understanding the intracellular dynamics of brain cells entails performing three-dimensional molecular simulations incorporating ultrastructural models that can capture cellular membrane geometries at nanometer scales. While there is an abundance of neuronal morphologies available online, e.g. fromNeuroMorpho.Org, converting those fairly abstract point-and-diameter representations into geometrically realistic and simulation-ready, i.e. watertight, manifolds is challenging. Many neuronal mesh reconstruction methods have been proposed, however, their resulting meshes are either biologically unplausible or non-watertight. We present an effective and unconditionally robust method capable of generating geometrically realistic and watertight surface manifolds of spiny cortical neurons from their morphological descriptions. The robustness of our method is assessed based on a mixed dataset of cortical neurons with a wide variety of morphological classes. The implementation is seamlessly extended and applied to synthetic astrocytic morphologies that are also plausibly biological in detail. Resulting meshes are ultimately used to create volumetric meshes with tetrahedral domains to perform scalablein silicoreaction-diffusion simulations for revealing cellular structure–function relationships.

Availability and implementation

Our method is implemented in NeuroMorphoVis, a neuroscience-specific open source Blender add-on, making it freely accessible for neuroscience researchers.

Key points

A plethora of neuronal morphologies is available in a point-and-diameter format, but there are no robust techniques capable of converting these morphologies into geometrically realistic models that can be used to conduct subcellular simulations.

We present a scalable method capable of synthesizing high fidelity watertight ultrastructural manifolds of complete neuronal models from their one-dimensional descriptions using the synaptic data obtained from the digitally reconstructed neuronal circuits of the Blue Brain Project.

Resulting manifold models comprise geometrically realistic somata and spine geometries, enabling accuratein silicoexperiments that can probe intricate structure-function relationships.

Our method is extensible and can be seamlessly applied to other cellular structures such as astroglial morphologies and even large networks of cerebral vasculature.
Prelimbic cortex perineuronal net expression and social behavior: Impact of adolescent intermittent ethanol exposure
Authors: Towner Trevor T. , Coleman Harper J. , Goyden Matthew A. , Vore Andrew S. , Papastrat Kimberly M. , Varlinskaya Elena I. , Werner David F.
Published: March 2024

Adolescent intermittent ethanol (AIE) exposure in rats leads to social deficits. Parvalbumin (PV) expressing interneurons in the prelimbic cortex (PrL) contribute to social behavior, and perineuronal nets (PNNs) within the PrL preferentially encompass PV interneurons, acting as significant regulators of these cells. AIE exposure increases PNNs, however, it is unknown if this upregulation contributes to AIE-induced social impairments. The current study was designed to determine the effect of AIE exposure on PNN expression in the PrL and to assess whether PNN dysregulation contributes to social deficits elicited by AIE. cFos-LacZ male and female rats were exposed every other day to tap water or ethanol (4g/kg, 25% w/v) via intragastric gavage between postnatal day (P) 25-45. We evaluated neuronal activation by β-galactosidase expression and PNN levels either at the end of the exposure regimen on P45 and/or in adulthood on P70. In addition, we used Chondroitinase ABC (ChABC) to deplete PNNs following adolescent exposure (P48) and allowed for PNN restoration before social testing in adulthhod. AIE exposure increased PNN expressionin the PrL of adult males, whereas a decrease in PNNs was evident immediately following AIE. Vesicular glutamate transporter 2 (vGlut2) and vesicular GABA transporter (vGat) near PNNs were moderately downregulated only in AIE-exposed females. Gene expression of PNN components were largely unaffected by AIE exposure. Removal and reestablishment of PNNs in the PrL led to upregulation of PNNs and social impairments in males, regardless of adolescent exposure. These data suggest that AIE exposure in males produces an upregulation of PrL PNNs that likely contribute to social impairments induced by AIE.
Functional characterization of QT interval associatedSCN5Aenhancer variants identify combined additive effects
Authors: Gunamalai Lavanya , Singh Parul , Berg Brian , Shi Leilei , Sanchez Ernesto , Smith Alexa , Breton Ghislain , Bedford Mark T , Balciunas Darius , Kapoor Ashish
Published: March 2024

Several empirical and theoretical studies suggest presence of multiple enhancers per gene that collectively regulate gene expression, and that common sequence variation impacting on the activities of these enhancers is a major source of inter-individual variability in gene expression. However, for vast majority of genes, enhancers and the underlying regulatory variation remains unknown. Even for the genes with well-characterized enhancers, the nature of the combined effects from multiple enhancers and their variants, when known, on gene expression regulation remains unexplored. Here, we have evaluated the combined effects from fiveSCN5Aenhancers and their regulatory variants that are known to collectively correlate withSCN5Acardiac expression and underlie QT interval association in the general population. Using small deletions centered at the regulatory variants in episomal reporter assays in a mouse cardiomyocyte cell line we demonstrate that the variants and their flanking sequences play critical role in individual enhancer activities, likely being a transcription factor (TF) binding site. By performing oligonucleotide-based pulldown assays on predicted TFs we identify the TFs likely driving allele-specific enhancer activities. Using all 32 possible allelic synthetic constructs in reporter assays, representing the five biallelic enhancers in tandem in their genomic order, we demonstrate combined additive effects on overall enhancer activities. Using transient enhancer assays in developing zebrafish embryos we demonstrate the four out the five enhancer elements act as enhancersin vivo. Together, these studies extend the previous findings to uncover the TFs driving the enhancer activities of QT interval associatedSCN5Aregulatory variants, reveal the additive effects from allelic combinations of these regulatory variants, and prove their potential to act as enhancersin vivo.
Drosophilaappear resistant to trans-synaptic tau propagation
Authors: Catterson James H , Mouofo Edmond N , Soler Inés López De Toledo , Lean Gillian , Dlamini Stella , Liddell Phoebe , Voong Graham , Katsinelos Taxiarchis , Wang Yu-Chun , Schoovaerts Nils , Verstreken Patrik , Spires-Jones Tara L , Durrant Claire S
Published: March 2024

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, prompting extensive efforts to pinpoint novel therapeutic targets for effective intervention. Among the hallmark features of AD is the development of neurofibrillary tangles comprised of hyperphosphorylated tau protein, whose progressive spread throughout the brain is associated with neuronal death. Trans-synaptic propagation of tau has been observed in mouse models and indirect evidence for tau spread via synapses has been observed in human AD. Halting tau propagation is a promising therapeutic target for AD, thus a scalable model system to screen for modifiers of tau spread would be very useful for the field. To this end, we sought to emulate the trans-synaptic spread of human tau (hTau) inDrosophila melanogaster. Employing the trans-Tango circuit mapping technique, we investigated whether tau spreads between synaptically connected neurons. Immunohistochemistry and confocal imaging were used to look for tau propagation. Examination of hundreds of flies expressing 4 different human tau constructs in two distinct neuronal populations reveal a robust resistance inDrosophilato the trans-synaptic spread of hTau. This resistance persisted in lines with concurrent expression of amyloid-β, in lines with global hTau knock-in to provide a template for human tau in downstream neurons, and with manipulations of temperature. These negative data are important for the field as we establish thatDrosophilaexpressing human tau in subsets of neurons are unlikely to be useful to perform screens to find mechanisms to reduce the trans-synaptic spread of tau. The inherent resistance observed inDrosophilamay serve as a valuable clue, offering insights into strategies for impeding tau spread in future studies.
Coupling hydrodynamic drifting simulations and seasonal demographics to forecast the occurrence of jellyfish blooms
Authors: Cant James , Jones Owen R. , Ellingsen Ingrid , Laverick Jack H. , Majaneva Sanna , Dierking Jan , Aberle Nicole , Javidpour Jamileh
Published: March 2024

Although jellyfish are an important component of coastal marine communities, their public perception is often tainted by their proclivity for aggregating in vast numbers, known as jellyfish blooms. Jellyfish blooms occur worldwide and are associated with major economic ramifications, particularly throughout the fisheries, aquaculture, and tourism sectors.

Forecasting jellyfish blooms is critical in order to manage and mitigate their ecological and economic impacts, but the complex life cycles and cryptic life stages exhibited by most jellyfish species largely precludes accurate predictions of their temporal and spatial occurrence.

Here we introduce a predictive framework, combining state-of-the-art hydrodynamic simulations and periodic population modelling approaches, to forecast spatial and temporal patterns in the formation of jellyfish blooms. While this framework is sufficiently flexible for accommodating various bloom-forming jellyfish species and impacted coastal regions worldwide, we focus on moon jellyfish (Aurelia aurita) populations within the Baltic Sea as an illustrative example.

We emphasise how, through the iterative process of forecasting and model validation, this framework can provide valuable insights for resolving key gaps in our understanding of the drivers of bloom events. Indeed, our framework offers an approach for identifying the, to date, unknown locations of polyp-beds; a crucial parameter in enhancing our capacity to accurately predict the occurrence of jellyfish blooms. Accordingly, our framework, represents a key decision-support tool for mitigating the socioeconomic impacts of bloom formation.
The Cyclin-Like Protein Spy1 Mediates Tumourigenic Potential of Triple Negative Breast Cancer
Authors: Fifield Bre-Anne , Pecoraro Claudia , Basilious Amy , Gramisteanu Catalin , Mailloux Emily , Ferraiuolo Rosa-Maria , Porter Lisa A.
Published: March 2024

Triple negative breast cancer is an aggressive subtype of breast cancer that relies on systemic chemotherapy as its primary means of treatment. Cell cycle regulators are enriched in drug resistant forms of the disease supporting the potential of targeting cell cycle checkpoints as a therapeutic direction to re-sensitize patients to treatment. Spy1 is an atypical cyclin-like protein that can override cell cycle checkpoints and is elevated in triple negative breast cancer. We report for the first time the effects of CRISPR-Cas9 mediated knockout of Spy1 on functional characteristics of triple negative breast cancer cells and perform unbiased analysis of protein expression to assess global changes in expression which correlate with functional changes in cell properties. Loss of Spy1 reduced rates of proliferation, decreased metastatic potential, and led to a reduction in stemness properties of triple negative breast cancer cells. Importantly, knockout of Spy1 delayed tumour onset in anin vivomodel and significantly increased response to chemotherapy, pushing cells towards a senescent state. This data reveals that changes in expression of proteins that are not essential for proliferation and only transiently expressed can have significant impacts on cell dynamics and provides support for targeting the Spy1-CDK2 complex as a new therapeutic avenue in triple negative breast cancer.

Statement of Significance

Targeting the atypical cell cycle regulator Spy1 induces senescence and increases responsiveness of triple negative breast cancer to standard of care chemotherapy.
Single-Domain Antibody-Based Protein Degrader for Synucleinopathies
Authors: Jiang Yixiang , Lin Yan , Tetlow Amber M. , Pan Ruimin , Ji Changyi , Kong Xiang-Peng , Congdon Erin E. , Sigurdsson Einar M.
Published: March 2024

Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic candidate enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic candidate for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies.
Impact of Reduced Spectral Resolution on Temporal-Coherence-Based Source Segregation
Authors: Viswanathan Vibha , Heinz Michael G. , Shinn-Cunningham Barbara G.
Published: March 2024

1.

Hearing-impaired listeners struggle to understand speech in noise, even when using cochlear implants (CIs) or hearing aids. Successful listening in noisy environments depends on the brain’s ability to organize a mixture of sound sources into distinct perceptual streams (i.e., source segregation). In normal-hearing listeners, temporal coherence of sound fluctuations across frequency channels supports this process by promoting grouping of elements belonging to a single acoustic source. We hypothesized that reduced spectral resolution—a hallmark of both electric/CI (from current spread) and acoustic (from broadened tuning) hearing with sensorineural hearing loss—degrades segregation based on temporal coherence. This is because reduced frequency resolution decreases the likelihood that a single sound source dominates the activity driving any specific channel; concomitantly, it increases the correlation in activity across channels. Consistent with our hypothesis, predictions from a physiologically plausible model of temporal-coherence-based segregation suggest that CI current spread reduces comodulation masking release (CMR; a correlate of temporal-coherence processing) and speech intelligibility in noise. These predictions are consistent with our behavioral data with simulated CI listening. Our model also predicts smaller CMR with increasing levels of outer-hair-cell damage. These results suggest that reduced spectral resolution relative to normal hearing impairs temporal-coherence-based segregation and speech-in-noise outcomes.
Environmental complexity modulates information processing and the balance between decision-making systems
Authors: Mugan Ugurcan , Hoffman Samantha L. , Redish A. David
Published: March 2024

Behavior in naturalistic scenarios occurs in diverse environments. Adaptive strategies rely on multiple neural circuits and competing decision-systems. However, past studies of rodent decision-making have largely measured behavior in simple environments. To fill this gap, we recorded neural ensembles from hippocampus (HC), dorsolateral striatum (DLS), and medial prefrontal cortex (mPFC) while rats foraged for food under changing rules in environments with varying topological complexity. Environmental complexity increased behavioral variability, lengthened HC nonlocal sequences, and modulated action caching. We found contrasting representations between DLS and HC, supporting a competition between decision systems. mPFC activity was indicative of setting this balance, in particular predicting the extent of HC non-local coding. Inactivating mPFC impaired short-term behavioral adaptation and produced long-term deficits in balancing decision systems. Our findings reveal the dynamic nature of decision-making systems and how environmental complexity modulates their engagement with implications for behavior in naturalistic environments.
Bridging Domains in Chronic Lower Back Pain: Large Language Models and Ontology-driven Strategies for Knowledge Graph Construction
Authors: Anderson Paul , Lin Damon , Davidson Jean , Migler Theresa , Ho Iris , Koenig Cooper , Bittner Madeline , Kaplan Samuel , Paraiso Mayumi , Buhn Nasreen , Stokes Emily , Hunt Tony , Ropella Glen , Lotz Jeffrey
Published: March 2024

Link prediction and entity resolution play pivotal roles in uncovering hidden relationships within networks and ensuring data quality in the era of heterogeneous data integration. This paper explores the utilization of large language models to enhance link prediction, particularly through knowledge graphs derived from transdisciplinary literature. Investigating zero-shot entity resolution techniques, we examine the impact of ontology-based and large language model approaches on the stability of link prediction results. Through a case study focusing on chronic lower back pain research, we analyze workflow decisions and their influence on prediction outcomes. Our research underscores the importance of robust methodologies in improving predictive accuracy and data integration across diverse domains.
Morphometric Analysis of the Thymic Epithelial Cell (TEC) Network Using Integrated and Orthogonal Digital Pathology Approaches
Authors: Lagou Maria K. , Argyris Dimitrios G. , Vodopyanov Stepan , Gunther-Cummins Leslie , Hardas Alexandros , Poutahidis Theofilos , Panorias Christos , DesMarais Sophia , Entenberg Conner , Carpenter Randall S. , Guzik Hillary , Nishku Xheni , Churaman Joseph , Maryanovich Maria , DesMarais Vera , Macaluso Frank P. , Karagiannis George S.
Published: March 2024

The thymus, a central primary lymphoid organ of the immune system, plays a key role in T cell development. Surprisingly, the thymus is quite neglected with regards to standardized pathology approaches and practices for assessing structure and function. Most studies use multispectral flow cytometry to define the dynamic composition of the thymus at the cell population level, but they are limited by lack of contextual insight. This knowledge gap hinders our understanding of various thymic conditions and pathologies, particularly how they affect thymic architecture, and subsequently, immune competence. Here, we introduce a digital pathology pipeline to address these challenges. Our approach can be coupled to analytical algorithms and utilizes rationalized morphometric assessments of thymic tissue, ranging from tissue-wide down to microanatomical and ultrastructural levels. This pipeline enables the quantitative assessment of putative changes and adaptations of thymic structure to stimuli, offering valuable insights into the pathophysiology of thymic disorders. This versatile pipeline can be applied to a wide range of conditions that may directly or indirectly affect thymic structure, ranging from various cytotoxic stimuli inducing acute thymic involution to autoimmune diseases, such as myasthenia gravis. Here, we demonstrate applicability of the method in a mouse model of age-dependent thymic involution, both by confirming established knowledge, and by providing novel insights on intrathymic remodeling in the aged thymus. Our orthogonal pipeline, with its high versatility and depth of analysis, promises to be a valuable and practical toolset for both basic and translational immunology laboratories investigating thymic function and disease.
In-Space Fabrication of Janus Base Nano-Matrix for Improved Assembly and Bioactivities
Authors: Yau Anne , Landolina Maxwell , Snow Mari Anne , Mesci Pinar , Williams Brandon , Hoying Jay , Duflo Derek , Wu Honglu , Stoudemire Jana , Hernandez Rose , Chen Yupeng
Published: March 2024

In-space manufacturing of nanomaterials is a promising concept while having limited successful examples. DNA-inspired Janus base nanomaterials (JBNs), used for therapeutics delivery and tissue regeneration, are fabricated via a controlled self-assembly process in water at ambient temperature, making them highly suitable for in-space manufacturing. For the first time, we designed and accomplished the production of JBNs on orbit during the Axiom-2 (Ax-2) mission demonstrating great promising and benefits of in-space manufacturing of nanomaterials.
Non-invasive laser speckle imaging of extra-embryonic blood vessels in intact few-days-old avian eggs
Authors: Dong Zhenyu , Mahler Simon , Readhead Carol , Chen Xi , Dickson Maya , Bronner Marianne E. , Yang Changhuei
Published: March 2024

Imaging blood vessels in early-stage avian embryos has a wide range of practical applications for developmental biology studies, drug and vaccine testing, and early sex determination. Optical imaging such as brightfield transmission imaging offers a compelling solution due to its safe non-ionizing radiation, and operational benefits. However, it comes with challenges such as eggshell opacity and light scattering. To address these, we have revisited an approach based on laser speckle contrast imaging (LSCI) and demonstrated a high quality, comprehensive and non-invasive visualization of blood vessels in few-days-old chicken eggs, with blood vessel as small as 100 µm in diameter (with LSCI profile full-width-at-half-maximum of 275 µm). We present its non-invasive use for monitoring blood flow, measuring the embryo’s heartbeat, and determining the embryo’s developmental stages using machine learning with 85% accuracy from stage HH15 to HH22. This method can potentially be used for non-invasive longitudinal studies of cardiovascular development and angiogenesis, as well as egg screening for the poultry industry.
Evaluation of ChatGPT’s Usefulness and Accuracy in Diagnostic Surgical Pathology
Authors: Guastafierro Vincenzo , Corbitt Devin Nicole , Bressan Alessandra , Fernandes Bethania , Mintemur Ömer , Magnoli Francesca , Ronchi Susanna , Rosa Stefano La , Uccella Silvia , Renne Salvatore Lorenzo
Published: March 2024

ChatGPT is an artificial intelligence capable of processing and generating human-like language. ChatGPT’s role within clinical patient care and medical education has been explored; however, assessment of its potential in supporting histopathological diagnosis is lacking. In this study, we assessed ChatGPT’s reliability in addressing pathology-related diagnostic questions across 10 subspecialties, as well as its ability to provide scientific references. We created five clinico-pathological scenarios for each subspecialty, posed to ChatGPT as open-ended or multiple-choice questions. Each question either asked for scientific references or not. Outputs were assessed by six pathologists according to: 1) usefulness in supporting the diagnosis and 2) absolute number of errors. All references were manually verified. We used directed acyclic graphs and structural causal models to determine the effect of each scenario type, field, question modality and pathologist evaluation. Overall, we yielded 894 evaluations. ChatGPT provided useful answers in 62.2% of cases. 32.1% of outputs contained no errors, while the remaining contained at least one error (maximum 18). ChatGPT provided 214 bibliographic references: 70.1% were correct, 12.1% were inaccurate and 17.8% did not correspond to a publication. Scenario variability had the greatest impact on ratings, followed by prompting strategy. Finally, latent knowledge across the fields showed minimal variation. In conclusion, ChatGPT provided useful responses in one-third of cases, but the number of errors and variability highlight that it is not yet adequate for everyday diagnostic practice and should be used with discretion as a support tool. The lack of thoroughness in providing references also suggests caution should be employed even when used as a self-learning tool. It is essential to recognize the irreplaceable role of human experts in synthesizing images, clinical data and experience for the intricate task of histopathological diagnosis.
Burden of renal anemia in 204 countries and territories, 1990-2021 : results from the Global Burden of Disease Study 2021
Authors: Chu Feifan , Ji Jinzhong , Ma Yuning , Guan Qing , Chen Lumin , Chen Zujie , Ji Qiwei , Sun Mingxin , Zhang Hui , Huang Tingyang , Song Haihan , Lin Xiuquan , Zhou Hao
Published: March 2024

Renal anemia has inflicted a certain degree of loss on global health. However, there are no systematically analyses on the burden of renal anemia.

We analyzed global prevalence and years lived with disability (YLDs) of renal anemia from 1990 to 2021. Based on the Socio-Demographic Index (SDI), combined with cross-national inequality analysis, frontier analysis and age-period-cohort (APC) model analysis, the prevalence and YLDs differences between different aspects were compared.

Since 1990, the prevalence and YLDs of renal anemia in 2021 have shown an upward trend. In countries with medium and low levels of development, the burden of renal anemia is particularly severe among people over 60 years. A series of analyses based on the SDI revealed a negative correlation between the prevalence of renal anemia and SDI.

Thus, Public health policies targeting renal anemia should give priority to the elderly in medium- and low-development areas.
Seq2MAIT: A Novel Deep Learning Framework for Identifying Mucosal Associated Invariant T (MAIT) Cells
Authors: ElAbd Hesham , Byron Rachel , Woodhouse Steven , Robinett Brittney , Sulc Joe , Franke Andre , Pesesky Mitchell , Zhou Wenyu , Chen-Harris Haiyin , Howie Bryan , Taniguchi Ruth , Robins Harlan
Published: March 2024

Mucosal-associated invariant T (MAIT) cells are a group of unconventional T cells that mainly recognize bacterial vitamin B metabolites presented on MHC-related protein 1 (MR1). MAIT cells have been shown to play an important role in controlling bacterial infection and in responding to viral infections. Furthermore, MAIT cells have been implicated in different chronic inflammatory diseases such as inflammatory bowel disease and multiple sclerosis. Despite their involvement in different physiological and pathological processes, a deeper understanding of MAIT cells is still lacking. Arguably, this can be attributed to the difficulty of quantifying and measuring MAIT cells in different biological samples which is commonly done using flow cytometry-based methods and single-cell-based RNA sequencing techniques. These methods mostly require fresh samples which are difficult to obtain, especially from tissues, have low to medium throughput, and are costly and labor-intensive. To address these limitations, we developed sequence-to-MAIT (Seq2MAIT) which is a transformer-based deep neural network capable of identifying MAIT cells in bulk TCR-sequencing datasets, enabling the quantification of MAIT cells from any biological materials where human DNA is available. BenchmarkingSeq2MAITacross different test datasets showed an average area-under-the-receiver-operator-curve (AU[ROC]) >0.80. In conclusion,Seq2MAITis a novel, economical, and scalable method for identifying and quantifying MAIT cells in virtually any biological sample.
Alteration of nociceptive Schwann cells in a mouse model of high-fat diet induced diabetic peripheral neuropathy
Authors: Rastoldo Guillaume , Jaafar Ali K. , Aurélie-Paulo-Ramos  , Thouvenot Katy , Planesse Cynthia , Bringart Matthieu , Gonthier Marie-Paule , Lambert Gilles , Bourane Steeve
Published: March 2024

Diabetic peripheral neuropathy (DPN) is characterized by progressive and symmetrical sensory abnormalities and constitutes one of the earliest and main complications of diabetes. DPN is characterized by heterogeneous sensory symptoms such as chronic pain, tingling, burning or loss of sensation. Nociceptive Schwann cells (nSCs), a recently identified subtypes of dermal Schwann cells support terminal nerve fibers in mouse skin and contribute to mechanical sensation and neuropathic pain. While terminal nerve fibers density is evaluated in DPN models, there is currently no data about nSCs number and integrity during the early stages of the disease. In the present study, we determined the quantitative differences in terminal nerve fiber density as well as nSCs number and cellular extensions between control and high-fat diet (HFD) induced diabetic mice presenting with a neuropathic phenotype. We also characterized L1CAM as a reliable and specific marker of nSCs, a cell type previously assessed by the expression of S100β and Sox10. Interestingly, we observed a decrease in intraepidermal nerve fiber density (IENFD) associated with a significant reduction of nSCs in the glabrous foot skin of neuropathic mice. Overall, this study identifies L1CAM as a new marker of nSCs and indicates that these cells are impacted in diabetic peripheral neuropathy.
Multi-modal comparison of molecular programs driving nurse cell death and clearance inDrosophila melanogasteroogenesis
Authors: Bandyadka Shruthi , Lebo Diane PV , Mondragon Albert , Serizier Sandy B , Kwan Julian , Peterson Jeanne S , Chasse Alexandra Y , Jenkins Victoria , Calikyan Anoush , Ortega Anthony , Campbell Joshua D , Emili Andrew , McCall Kimberly
Published: March 2024

The death and clearance of nurse cells is a consequential milestone inDrosophila melanogasteroogenesis. In preparation for oviposition, the germline-derived nurse cells bequeath to the developing oocyte all their cytoplasmic contents and undergo programmed cell death. The death of the nurse cells is controlled non-autonomously and is precipitated by epithelial follicle cells of somatic origin acquiring a squamous morphology and acidifying the nurse cells externally. Alternatively, stressors such as starvation can induce the death of nurse cells earlier in mid-oogenesis, manifesting apoptosis signatures, followed by their engulfment by epithelial follicle cells. To identify and contrast the molecular pathways underlying these morphologically and genetically distinct cell death paradigms, both mediated by follicle cells, we compared their genome-wide transcriptional, translational, and secretion profiles before and after differentiating to acquire a phagocytic capability, as well as during well-fed and nutrient-deprived conditions. By coupling the GAL4-UAS system to Translating Ribosome Affinity Purification (TRAP-seq) and proximity labeling (HRP-KDEL) followed by Liquid Chromatography tandem mass-spectrometry, we performed high-throughput screens to identify pathways selectively activated or repressed by follicle cells to employ nurse cell-clearance routines contextually and preferentially. We also integrated two publicly available single-cell RNAseq atlases of theDrosophilaovary to define the transcriptomic profiles of follicle cells. In this report, we describe the genes and major pathways identified in the screens and the striking consequences toDrosophila melanogasteroogenesis caused by RNAi perturbation of prioritized candidates. To the best of our knowledge, our study is the first of its kind to comprehensively characterize two distinct apoptotic and non-apoptotic cell death paradigms in the same multi-cellular system. Beyond molecular differences in cell death, our investigation may also provide insights into how key systemic trade-offs are made between survival and reproduction when faced with physiological stress.
Lowering glucose enhances BACE1 activity and Aβ generation in mouse brain slice cultures
Authors: Sheppard Olivia , Humphrey Robert , Durrant Claire S. , Coleman Michael P.
Published: March 2024

Numerous environmental risk factors are now recognised as contributors to the onset and progression of Alzheimer’s disease (AD). It is probable that, in most instances, AD arises from a combination of genetic predisposition and environmental influences. In particular, there is a strong correlation between vascular impairment and dementia, yet the specific mechanisms by which vascular impairment and AD are linked, remain unknown. Hypoglycaemia can occur both due to vascular impairment, and due to fluctuating glucose levels in the context of diabetes, another risk factor for AD, and could potentially be involved in disease pathogenesis. To assess whether low glucose could contribute to the build-up of brain amyloid-β (Aβ) seen in AD, we exposed wildtype mouse organotypic hippocampal slice cultures (OHSCs) to varying glucose concentrations. Lowering glucose levels leads to an elevation in both Aβ1-42and Aβ1-40secreted into the culture medium, accompanied by an increased accumulation of Aβ within the slice tissue. This effect is replicated in OHSCs derived from the TgCRND8 mouse model of overexpressed, mutant APP and in human SH-SY5Y cells. The heightened Aβ levels are likely attributed to an upregulation of BACE1 activity, which is also observed with lowered glucose levels. In contrast, OHSCs subject to hypoxia exhibited no alterations in Aβ levels whether singularly, or in combination of hypoglycaemia. Finally, we found that alternative energy sources such as pyruvate, fructose 1,6-bisphosphate, and lactate can alleviate heightened Aβ levels, when given in combination with lowered glucose. This study underscores the capacity to induce an increase in Aβ in a wildtypeex vivosystem by selectively decreasing glucose levels.
Transcriptional characterization of cocaine withdrawal versus extinction within nucleus accumbens
Authors: Martínez-Rivera Freddyson J. , Holt Leanne M. , Minier-Toribio Angélica , Estill Molly , Yeh Szu-Ying , Tofani Solange , Futamura Rita , Browne Caleb J. , Mews Philipp , Shen Li , Nestler Eric J.
Published: March 2024

Substance use disorder is characterized by a maladaptive imbalance wherein drug seeking persists despite negative consequences or drug unavailability. This imbalance correlates with neurobiological alterations some of which are amplified during forced abstinence, thereby compromising the capacity of extinction-based approaches to prevent relapse. Cocaine use disorder (CUD) exemplifies this phenomenon in which neurobiological modifications hijack brain reward regions such as the nucleus accumbens (NAc) to manifest craving and withdrawal-like symptoms. While increasing evidence links transcriptional changes in the NAc to specific phases of addiction, genome-wide changes in gene expression during withdrawal vs. extinction (WD/Ext) have not been examined in a context- and NAc-subregion-specific manner. Here, we used cocaine self-administration (SA) in rats combined with RNA-sequencing (RNA-seq) of NAc subregions (core and shell) to transcriptionally profile the impact of experiencing withdrawal in the home cage or in the previous drug context or experiencing extinction training. As expected, home-cage withdrawal maintained drug seeking in the previous drug context, whereas extinction training reduced it. By contrast, withdrawal involving repetitive exposure to the previous drug context increased drug-seeking behavior. Bioinformatic analyses of RNA-seq data revealed gene expression patterns, networks, motifs, and biological functions specific to these behavioral conditions and NAc subregions. Comparing transcriptomic analysis of the NAc of patients with CUD highlighted conserved gene signatures, especially with rats that were repetitively exposed to the previous drug context. Collectively, these behavioral and transcriptional correlates of several withdrawal-extinction settings reveal fundamental and translational information about potential molecular mechanisms to attenuate drug-associated memories.