bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transfer learning predicts species-specific drug interactions in emerging pathogens
Authors: Chung Carolina H. , Chang David C. , Rhoads Nicole M. , Shay Madeline R. , Srinivasan Karthik , Okezue Mercy A. , Brunaugh Ashlee D. , Chandrasekaran Sriram 
Published: June 2024

AbstractMachine learning (ML) algorithms are necessary to efficiently identify potent drug combinations within a large candidate space to combat drug resistance. However, existing ML approaches cannot be applied to emerging and under-studied pathogens with limited training data. To address this, we developed a transfer learning and crowdsourcing framework (TACTIC) to train ML models on data from multiple bacteria. TACTIC was built using 2,965 drug interactions from 12 bacterial strains and outperformed traditional ML models in predicting drug interaction outcomes for species that lack training data. Top TACTIC model features revealed genetic and metabolic factors that influence cross- species and species-specific drug interaction outcomes. Upon analyzing ∼600,000 predicted drug interactions across 9 metabolic environments and 18 bacterial strains, we identified a small set of drug interactions that are selectively synergistic against Gram- negative (e.g.,A. baumannii) and non-tuberculous mycobacteria (NTM) pathogens. We experimentally validated synergistic drug combinations containing clarithromycin, ampicillin, and mecillinam againstM. abscessus, an emerging pathogen with growing levels of antibiotic resistance. Lastly, we leveraged TACTIC to propose selectively synergistic drug combinations to treat bacterial eye infections (endophthalmitis).
GnRH pulse generator activity in mouse models of polycystic ovary syndrome
Authors: Zhou Ziyue , Han Su Young , Pardo-Navarro Maria , Wall Ellen , Desai Reena , Vas Szilvia , Handelsman David J. , Herbison Allan E 
Published: June 2024

AbstractOne in ten women in their reproductive age suffer from polycystic ovary syndrome (PCOS) that, alongside subfertility and hyperandrogenism, typically presents with increased luteinizing hormone (LH) pulsatility. As such, it is suspected that the arcuate kisspeptin (ARNKISS) neurons that represent the GnRH pulse generator are dysfunctional in PCOS. We used herein vivoGCaMP fiber photometry and other approaches to examine the behavior of the GnRH pulse generator in two mouse models of PCOS. We began with the peripubertal androgen (PPA) mouse model of PCOS but found that it had a reduction in the frequency of ARNKISSneuron synchronization events (SEs) that drive LH pulses. Examining the prenatal androgen (PNA) model of PCOS, we observed highly variable patterns of pulse generator activity with no significant differences detected in ARNKISSneuron SEs, pulsatile LH secretion, or serum testosterone, estradiol, and progesterone concentrations. However, an unsupervised machine learning approach identified that the ARNKISSneurons of acyclic PNA mice continued to exhibit cyclical patterns of activity similar to that of normal mice. The frequency of ARNKISSneuron SEs was significantly increased in algorithm-identified “diestrous stage” PNA mice compared to controls. In addition, ARNKISSneurons exhibited reduced feedback suppression to progesterone in PNA mice and their pituitary gonadotrophs were also less sensitive to GnRH. These observations demonstrate the importance of understanding GnRH pulse generator activity in mouse models of PCOS. The existence of cyclical GnRH pulse generator activity in the acyclic PNA mouse indicates the presence of a complex phenotype with deficits at multiple levels of the hypothalamo-pituitary-gonadal axis.
CSPG4-targeting CAR-macrophages inhibit melanoma growth
Authors: Greiner Daniel , Xue Qian , Waddell Trinity QA , Kurudza Elena , Belote Rachel L , Dotti Gianpietro , Judson-Torres Robert L , Reeves Melissa Q , Cheshier Samuel H , Roh-Johnson Minna 
Published: June 2024

ABSTRACTChimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematological malignancies but has been clinically less effective in solid tumors. Engineering macrophages with CARs has emerged as a promising approach to overcome some of the challenges faced by CAR-T cells due to the macrophage’s ability to easily infiltrate tumors, phagocytose their targets, and reprogram the immune response. We engineered CAR-macrophages (CAR-Ms) to target chondroitin sulfate proteoglycan 4 (CSPG4), an antigen expressed in melanoma, and several other solid tumors. CSPG4-targeting CAR-Ms exhibited specific phagocytosis of CSPG4-expressing melanoma cells. Combining CSPG4-targeting CAR-Ms with CD47 blocking antibodies synergistically enhanced CAR-M-mediated phagocytosis and effectively inhibited melanoma spheroid growth in 3D. Furthermore, CSPG4-targeting CAR-Ms inhibited melanoma tumor growth in mouse models. These results suggest that CSPG4-targeting CAR-M immunotherapy is a promising solid tumor immunotherapy approach for treating melanoma.STATEMENT OF SIGNIFICANCEWe engineered macrophages with CARs as an alternative approach for solid tumor treatment. CAR-macrophages (CAR-Ms) targeting CSPG4, an antigen expressed in melanoma and other solid tumors, phagocytosed melanoma cells and inhibited melanoma growthin vivo. Thus, CSPG4-targeting CAR-Ms may be a promising strategy to treat patients with CSPG4-expressing tumors.
Nanofibrous Wound Dressing with a Smart Drug Delivery System: Poly(N-Isopropylacrylamide)-Conjugated Polycaprolactone Nanofibers Loaded with Curcumin
Authors: Khan Dawood , Jyoti Anirban , Aliaa Nik , Patel Kapil D. , Tan Renjian , Kim Hae-Won , Chau David , Nguyen Linh 
Published: June 2024

AbstractIn response to clinical demands for advanced wound dressings, a "smart bandage" was developed by combining polycaprolactone (PCL) nanofibers and the thermoresponsive polymer poly(N-isopropylacrylamide) (PNIPAAm). This bandage incorporates curcumin, an anti-inflammatory and antioxidant agent, to enhance wound healing. The LCST of PNIPAAm (32°C) enables an "on-off" drug delivery system, transitioning from a hydrophilic coil to a hydrophobic state. The nanofiber matrix was characterized using FTIR spectroscopy, SEM, water contact angle, and dynamic mechanical analysis. Curcumin release was assessed both above and below the LCST. The bandage is comfortable, easy to apply and remove, and promotes rapid wound healing. In vitro studies confirmed its non-toxicity to human dermal fibroblast cells. This "smart bandage" represents a significant advancement in wound care, with the potential to meet clinical requirements and enhance patient compliance, offering controlled drug delivery combined with the therapeutic benefits of curcumin.
Hippocampal volumes in UK Biobank are associated with APOE only in older adults
Authors: Chaloemtoem Ariya , Thornton Vera , Chang Yoonhoo , Anokhin Andrey P. , Belloy Michaël E. , Bijsterbosch Janine , Gordon Brian A. , Hartz Sarah M. , Bierut Laura J. 
Published: June 2024

AbstractINTRODUCTIONThe hippocampus atrophies with age and is implicated in neurodegenerative disorders including Alzheimer’s disease (AD). We examined the interplay between age andAPOEgenotype on total hippocampal volume.METHODSUtilizing neuroimaging data from 37,463 UK Biobank participants, we applied linear regression to quantify the association of age andAPOEwith hippocampal volume and identified the age when volumes of ε2/ε3, ε3/ε4, and ε4/ε4 carriers significantly deviated from ε3/ε3 using generalized additive modeling.RESULTSTotal hippocampal volume declined with age, with significant differences byAPOEgenotype emerging after age 60. ε3/ε4 and ε4/ε4 carriers displayed reduced volumes from ages 69 and 61, respectively, while ε2/ε3 showed delayed decline starting at age 76.DISCUSSIONThe association ofAPOEand hippocampal volume is age-dependent, with differences in volumes of ε4/ε4 carriers detected as early as age 61. This work underscores the importance ofAPOEgenotype in determining when to begin screening for AD.
Healthcare providers’ knowledge and use of psychological and psychoSOCIAL screening and interventions in the management of patients with tendinopathy: An International Survey of Practice
Authors: O’Neill Seth , English Laura , Mallows Adrian , Stubbs Carl , Stephens Gareth , Briggs-Price Sam , Kirwan Paul , Lee Matt , McAuliffe Sean , Kenyon Matt 
Published: June 2024

AbstractBackgroundPsychological and psychosocial factors play an important role in the management of patients with musculoskeletal disorders. Currently, there is no information exploring how clinicians current practice is informed by these factors in the people with tendinopathy exists.ObjectivesTo explore healthcare providers knowledge and use of psychological and social screening and interventions in the management of patients with tendinopathyMethodsAn online survey was developed by a group of tendon experts. The survey was disseminated via special interest groups, social networks and professional organisations internationally.ResultsThe survey had 103 completed responses. The majority of respondents used the subjective, 53% (N=55), subjective and objective, 28%(n=29), or objective 6% (n=6) examination to screen for psychological factors using both verbal and nonverbal methods. Psychosocial factors were screened for during the subjective assessment by 75% (n=77) of respondents. A further 15% (n=15) screened during the subjective and objective combined whilst 5% (n=5) examined this factor in the objective assessment in isolation.Psychological screening tools were used by 25% (n= 26) of respondents and psychosocial factors by 12% (n=12) of respondents.Treatment typically comprised of individualised education, reassurance, addressing mal-adaptive behaviours and behaviour change. Confidence in assessment and treatment was mixed and clinicians identified a desire for more specific training and self-development.ConclusionThe proportion of clinicians screening and measuring psychological and psychosocial factors in clinical practice is high, but few use validated tools due to a lack of time and confidence.Implication for clinical practiceClinicians commonly assess psychological and social factors during assessment of individuals with tendinopathy, as part of their subjective and objective assessments. It is unclear how successfully clinicians identify these factors during their assessments, as they rarely use validated screening tools.Key message –Clinicians and researchers should examine and modify: fear of movement, Negative pain beliefs, Maladaptive/avoidance behaviors, catastrophisation and Anxiety (psychological constructs) and Quality of life, work related constructs, sleep quality, education health literacy and social interactions(psychoSOCIAL constructs) during clinical or research work.Training needs to be developed to improve clinician confidence when assessing and treating psychological and psychoSOCIAL factors in patients with tendinopathyFurther work is needed to examine the barriers and facilitators to the use of appropriate validated psychological and psychoSOCIAL tools in clinical care.
Validation of the GCS-Pupil scale in Traumatic Brain Injury Incremental prognostic performance of pupillary reactivity with GCS in the prospective observational cohorts CENTER-TBI and TRACK-TBI
Authors: Vreeburg Rick J.G. , van Leeuwen Florian D. , Manley Geoffrey T. , Yue John K. , Brennan Paul M. , Sun Xiaoying , Jain Sonia , van Essen Thomas A. , Peul Wilco C. , Maas Andrew I.R. , Menon David K. , Steyerberg Ewout W. 
Published: June 2024

AbstractObjectiveTo compare the incremental prognostic value of pupillary reactivity as captured in the GCS-Pupils score (GCS-P) or added as separate variable to the Glasgow Coma Scale (GCS) in traumatic brain injury (TBI).MethodsWe analyzed patients enrolled between 2014 and 2018 in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI, n=3521) and the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI, n=1439) cohorts. We used logistic regression to quantify the prognostic performances of GCS-P versus GCS according to Nagelkerke’s R2. Endpoints were mortality and unfavorable outcome (Glasgow Outcome Scale-Extended score 1-4) at 6 months after injury. We estimated 95% confidence intervals with bootstrap resampling to summarize the improvement in prognostic capability.ResultsGCS as a linear score had a R2of 24% (95% confidence interval [CI] 17-30) and 30% (95%CI 17-43) for mortality and 29% (95%CI 25-34) and 38% (95%CI 29-47) for unfavorable outcome in CENTER-TBI and TRACK-TBI respectively. In the meta-analysis, pupillary reactivity as a separate variable improved the R2by an absolute value of 6% and 2% for mortality and unfavorable outcome (95%CI 4.0-7.7 and 1.2-3.0, respectively), with half the improvement captured in the GCS-P score (3%, 95%CI 2.1-3.3 and 1%, 95%CI 1-1.7, respectively).ConclusionsGCS-P has a stronger association with outcome after TBI than the GCS alone. However, for prognostic models, inclusion of GCS and pupillary reactivity as separate scores is preferable.
Mutation Pathogenicity Prediction by a Biology Based Explainable AI Multi-Modal Algorithm
Authors: Kellerman Raizy , Nayshool Omri , Barel Ortal , Paz Sharon , Amariglio Ninette , Klang Eyal , Rechavi Gideon 
Published: June 2024

AbstractMost known pathogenic mutations occur in protein-coding regions of DNA and change the way proteins are made. Deciphering the protein structure therefore provides great insight into the molecular mechanisms underlying biological functions in human disease. While there have recently been major advances in the artificial intelligence-based prediction of protein structure, the determination of the biological and clinical relevance of specific mutations is not yet up to clinical standards. This challenge is of utmost medical importance when decisions, as critical as suggesting termination of pregnancy or recommending cancer-directed rational drugs, depend on the accuracy of prediction of the effect of the specific mutation. Currently, available tools are aiming to characterize the effect of a mutation on the functionality of the protein according to biochemical criteria, independent of the biological context. A specific change in protein structure can result either in loss of function (LOF) or gain-of-function (GOF) and the ability to identify the directionality of effect needs to be taken into consideration when interpreting the biological outcome of the mutation. Here we describeTriple-modalitiesVariant Interpretation andAnalysis (TriVIAI), a tool incorporating three complementing modalities for improved prediction of missense mutations pathogenicity: protein language model (pLM), graph neural network (GNN) and a tabular model incorporating physical properties from the protein structure. The TriVIAl ensemble’s predictions compare favorably with the existing tools across various metrics, achieving an AUC-ROC of 0.887, a precision-recall curve (PRC) score of 0.68, and a Brier score of 0.16. The TriVIAI ensemble is also endowed with two major advantages compared to other available tools. The first is the incorporation of biological insights which allow to differentiate between GOF mutations that tend to cluster in specific hotspots and affect structure in a specific functional way versus LOF mutations that are usually dispersed and can cripple the protein in a variety of different ways. Importantly, the advantage over other available tools is more noticeable with GOF mutations as their effect on the protein structure is less disruptive and can be misinterpreted by current variant prioritization strategies. Until now available AI-based pathogenicity predicting algorithms were a black box for the users. The second significant advantage of TriVIAI is the explainability of the ensemble which contrasts the other available AI-based pathogenicity predicting algorithms which constitute a black box for the users. This explainability feature is of major importance considering the clinical responsibility of the medical decision-makers using AI-based pathogenicity predictors.
Consistent Multi-Omic Relationships Uncover Molecular Basis of Pediatric Asthma IgE Regulation
Authors: Eicher Tara , Kelly Rachel S. , Braisted John , Siddiqui Jalal K. , Celedón Juan , Clish Clary , Gerszten Robert , Weiss Scott T. , McGeachie Michael , Machiraju Raghu , Lasky-Su Jessica , Mathé Ewy A. 
Published: June 2024

AbstractSerum total immunoglobulin E levels (total IgE) capture the state of the immune system in relation to allergic sensitization. High levels are associated with airway obstruction and poor clinical outcomes in pediatric asthma. Inconsistent patient response to anti-IgE therapies motivates discovery of molecular mechanisms underlying serum IgE level differences in children with asthma. To uncover these mechanisms using complementary metabolomic and transcriptomic data, abundance levels of 529 named metabolites and expression levels of 22,772 genes were measured among children with asthma in the Childhood Asthma Management Program (CAMP, N=564) and the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS, N=309) via the TOPMed initiative. Gene-metabolite associations dependent on IgE were identified within each cohort using multivariate linear models and were interpreted in a biochemical context using network topology, pathway and chemical enrichment, and representation within reactions. A total of 1,617 total IgE-dependent gene-metabolite associations from GACRS and 29,885 from CAMP met significance cutoffs. Of these, glycine and guanidinoacetic acid (GAA) were associated with the most genes in both cohorts, and the associations represented reactions central to glycine, serine, and threonine metabolism and arginine and proline metabolism. Pathway and chemical enrichment analysis further highlighted additional related pathways of interest. The results of this study suggest that GAA may modulate total IgE levels in two independent pediatric asthma cohorts with different characteristics, supporting the use of L-Arginine as a potential therapeutic for asthma exacerbation. Other potentially new targetable pathways are also uncovered.
Diagnostic Accuracy of Nanopore Sequencing for DetectingMycobacterium tuberculosisand Drug-Resistant Strains: A Systematic Review and Meta-Analysis
Authors: Carandang Timothy Hudson David Culasino , Cunanan Dianne Jaula , Co Gail S. , Pilapil John David , Garcia Juan Ignacio , Restrepo Blanca I. , Yotebieng Marcel , Torrelles Jordi B. , Notarte Kin Israel 
Published: June 2024

ABSTRACTTuberculosis (TB), caused byMycobacterium tuberculosis(MTB) infection, remains a significant public health threat. The timeliness, portability, and capacity of nanopore sequencing for diagnostics can aid in early detection and drug susceptibility testing (DST), which is crucial for effective TB control. This study synthesized current evidence on the diagnostic accuracy of the nanopore sequencing technology in detecting MTB and its DST profile. A comprehensive literature search in PubMed, Scopus, MEDLINE, Cochrane, EMBASE, Web of Science, AIM, IMEMR, IMSEAR, LILACS, WPRO, HERDIN Plus, MedRxiv, and BioRxiv was performed. Quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Pooled sensitivity, specificity, predictive values (PV), diagnostic odds ratio (DOR), and area under the curve (AUC) were calculated. Thirty-two studies were included; 13 addressed MTB detection only, 15 focused on DST only, and 4 examined both MTB detection and DST. No study used Flongle or PromethION. Seven studies were eligible for meta-analysis on MTB detection and five for DST; studies for MTB detection used GridION only while those for DST profile used MinION only. Our results indicate that GridION device has high sensitivity [88.61%; 95% CI (83.81–92.12%)] and specificity [93.18%; 95% CI (85.32–96.98%)], high positive predictive value [94.71%; 95% CI (89.99–97.27%)], moderately high negative predictive value [84.33%; 95% CI (72.02–91.84%)], and excellent DOR [107.23; 95% CI (35.15–327.15)] and AUC (0.932) in detecting MTB. Based on DOR and AUC, the MinION excelled in detecting pyrazinamide and rifampicin resistance; however, it underperformed in detecting isoniazid and ethambutol resistance. Additional studies will be needed to provide more precise estimates for MinION’s sensitivity in detecting drug-resistance, as well as DOR in detecting resistance to pyrazinamide, streptomycin, and ofloxacin. Studies on detecting resistance to bedaquiline, pretomanid, and linezolid are lacking.
Exploring the Gender Gap in Young Adult Mental Health during COVID-19: Evidence from the UK
Authors: Webster Mhairi , Manoukian Sarkis , McKendrick John H. , Biosca Olga 
Published: June 2024

AbstractAimsTo explore the prevalence of a mental health gender gap within a young adult sample during the COVID-19 pandemic, and to identify the impact of loneliness and domestic time use on young people’s, and particularly young women’s mental health.MethodUsing data from the UK Longitudinal Household Survey (UKHLS), this research examines mental health prior to the pandemic (2019) and during the pandemic (April 2020 until September 2021). A random-effects regression analysis was conducted to examine the effects of loneliness, and domestic factors across age and gender to ascertain their contribution to the mental health gender gap in a young adult population.ResultsAverage mental health decline was consistently higher for women compared to men, and young people (ages 16-24) saw a reduction in mental health twice as much as those in the oldest age category (over 65). Loneliness accounted for a share of the mental health gender gap, and a more decrease in mental health was recorded for young women experiencing loneliness, compared to older age groups. Domestic and familial factors did not have a significant impact on young people’s mental health.ConclusionsAlthough across all ages and genders, mental health had returned to near pre-pandemic levels by September 2021, young people and especially women continue to have worse mental health compared to other age groups, which is consistent with pre-COVID age and gender inequalities. Loneliness is a key driver in gendered mental health inequalities during the pandemic in a young adult population.
N-Cadherin mediated cell rearrangements shape embryonic macrophage cluster
Authors: Hasenauer Jacob , Meng Xiang , Scarborough Honor , Stanley-Ahmed Jasmine A. , Köster Darius Vasco , Ratheesh Aparna 
Published: June 2024

AbstractDrosophila embryonic macrophages are highly motile phagocytic and secretory cells which are essential for embryonic development. Embryonic migration and dispersal of these cells along pre-determined routes is invariably tied to their functions such that misrouting or delay in macrophage migration has serious consequences for embryogenesis and adult homeostasis. In this study, we describe early steps of macrophage migration from their site of origin in the head mesoderm to the germband and show that hemocytes start moving as an epithelial-like cluster with N-Cadherin based Adherens junctions. The cells within the cluster move in a co-ordinated manner and exhibit cell rearrangements mediated through junction shrinkage. We found that N-Cadherin is dynamically relocalized during cluster extension and modulating N-Cadherin levels results in hemocyte dispersal away from their main axis of migration which affects migration into the germband. We therefore elucidate a novel multi-tiered mechanism which ensures that macrophages are positioned appropriately to regulate their distribution in the embryo.