bluuebunny/crossref_metadata_2025_split huggingface dataset:
X-Tracker: Automated Analysis of Xenopus Tadpole Visual Avoidance Behavior
Authors: McKeown Caroline R. , Ta Aaron C. , Marshall Christopher L. , McLain Natalie J. , Archuleta Kailey J. , Cline Hollis T. 
Published: October 2024

AbstractXenopus laevistadpoles exhibit an avoidance behavior when they encounter a moving visual stimulus. A visual avoidance event occurs when a moving object approaches the eye of a free-swimming animal at an approximately 90-degree angle and the animal turns in response to the encounter. Analysis of this behavior requires tracking both the free-swimming animal and the moving visual stimulus both prior to and after the encounter. Previous automated tracking soft-ware does not discriminate the moving animal from the moving stimulus, requiring time-consuming manual analysis. Here we present X-Tracker, an automated behavior tracking code that can detect and discriminate moving visual stimuli and free-swimming animals and score encounters and avoidance events. X-Tracker is as accurate as human analysis without the human time commitment. We also present software improvements to our previous visual stimulus presentation and image capture that optimize videos for automated analysis, and hardware improvements that increase the number of animal-stimulus encounters. X-Tracker is a high throughput, unbiased, and significant time-saving analysis system that will greatly facilitate visual avoidance behavior analysis ofXenopus laevistadpoles, and potentially other free-swimming organisms. The tool is available athttps://github.com/ClineLab/Tadpole-Behavior-Automation.
Hippocampal-cortical interactions in the consolidation of social memory
Authors: Park Gaeun , Kim Min Seok , Lee Young-Beom , Shin Soonho , Lee Doyun , Kim Sang Jeong , Lee Yong-Seok 
Published: October 2024

AbstractEpisodic memories are initially encoded in the hippocampus and subsequently undergo systems consolidation into the neocortex. The nature of memory stored in the hippocampus and neocortex also differs, with the cortex shown to encode memories in more generalized forms. Although several brain regions are known to encode social information, the specific cortical regions and circuits involved in the consolidation of social memory and the nature of the information encoded in the cortex remain unclear. Usingin vivoCa2+imaging and optogenetic manipulations, we found that infralimbic (IL) neurons projecting to the nucleus accumbens shell (IL→NAcSh) neurons store consolidated social memory. Inactivating IL→NAcShneurons that responded to a familiar conspecific impaired the recognition of other familiar mice including littermates, demonstrating that these neuronal activities support social familiarity. Furthermore, inactivating hippocampal ventral CA1 neurons projecting to the IL disrupted the consolidation of memory for newly familiarized mice while sparing the recognition of littermates. These findings demonstrate the critical role of hippocampal-cortical interactions in the consolidation of social memory.
Learning good therapeutic targets in ALS, neurodegeneration, using observational studies
Authors: Alidoost Mohammadali , Huang Jeremy Y. , Dermentzaki Georgia , Blazier Anna S. , Gaglia Giorgio , Hammond Timothy R. , Frau Francesca , Mccorry Mary Clare , Ofengeim Dimitry , Wilson Jennifer L. 
Published: October 2024

AbstractAnalysis of real-world data (RWD) is attractive for its applicability to real-world scenarios but RWD is typically used for drug repurposing and not therapeutic target discovery. Repurposing studies have identified few effective options in neuroinflammatory diseases with relatively few patients such as amyotrophic lateral sclerosis (ALS), which is characterized by progressive muscle weakness and death with no disease-modifying treatments available. We previously reclassified drugs by their simulated effects on proteins downstream of drug targets and observed class-level effects in the EHR, implicating the downstream protein as the source of the effect. Here, we developed a novel ALS-focused pathways model using data from patient samples, the public domain, and consortia. With this model, we simulated drug effects on ALS and measured class effects on overall survival in retrospective EHR studies. We observed an increased but non-significant risk of death for patients taking drugs associated with the complement system downstream of their targets and experimentally validated drug effects on complement activation. We repeated this for six protein classes, three of which, including multiple chemokine receptors, were associated with a significant increased risk for death, suggesting that targeting proteins such as chemokine receptors could be advantageous for these patients. We recovered effects for drugs associated with complement activation and chemokine receptors in Parkinson’s and Myasthenia Gravis patients. We demonstrated the utility of network medicine for testing novel therapeutic effects using RWD and believe this approach may accelerate target discovery in neuroinflammatory diseases, addressing the critical need for new therapeutic options.
The impact of differentiated service delivery (DSD) on retention in care and viral suppression in South Africa: A target trial emulation of routine care data
Authors: Huber Amy N. , Jamieson Lise , Fox Matthew P , Manganye Musa , Malala Lufuno , Chidarikire Thato , Khoza Nthabiseng , Nichols Brooke E , Rosen Sydney , Pascoe Sophie 
Published: October 2024

Introduction Replacing conventional, facility-based HIV treatment with less intensive differentiated service delivery (DSD) models could benefit DSD clients and the health system, but its value depends on maintaining or improving clinical outcomes. We compared retention and viral suppression between antiretroviral therapy (ART) clients enrolled in DSD models to those eligible for but not enrolled in DSD models in South Africa. Methods We applied a target trial emulation (TTE) methodology to data from South Africa’s electronic medical record system (TIER.Net) for 18 clinics across 3 provinces and estimated retention in care (attended clinic visit within 12 months) and viral suppression (<400 copies/ml3) at 12, 24, and 36 months after follow-up start date, defined as DSD enrollment date for the intervention arm and the first trial enrollment period clinic visit for the comparison arm. Clients were eligible for DSD models if they were ≥18 years old, on ART ≥12 months, and had two suppressed viral load (VL) measurements, per prevailing national guidelines. For the TTE, we designated eight 6-month target trial enrolment periods between 1 July 2017 and 1 July 2021. For each period, we estimated the risk differences for retention in care and viral suppression by comparing those enrolled in DSD models to those not enrolled, using a Poisson distribution with an identity link function. We report adjusted and unadjusted risk differences for clients enrolled in DSD models and for DSD-eligible clients not enrolled in a DSD model. Results and discussion 49,595 unique individuals were eligible for DSD enrolment over eight target trials, contributing to a total of 148,943 trial-clients, of whom 17% (25,775) were enrolled in DSD models. The pooled adjusted risk difference for retention in care between clients enrolled in DSD and those not enrolled in DSD was 3.2% (95% confidence interval (CI) 1.6%; 4.7%) at 12 months, 4.2% (2.4%; 6.0%) at 24 months, and 4.4% (2.0%; 6.8%) at 36 months. For viral suppression, the adjusted risk difference comparing DSD to non-DSD was estimated to be 1.4% (-0.5%; 3.2%) at 12 months, 1.7% (-0.5%; 4.0%) at 24 months, and 1.4% (-0.6%; 4.4%) at 36 months. Results remained consistent across target trials. Clients who were younger, lived in urban settings, or had less ART experience at trial enrolment had lower retention. Conclusions Clients enrolled in DSD models in South Africa had slightly better retention in care and similar viral suppression to those who were eligible for but not enrolled in DSD. With better or equivalent outcomes, DSD models can be assessed on the basis of non-clinic costs and benefits, such as changes in quality of care and resource utilization.
Discovering Subtypes with Imaging Signatures in the Motoric Cognitive Risk Syndrome Consortium using Weakly-Supervised Clustering
Authors: Nallapu Bhargav Teja , Ezzati Ali , Blumen Helena M. , Petersen Kellen K. , Lipton Richard B. , Ayers Emmeline , Kumar V G Pradeep , Velandai Srikanth , Beare Richard , Beauchet Olivier , Doi Takehiko , Shimada Hiroyuki , Milman Sofiya , Aleksic Sandra , Verghese Joe 
Published: October 2024

STRUCTURED ABSTRACTINTRODUCTIONUnderstanding the heterogeneity of brain structure in individuals with the Motoric Cognitive Risk Syndrome (MCR) may improve the current risk assessments of dementia.METHODSWe used data from 6 cohorts from theMCR consortium(N=1987). A weakly- supervised clustering algorithm called HYDRA was applied to volumetric MRI measures to identify distinct subgroups in the population with gait speeds lower than one standard deviation (1SD) above mean.RESULTSThree subgroups (Groups A, B & C) were identified through MRI-based clustering with significant differences in regional brain volumes, gait speeds, and performance on Trail Making (Part-B) and Free and Cued Selective Reminding Tests.DISCUSSIONBased on structural MRI, our results reflect heterogeneity in the population with moderate and slow gait, including those with MCR. Such a data-driven approach could help pave new pathways toward dementia at-risk stratification and have implications for precision health for patients.
Associations of perceived discrimination with health outcomes and health disparities in theAll of Uscohort
Authors: Lam Vincent , Gupta Sonali , Jordan I. King , Mariño-Ramírez Leonardo 
Published: October 2024

ABSTRACTObjectiveThe goal of this study was to investigate the association of perceived discrimination with health outcomes and disparities.Materials and MethodsThe study cohort consists of 60,180 participants from the four largest SIRE groups in theAll of UsResearch Program participant body: Asian (1,291), Black (4,726), Hispanic (5,336), and White (48,827). A perceived discrimination index (PDI) was derived from participant responses to the “Social Determinants of Health” survey, and theAll of UsResearcher Workbench was used to analyze associations and mediation effects of PDI and self-identified race and ethnicity (SIRE) with 1,755 diseases.ResultsThe Black SIRE group has the greatest median PDI, followed by the Asian, Hispanic, and White groups. The Black SIRE group shows the greatest number of diseases with elevated risk relative to the White reference group, followed by the Hispanic and Asian groups. PDI was found to be positively and significantly associated with 489 out of 1,755 (27.86%) diseases. ‘Mental Disorders’ is the disease category with the greatest proportion of diseases positively and significantly associated with PDI: 59 out of 72 (81.94%) diseases. Mediation analysis showed that PDI mediates 69 out of 351 (19.66%) Black-White disease disparities.DiscussionPerceived discrimination is significantly associated with risk for numerous diseases and mediates Black-White disease disparities in theAll of Usparticipant cohort.ConclusionThis work highlights the role of discrimination as an important social determinant of health and provides a means by which it can be quantified and modeled on theAll of Usplatform.
APOE4 carriers display loss of anticipatory cerebral vascular regulation over AD progression
Authors: Palmer Jacqueline A. , Kaufman Carolyn S. , Whitaker-Hilbig Alicen A. , Billinger Sandra A. 
Published: October 2024

AbstractINTRODUCTIONMaintenance of cerebral blood flow during orthostasis is impaired with aging and associated with cognitive decline, but the effect of Apolipoprotein L4-allele (APOE4) is unknown.METHODSOlder adults (n=108) (APOE4carriers, n=47; noncarriers, n=61) diagnosed as cognitively-normal (NC), MCI, or AD participated. Middle cerebral artery blood velocity (MCAv), assessed using Transcranial Doppler ultrasound, and beat-to-beat mean arterial blood pressure (MAP) were continuously recorded during a sit-to-stand transition. Anticipatory and orthostatic-induced MCAv and MAP responses were compared between genotypes and across disease progression.RESULTSCognitively-normalAPOE4carriers showed greater anticipatory MCAv increase, greater MCAv decrease with orthostasis, and shorter latency of peripheral MAP responses to orthostasis compared to noncarriers. MCAv and MAP responses were delayed and attenuated across theAPOE4disease progression, with no differences between genotypes in MCI and AD.DISCUSSIONAPOE4carriers and noncarriers present with distinct phenotypes of cerebral vascular dysfunction during hemodynamic orthostatic challenge. Unique cerebral and peripheral vascular compensation observed inAPOE4carriers may be lost as AD progresses.
Unraveling Interoceptive Processing and Action Dynamics: Exploring Neural and Psychological Responses to Food Cues Using fMRI
Authors: Malmir Nastaran , Ekhtiari Hamed , Farhoudian Ali , Robatmili Somaye , Nistche Michael 
Published: October 2024

AbstractInteroception, the perception of body signals, which is crucial for maintaining metabolic homeostasis, is asserted to play a vital role in obesity. Despite conceptual assumptions that impaired insular interoceptive processing contributes to overeating behaviors predominantly through modulating motor cortices, this link has not been extensively explored. Therefore, to further investigate neural mechanisms underlying insula-based interoceptive processing, this pre-registered (PMC9003175) study assessed blood oxygenation level-dependent (BOLD) responses via functional magnetic resonance tomography (fMRI) in 45 healthy participants (31 females/14 males, age 35.78 ± 10 years, BMI 29.52 ± 3.5 kg/m2) during a block-designed food cue reactivity task. Region of interest (insula) and whole brain voxel-wise correlation analyses explored neural correlates of visceral interoception. Furthermore, group factor analysis (GFA) unveiled coherence patterns between neural (fMRI) and psychological/behavioral measures. At the psychological level, self-reported hunger (P < 0.01, d = 0.82) and food craving (P < 0.01, d = 0.68) significantly increased, while craving control (P = 0.04, d = 0.37) decreased after cue exposure. Voxel-wise correlation analysis identified positive correlations (P < 0.01) between visceral interoception and activation of the precentral gyrus (PrG or motor cortex), insula, inferior frontal gyrus (IFG), posterior cingulate cortex (PCC), and superior parietal lobule (SPL). Moreover, altered functional connectivity dynamics were noted within the insula-PrG-IFG network during food cue exposure, with a significant reduction of IFG-PrG connections (P = 0.05). Interestingly, GFA identified a cross-unit latent factor across neural and psychological/behavioral measures. Overall, our findings indicate that altered interoceptive processing (insula activity), motor planning (motor cortex activity), and diminished inhibitory control (negative IFG-PrG connectivity) collectively contribute to food craving generation and potentially subsequent actions toward food consumption.
ReducedBacille Calmette-Guérin-specific IgG titres among babies born to mothers with Active Tuberculosis Disease in Uganda
Authors: Sitenda Diana , Ssekamatte Phillip , Nakavuma Rose , Kyazze Andrew Peter , Bongomin Felix , Baluku Joseph , Nabatanzi Rose , Kibirige Davis , Nakimuli Annette , Cose Stephen , Andia-Biraro Irene 
Published: October 2024

AbstractBackgroundBabies born to mothers with active tuberculosis disease (ATB) are at risk of poor clinical outcomes such as low birth weight and perinatal mortality. However, little is known about the influence of maternal ATB exposure on their vaccine responses during infancy. The study aimed to explore how maternal ATB affects infants’ vaccine responses, hypothesising reduced responses to BCG and other infant vaccines.MethodsThis was a case-control study with a longitudinal component of babies born to mothers with bacteriologically confirmed ATB (cases) and babies born to mothers without ATB (controls) carried out between September 2021 and June 2022. Quantitative BCG, diphtheria, tetanus, and measles-specific IgG ELISA assays were performed on infant plasma harvested from lithium-heparin blood collected on first encounter after birth (0), at 3, 6, and 9 months. We used prism v10.1.2, Mixed-effects modelling, and Tukey’s multiple comparison testing to determine mean differences (MD) between the cases and controls at all time points.ResultsInfants cases had reduced IgG titres to BCG at baseline compared to the controls (p=0.04), with a mean of 125.8/141.1 IU/mL, respectively. This difference was, however, not sustained at the other time points. Similarly, we demonstrated strong trends of reduced responses to tetanus, diphtheria, and measles vaccines among infant cases at baseline and three-month time points and weakly at months six and nine. The mean titres for tetanus at baseline and 3 months for cases versus controls are 1.744/2.917 IU/mL and 1.716/2.344 IU/mL (p<0.0001/0.018), respectively. The mean titres for diphtheria at 3 months were 0.022/0.075 IU/mL (p=0.006), respectively.ConclusionWe have demonstrated that maternal TB disease influences vaccine responses to BCG and other infant vaccines. This has implications for increased risk of childhood TB and other preventable diseases.
Cannabinoids shift the basal ganglia microRNA m6A methylation profile towards an anti-inflammatory phenotype in SIV-infected rhesus macaques
Authors: Okeoma Chioma M. , Premadasa Lakmini S. , Tan Chen S. , Ghiran Ionita C. , Mohan Mahesh 
Published: October 2024

AbstractBackgroundEpitranscriptomic modifications modulate diverse biological processes like regulation of gene expression, abundance, location and function. N6-methyladenosine (m6A) methylation has been shown to regulate various diseases, including cancer and inflammation. While there is evidence that m6A modification is functionally relevant in neural development and differentiation, the role of m6A modification in HIV neuropathogenesis is unknown.MethodsHere, we used anti-N6-methyladenosine (m6A) antibody immunoprecipitation and microarray profiling to identify m6A modifications in miRNAs in basal ganglia (BG) of Rhesus macaques (RMs) that were uninfected (VEH) and SIV-infected on combination anti-retroviral therapy (cART) and either VEH-treated (VEH/SIV/cART), or THC:CBD-treated (THC:CBD/SIV/cART). Ingenuity pathway analysis was conducted to understand the biological implications of miRNA m6A methylation in HIV neuropathogenesis. Finally, to understand the functional significance of m6A modifications in miRNAs, we overexpressed FAM-labeled wild-type or m6A-modified miR-194-5p in SCC-25 cells and determined its impact on the expression of its target, STAT1, an interferon-stimulated transcription factor known to drive persistent neuroinflammation in several neurodegenerative diseases.ResultsHIV/SIV infection promoted an overall hypomethylated miRNA m6A profile. While the overall hypomethylated m6A profile was not significantly impacted by THC:CBD, specific miRNAs predicted to target proinflammatory genes showed markedly reduced m6A methylation levels compared to the VEH-treated RMs. Additionally, specific BG tissue miRNAs bearing m6A epi-transcriptomic marks were transferred and detected in BG-derived extracellular vesicles. Mechanistically, the DRACH motif in the seed region of miR-194-5p was significantly m6A hypomethylated in THC:CBD/SIV/cART RMs. In SCC-25 cells, unlike wild-type miR-194-5p, transfected m6A-modified miR-194-5p mimics failed to downregulate STAT1 protein expression. Further, compared to VEH/SIV/cART RMs, THC:CBD administration significantly reduced m6A methylation of 44 miRNAs directly involved in regulating CNS network genes.ConclusionsThese results underscore the need for investigating the qualitative, and posttranscriptional modifications in RNA along with the more traditional, quantitative alterations in pathological conditions or in response to disease modifying treatments. Our findings indicate that m6A epitranscriptomic marks in the seed nucleotide region can impair miRNA function and that cannabinoids may preserve it by reducing m6A methylation levels. Finally, these findings provide a novel mechanistic (miRNA m6A hypomethylation) explanation underlying the anti-neuroinflammatory effects of phytocannabinoids in HIV/SIV infection.
Evidence forin vivomRNA Transport Between Mammalian Cells
Authors: Shubin Andrey , Liu Songlei , Church George , Hunter Craig 
Published: October 2024

AbstractThe prevalence and significance of intercellular mRNA transport remains unknown. Direct detection of mRNA transfer between cells within an organism is challenging due to technical limitations associated with transgene encoded molecular labels and cell sorting techniques. In this study we analyzed human-to-mouse xenograft single-cell RNA sequencing data to identify mouse transcripts in recovered human cells. The murine transcriptome analysis implicates macrophages as a frequent mRNA donor cell type. We then developed anin vitrosystem using mouse RAW264.7 macrophages and human HeLa and HEK293 cells and confirmed the transfer of Ftl1 mRNA from mouse to human cells. Overall, our study provides compellingin vivoevidence for prevalent intercellular mRNA transfer in human-to-mouse xenograft models.
Novel correlative microscopy approach for nano-bio interface studies of ultrafine particle-induced lung epithelial cell damage
Authors: Podlipec Rok , Pirker Luka , Krišelj Ana , Hlawacek Gregor , Gianoncelli Alessandra , Pelicon Primož 
Published: October 2024

AbstractCorrelative light and electron microscopy (CLEM) has attracted widespread interest in the life sciences community, particularly in light of recent developments in imaging resolution and sensitivity, and sample preservation. One of the highly relevant scientific areas that can be addressed by CLEM is nanotoxicology, the study of the environmental and, in particular, health effects of the ubiquitous particulate matter in polluted air. To assess safety and predict outcomes, particularly those induced by highly penetrating ultrafine particles (UFPs), it is invaluable to understand the mode of action at the molecular level, from the moment the particles interact with lung tissue. In our study we address these challenges by combining novel multimodal high-resolution live and fixed cell microscopy, from fluorescence lifetime imaging microscopy (FLIM), hyperspectral fluorescence imaging (fHSI), scanning electron microscopy (SEM), ultra-high resolution helium ion microscopy (HIM) to synchrotron micro X-ray fluorescence (SR µXRF). These provided a comprehensive insight into the structural and functional properties of the nano-bio interface formed on the surface of lung epithelial cells exposed to titanium dioxide nanotubes (TiO2NTs) and for the first time, we report several important initial cellular responses. Besides the characterization of extensive biomolecule binding to TiO₂, including DNA and its accumulation-related plausible implications for apoptosis and inflammation, we show acute changes due to fibrin-like fibrous network formation over aggregated nano-bio composites and accumulated iron-induced changes in the molecular environment at the nano-bio interface. The applied CLEM approach demonstrates high applicability for studying the initial cellular responses to nanoparticles, which can play a crucial role in the body’s immune response and the development of inflammation. The methodology provides a robust framework for future research into nanoparticle toxicity and its impact on human health.