bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of deep learning algorithms for segmentation of microelectrode arrays electrograms in the study of changes in myocardial bioelectrical activity
Authors: Kotikhina Elena , Karchkov Denis , Moskalenko Viktor , Rybkin Anton , Smirnov Ruslan , Osipov Grigory , Smirnov Lev 
Published: November 2024

AbstractThe using of modern electrophysiological methods during scientific research implies processing of huge data sets which becomes a significant problem. Progress in the development of equipment for registration of multiple local field potentials from the tissue surface contributes to the study of spatio-temporal characteristics of myocardial bioelectrical activity at a more detailed level. But it also raises the need for automation of data analysis, which can be accomplished by algorithms based on machine learning. New scientific approaches can contribute to the discovery of new facts about substances widely used but with under-researched efficacy. The paper presents the results of epicardial mapping by flexible microelectrode arrays of myocardium of isolated rat heart perfused with a solution containing L-carnitine, nutritional supplement that may be recommended for people suffering from cardiovascular disease. Electrograms from microelectrode arrays were analyzed using a neural network model based on U-Net architecture adapted for segmentation of one-dimensional signal. It was shown that the presence of L-carnitine in the perfusion solution caused a decrease in heart rate, myocardial excitation conduction velocity, coronary blood flow intensity of the isolated rat heart and suppressed physiological responses of the heart to adrenaline stimulation.
Negative resilience trends to more frequent extreme droughts in Mediterranean oak species
Authors: Borreguero I. J. , Sánchez-Miranda Á. , Martínez-Sancho E. , Rubio-Casal A. E. , Sánchez-Salguero R. , Matías L. 
Published: November 2024

AbstractRecent changes in climate have triggered widespread mortality events in oak forests worldwide. Despite the ecological importance of these ecosystems, limited information exists on the long-term resilience of oak forests in response to extreme climate events.Quercus canariensis, a semi-deciduous oak sensitive to summer drought characteristic of the Mediterranean climate, is currently showing defoliation and mortality episodes in the drier areas of its natural range. Here, we investigated the long-term impacts of climate on the radial growth ofQ. canariensisand assessed changes in resilience to extreme droughts across eight populations in S Spain following an environmental gradient. We observed a clear latitudinal gradient in growth performance, as reflected by resilience indices across populations. Since 1970,Q. canariensishas shown a marked decline in resilience to extreme drought events at the wettest region, resulting in a diminished capacity to recover pre-drought growth levels. This trend has preceded growth declines in certain populations, suggesting increased vulnerability to the increasing frequency of extreme climatic events. Through growth analyses, we identified early-warning signals of forest decline in this Mediterranean oak species, highlighting the most sensitive populations and its high susceptibility to extreme droughts impacts.
Combining the CRISPR Activation and Interference Capabilities Using dCas9 and G-Quadruplex Structures
Authors: Kabir Mohammad Lutful , Kodikara Sineth G. , Hoque Mohammed Enamul , Shiekh Sajad , Alfehaid Janan , Basu Soumitra , Balci Hamza 
Published: November 2024

ABSTRACTWe demonstrate that both CRISPR interference and CRISPR activation can be achieved at RNA and protein levels by targeting the vicinity of a putative G-quadruplex forming sequence (PQS) in thec-Mycpromoter with nuclease-dead Cas9 (dCas9). The achieved suppression and activation in Burkitt’s Lymphoma cell line and inin vitrostudies are at or beyond those reported with alternative approaches. When the template strand (contains the PQS) was targeted with CRISPR-dCas9, the G-quadruplex was destabilized andc-MycmRNA and protein levels increased by 2.1-fold and 1.6-fold, respectively, compared to controls in the absence of CRISPR-dCas9. Targeting individual sites in the non-template strand with CRISPR-dCas9 reduced both thec-MycmRNA and protein levels (by 1.8-fold and 2.5-fold, respectively), while targeting two sites simultaneously further suppressed both the mRNA (by 3.6-fold) and protein (by 9.8-fold) levels. These were consistent with cell viability assays when single or dual sites in the non-template strand were targeted (1.7-fold and 4.7-fold reduction in viability, respectively). We also report extensivein vitrobiophysical studies which are in quantitative agreement with these cellular studies and provide important mechanistic details about how the transcription is modulated via the interactions of RNA polymerase, CRISPR-dCas9, and the G-quadruplex.
Desmoplakin is a desmosomal mechanosensor
Authors: Dong Yinchen , Elgerbi Ahmed , Xie Bin , Choy John S. , Sivasankar Sanjeevi 
Published: November 2024

AbstractDesmosomes are essential cell-cell adhesion organelles that enable tension-prone tissue, like the skin and heart, withstand mechanical stress. Desmosomal anomalies are associated with numerous epidermal disorders and cardiomyopathies. Despite their critical role in maintaining tissue resilience, an understanding of how desmosomes respond to mechanical stimuli is lacking. Here we demonstrate, in human breast cancer MCF7 cells, that actomyosin forces induce a conformational change in the N-terminal region of desmoplakin, a critical cytoplasmic desmosomal protein. Using super-resolution fluorescence microscopy, biochemical assays, and atomistic computer simulations, we show that actomyosin forces are directed to desmoplakin along keratin-19 filaments. These forces induce a conformational change in the N-terminal plakin domain of desmoplakin, converting this domain from a folded (closed) to an extended (open) conformation. Functional adhesion assays show that MCF7 cells with desmoplakin in an open conformation are more adhesive than cells with desmoplakin in a closed state. Our findings establish that desmoplakin is mechanosensitive and undergoes force-induced conformational changes which enhance the mechanical resilience of desmosomes.Significance StatementDesmosomes are essential cell-cell adhesion junctions that enable tension-prone tissue, like the skin and heart, withstand mechanical stress. Despite their critical role in maintaining tissue integrity, it is unclear how desmosomes respond to mechanical forces. Here we demonstrate that force induces a conformational change in desmoplakin, a critical intracellular desmosomal protein. This force-induced change in the desmoplakin’s structure enhances the resilience of desmosomes and enables them to withstand mechanical stress.
Deep Kernel Inversion: Rapid and Accurate Molecular Interaction Prediction for Drug Design
Authors: Myers Seth A. , Miller Chad , Lugo Kyler , Trinh Thi , Lee Chang-wook , Arunachalam Naveen , Chen Hannah , Drygin Denis , Martineau James 
Published: November 2024

AbstractComputational drug design offers the opportunity to dramatically accelerate novel therapeutics for untreated diseases. Designing compounds with optimal efficacy and specificity, however, requires understanding and optimizing immense numbers of molecular interactions. While advances in predicting one-to-one molecular interactions continue, there has been limited progress in scaling one-to-many or many-to-many molecular interaction models. In this paper, we introduce a deep learning framework that embeds molecules into a high-dimensional vector space, which we have named Deep Kernel Inversion. In this framework, the dot product between vectors accurately predicts molecular interactions. This approach reduces the complexity of predicting an entire molecular interaction network fromO(n2) toO(n), enabling new molecular design tasks previously inaccessible to computational approaches. In the case of human protein-protein interactions (PPI), we demonstrate a100,000 folddecrease in the computation required to map the full human PPI network. We also demonstrate best-in-class performance across multiple molecular interaction tasks with this approach. This work offers a new way forward in scaling accurate molecular interaction predictions with applications in mapping biological pathways, target discovery, drug design, and therapeutic development.
Mapping object space dimensions: new insights from temporal dynamics
Authors: Kidder A. , Quek G. L. , Grootswagers T. 
Published: November 2024

AbstractHow is object information organized in high-level visual cortex? Recently, a comprehensive model of object space in macaques was proposed, defined by the orthogonal axes of animacy and aspect ratio (Bao et al., 2020). However, when using stimuli that dissociated category, animacy, and aspect ratio in humans, no tuning of aspect ratio was observed in fMRI data (Yargholi & Op de Beeck, 2023). This difference could be a result of different stimuli, the limited temporal resolution of fMRI, or information available about the presented stimuli. Here, we asked if and when information about aspect ratio, animacy, and category is available over time. We collected whole-brain electroencephalography (EEG) data while participants (N = 20) viewed the stimulus set used by Yargholi & Op de Beeck (2023). To mask object details and increase reliance on shape information, we also presented silhouette versions of the stimuli. Stimuli were presented in 5Hz streams using rapid serial visual presentation, with intact and silhouette stimuli sets were shown in separate streams. Using standard multivariate decoding pipelines and representational similarity analysis, we found that aspect ratio, category, and animacy were represented during visual object processing. The dominant dimension was modulated by stimulus type, demonstrating that the observable dimensions of object space depend on the nature of the stimuli presented. Taken together, these findings demonstrate that aspect ratio is represented during object processing, however earlier and more transiently than categorical dimensions, such as animacy. By focusing on underlying temporal dynamics, our results provide clear new insights into the contradicting findings reported in previous work and reveal a more nuanced understanding of how object space evolves over time.
Index Case Testing in Mozambique: a descriptive analysis of 7 years of implementation
Authors: Honwana Nely , Amane Guita , Lisboa Miguelhete , Templin Lindsay , Swor Meghan , Simbine Ana Paula , Samussone Ema , Couto Aleny 
Published: November 2024

IntroductionIn 2014, Mozambique introduced index case testing (ICT) to increase the identification of people living with HIV (PLHIV), including among hard-to-reach populations. The strategy elicits PLHIV’s sexual contacts and biological children for testing at the community and facility levels, improving testing efficiency in detecting HIV among people. We analyzed HIV program data to understand ICT contributions to case identification since 2017.MethodsRoutine aggregated program data from the President’s Emergency Plan for AIDS Relief (PEPFAR) Monitoring, Evaluation, and Reporting data were abstracted for 2017–2023. Test positivity was calculated as positive tests over the total number of tests conducted by modality. Data were analyzed by calendar year (January–December), sex, age group (<15, 15– 49, ≥50 years), and ICT setting (community-based, facility-based).ResultsDuring 2017–2023, overall test positivity for all modalities combined decreased from 5.7% (410,430/7,207,532) to 2.9% (297,012/10,190,365), and ICT increased by 92% (from 389,940 tests done in 2017 to 748,265 in 2023). The contribution of ICT to the total number of positive tests increased from 9.0% to 24.5% (37,076/410,430 to 72,622/297,012); among men tested, the contribution of ICT to positive tests increased from 10.2% to 29.9%; among children <15 years tested, from 20.3% to 35.3%; and among 15–49-year-olds tested, from 10.3% to 25.3%. Almost two-thirds (65.3%) of positive tests through ICT were community-based (276,356/ 423,166), with a testing positivity rate of 10.5% (276,356/2,632,862). The overall ICT test positivity rate was 12.0% (423,166/3,535,787) compared to the overall test positivity rate of 4.1% (2,373,985/57,909,176).ConclusionOver the 7-year period, HIV testing through ICT almost doubled, and one of every four people who tested positive for HIV was detected through ICT. ICT efficiency is demonstrated by a test positivity that is three times higher (12%) than the overall test positivity (4%), with particular efficiencies among hard-to-reach age and sex groups.
“CD4+T Cells drive Inflammation in Type 2 Diabetes Mellitus via the TNF-α/STAT-3 Signaling Pathway”
Authors: Shaw Shubham K , Sengupta Soumya , Jha Rohila , Pattanaik Chandrasekhar , Behera Harapriya , Barik Prakash K , Meher Dayanidhi , Sarangi Rajlaxmi , Devadas Satish 
Published: November 2024

Abstract1)ObjectivesTo establish adaptive immune cells specifically T helpers as mediators of meta-inflammation in Type 2 Diabetes Mellitus, correlate biochemical and immunological parameters and delineate the specific signaling proteins responsible for it.2)Research Design and Methods100 T2DM patients with no other clinical disease, autoimmunity or infection were recruited and analyzed for their biochemical and immune parameters. Bioplexing and flow cytometry was employed to analyse total and cell specific protein secretion respectively.Ex-vivoinhibition studies were performed using targeted monoclonal antibodies or small molecule STAT inhibitors.3)ResultsCD4+T-cells were found to be the primary source for meta-inflammation in T2DM patients with multiple pro-inflammatory cytokines and antibody isotypes. TNF-α acting through STAT-3 was shown as the primary pathway implicating meta-inflammation through CD4+T-cells, wherein inhibitor studies revealed subtle pathways differences between TNF-α or STAT-3 inhibition.4)ConclusionsOur result suggests that chronic meta-inflammation with a dysregulated biochemical profile have severe implications on immune function. Additionally, TNF-α and STAT-3 inhibition are good therapeutic targets for better T2MD treatment in ameliorating meta-inflammation.
Prevalence of Physical Activity Initiatives in Australian Primary Schools: A Cross-Sectional Survey
Authors: O’Brien Kate M , Bell Jessica , Wolfenden Luke , Nathan Nicole , Yoong Serene , Bauman Adrian , Lecathelinais Christophe , Leigh Lucy , Hodder Rebecca K 
Published: November 2024

AbstractIntroductionSchools play a significant role in influencing children’s physical activity and sedentary behaviours and are a key recommended setting for physical activity initiative globally. To achieve population-wide health benefits, they must be guideline-informed and widely adopted. However, evidence on their implementation in Australian primary schools is limited.ObjectiveTo assess the reported implementation of recommended physical activity initiatives in Australian primary schools and explore their associations with school characteristics.MethodsA cross-sectional study surveyed a nationally representative sample of Australian primary school principals (August 2022-October 2023). Principals reported on 33 physical activity initiatives categorised by delivery context: in the classroom; outside the classroom and during break times; outside of school outside or involving families; or other. Prevalence estimates were weighted to the Australian school population, and logistic regression models assessed associations with school characteristics.ResultsA total of 669 schools participated, with 360 principals completing the survey. Reported implementation rates varied from 4% to 98%. The most frequently implemented initiative in classrooms wasPhysical activity units of work in PDHPE/HPE curriculum across all year groups(98%); outside the classroom/break times wasSchool infrastructure that supports physical activity during breaks everyday (e.g. play areas)(96%); and outside of school/involving families wasSchool provides end of trip facilities to encourage active school travel(75%). Implementation of nine initiatives was associated with school size (n=6), geographic location (n=4), or socio-economic status (n=1).ConclusionThis first national study provides critical information on current implementation levels individual physical activity initiatives in Australian primary schools and highlights where policy and practice investment in implementation support is required.
Trikafta rescues F508del-CFTR by tightening specific phosphorylation-dependent interdomain interactions
Authors: Wang Guangyu 
Published: November 2024

AbstractTrikafta is well-known for correcting the thermal and gating defects caused by the most common cystic fibrosis mutation F508del in the human cystic fibrosis transmembrane conductance regulator even at physiological temperature. However, the exact pathway is still unclear. Here, the noncovalent interactions among two transmembrane domains (TMD 1 and TMD2), the regulatory (R) domain and two nucleotide binding domains (NBD1 and NBD2), along with the thermoring structures of NBD1, were analyzed around the active gating center. The results demonstrated that Trikafta binding to TMD1 and TMD2 rearranged their interactions with the R domain, releasing the C-terminal region from NBD1 for its tight ATP-dependent dimerization with NBD2, stabilizing NBD1. Taken together, although the deletion of F508 induces the primary thermal defect of NBD1 and then the gating defect at the TMD1-TMD2 interface, Trikafta rescued them in a reverse manner allosterically. Thus, the thermoring structure can be used to uncover the pathway of a drug to correct the thermal defect of health-related protein.SignificanceTrikafta modulators have been approved by the FDA to treat the most common cystic fibrosis– causing mutation F508del CFTR. However, the molecular action mechanisms of these modulators are still unknown. Following the identification of the gating center in CFTR, this study further revealed that the specific noncovalent interactions of the phosphorylated S813 site with cytoplasmic loops 1 and 4 and N-/C- terminal tails of TMD1 upon Trikafta-triggered tight TMD1- TMD2 interactions at the gating center play a pivotal role in rescuing the primary gating defect and then the thermal defect of F508del CFTR.HighlightsTrikafta strengthened TMD1-TMD2 interactions at the gating center of ΔF508-CFTR Tight TMD1-TMD2 interactions allowed specific interactions of the R domain with the ICL1- ICL4 interface and the N-/C- terminal tails of TMD1 Subsequently, the C-terminal region was released from NBD1 for tight ATP-dependent NBD1-NBD2 dimerization, stabilizing NBD1 of ΔF508-CFTR
Advancements in Inflammation Parallels Myopenia inWinnieMice Model of Spontaneous Chronic Colitis
Authors: Sharma Shilpa , Debruin Danielle , Devereaux Jeannie , Nurgali Kulmira , Hayes Alan , Duque Gustavo 
Published: November 2024

AbstractBackgroundInflammatory bowel disease (IBD) is characterized by gastrointestinal inflammation and systemic complications, including muscle wasting. Musculoskeletal conditions have remained an unappreciated aspect of IBD. This study aimed to describe the Winnie mouse model’s skeletal muscle phenotype and functional alterations. This model spontaneously develops chronic colitis that closely resembles human IBD.MethodsWinniemice and C57BL/6 (littermate) controls were evaluated at 5-6 weeks (pre-colitis) and 15-16 weeks (active colitis). Assessments included disease activity, inflammation, muscle function tests, andex vivoanalyses of the soleus (SOL) and tibialis anterior (TA) muscles for mass and histology.ResultsAt 5-6 weeks,Winniemice showed no disease activity or muscle changes. At 15 weeks,Winniemice exhibited significantly higher disease activity index (DAI) and elevated lipocalin-2 (LCN-2) levels than controls. SOL and TA muscles showed decreased weights and fibre sizes, which correlated significantly with LCN-2 levels. Wheel-running activity was reduced, which correlated with increased LCN-2 levels and DAI. DAI negatively correlated with muscle mass and fibre size. Grip strength remained unaltered despite these changes.ConclusionTheWinniemouse model develops significant skeletal muscle alterations paralleling intestinal inflammation progression, characterized by reduced muscle mass and size with preserved strength but impaired functional endurance capacity. These findings establish theWinniemodel as a valuable tool for investigating IBD-associated muscle wasting.Key Messages:1. What is already known?Inflammatory bowel disease (IBD) is associated with systemic complications, including muscle dysfunction.2. What is new here?TheWinniemouse model of chronic colitis develops skeletal muscle alterations that correlate with the progression of intestinal inflammation.Muscle changes inWinniemice include reduced muscle mass, decreased fibre size, and, functional decline but preserved grip strength.3. How can this study help patient care?This research highlights the importance of monitoring muscle health in IBD patients and suggests potential targets for interventions to preserve muscle function.TheWinniemodel provides a valuable tool for testing therapies aimed at addressing muscle dysfunction in IBD.
ERGA-BGE Reference Genome of the Northern chamois (Rupicapra rupicapra): Europe’s most abundant mountain ungulate
Authors: Buzan Elena , Bončina Aja , Pokorny Boštjan , Escudero Nuria , Fernández Rosa , Böhne Astrid , Monteiro Rita , Gut Marta , Câmara Ferreira Francisco , Cruz Fernando , Gómez-Garrido Jèssica , Alioto Tyler S. , Haggerty Leanne , Martin Fergal , De Panis Diego 
Published: November 2024

AbstractThe reference genome ofRupicapra rupicapra(subsp.rupicapra) provides insights into the genetic makeup that enabled this iconic mountain ungulate to adapt to its harsh environment, including its ability to survive in extreme weather and high altitudes—factors that are increasingly important in the face of climate change. A total of 29 contiguous chromosomal pseudomolecules were assembled from the genome sequence. This chromosome-level assembly encompasses 2.62 Gb, composed of 124 contigs and 76 scaffolds, with contig and scaffold N50 values of 77 Mb and 101 Mb, respectively.