bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Molecular Image-based Explainable Artificial intelligence Framework Identifies Novel Candidate Antibiotics
Authors: Lin Kingsten , Yang Yuxin , Cheng Feixiong 
Published: July 2024

AbstractThe continued growth of antibiotic resistance and the slowing of antibiotic discovery poses a large challenge in fighting infectious diseases. Recent advances in Artificial intelligence (AI) technologies offer a time- and cost-effective solution for the rapid development of effective antibiotics. In this study, we presented an explainable AI framework from a pre-trained model using 10 million drug-like molecular images. Specifically, we created a fine-tuned ImageMol from experimentalStaphylococcus aureusinhibition assays which contained 24,521 molecules consisting of 516 active compounds and 24,005 non-active compounds. Our optimized AI model achieved a strong AUROC of 0.926. The model was then used to predict the antibiotic activities from 10,247 FDA-approved, clinically investigational, or experimental molecules from the DrugBank database. After further filtering, 340 molecules were identified to have antibacterial behavior while simultaneously being dissimilar to known antibiotics. Finally, 76 candidates were identified as FDA-approved drugs for other applications. Thus, those candidates can be repurposed into needed novel antibiotics. We further illustrated explainable molecular images for top predicted candidate drugs via Gradient-weighted Class Activation Mapping (Grad-CAM) heatmap analysis. In summary, the presented molecular image-based AI model in drug discovery could be highly favorable due to its high performance, speed, and biological interpretation.
The multifaceted process of human coronary atherosclerotic cap destabilisation
Authors: Bruijn L.E. , Neves N. Fonseca , van Rhijn C.M. , Hamming J.F. , van den Bogaerdt AJ , Lindeman J.H.N. 
Published: July 2024

AbstractIntroductionPlaque rupture is the primary trigger of the acute clinical manifestations of atherosclerotic disease. So far, factual insight in the processes leading up to cap destabilization is largely missing. In order to overcome this knowledge gap, a pseudo-timeline of atherosclerosis progression was established in order to systematically map the qualitative changes in cap characteristics during lesion progression and destabilization.Material and MethodsA pseudo-timeline was created by randomly selecting preclassified (revised AHA classification, at least 10 per stage) left coronary artery FFPE specimens obtained during tissue donation (aortic valve procurement). Qualitative changes were visualized by (immuno)histochemistry, immunofluorescence and confocal microscopy. Scoring was performed by two observers using semiquantitative scoring estimates.ResultsThe median age of the donors was 56 years (IQR 51.5-59), and 67% of the patients was male. Movat staining indicated a consistent pattern of cap formation, maturation and destabilization. A distinctive cap emerged in the early fibroatheroma stage of progressive atherosclerosis. Disease progression was accompanied by profound fibrotic changes in the gap, and a progressive presence of inanotic (nutritional deprivation leading to dissolution) mesenchymal cells. Plaque rupture was preceded by thinning of the collagen fibers and accumulation of foam cells in the central portion of the thin cap. No evidence was found for a direct involvement of neovascularization in the destabilization process.ConclusionThe pseudo-time line of atherosclerotic lesion development characterizes the development of an unstable cap as a degenerative and fibrotic process with progressive exhaustion of the mesenchymal cell population. This study provides a rationale for the limited efficacy of medical strategies aimed at plaque stabilization.
Molecular basis of enhanced GLP-1 signaling mediated by GLP-1(9-36) in conjunction with LSN3318839
Authors: Li Jie , Li Guanyi , Mai Yiting , Liu Xiao , Yang Dehua , Zhou Qingtong , Wang Ming-Wei 
Published: July 2024

AbstractGlucagon-like peptide-1 (GLP-1) receptor (GLP-1R) is essential for glucose metabolism and energy balance. It is primarily activated by the endogenous hormone GLP-1(7-36) and its weaker metabolite GLP-1(9-36). Although GLP-1(9-36) was previously considered biologically inactive, emerging evidence indicate that it exerts cardioprotective and insulinotropic actions. Here, we present cryo-electron microscopy structures showing that GLP-1(9-36) binds to an atypical site composed of the upper halves of transmembrane helices 1 (TM1) and 2 (TM2), extracellular loop 1, and the extracellular domain, distinct from the binding site of GLP-1(7-36). Meanwhile, LSN3318839, an orally effective positive allosteric modulator selective for GLP-1(9-36), anchors in the TM1-TM2 cleft and repositions GLP-1(9-36) to adopt a binding pose like GLP-1(7-36), thereby enhancing GLP-1R-mediated signal transduction. Mutagenesis and molecular dynamics simulations confirmed the crucial interactions and structural adjustments involved in this modulation. Our study uncovers a novel binding mode of GLP-1 metabolite and allosteric modulation that augments GLP-1R signaling, both are potentially insightful to unveil the physiological role of GLP-1(9-36) and design better small molecule therapeutics targeting GLP-1R.
Standards for Health Promoting Hospitals and Health Services: Development and tools for implementation and measurement
Authors: Groene Oliver , Katsaros Keriin , Chiarenza Antonio , Fawkes Sally , Kristenson Margareta 
Published: July 2024

AbstractThe need to reorient health services towards health promotion is greater than ever. Health systems are overburdened by treating an ever-growing number of chronic patients, many of which seek care for problems that could partly be avoided or postponed through better health promotion implementation. Since its establishment, the International Network of Health Promoting Hospitals and Health Services has explicitly addressed this issue by developing specific standards on evidence-based health promotion approaches and interventions that should be implemented in health services organizations. These approaches and interventions not only address the health of patients, but also of staff and the wider community. Since the development of the standards in 2006, health systems and legitimate patient demands have evolved considerably. At the same time, topics emerged that are strongly associated with health promotion strategies, such as the climate impact of health services. An update of the 2006 standards was therefore overdue.The purpose of this paper is, firstly, to describe the methodology used to develop and outline the 2020 Standards for Health Promoting Hospitals and Health Services. Secondly, we present a self-assessment tool, which was developed to operationalize and provide concrete measurable elements for each standard against which performance and progress towards implementation can be measured and tracked. The 2020 standards are health-oriented, continue to uphold the strategies defined in the Ottawa Charter for Health Promotion, and respond to recent international declarations and charters.
Autistic voice: Sharing autistic children’s experiences and insights
Authors: Mullally Sinéad L. , Wood Alice E. , Edwards Cherice C. , Connolly Sophie E. , Constable Hannah , Watson Stuart , Rodgers Jacqui , Rose Kieran , King Nic 
Published: July 2024

AbstractAutism research rarely amplifies the voices of autistic children. Here, we aim to counter this by collating and sharing the first-hand experiences and insights of autistic children. A total of 136 children (8-14 years of age) self-reported their experiences of being autistic via a semi-structured online questionnaire/video call. Both qualitative and quantitative data was gathered, and inductive thematic analysis used to analyse qualitative responses. Four core themes were identified: ‘Safety and Security’, ‘Conformity, Fitting in and Masking’, ‘Identity’, and ‘Sensory Sensitivity. The initial theme of safety and security permeated the children’s narratives and overwhelmingly, the children spoke of the need for them to be alert to who in their lives is a safe person and who is not. They were also highly attuned to whether specific places are safe for them, as past experiences appear to have taught them that their safety in everyday places cannot be assumed. Teachers, health and social care professionals, and neurotypical peers were frequently singled out as unsafe people and school as an unsafe place, whilst parents, home, and autistic peers were often referred to as safe. This distinction was also evident in the statistical analysis of the quantitative data, whereby autistic children were significantly more likely to report that it is okay for them to be autistic at home, relative to when they are at school or with their friends/peers. Judging a person as safe was closely linked to that persons’ understanding of the child and of their autistic experiences, and understanding was important in establishing trust. When trust was established, it appeared possible for trusted people to facilitate a sense of safety for the children even within otherwise unsafe places. A sense of belonging within autistic/neurodivergent communities was positively linked to the core theme of safety and security and to having a positive autistic identity, whilst masking and sensory distress were linked to feeling unsafe and insecure. These first-hand accounts provide valuable insights into autistic children’s lives and demand that we urgently explore how places outside of the family home (including places of education) can be transformed into safe spaces for autistic children.
Enhanced Discrimination ofClostridioides difficileTransmission Using Whole Genome Sequencing andIn-SilicoMulti-locus Variable Number Tandem Repeat Analysis
Authors: Sundermann Alexander J. , Mills Emma G. , Srinivasa Vatsala Rangachar , Griffith Marissa P. , Ereifej Deena , Waggle Kady D. , Snyder Graham M. , Van Tyne Daria , Pless Lora Lee , Harrison Lee H. 
Published: July 2024

ABSTRACTWhole genome sequencing (WGS) is used to establish genetic relatedness of bacteria and track outbreaks in healthcare settings. While WGS provides sufficient discriminatory power to make inferences about genetic relatedness and transmission for most bacterial species, WGS forClostridioides difficileoften fails to provide discriminatory power, even at low single nucleotide polymorphism (SNP) differences. Multi-locus variable number tandem repeat analysis (MLVA), which analyzes rapidly mutating tandem repeat loci has previously been shown to be useful for this purpose forC. difficile. We investigated whetherin silicoMLVA can further elucidate genetic relatedness ofC. difficileclusters identified by short-read WGS but lacking epidemiological links. Potential healthcare-associated toxin-positiveC. difficileisolates were collected at our hospital from November 2016 to November 2019. Short-read WGS was performed on the Illumina platform to cluster isolates with ≤2 SNPs, and Nanopore long-read sequencing was used to resolve MLVA loci within these clustered isolates. Among 666 isolates, 62 unique patient isolates met the ≤2 SNP criterion and underwent MinION sequencing. Of the 105 pairs with 0-2 SNP differences, 79.0% had a summed tandem-repeat difference (STRD) of 0-5, 10.5% had an STRD of 6-10, and 10.5% had an STRD of 11-20. A significant correlation was found between a lower STRD value and the presence of a unit/procedure epidemiological link within low SNP clusters (OR: 0.45; 95% CI: 0.29, 0.70). Our findings demonstrate that MLVA provides additional genomic discrimination for closely relatedC. difficileisolates identified by WGS, enhancing outbreak investigation precision.
Early morphogenetic patterns of protonemata and gametophores ofPhyscomitrium patens(Hedw.) Mitt
Authors: Raju M.V.S. , Ashton N.W. 
Published: July 2024

AbstractIn axenic culture, protonemata ofPhyscomitrium(formerlyPhyscomitrella)patens(Hedw.) Mitt. are comprised of chloronemata and caulonemata that can be distinguished morpho-structurally. On solid nutrient agar medium, a protonemal inoculum proliferates, initially generating primary chloronemata, and expands radially across the surface of the substratum forming approximately round colonies. The expansion of the colonies derives mainly from centrifugal elongation of newly formed caulonemata, which arise by differentiation of primary chloronemal apical cells in the central region. Most commonly, oblique cross walls separate cells of the uniseriate caulonemal filaments. Each oblique wall organises a smaller and a larger angle with the outer wall of a tubular caulonemal cell. The smaller angle may lie in four different positions, vertically upward or downward, and laterally, to the right or left, parallel to the surface of the solid medium. Chloronemal filaments, which contain cells separated by transverse cross walls, develop from side branch initials (SBIs) at or near the smaller angle at the distal end of caulonemal cells. Like the smaller angle of the oblique cross walls in caulonemata, these secondary chloronemata also show four different orientations, vertically, upward or downward, and laterally, right or left. A strong inverse correlation exists between the placement of SBIs and secondary chloronemata and the direction of caulonemal tip growth. If the caulonemal tips curve downward into the medium, chloronemata are situated vertically on the upper side of caulonemata; similarly, if they turn upward, chloronemata are situated on the lower side. A similar correlation exists when caulonemal tips curve to the right or left on the surface of solid medium, in which case laterally directed chloronemata grow in the opposite direction, i.e. on the outside of the curve. The procumbent caulonemata with their associated protruding secondary chloronemal branches are reminiscent of the heterotrichous branching habit of filaments of some green algae. Gametophore buds develop from a minority of caulonemal SBIs and also occasionally from chloronemata; a stalk cell, which resembles a chloronemal cell, supports each bud. Buds develop into leafy gametophores that are arranged in a fairy ring. We discuss the relative merits of several models that might explain the temporally and spatially regulated clustering of buds resulting in the formation of a fairy ring.
The Orphan G Protein-Coupled Receptor GPR52 is a Novel Regulator of Breast Cancer Multicellular Organization
Authors: Hanif Sarah Z. , Au CheukMan Cherie , Torregroza Ingrid , Jannath Syeda Y. , Fabiha Tabassum , Bhinder Bhavneet , Washburn Michael , Devost Dominic , Liu Shuchen , Bhardwaj Priya , Evans Todd , Anand Pradeep Kumar , Tarran Robert , Palikhe Sailesh , Elemento Olivier , Dow Lukas , Blenis John , Hébert Terence E. , Brown Kristy A. 
Published: July 2024

AbstractG protein-coupled receptors (GPCRs) are the largest class of membrane-bound receptors and transmit critical signals from the extracellular to the intracellular spaces. Transcriptomic data of resected breast tumors shows that low mRNA expression of the orphan GPCR GPR52 correlates with reduced overall survival in breast cancer patients, leading to the hypothesis that loss of GPR52 supports breast cancer progression. CRISPR-Cas9 was used to knockout GPR52 in human triple-negative breast cancer (TNBC) cell lines MDA-MB-468 and MDA-MB-231, and in the non-cancerous breast epithelial cell line, MCF10A. Loss of GPR52 was found to be associated with increased cell-cell interaction in 2D cultures, altered 3D spheroid morphology, and increased propensity to organize and invade collectively in Matrigel. Furthermore, GPR52 loss was associated with features of EMT in MDA-MB-468 cells. To determine thein vivoimpact of GPR52 loss, MDA-MB-468 cells were injected into zebrafish and loss of GPR52 was associated with a greater total cancer area compared to control cells. RNA-sequencing and proteomic analyses of GPR52-null breast cancer cells reveal an increased cAMP signaling signature. Consistently, we found that treatment of wild-type (WT) cells with forskolin, which stimulates production of cAMP, induces some phenotypic changes associated with GPR52 loss, and inhibition of cAMP production rescued some of the GPR52 KO phenotypes. Overall, our results reveal GPR52 loss as a potential mechanism by which breast cancer progression may occur and support the investigation of GPR52 agonism as a therapeutic option in breast cancer.Statement of SignificanceWe show that loss of the orphan G protein-coupled receptor GPR52 in human breast cell lines leads to increased cell clustering, hybrid/partial EMT, and increased tumor burden in zebrafish.
Bacterial Wastewater-Based Epidemiology Using Surface-Enhanced Raman Spectroscopy and Machine Learning
Authors: Herndon Liam K. , Zhang Yirui , Safir Fareeha , Ogunlade Babatunde , Balch Halleh B. , Boehm Alexandria B. , Dionne Jennifer A. 
Published: July 2024

AbstractWastewater-based epidemiology (WBE) is a powerful tool for monitoring community disease occurrence, but current methods for bacterial detection suffer from limited scalability, the need fora prioriknowledge of the target organism, and the high degree of genetic similarity between different strains of the same species. Here, we show that surface-enhanced Raman spectroscopy (SERS) can be a scalable, label-free method for detection of bacteria in wastewater. We preferentially enhance Raman signal from bacteria in wastewater using positively-charged plasmonic gold nanorods (AuNRs) that electrostatically bind to the bacterial surface. Transmission cryoelectron microscopy (cryoEM) confirms that AuNRs bind selectively to bacteria in this wastewater matrix. We spike the bacterial speciesStaphylococcus epidermidis, Staphylococcus aureus, Serratia marcescens, andEscerichia coliand AuNRs into filter-sterilized wastewater, varying the AuNR concentration to achieve maximum signal across all pathogens. We then collect 540 spectra from each species, and train a machine learning (ML) model to identify bacterial species in wastewater. For bacterial concentrations of 109cells/mL, we achieve an accuracy exceeding 85%. We also demonstrate that this system is effective at environmentally-realistic bacterial concentrations, with a limit of bacterial detection of 104cells/mL. These results are a key first step toward a label-free, high-throughput platform for bacterial WBE.
Pheno-morphological screening and acoustic sorting of 3D multicellular aggregates using drop millifluidics
Authors: Rembotte Leon , Beneyton Thomas , Buisson Lionel , Badon Amaury , Boyreau Adeline , Douillet Camille , Hermant Loic , Jana Anirban , Nassoy Pierre , Baret Jean-Christophe 
Published: July 2024

AbstractThree-dimensional multicellular aggregates like organoids and spheroids have become essential tools to study the biological mechanisms involved in the progression of diseases. In cancer research, they are now widely used as in vitro models for drug testing. However, their analysis still relies on tedious manual procedures, which hinders their routine use in large-scale biological assays. Here, we introduce a novel drop millifluidic approach to screen and sort large populations containing over one thousand multicellular aggregates. Our system utilizes real-time image processing to detect pheno-morphological traits in cellular aggregates. They are then encapsulated in millimetric drops, actuated on-demand using the acoustic radiation force. We demonstrate the performance of our system by sorting spheroids with uniform sizes from a heterogeneous population, and by isolating organoids from spheroids with different phenotypes. We anticipate that this work offers the potential to standardize drug testing on multicellular aggregates, which promises accelerated progress in biomedical research.
Protein restriction associated with high fat induces metabolic dysregulation without obesity in juvenile mice
Authors: Joly Amélie , Thoumas Jean-Louis , Lambert Anne , Caillon Estelle , Leulier François , De Vadder Filipe 
Published: July 2024

AbstractDysregulation of energy metabolism, including hyperglycemia, insulin resistance and fatty liver have been reported in a substantial proportion of lean children. However, non-obese murine models recapitulating these features are lacking to study the mechanisms underlying the development of metabolic dysregulations in lean children. Here, we develop a model of diet-induced metabolic dysfunction without obesity in juvenile mice by feeding male and female mice a diet reflecting Western nutritional intake combined with protein restriction (mWD) during 5 weeks after weaning. mWD-fed mice (33% fat, 8% protein) do not exhibit significant weight gain and have moderate increase in adiposity compared to control mice (16% fat, 20% protein). After 3 weeks of mWD, juvenile mice have impaired glucose metabolism including hyperglycemia, insulin resistance and glucose intolerance. mWD also triggers hepatic metabolism alterations, as shown by the development of simple liver steatosis. Both male and female mice fed with mWD displayed metabolic dysregulation, which a probiotic treatment withLactiplantibacillus plantarumWJL failed to improve. Overall, mWD-fed mice appear to be a good preclinical model to study the development of diet-induced metabolic dysfunction without obesity in juveniles.
Dynamic B0field shimming for improving pseudo-continuous arterial spin labeling at 7 Tesla
Authors: Ji Yang , Woods Joseph G. , Li Hongwei , Okell Thomas W. 
Published: July 2024

AbstractPurposeB0inhomogeneity within the brain-feeding arteries is a major issue for pseudo-continuous arterial spin labeling (PCASL) at 7T because it reduces labeling efficiency and leads to a loss of perfusion signal. This study aimed to develop a vessel-specific dynamic B0field shimming method for 7T PCASL to enhance labeling efficiency by correcting off-resonance in the arteries within the labeling region.MethodsWe implemented a PCASL sequence with dynamic B₀ shimming at 7T that compensates for B0field offsets at the brain-feeding arteries by updating linear shimming terms and adding a phase increment to the PCASL RF pulses. Rapidly acquired vessel-specific B₀ field maps were used to calculate dynamic shimming parameters. We evaluated both 2D and 3D variants of our method, comparing their performance against established global frequency offset and optimal-encoding-scheme (OES)-based corrections. Cerebral blood flow (CBF) maps were quantified before and after corrections. CBF values from different methods in the whole brain, white matter, and grey matter regions were compared.ResultsAll off-resonance correction methods significantly enhanced perfusion signals across the brain. The proposed vessel-specific dynamic B₀ shimming method improved labeling efficiency while maintaining optimal static shimming in the imaging region. Perfusion-weighted images demonstrated the superiority of 3D dynamic B₀ shimming method compared to global or 2D-based correction approaches. CBF analysis revealed that 3D dynamic B₀ shimming significantly increased CBF values relative to the other methods.ConclusionOur proposed dynamic B0shimming method offers a significant advancement in PCASL robustness and effectiveness, enabling full utilization of 7T ASL’s high sensitivity and spatial resolution.