bluuebunny/crossref_metadata_2025_split huggingface dataset:
A high-throughput phenotypic screen combined with an ultra-large-scale deep learning-based virtual screening reveals novel scaffolds of antibacterial compounds
Authors: Scalia Gabriele , Rutherford Steven T. , Lu Ziqing , Buchholz Kerry R. , Skelton Nicholas , Chuang Kangway , Diamant Nathaniel , Hütter Jan-Christian , Luescher Jerome-Maxim , Miu Anh , Blaney Jeff , Gendelev Leo , Skippington Elizabeth , Zynda Greg , Dickson Nia , Koziarski Michał , Bengio Yoshua , Regev Aviv , Tan Man-Wah , Biancalani Tommaso 
Published: September 2024

ABSTRACTThe proliferation of multi-drug-resistant bacteria underscores an urgent need for novel antibiotics. Traditional discovery methods face challenges due to limited chemical diversity, high costs, and difficulties in identifying structurally novel compounds. Here, we explore the integration of small molecule high-throughput screening with a deep learning-based virtual screening approach to uncover new antibacterial compounds. Leveraging a diverse library of nearly 2 million small molecules, we conducted comprehensive phenotypic screening against a sensitizedEscherichia colistrain that, at a low hit rate, yielded thousands of hits. We trained a deep learning model, GNEprop, to predict antibacterial activity, ensuring robustness through out-of-distribution generalization techniques. Virtual screening of over 1.4 billion compounds identified potential candidates, of which 82 exhibited antibacterial activity, illustrating a 90X improved hit rate over the high-throughput screening experiment GNEprop was trained on. Importantly, a significant portion of these newly identified compounds exhibited high dissimilarity to known antibiotics, indicating promising avenues for further exploration in antibiotic discovery.
Pro-inflammatory mediators sensitise Transient Receptor Potential Melastatin 3 cation channel (TRPM3) signalling in mouse sensory neurons
Authors: Aguilera-Lizarraga Javier , Lim Tony K. , Pattison Luke A. , Paine Luke W. , Bulmer David C. , Smith Ewan St. John 
Published: September 2024

AbstractPro-inflammatory mediators can directly activate pain-sensing neurons, known as nociceptors. Additionally, these mediators can potentiate or sensitise ion channels and receptors expressed by these cells through transcriptional and post-translational modulation, leading to nociceptor hypersensitivity. A well-characterised group of ion channels that subserve nociceptor sensitisation is the transient receptor potential (TRP) superfamily of cation channels. For example, the roles of TRP channels vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) in nociceptor sensitisation and inflammatory pain have been extensively documented. In the case of TRP melastatin 3 (TRPM3), however, despite the increasing recognition of this channel’s role in inflammatory pain, the mechanisms driving its sensitisation during inflammation remain poorly understood. Here, we found that an inflammatory soup of bradykinin, interleukin 1β (IL-1β) and tumour necrosis factor α (TNFα) sensitised TRPM3 function in isolated mouse sensory neurons; IL-1β and TNFα, but not bradykinin, independently potentiated TRPM3 function. TRPM3 expression and translocation to the membrane remained unchanged upon individual or combined exposure to these inflammatory mediators, which suggests post-translational modification occurs. Finally, using the model of complete Freund’s adjuvant-induced knee inflammation, we found that pharmacological blockade of TRPM3 does not alleviate inflammatory pain, which contrasts with previous reports using different pain models. We propose that the nuances of the immune response may determine the relative contribution of TRPM3 to nociceptive signalling in different neuro-immune contexts. Collectively, our findings improve insight into the role of TRPM3 sensitisation in inflammatory pain.Abstract FigureGraphical abstract
DYF-5 regulates intraflagellar transport by affecting train turnaround
Authors: Mul Wouter , Mitra Aniruddha , Prevo Bram , Peterman Erwin J.G. 
Published: September 2024

AbstractIntraflagellar transport (IFT) coordinates the transport of cargo in cilia and is essential for ciliary function. CILK1 has been identified as a key regulator of IFT. The mechanism by which it acts has, however, remained unclear. In this study, we use fluorescence imaging and single-molecule tracking in the phasmid cilia of liveC. elegansto study the effect of the CILK1 homolog DYF-5 on the dynamics of the IFT. We show that in the absence of DYF-5, IFT components accumulate at the ciliary tip. kinesin-II is no longer restricted to the proximal segment of the cilium but is present all throughout the cilium, while its velocity is different from that of OSM-3. The frequency of IFT trains is reduced and in particular retrograde trains were rarely observed. In the absence of DYF-5, retrograde transport is vastly reduced, resulting in the accumulation of IFT components at the tip and depletion at the base. The latter results in impeded anterograde train assembly, resulting in fewer trains with irregular composition. Our results show that DYF-5 plays a key role in regulating the turnarounds of IFT trains at the ciliary tip.
Nutritional analysis of commercially available, complete plant- and meat-based dry dog foods in the UK
Authors: Brociek R.A. , Li D. , Broughton R. , Gardner D.S. 
Published: September 2024

AbstractBackgroundAdoption of a plant-based diet is a popular lifestyle choice for many owners of canine companion animals. Increasingly, owners would like to feed their canine companions a similar diet. A plant-based dietary pattern has been reported to be associated with some micronutrient deficiencies. Complete dog foods are, by definition, supposed to be nutritionally replete in all macro- and micronutrients. Few studies have reported a full nutritional analysis of complete, dry plant-versus meat-based dog foods.MethodHere, 31 pet foods (n=19 meat-based, n=6 veterinary and n=6 plant-based) were analysed for total protein content and individual amino acids, fatty acids, major and trace elements, vitamin D and all B-vitamins.ResultsNutritional composition of meat and plant-based foods were similar, except for iodine and B-vitamins, which were lower in plant-based foods. The majority (66%) of veterinary diets with lower total protein by design, were also deficient in one or more essential amino acids. Isolated instances of non-compliance to nutritional guidelines were observed across all food-groups. Of the tested nutrients 55%, 16%, 24% and 100% of foods met all amino acid, mineral, B-vitamin, and vitamin D guidelines, respectively.ConclusionsAdopting a plant-based dietary pattern for your companion canine can provide nutritional adequacy with respect to the majority of macro- and micronutrients, but feeding supplemental iodine and B-vitamins should be considered. Veterinary diets, purposely low in crude protein, often have less than optimal essential amino acid composition. These data provide important new information for owners of companion canines being fed plant-based or veterinary diets.
Transcriptomic and Multi-scale Network Analyses Reveal Key Drivers of Cardiovascular Disease
Authors: Tumenbayar Bat-Ider , Pham Khanh , Biber John C. , Drewes Rhonda , Bae Yongho 
Published: September 2024

ABSTRACTCardiovascular diseases (CVDs) and pathologies are often driven by changes in molecular signaling and communication, as well as in cellular and tissue components, particularly those involving the extracellular matrix (ECM), cytoskeleton, and immune response. The fine-wire vascular injury model is commonly used to study neointimal hyperplasia and vessel stiffening, but it is not typically considered a model for CVDs. In this paper, we hypothesize that vascular injury induces changes in gene expression, molecular communication, and biological processes similar to those observed in CVDs at both the transcriptome and protein levels. To investigate this, we analyzed gene expression in microarray datasets from injured and uninjured femoral arteries in mice two weeks post-injury, identifying 1,467 significantly and differentially expressed genes involved in several CVDs such as including vaso-occlusion, arrhythmia, and atherosclerosis. We further constructed a protein-protein interaction network with seven functionally distinct clusters, with notable enrichment in ECM, metabolic processes, actin-based process, and immune response. Significant molecular communications were observed between the clusters, most prominently among those involved in ECM and cytoskeleton organizations, inflammation, and cell cycle. Machine Learning Disease pathway analysis revealed that vascular injury-induced crosstalk between ECM remodeling and immune response clusters contributed to aortic aneurysm, neovascularization of choroid, and kidney failure. Additionally, we found that interactions between ECM and actin cytoskeletal reorganization clusters were linked to cardiac damage, carotid artery occlusion, and cardiac lesions. Overall, through multi-scale bioinformatic analyses, we demonstrated the robustness of the vascular injury model in eliciting transcriptomic and molecular network changes associated with CVDs, highlighting its potential for use in cardiovascular research.
Biofabrication of engineered tissues by 3D bioprinting of tissue specific high cell-density bioinks
Authors: Jeon Oju , Park Hyoeun , Leach J. Kent , Alsberg Eben 
Published: September 2024

AbstractBioprinting of high cell-density bioinks is a promising technique for cellular condensation-based tissue engineering and regeneration medicine. However, it remains difficult to create precisely controlled complex structures and organization of tissues with high cell-density bioink-based bioprinting for tissue specific condensation. In this study, we present newly biofabricated tissues from directly assembled, tissue specific, high cell-density bioinks which have been three-dimensionally printed into a photocrosslinkable and biodegradable hydrogel microparticle supporting bath. Three types of tissue specific high cell-density bioinks have been prepared with individual stem cells or stem cell aggregates by incorporation of growth factor-loaded gelatin microparticles. The bioprinted tissue specific high cell-density bioinks in the photocrosslinked microgel supporting bath condense together and differentiate down tissue-specific lineages to form multi-phase tissues (e.g., osteochondral tissues). By changing the growth factors and cell types, these tissue specific high cell-density bioinks enable engineering of various functional tissues with controlled architecture and organization of cells.
Differential Immunoregulation by Human Surfactant Protein A Variants Determines Severity of SARS-CoV-2-induced Lung Disease
Authors: Jacob Ikechukwu B. , Lawal Akinkunmi O. , Mahmoud Salma S. , Kopsack Emerson M. , Reynolds Erin S. , Meng Qinghe , Fan Hongkuan , Massa Paul T. , Thangamani Saravanan , Jia Hongpeng , Wang Guirong 
Published: September 2024

AbstractCOVID-19 remains a significant threat to public health globally. Infection in some susceptible individuals causes life-threatening acute lung injury (ALI/ARDS) and/or death. Human surfactant protein A (SP-A) is a C-type lectin expressed in the lung and other mucosal tissues, and it plays a critical role in host defense against various pathogens. The human SP-A genes (SFTPA1andSFTPA2) are highly polymorphic and comprise several common genetic variants, i.e., SP-A1 (variants 6A2, 6A4) and SP-A2 (variants 1A0, 1A3). Here, we elucidated the differential antiviral and immunoregulatory roles of SP-A variants in response to SARS-CoV-2 infectionin vivo. Six genetically-modified mouse lines, expressing both hACE2 (SARS-CoV-2 receptor) and individual SP-A variants: (hACE2/6A2(6A2), hACE2/6A4(6A4), hACE2/1A0(1A0), and hACE2/1A3(1A3), one SP-A knockout (hACE2/SP-A KO (KO) and one hACE2/mouse SP-A (K18) mice, were challenged intranasally with 103PFU SARS-CoV-2 or saline (Sham). Infected KO and 1A0mice had more weight loss and mortality compared to other mouse lines. Relative to other infected mouse lines, a more severe ALI was observed in KO, 1A0, and 6A2mice. Reduced viral titers were generally observed in the lungs of infected SP-A mice relative to KO mice. Transcriptomic analysis revealed an upregulation in genes that play central roles in immune responses such asMyD88,Stat3,IL-18, andJak2in the lungs of KO and 1A0mice. However,Mapk1was significantly downregulated in 6A2versus 1A0mice. Analysis of biological pathways identified those involved in lung host defense and innate immunity, including pathogen-induced cytokine, NOD1/2, and Trem1 signaling pathways. Consistent with the transcriptomic data, levels of cytokines and chemokines such as G-CSF, IL-6 and IL-1β were comparatively higher in the lungs and sera of KO and 1A0mice with the highest mortality rate. These findings demonstrate that human SP-A variants differentially modulate SARS-CoV-2-induced lung injury and disease severity by differentially inhibiting viral infectivity and regulating immune-related gene expressions.
Visually-evoked activity and variable modulation of auditory responses in the macaque inferior colliculus
Authors: Schmehl Meredith N. , Herche Jesse L. , Groh Jennifer M. 
Published: September 2024

AbstractHow multisensory cues affect processing in early sensory brain areas is not well understood. The inferior colliculus (IC) is an early auditory structure that is visually responsive (Porter et al. 2007; Bulkin and Groh 2012a, 2012b), but little is known about how visual signals affect the IC’s auditory representation. We explored how visual cues affect both spiking and local field potential (LFP) activity in the IC of two monkeys performing a task involving saccades to auditory, visual, or combined audiovisual stimuli. We confirm that LFPs are sensitive to the onset of fixation lights as well as the onset of visual targets presented during steady fixation. The LFP waveforms evoked by combined audiovisual stimuli differed from those evoked by sounds alone. In single-unit spiking activity, responses were weak when visual stimuli were presented alone, but visual stimuli could modulate the activity evoked by sounds in a stronger way. Such modulations could involve either increases or decreases in activity, and whether increases or decreases were observed was variable and not obviously correlated with the responses evoked by visual or auditory stimuli alone. These findings indicate that visual stimuli shape the IC’s auditory representation in flexible ways that differ from those observed previously in multisensory areas.New & NoteworthyWe find that the inferior colliculus, a primarily auditory brain area, displays distinct population-level responses to visual stimuli. We also find that visual cues can influence the auditory responses of individual neurons. Together, the results provide insight into how relatively early sensory areas may play a role in combining multiple sensory modalities to refine the perception of complex environments.
Distinct roles of general anesthesia activated CeA neurons in acute versus late phase of neuropathic pain
Authors: Zhao Junli , Furutani Kenta , McGinnis Aidan , Mathew Joseph P , Wang Fan , Ji Ru-Rong 
Published: September 2024

AbstractA previous study discovered a distinct population of GABAergic neurons in thecentralamygdala (CeA) that can be activated bygeneralanesthesia (CeAGA) and exert analgesic functions (Hua et al., 2020). To independently reproduce these prior findings and to investigate the electrophysiological properties of CeAGAneurons, we first used 1.2% isoflurane to induce c-Fos activation in the mouse brain and validated theFosexpression by RNAscopein situhybridization. Indeed, isoflurane induced robust Fos expression in CeA and these Fos+CeAGAneurons are GABAergic neurons (Vgat+). We next used Fos-TRAP2 method (different from the CANE method used in the prior study) to label CeAGAneurons (tdTomato+). Ourex vivoelectrophysiological recordings in brain slices revealed that compared to Fos-negative CeA neurons, CeAGAneurons had significantly higher excitability and exhibited distinct patterns of action potentials. Chemogenetic activation of Fos-TRAPed CeAGAneurons was effective at increasing pain thresholds in naïve mice and mice with early-phase neuropathic pain 2 weeks after spared nerve injury (SNI). However, the same chemogenetic activation of CeAGAneurons only had modest analgesia in the late phase of SNI at 8 weeks, although it was highly effective in reducing chronic pain-associated anxiety behaviors at this stage. We found that Fos-negative CeA neurons, but not CeAGAneurons, exhibited increased excitability in the late-phase of SNI, suggesting that chronic pain causes a shift in the relative activity of the CeA microcircuit. Interestingly, Fos-negative neurons exhibited much higher expression of K+-Cl−cotransporter-2 (KCC2), and KCC2 expression was downregulated in the CeA in the late-phase of neuropathic pain. These results support the idea that targeting CeAGAneurons may provide therapeutic benefits for pain relief and chronic pain-associated anxiety. Our findings also suggest distinct roles of CeAGAneurons in regulating physiological pain, acute pain, and chronic pain with a possible involvement of KCC2.
Direct and indirect genetic pathways between parental neuroticism and offspring emotional problems across development: evidence from 7 cohorts across 5 European nations
Authors: Sallis Hannah M. , Costantini Ilaria , Chuong Melisa T. , Kantojärvi Katri , Wootton Robyn E. , Jones Hannah J. , Sirignano Lea , Frank Josef , Streit Fabian , Witt Stephanie H. , Zillich Lea , Gilles Maria , Ask Helga , Kwong Alex S. F. , Adams Mark J , Tilling Kate , Lawlor Deborah A. , Timpson Nicholas J. , Paunio Tiina , Havdahl Alexandra , McIntosh Andrew M. , Stein Alan , James Deborah , Pearson Rebecca M. 
Published: September 2024

AbstractDisentangling direct and indirect genetic pathways underlying the intergenerational transmission of emotional problems could guide preventative strategies and further the understanding of the role of parental mental health in children’s outcomes. This study aimed to estimate the extent to which genetic pathways that aredirect(via child genotype) andindirect(e.g., via parental phenotype) explain the well-established association between parent and child emotional problems. We leveraged data from seven European cohort studies with a combined population of Ntrios=15,475. Polygenic scores were calculated for parental and offspring neuroticism, as it represents a dispositional trait underlying emotional problems. Emotional problems in offspring were measured using validated scales across various developmental stages from early childhood to adulthood. We used neuroticism polygenic scores within a structural equation modelling framework to distinguish between direct genetic pathways from parental genotype to offspring outcome (acting through offspring genotype), and indirect genetic pathways (acting through parental phenotype and associated environment). Standard errors for direct genetic, indirect genetic and total effects were bootstrapped and meta-analyses pooled effect estimates at three developmental stages (childhood: 3-4 years, adolescence: 11-13 years, adulthood: 18+ years). We found evidence suggesting an indirect genetic pathway between mothers and child emotional problems during early childhood (pooled estimate, mean difference in standardised child emotional problems score per 1SD increase in maternal PGS for neuroticism=0.04, 95% CI: 0.01, 0.07). This association attenuated over child development, while direct genetic pathways strengthened. High attrition rates, measurement error and low variance explained by polygenic scores may have altered precision of the estimates, influencing the interpretation of the results. However, we provide the first multi-cohort study to provide evidence for anindirectgenetic pathway from maternal neuroticism to early child emotional problems. This suggests that there are likely processesotherthan direct genetic pathways involved in the intergenerational transmission of emotional problems, highlighting the importance of timely support to prevent and reduce emotional issues in mothers as a preventative strategy for emotional difficulties.
Exploring the intersection between orthostatic hypotension and daytime sleepiness in Parkinson’s disease
Authors: Mahajan Abhimanyu , Duque Kevin R. , Dwivedi Alok K. , Abanto Jesus , Marsili Luca , Hill Emily J. , Saraf Ameya , McDonald Kelsey J. , Arowosegbe Adebukunola , Deraz Heba A. , Bloemer Aaron , Espay Alberto J. 
Published: September 2024

AbstractIntroductionDaytime sleepiness, reported in about 50% of patients with Parkinson’s disease (PD), is associated with high morbidity, poor quality of life and increased risk for accidents. While an association between dysautonomia and daytime sleepiness in early, de-novo PD has been reported, our understanding of the role of medications, cognitive status and co-morbidites on this relationship is inadequate.MethodsData were analyzed from the prospective Cincinnati Cohort Biomarkers Program. The primary outcome of interest was excessive daytime sleepiness (EDS), as measured by the Epworth Sleepiness Scale (ESS; ESS score > 10). The primary exposure variable was orthostatic hypotension (OH). Linear and logistic regression analyses followed by moderated graphical network analyses were conducted to explore the complex association between OH and ESS. Edge weight from graphical network analysis indicates the strength of the association.ResultsData on 453 subjects with PD were analyzed. Median disease duration was 5.8 years and nearly 90% were H&Y stage <3. OH was not associated with EDS. OH was associated with depression (edge weight, 0.22) in cognitively impaired patients but not in cognitively normal patients. In addition, depression was associated with ESS (edge weight, 0.37; moderation weight, 0.22) in cognitively impaired patients to a greater extent than in cognitively normal patients (edge weight, 0.22).ConclusionsOH is not directly associated with daytime sleepiness in early, treated PD. However, OH seems to be associated with ESS via depression in cognitively impaired patients. This complex relationship deserves additional study.
Conspiratorial thinking in a 50-state survey of American adults
Authors: Perlis Roy H. , Uslu Ata , Barroilhet Sergio A. , Vohringer Paul A. , Santillana Mauricio , Baum Matthew A. , Druckman James N. , Ognyanova Katherine , Lazer David 
Published: September 2024

AbstractBackgroundWhile the NIMH Research Domain Criteria framework stresses understanding how neuropsychiatric phenotypes vary across populations, little is known outside of small clinical cohorts about conspiratorial thoughts as an aspect of cognition.MethodsWe conducted a 50-state non-probability internet survey conducted in 6 waves between October 6, 2022 and January 29, 2024, with respondents age 18 and older. Respondents completed the American Conspiratorial Thinking Scale (ACTS) and the 9-item Patient Health Questionnaire (PHQ-9). Survey-weighted regression models were used to examine sociodemographic and clinical associations with ACTS score, and associations with vaccination status.ResultsAcross the 6 survey waves, there were 123,781 unique individuals. After reweighting, a total of 78.6% of respondents somewhat or strongly agreed with at least one conspiratorial idea; 19.0% agreed with all four of them. More conspiratorial thoughts were reported among those age 25 - 54, males, individuals who finished high school but did not start or complete college, those with household income between $25,000 and $50,000 per year, and those who reside in rural areas, as well as those with greater levels of depressive symptoms. Endorsing more conspiratorial thoughts was associated with a significantly lower likelihood of being vaccinated against COVID-19.DiscussionA substantial proportion of US adults endorsed at least some conspiratorial thinking, which varied widely across population subgroups. The extent of correlation with non-vaccination suggests the importance of considering such thinking in designing public health strategies.