bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery of novel 1,4-dicarbonylthiosemicarbazides as DNA gyrase inhibitors for the treatment of MRSA infection
Authors: Zhang Gao , Liang Jiaxin , Wen Gang , Yao Mingli , Jia Yuqing , Feng Bo , Li Jishun , Han Zunsheng , Liu Qingxin , Li Tianlei , Zhang Wenxuan , Jin Hongwei , Xia Jie , Peng Liang , Wu Song 
Published: September 2024

AbstractAntibiotic resistance has become a serious threat to public health, thus novel antibiotics are urgently needed to combat drug-resistant bacteria including MRSA (methicillin-resistantS. aureus). The 1,4-dicarbonylthiosemicarbazide is an interesting chemotype that could exhibit antibacterial activity. However, the currently available compounds are not as potent as clinical antibiotics. Herein, we adopted the computer-aided drug design strategy, substructure search, to retrieve antibacterial 1,4-dicarbonylthiosemicarbazide derivatives, and identified compoundB5(Specs ID: AG-690/15432331) from the Specs chemical library that exhibited moderate activity (minimum inhibitory concentration (MIC): 6.25 µg/mL) againstS. aureus(ATCC 29213). Based on that compound, we further designed and synthesized 45 derivatives, and evaluated their antibacterial activity. Eight derivatives were more potent than or equivalent to vancomycin (MIC: 1.56 µg/mL). We compared the three most potent ones for their cytotoxicity to HepG2 and HUVEC cells and selected compound1bas our lead compound for comprehensive biological evaluation. As a result, compound1bexhibited a bacteriostatic mode, and was active against a panel of gram-positive bacteria strains, metabolically stable, and effective to protect the mice from MRSA infection. More importantly, we applied 2D similarity calculation and reverse docking to predict potential targets of compound1b. Through experimental validation and molecular dynamics simulation, we were able to confirm that compound1binhibitedS. aureusDNA gyrase (IC50: 1.81 µM) and DNA supercoiling, potentially by binding to the ATPase domain, where ASP81, GLU58 and GLN91 formed key hydrogen bonds. Taken together, we have discovered a new class of DNA gyrase inhibitors represented by compound1bfor the treatment of MRSA infection, through the design, synthesis, and biological evaluation of novel 1,4-dicarbonylthiosemicarbazides.Graphic AbstractHighlightsAn interesting 1,4-dicarbonylthiosemicarbazide derivativeB5with moderate antibacterial activity forS. aureuswas discovered by substructure search.Based onB5, 45 new 1,4-dicarbonylthiosemicarbazides were designed, synthesized and biologically evaluated, which led to the discovery of a promising lead compound1b.Compound1bexhibited good antibacterial activity for a panel of gram-positive bacteria strains, and was effective to protect mice from MRSA infection.The 1,4-dicarbonylthiosemicarbazides represented by compound1bwere discovered as a new class of DNA gyrase inhibitors, by target prediction and experimental validation.
Comparative analysis of transcriptomic and proteomic expression between two non-small cell lung cancer subtypes
Authors: Nicholas Ben , Bailey Alistair , McCann Katy J , Johnson Peter , Elliott Tim , Ottensmeier Christian , Skipp Paul 
Published: September 2024

AbstractNon-small cell lung cancer (NSCLC) is frequently diagnosed at an advanced stage and has poor survival. NSCLC subtypes require different treatment regimes, hence there are extensive efforts to find more precise and non-invasive differential diagnostics tools. Complementing these efforts, we examined two NSCLC subtypes for differences that may inform treatment options and identify potential novel therapeutic pathways.Here we present a comparative analysis of transcriptomic and proteomic expression in tumours from a cohort of 22 NSCLC patients: 8 squamous cell carcinoma (LUSC), 14 adenocarcinoma (LUAD). We examined differential gene and differential protein expression between LUSC and LUAD, and between NSCLC subtypes and either PBMCs or normal adjacent lung tissue (NAT).We found that both NSCLC subtypes shared common differences in gene expression to PBMC relating to developmental and structural changes, and common protein expression differences to NAT relating to protein translation and RNA related processing and splicing.Between NSCLC subtypes we found differential gene expression relating to cell differentiation for LUSC and cellular structure and immune response regulation for LUAD. Differential protein expression between NSCLC subtypes related to extracellular structure for LUSC and metabolic processes, including glucose metabolism for LUAD.Many of our observations of differentially expressed genes and proteins between NSCLC subtypes support and inform existing observations, aiding both basic and clinical research seeking to identify subtype biomarkers or druggable targets.
Uncertainty in cardiovascular digital twins despite non-normal errors in 4D flow MRI: identifying reliable biomarkers such as ventricular relaxation rate
Authors: Tunedal Kajsa , Ebbers Tino , Cedersund Gunnar 
Published: September 2024

AbstractCardiovascular digital twins and mechanistic models can be used to obtain new biomarkers from patient-specific hemodynamic data. However, such model-derived biomarkers are only clinically relevant if the variation between timepoints/patients is smaller than the uncertainty of the biomarkers. Unfortunately, this uncertainty is challenging to calculate, as the uncertainty of the underlying hemodynamic data is largely unknown and has several sources that are not additive or normally distributed. This violates normality assumptions of current methods; implying that also biomarkers have an unknown uncertainty. To remedy these problems, we herein present a method, with attached code, for uncertainty calculation of model-derived biomarkers using non-normal data. First, we estimated all sources of uncertainty, both normal and non-normal, in hemodynamic data used to personalize an existing model; the errors in 4D flow MRI-derived stroke volumes were 5-20% and the blood pressure errors were 0±8 mmHg. Second, we estimated the resulting model-derived biomarker uncertainty for 100 simulated datasets, sampled from the data distributions, by: 1) combining data uncertainties 2) parameter estimation, 3) profile-likelihood. The true biomarker values were found within a 95% confidence interval in 98% (median) of the cases. This shows both that our estimated data uncertainty is reasonable, and that we can use profile-likelihood despite the non-normality. Finally, we demonstrated that e.g. ventricular relaxation rate has a smaller uncertainty (∼10%) than the variation across a clinical cohort (∼40%), meaning that these biomarkers have clinical usefulness. Our results take us one step closer to the usage of model-derived biomarkers for cardiovascular patient characterization.HighlightsDigital twin models provide physiological biomarkers using e.g. 4D-flow MRI dataHowever, the data has several non-normal uncertainty componentsFor this reason, we do not know which biomarkers are reliable and clinically usefulNew method for data uncertainty and for calculation of biomarker uncertaintyWe identified several reliable biomarkers: e.g. ventricular relaxation rateGraphical abstract
A trans-synaptic IgLON adhesion molecular complex directly contacts and clusters a nicotinic receptor
Authors: Mialon Morgane , Patrash Liubov , Weinreb Alexis , Özkan Engin , Bessereau Jean-Louis , Pinan-Lucarre Berangere 
Published: September 2024

SUMMARYThe localization and clustering of neurotransmitter receptors at appropriate postsynaptic sites is a key step in the control of synaptic transmission. Here, we identify a novel paradigm for the synaptic localization of an ionotropic acetylcholine receptor (AChR) based on the direct interaction of its extracellular domain with a cell adhesion molecule of the IgLON family. Our results show that RIG-5 and ZIG-8, which encode the sole IgLONs inC. elegans,are tethered in the pre- and postsynaptic membranes, respectively, and interactin vivothrough their first immunoglobulin-like (Ig) domains. In addition, ZIG-8 traps ACR-16 via a directcis-interaction between the ZIG-8 Ig2 domain and the base of the large extracellular AChR domain. Such mechanism has never been reported, but all these molecules are conserved during evolution. Similar interactions may directly couple Ig superfamily adhesion molecules and members of the large family of Cys-loop ionotropic receptors, including AChRs, in the mammalian nervous system, and may be relevant in the context of IgLON-associated brain diseases.
Inpatient Hospitalizations for COVID-19 Among Patients with Prader-Willi Syndrome: a National Inpatient Sample Analysis
Authors: Luccarelli James , Strong Theresa V. , Rubin Emily B. , McCoy Thomas H. 
Published: September 2024

AbstractBackgroundPrader-Willi syndrome (PWS) is a genetic disorder associated with baseline respiratory impairment caused by multiple contributing etiologies. While this may be expected to increase the risk of severe COVID-19 infections in PWS patients, survey studies have suggested paradoxically low disease severity. To better characterize the course of COVID-19 infection in patients with PWS, this study analyzes the outcomes of hospitalizations for COVID-19 among patients with and without PWS.MethodsThe National Inpatient Sample, an all-payors administrative claims database of hospitalizations in the United States, was queried for patients with a coded diagnosis COVID-19 in 2020 and 2021. Hospitalizations for patients with PWS compared to those for patients without PWS using Augmented Inverse Propensity Weighting (AIPW).ResultsThere were 295 (95% CI: 228 to 362) COVID-19 hospitalizations for individuals with PWS and 4,112,400 (95% CI: 4,051,497 to 4,173,303) for individuals without PWS. PWS patients had a median age of 33 years compared to 63 for those without PWS. Individuals with PWS had higher baseline rates of obesity (47.5% vs. 28.4%). AIPW models show that PWS diagnosis is associated with increased hospital length of stay by 7.43 days, hospital charges by $80,126, and the odds of mechanical ventilation and in-hospital death (odds ratios of 1.79 and 1.67, respectively).ConclusionsPWS patients hospitalized with COVID-19 experienced longer hospital stays, higher charges, and increased risk of mechanical ventilation and death. PWS should be considered a risk factor for severe COVID-19, warranting continued protective measures and vaccination efforts. Further research is needed to validate coding for PWS and assess the impact of evolving COVID-19 variants and population immunity on this vulnerable population.
Development and validation of domain-specific clinical prediction models of post-stroke cognitive impairment
Authors: Kusec Andrea , Snell Kym IE , Demeyere Nele 
Published: September 2024

BackgroundPost-stroke cognitive impairment (PSCI) is highly prevalent across multiple cognitive domains. Individualised PSCI prognosis has mainly been researched using global cognitive outcomes. Here, we develop and externally validate clinical prediction models for overall and domain-specific PSCI, including language, memory, attention, executive function, numeracy, and praxis.MethodsN=430 stroke survivors completed the Oxford Cognitive Screen (OCS) in acute care and at 6-month follow-up (binarized outcome; impaired vs unimpaired). Logistic regression models were fitted comprising both mandatory clinically-relevant (age, sex, stroke severity, education, stroke hemisphere, acute PSCI) and data-driven (acute mood difficulties, length of stay in acute care, multimorbidity) predictors using backward elimination (p< 0.10) on multiply imputed data. Internal validation used bootstrapping to obtain optimism-adjusted performance estimates. External validation used the optimism-adjusted C-Slope as a uniform shrinkage factor.ResultsCompared to the overall PSCI model (C-Statistic=0.76 [95% CI=0.71–0.80]), comparable or improved optimism-adjusted performance was observed in models of language (C-Statistic=0.77 [95% CI=0.72–0.81]) memory (C-Statistic=0.72 [95% CI=0.65–0.75]), and attention (C-Statistic=0.74 [0.69–0.78]). Numeracy (C-Statistic=0.69 [95% CI=0.63–0.74]), executive function (C-Statistic=0.71 [95% CI=0.65–0.76]), and praxis (C-Statistic=0.60 [95% CI=0.53–0.65]) models showed weaker performance. In external validation, the overall PSCI model was comparable to development data (C-Statistic=0.74 [95% CI=0.67–0.79]).ConclusionsDomain-specific prediction models have the potential to offer more meaningful PSCI prognoses compared to overall PSCI models. External performance of overall PSCI models show promise in different stroke severity cohorts. Future recalibration of memory, numeracy, executive function, and praxis models would be beneficial.
CD300f immune receptor is a microglial tissue damage sensor and regulates efferocytosis after brain damage
Authors: Negro-Demontel María Luciana , Evans Frances , Cawen Andrés , Fitzpatrick Zach , Mason Hannah D. , Alí Daniela , Peluffo Hugo 
Published: September 2024

AbstractMicroglia, the resident phagocytes of the central nervous system (CNS), continuously monitor the parenchyma and surrounding borders and are the primary responders to brain damage. CD300f is a lipid-sensing immunoreceptor present in the microglial cell membrane, which binds to phosphatidylserine and other lipid mediators. Defining the functional microglial sensome is critical to understand their function and cell state determination. Using intravital two-photon microscopy we show that microglia lacking the CD300f receptor fail to detect environmental damage cues after a laser ablation injury. After a mild traumatic brain injury or after the intracortical injection of apoptotic cells, CD300f-/-microglia showed reduced capacity for detecting and phagocytosing dyeing cells, leading to the accumulation of dead cells in the neural parenchyma. Moreover, at later timepoints, increased accumulation of dyeing cells was found inside CD300f-/-microglia in vivo and in bone marrow-derived macrophages in vitro, suggesting that these cells display a reduced capacity for metabolizing phagocytosed cells. Finally, CD300f deficiency increased functional compromise after a contusive traumatic brain injury, associated to increased conservation of brain tissue. Collectively, these results suggest that CD300f function as a damage-associated molecular pattern (DAMP) receptor that coordinates microglial process reaction towards tissue debris and highlights its central role in microglial sensome machinery and in the modulation of in vivo microglial efferocytosis.
A physiologically inspired hybrid CPG/Reflex controller for cycling simulations that generalizes to walking
Authors: Severini Giacomo , Muñoz David 
Published: September 2024

AbstractPredictive simulations based on explicit, physiologically inspired, control policies, can be used to test theories on motor control and to evaluate the effect of interventions on the different components of control. Several control architectures have been proposed for simulating locomotor tasks, based on fully feedback, reflex-based, controllers, or on feedforward architectures mimicking the Central Pattern Generators. Recently, hybrid architectures integrating both feedback and feedforward components have been shown to represent a viable alternative to fully feedback or feedforward controllers. Current literature on controller-based simulations, however, almost exclusively presents task-specific controllers that do not generalize across different tasks. The task-specificity of current controllers limits the generalizability of the neurophysiological principles behind such controllers. Here we propose a hybrid controller for predictive simulations of cycling based where the feedforward component is based on a well-known theoretical model, the Unit Burst Generation model, and the feedback component includes a limited set of reflex pathways, expected to be active during submaximal steady cycling. We show that this controller can simulate physiological cycling patterns at different desired speeds. We also show that the controller can generalize to walking behaviors by just adding an additional control component for accounting balance needs. The controller here proposed, although simple in design, represent an instance of physiologically inspired generalizable controller for cyclical lower limb tasks.Author SummaryPredictive simulations allow to synthesize human movements and their associated biomechanical quantities without using experimental data. Such simulations can help understand how humans may perform movement tasks in different scenarios and could provide useful information in fields like rehabilitation. One of the methodologies used for developing predictive simulations is based on creating models of the neural control architectures that generate the activation of the muscles. In this work we propose the first neural control architecture for cycling behaviors. We show that our architecture can be used to develop predictive simulations of cycling at different speeds and that the associated biomechanical quantitites are consistent with experimental data. Moreover, we show that our control architecture can also replicate walking behaviors with minimal modifications.
Behavioral Interactions in Two Ant Species in The Southeast United States and Evidence for a Native Supercolony
Authors: Kanwar Shreyas , Nowicki Renee , Mavourneen Isabella R.E. , Gibson Joshua D. 
Published: September 2024

ABSTRACTAnts vary extensively in their colony structure, ranging from occupying single nests to tremendous supercolonies that occupy territories spanning large areas. Fewer than 1% of ants are known to produce supercolonies, yet they are disproportionately overrepresented in highly invasive ants. A broader understanding of supercolonial ants in their native range, therefore, may provide key insights into the factors that allow some ants to become invasive. Here, we show the results of behavioral assays of two native species of ants,Dorymyrmex bureniandD. smithi(Hymenoptera: Formicidae: Dolichoderinae) across geographically separated sites in southeastern Georgia, USA. We show thatD. smithihas extremely low incidence of aggression in ants from sites up to 35 km apart, indicating that this may be a supercolonial species. In contrast, we show thatD. bureniexhibits high levels of aggression between nest sites.Dorymyrmex smithiis also a temporary social parasite ofD. bureniand these two species form mixed nests with no apparent interspecific aggression between workers, but we show that both species interact aggressively in assays within and between sites when the workers are derived from pure species nests. These findings represent an important addition to our knowledge of supercolonial species, and they also lay the groundwork for further studies of the parasitic relationship between these species.
Prolonged thermal stress enhances mosquito tolerance to viral infection
Authors: Perdomo Hugo D. , Khorramnejad Ayda , Cham Nfamara M. , Kropf Alida , Sogliani Davide , Bonizzoni Mariangela 
Published: September 2024

SummaryHow and to what extent mosquito-virus interaction is influenced by climate change is a complex question of ecological and epidemiological relevance. We worked at the intersection between thermal biology and vector immunology and studied shifts in tolerance and resistance to the cell fusing agent virus (CFAV), a prominent component of the mosquito virome know to contribute to shaping mosquito vector competence, in warm-acclimated and warm-evolvedAedes albopictusmosquitoes. We show that the length of the thermal challenge influences the outcome of the infection with warm-evolved mosquitoes being more tolerant to CFAV infection, while warm-acclimated mosquitoes being more resistant and suffering from extensive fitness costs. These results highlight the importance of considering fluctuations in vector immunity in relation to the length of a thermal challenge to understand natural variation in vector response to viruses and frame realistic transmission models.
An RNA binding regulatory cascade controls the switch from proliferation to differentiation in theDrosophilamale germ cell lineage
Authors: Harris Devon E. , Kim Jongmin J. , Stern Sarah R. , Vicars Hannah M. , Matias Neuza R. , Gallicchio Lorenzo , Baker Catherine C. , Fuller Margaret T. 
Published: September 2024

AbstractThe switch from precursor cell proliferation to onset of differentiation in adult stem cell lineages must be carefully regulated to produce sufficient progeny to maintain and repair tissues, yet prevent overproliferation that may enable oncogenesis. In theDrosophilamale germ cell lineage, spermatogonia produced by germ line stem cells undergo a limited number of transit amplifying mitotic divisions before switching to the spermatocyte program that sets up meiosis and eventual spermatid differentiation. The number of transit amplifying divisions is set by accumulation of thebag-of-marbles(Bam) protein to a critical threshold. Inbammutants, spermatogonia proliferate through several extra rounds of mitosis then die without becoming spermatocytes. Here we show that a key role of Bam for the mitosis to differentiation switch is repressing expression of Held Out Wings (how), homolog of mammalian Quaking. Knockdown ofhowin germ cells was sufficient to allow spermatogonia mutant forbamor its partnerbenign gonial cell neoplasm(bgcn) to differentiate, while forced expression of nuclear-targeted How protein in spermatogonia wild-type forbamresulted in continued proliferation at the expense of differentiation. Our findings suggest that Bam targetshowRNA for degradation by acting as an adapter to recruit the CCR4-NOT deadenylation complex via binding its subunit, Caf40. As How is itself an RNA binding protein with roles in RNA processing, our findings reveal that the switch from proliferation to meiosis and differentiation in theDrosophilamale germ line adult stem cell lineage is regulated by a cascade of RNA-binding proteins.
Reversible Transcriptomic Age Shifts from Physiological Stress in Whole Blood
Authors: An Kyungwhan , Kwon Yoonsung , Bhak Jihun , Ryu Hyojung , Jeon Sungwon , Nam Dougu , Bhak Jong 
Published: September 2024

AbstractWe developed a genome-wide transcriptomic clock for predicting chronological age using whole blood samples from 463 healthy individuals. Our findings reveal profound age acceleration, up to 24.47 years, under perturbed homeostasis in COVID-19 patients, which reverted to baseline upon recovery. This study demonstrates that the whole blood transcriptome can track reversible changes in biological age induced by stressors in real physiological time, suggesting a potential role for anti-aging interventions in disease management.