bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors associated with hospital revisitation within 7 days among patients discharged at triage: a case–control study
Authors: Ylä-Mattila Jari , Koivistoinen Teemu , Siippainen Henna , Huhtala Heini , Mustajoki Sami 
Published: July 2024

Background and importance
Existing data are limited for determining the medical conditions best suited for an emergency department (ED) redirection strategy in a heterogeneous, nonurgent patient population.

Objective
The aim was to establish factors associated with hospital revisits within 7 days among patients discharged or redirected by a triage team.

Design, settings, and participants
An observational single-center case–control study was conducted at the Tampere University Hospital ED for the full calendar year of 2019. The cases comprised unplanned hospital revisits within 7 days of being discharged or redirected by triage, while the controls were discharged or redirected but did not revisit.

Outcome measures and analysis
The primary outcome was an unplanned hospital revisit within 7 days. A subgroup analysis was conducted for revisits leading to hospitalization. Basic demographics, comorbidities before triage, and triage visit characteristics were considered as predictive factors for the revisit. A backward stepwise conditional logistic regression analysis was performed.

Main Results
During the calendar year of 2019, there were a total of 92 406 ED visits. Of these, 7216 (7.8%) visits were discharged or redirected by triage, and 6.5% (n = 467) of all these patients revisited. Of the revisiting patients, 25% (n = 117) were hospitalized. In multivariable analysis, higher age was associated with both revisitation [odds ratio (OR): 1.01, 95% confidence interval (CI): 1.00–1.02] and hospitalization (OR: 1.02, 95% CI: 1.00–1.04). Furthermore, using other visits as a reference, abdominal pain was associated with revisitation and hospitalization (OR: 3.70, 95% CI: 2.24–6.11 and OR: 5.28, 95% CI: 2.08–13.4, respectively).

Conclusion
Higher age and abdominal pain were associated with hospital revisitation and hospitalization within 7 days among patients directly discharged or redirected by the triage team. Regardless of the triage system in use, there might be patient groups that should be evaluated more cautiously if a triage-based discharge or redirection strategy is to be considered.
Inactivation of highly pathogenic avian influenza virus with high temperature short time continuous flow pasteurization and virus detection in bulk milk tanks
Authors: Spackman Erica , Anderson Nathan , Walker Stephen , Suarez David L. , Jones Deana R. , McCoig Amber , Colonius Tristan , Roddy Timothy , Chaplinski Nicholas J. 
Published: July 2024

AbstractInfections of dairy cattle with clade 2.3.4.4b H5N1 highly pathogenic avian influenza virus (HPAIV) were reported in March 2024 in the U.S. and viable virus was detected at high levels in raw milk from infected cows. This study aimed to determine the potential quantities of infectious HPAIV in raw milk in affected states where herds were confirmed positive by USDA for HPAIV (and therefore were not representative of the entire population), and to confirm that the commonly used continuous flow pasteurization using the FDA approved 72°C (161°F) for 15 s conditions for high temperature short time (HTST) processing, will inactivate the virus. Double-blinded raw milk samples from bulk storage tanks from farms (n=275) were collected in four affected states. Samples were screened for influenza A using quantitative real-time RT-PCR (qrRT-PCR) of which 158 (57.5%) were positive and were subsequently quantified in embryonating chicken eggs. Thirty-nine qrRT-PCR positive samples (24.8%) were positive for infectious virus with a mean titer of 3.5 log1050% egg infectious doses (EID50) per mL. To closely simulate commercial milk pasteurization processing systems, a pilot-scale continuous flow pasteurizer was used to evaluate HPAIV inactivation in artificially contaminated raw milk using the most common legal conditions in the US: 72°C (161°F) for 15s. Among all replicates at two flow rates (n=5 at 0.5L/min; n=4 at 1L/min), no viable virus was detected. A mean reduction of ≥5.8 ± 0.2 log10EID50/mL occurred during the heating phase where the milk is brought to 72.5°C before the holding tube. Estimates from heat-transfer analysis support that standard U.S. continuous flow HTST pasteurization parameters will inactivate >12 log10EID50/mL of HPAIV, which is ~9 log10EID50/mL greater than the mean quantity of infectious virus detected in raw milk from bulk storage tank samples. These findings demonstrate that the milk supply is safe.
PFHpA alters lipid metabolism and increases the risk of metabolic dysfunction-associated steatotic liver disease in youth—a translational research framework
Authors: Baumert Brittney O. , Maretti-Mira Ana C. , Li Zhenjiang , Stratakis Nikos , Zhao Yinqi , Walker Douglas I. , Wang Hongxu , Fischer Fabian Christoph , Jia Qiran , Valvi Damaskini , Bartell Scott M. , Chen Carmen , Inge Thomas , Ryder Justin , Jenkins Todd , Sisley Stephanie , Xanthakos Stavra , Kohli Rohit , Rock Sarah , Eckel Sandrah P. , La Merrill Michele A. , Aung Max M. , Salomon Matthew P. , McConnell Rob , Goodrich Jesse , Conti David V. , Golden-Mason Lucy , Chatzi Lida 
Published: July 2024

AbstractTo address the growing epidemic of liver disease, particularly in pediatric populations, it is crucial to identify modifiable risk factors for the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Per- and polyfluoroalkyl substances (PFAS) are persistent ubiquitous chemicals and have emerged as potential risk factors for liver damage. However, their impact on the etiology and severity of MASLD remains largely unexplored in humans. This study aims to bridge the gap between human and in vitro studies to understand how exposure to perfluoroheptanoic acid (PFHpA), one of the emerging PFAS replacements which accumulates in high concentrations in the liver, contributes to MASLD risk and progression. First, we showed that PFHpA plasma concentrations were significantly associated with increased risk of MASLD in obese adolescents. Further, we examined the impact of PFHpA on hepatic metabolism using 3D human liver spheroids and single-cell transcriptomics to identify major hepatic pathways affected by PFHpA. Next, we integrated thein vivoandin vitromulti-omics datasets with a novel statistical approach which identified signatures of proteins and metabolites associated with MASLD development triggered by PFHpA exposure. In addition to characterizing the contribution of PFHpA to MASLD progression, our study provides a novel strategy to identify individuals at high risk of PFHpA-induced MASLD and develop early intervention strategies. Notably, our analysis revealed that the proteomic signature exhibited a stronger correlation between both PFHpA exposure and MASLD risk compared to the metabolomic signature. While establishing a clear connection between PFHpA exposure and MASLD progression in humans, our study delved into the molecular mechanisms through which PFHpA disrupts liver metabolism. Ourin vitrofindings revealed that PFHpA primarily impacts lipid metabolism, leading to a notable increase of lipid accumulation in human hepatocytes after PFHpA exposure. Among the pathways involved in lipid metabolism in hepatocytes, regulation of lipid metabolism by PPAR-a showed a remarkable activation. Moreover, the translational research framework we developed by integrating human and in vitro data provided us biomarkers to identify individuals at a high risk of MASLD due to PFHpA exposure. Our framework can inform policies on PFAS-induced liver disease and identify potential targets for prevention and treatment strategies.
Immune Checkpoint Inhibition-related Neuroinflammation Disrupts Cognitive Function
Authors: Ifejeokwu Onwodi V. , Do An , El Khatib Sanad M. , Ho Nhu H. , Zavala Angel , Othy Shivashankar , Acharya Munjal M. 
Published: July 2024

ABSTRACTCombinatorial blockade of Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and Programmed Cell Death Protein 1 (PD-1) significantly improve the progression-free survival of individuals with metastatic cancers, including melanoma. In addition to unleashing anti-tumor immunity, combination immune checkpoint inhibition (ICI) disrupts immune-regulatory networks critical for maintaining homeostasis in various tissues, including the central nervous system (CNS). Although ICI- and cancer-related cognitive impairments (CRCI) in survivors are increasingly becoming evident, our understanding of ICI-induced immune-related adverse effects (IREA) in the CNS remains incomplete. Here, our murine melanoma model reveals that combination ICI impairs hippocampal-dependent learning and memory, as well as memory consolidation processes. Mechanistically, combination ICI disrupted synaptic integrity, and neuronal plasticity, reduced myelin, and further predisposed CNS for exaggerated experimental autoimmune encephalomyelitis. Combination ICI substantially altered both lymphoid and myeloid cells in the CNS. Neurogenesis was unaffected, however, microglial activation persisted for two-months post- ICI, concurrently with cognitive deficits, which parallels clinical observations in survivors. Overall, our results demonstrate that blockade of CTLA-4 and PD-1 alters neuro-immune homeostasis and activates microglia, promoting long-term neurodegeneration and driving cognitive impairments. Therefore, limiting microglial activation is a potential avenue to mitigate CNS IRAE while maintaining the therapeutic benefits of rapidly evolving ICIs and their combinations.SIGNIFICANCEDespite the superior therapeutic efficacy of immune checkpoint inhibition (ICI) for cancers, its undesired effects on brain function are not fully understood. Here, we demonstrate that combination ICI elevates neuroinflammation, activates microglia, leading to detrimental neurodegenerative and neurocognitive sequelae.
Parallel Synapses with Transmission Nonlinearities Enhance Neuronal Classification Capacity
Authors: Song Yuru , Benna Marcus K. 
Published: July 2024

AbstractCortical neurons often establish multiple synaptic contacts with the same postsynaptic neuron. To avoid functional redundancy of these parallel synapses, it is crucial that each synapse exhibits distinct computational properties. Here we model the current to the soma contributed by each synapse as a sigmoidal transmission function of its presynaptic input, with learnable parameters such as amplitude, slope, and threshold. We evaluate the classification capacity of a neuron equipped with such nonlinear parallel synapses, and show that with a small number of parallel synapses per axon, it substantially exceeds that of the Perceptron. Furthermore, the number of correctly classified data points can increase superlinearly as the number of presynaptic axons grows.When training with an unrestricted number of parallel synapses, our model neuron can effectively implement an arbitrary aggregate transmission function for each axon, constrained only by monotonicity. Nevertheless, successful learning in the model neuron often requires only a small number of parallel synapses.We also apply these parallel synapses in a feedforward neural network trained to classify MNIST images, and show that they can increase the test accuracy. This demonstrates that multiple nonlinear synapses per input axon can substantially enhance a neuron’s computational power.
Reduction of Deformed Wing Virus-B levels in Colonies of the Honey beeApis melliferaafter Queen Vaccination with inactivatedPaenibacillus larvae
Authors: Weinberg Isaac , Floyd Amy , Reid Nathan , Swift Nigel 
Published: July 2024

AbstractDeformed wing virus (DWV) is a virulent and ubiquitous disease that affects honey bee colonies. DWV infects bees at all life stages, but is most noticeable in adult bees, where clinical symptoms include shriveled, non-functional wings, and a drastically shortened lifespan. DWV is recorded in upwards of 90% of honey bee colonies worldwide, and has been linked to colony loss in symptomatic hives. DWV is primarily spread byVarroa destructormites, who feed on the fat bodies of honey bee adults and pupae. There is currently no direct treatment or preventative for DWV, with the primary method of reduction being vector control using acaracides. In this study, we tested the effect that vaccinating honey bee queens using killedPaenibacillus larvaebacterin, the causative agent of the honey bee disease American Foulbrood, had on deformed wing virus load in honey bee colonies. We placed vaccinated queens in 200 honey bee colonies, and unvaccinated queens in 200 colonies, and measured quantities of DWV-B in both groups immediately before, and 4 months after vaccination. We found that levels of DWV-B were identical before vaccination, but were significantly reduced in colonies 4 months post vaccination. This change was found despite no difference in mite quantities between groups. Overall, these data provide evidence that vaccination of queens withP. larvaebacterin is an effective method for reduction of DWV-B quantities in honey bee colonies in a commercially relevant field setting.
Comparative analysis of the syncytiotrophoblast in placenta tissue and trophoblast organoids using snRNA sequencing
Authors: Keenen Madeline M , Yang Liheng , Liang Huan , Farmer Veronica J , Worota Rizban E , Singh Rohit , Gladfelter Amy S , Coyne Carolyn B 
Published: July 2024

AbstractThe outer surface of chorionic villi in the human placenta consists of a single multinucleated cell called the syncytiotrophoblast (STB). The unique cellular ultrastructure of the STB presents challenges in deciphering its gene expression signature at the single-cell level, as the STB contains billions of nuclei in a single cell. There are many gaps in understanding the molecular mechanisms and developmental trajectories involved in STB formation and differentiation. To identify the underlying control of the STB, we performed comparative single nucleus (SN) and single cell (SC) RNA sequencing on placental tissue and tissue-derived trophoblast organoids (TOs). We found that SN RNA sequencing was essential to capture the STB population from both tissue and TOs. Differential gene expression and pseudotime analysis of TO-derived STB identified three distinct nuclear subtypes reminiscent of those recently identifiedin vivo. These included a juvenile nuclear population that exhibited both CTB and STB marker expression, a population enriched in genes involved in oxygen sensing, and finally a subtype enriched in transport and GTPase signaling molecules. Notably, suspension culture conditions of TOs that restore the native orientation of the STB (STBout) showed elevated expression of canonical STB markers and pregnancy hormones, along with a greater proportion of the STB nucleus subtype specializing in transport and GTPase signaling, compared to those cultivated with an inverted STB polarity (STBin). Gene regulatory analysis identified novel markers of STB differentiation conserved in tissue and TOs, including the chromatin remodeler RYBP, that exhibited STB-specific RNA and protein expression. CRISPR/Cas9 knockout of RYBP in STBinTOs did not impact cell-cell fusion; however, bulk RNA sequencing revealed downregulation of the pregnancy hormone CSH1 and upregulation of multiple genes associated with the oxygen-sensing STB nuclear subtype. Finally, we compared STB gene expression signatures amongst first trimester tissue, full-term tissue, and TOs, identifying many commonalities but also notable variability across each sample type. This indicates that STB gene expression is responsive to its environmental context. Our findings emphasize the utility of TOs to accurately model STB differentiation and the distinct nuclear subtypes observedin vivo, offering a versatile platform for unraveling the molecular mechanisms governing STB functions in placental biology and disease.
The metabolic benefits of thermogenic stimulation are preserved in aging
Authors: Natarajan Duraipandy , Plakkot Bhuvana , Tiwari Kritika , Ekambaram Shoba , Wang Weidong , Rudolph Michael , Mohammad Mahmoud A. , Chacko Shaji K. , Subramanian Madhan , Tarantini Stefano , Yabluchanskiy Andriy , Ungvari Zoltan , Csiszar Anna , Balasubramanian Priya 
Published: July 2024

AbstractAdipose thermogenesis has been actively investigated as a therapeutic target for improving metabolic dysfunction in obesity. However, its applicability to middle-aged and older populations, which bear the highest obesity prevalence in the US (approximately 40%), remains uncertain due to age-related decline in thermogenic responses. In this study, we investigated the effects of chronic thermogenic stimulation using the β3-adrenergic (AR) agonist CL316,243 (CL) on systemic metabolism and adipose function in aged (18-month-old) C57BL/6JN mice. Sustained β3-AR treatment resulted in reduced fat mass, increased energy expenditure, increased fatty acid oxidation and mitochondrial activity in adipose depots, improved glucose homeostasis, and a favorable adipokine profile. At the cellular level, CL treatment increased uncoupling protein 1 (UCP1)-dependent thermogenesis in brown adipose tissue (BAT). However, in white adipose tissue (WAT) depots, CL treatment increased glycerol and lipid de novo lipogenesis (DNL) and turnover suggesting the activation of the futile substrate cycle of lipolysis and reesterification in a UCP1-independent manner. Increased lipid turnover was also associated with the simultaneous upregulation of proteins involved in glycerol metabolism, fatty acid oxidation, and reesterification in WAT. Further, a dose-dependent impact of CL treatment on inflammation was observed, particularly in subcutaneous WAT, suggesting a potential mismatch between fatty acid supply and oxidation. These findings indicate that chronic β3-AR stimulation activates distinct cellular mechanisms that increase energy expenditure in BAT and WAT to improve systemic metabolism in aged mice. Our study provides foundational evidence for targeting adipose thermogenesis to improve age-related metabolic dysfunction.
CRISPR-GEM: A Novel Machine Learning Model for CRISPR Genetic Target Discovery and Evaluation
Authors: Graham Josh P. , Zhang Yu , He Lifang , Gonzalez-Fernandez Tomas 
Published: July 2024

AbstractCRISPR gene editing strategies are shaping cell therapies through precise and tunable control over gene expression. However, achieving reliable therapeutic effects with improved safety and efficacy requires informed target gene selection. This depends on a thorough understanding of the involvement of target genes in gene regulatory networks (GRNs) that regulate cell phenotype and function. Machine learning models have been previously used for GRN reconstruction using RNA- seq data, but current techniques are limited to single cell types and focus mainly on transcription factors. This restriction overlooks many potential CRISPR target genes, such as those encoding extracellular matrix components, growth factors, and signaling molecules, thus limiting the applicability of these models for CRISPR strategies. To address these limitations, we have developed CRISPR-GEM, a multi-layer perceptron (MLP)-based synthetic GRN constructed to accurately predict the downstream effects of CRISPR gene editing. First, input and output nodes are identified as differentially expressed genes between defined experimental and target cell/tissue types respectively. Then, MLP training learns regulatory relationships in a black-box approach allowing accurate prediction of output gene expression using only input gene expression. Finally, CRISPR-mimetic perturbations are made to each input gene individually and the resulting model predictions are compared to those for the target group to score and assess each input gene as a CRISPR candidate. The top scoring genes provided by CRISPR-GEM therefore best modulate experimental group GRNs to motivate transcriptomic shifts towards a target group phenotype. This machine learning model is the first of its kind for predicting optimal CRISPR target genes and serves as a powerful tool for enhanced CRISPR strategies across a range of cell therapies.
Redox signaling by hydrogen peroxide modulates axonal microtubule organization and induces a specific phosphorylation signature of microtubule proteins distinct from distress
Authors: Conze Christian , Trushina Nataliya I. , Monteiro-Abreu Nanci , Villar Romero Daniel , Wienbeuker Eike , Schwarze Anna-Sophie , Holtmannspötter Michael , Bakota Lidia , Brandt Roland 
Published: July 2024

ABSTRACTMany life processes are regulated by physiological redox signals, referred to as oxidative eustress. However, excessive oxidative stress can damage biomolecules and contribute to disease. The neuronal microtubule system is critically involved in axon homeostasis, regulation of axonal transport, and neurodegenerative processes. However, whether and how physiological redox signals affect axonal microtubules is largely unknown. Using live cell imaging and super- resolution microscopy, we show that subtoxic concentrations of the central redox metabolite hydrogen peroxide increase axonal microtubule dynamics, alter the structure of the axonal microtubule array, and affect the efficiency of axonal transport. We report that the mitochondria-targeting antioxidant SkQ1 and the microtubule stabilizer EpoD abolish the increase in microtubule dynamics. We found that oxidative eustress and distress specifically modulate the phosphorylation state of the microtubule system and induce a largely non- overlapping phosphorylation pattern of MAP1B as the main target. Cell-wide phosphoproteome analysis revealed that different signaling pathways are inversely activated by oxidative eustress and distress. Signaling via casein kinase (CK2) and pyruvate dehydrogenase kinases (PDK) is activated during eustress and signaling via mammalian target of rapamycin (mTOR) and serum/glucocorticoid-regulated protein kinase (SGK) is activated during distress. The results suggest that the redox metabolite and second messenger hydrogen peroxide induces rapid and local reorganization of the microtubule array in response to mitochondrial activity or as a messenger from neighboring cells by activating specific signaling cascades.
Altered dynamic functional connectivity in antagonistic state in first-episode, drug-naive patients with major depressive disorder
Authors: Wang Min , Chen Tao , He Zhongyi , Chan Lawrence Wing-Chi , Guo Qinger , Cai Shuyang , Duan Jingfeng , Zhang Danbin , Wang Xunda , Fang Yu , Yang Hong 
Published: July 2024

AbstractMajor depressive disorder (MDD) is characterized by disrupted functional network connectivity (FNC), with unclear underlying dynamics. We investigated both static FNC (sFNC) and dynamic FNC (dFNC) on resting-state fMRI data from drug-naive first-episode MDD patients and healthy controls (HC). MDD patients exhibited lower sFNC within and between sensory and motor networks than HC. Four dFNC states were identified, including a globally-weakly-connected state, a cognitive-control-dominated state, a globally-positively-connected state, and an antagonistic state. The antagonistic state was marked by strong positive connections within the sensorimotor domain and their anti-correlations with the executive-motor control domain. Notably, MDD patients exhibited significantly longer time dwelling in the globally-weakly-connected state, at the cost of significantly shorter time dwelling in the antagonistic state. Further, only the mean dwell time of this antagonistic state was significantly anticorrelated to disease severity measures. Our study highlights the altered dynamics of the antagonistic state as a fundamental aspect of disrupted FNC in early MDD.