bluuebunny/crossref_metadata_2025_split huggingface dataset:
GLP-1 Receptor Agonists and Risk of Paralytic Ileus: A drug-target Mendelian Randomization Study
Authors: Ding Pingjian , Gao Zhenxiang , Gorenflo Maria P. , Xu Rong 
Published: October 2024

AbstractBackgroundParalytic ileus (PI), a condition characterized by reduced bowel motor activity without physical obstruction, can be affected by complications from type 2 diabetes (T2D) and anti-diabetic medications. It is unclear of the causal associations of glucagon-like peptide-1 receptor agonists (GLP-1RAs) with the risk of PI in the context of T2D management.MethodsTo investigate the causal relationship of GLP-1RAs with PI, we conducted a 2-sample mendelian randomization (MR) study based on summary statistics from genome-wide association studies (GWAS). Genetic variants in the GLP1R were identified as genetical proxies of GLP-1RAs by the glycemic control therapy, based on genetic associations with glycated hemoglobin (GWAS n=344,182) and T2D (ncases/controls=228,499/1,178,783). The effects of GLP-1RAs were estimated for PI risk (ncases/controls=517/182,423) using GWAS data from the FinnGen project.ResultsBased on MR analysis, GLP-1RAs are causally associated with a decreased risk of PI (OR per 1 mmol/mol decrease in glycated hemoglobin: 0.21; 95% confidence interval [CI]=0.06-0.69). The magnitude of these benefit exceeded those expected from improved glycemic control more generally.ConclusionsOur study’s findings show that GLP-1RAs are causally associated with a lower risk for PI, which provides information to guide clinicians in the selection of appropriate therapies for individuals with T2D while mitigating the risk of developing PI. Investigating the underlying mechanisms that contribute to the lower PI risk associated with GLP-1RAs is essential for a deeper understanding of these associations.
Task-oriented vs. Goal-oriented: A New Paradigm for “Rooming” Patients
Authors: Tsige Temesgen , Bacchus Matthew , Flora Anthony , Ahn Gabriella , LoGalbo Sandhya , Sahadeo Vinayak , Sahadeo Prajna , Richman Mark 
Published: October 2024

ABSTRACTINTRODUCTIONIn the fast-paced setting of the Emergency Department (ED), efficiency is important to delivering timely, effective care. A key aspect of this involves preparing patients by providing hospital gowns and connecting them to cardiac/vital signs monitors. These seemingly basic steps are crucial for ensuring patient safety and streamlining the provider’s evaluation process. However, in the ED, patients are often not fully prepared before a provider enters the room, leading to delays and inefficiencies. This study examines the rates at which patients are properly gowned and monitored upon rooming, to identify areas where ED workflows can be optimized to improve care delivery and better utilize staff and resources.MATERIALS AND METHODSThe study was conducted in the adult Emergency Department at Long Island Jewish Medical Center. Data were collected from 100 randomly selected patients between June and October 2024. Patients were excluded if they wore loose-fitting clothing that allowed easy access to the area being evaluated, or if their chief complaint involved a visibly accessible body part (e.g., face), eliminating the need for disrobing or monitoring. The need for a hospital gown or connection to a cardiac/vital signs monitor was determined based on standard triage criteria, such as cardiopulmonary symptoms or the need to examine areas not easily accessible through clothing. We measured the percentage of patients who were appropriately gowned or monitored prior to the provider entering the room.RESULTSOf the 100 patients, 89 required a hospital gown, but only 61 (69%) received one. Regarding cardiac monitoring, 46 patients required a monitor, but only 20 (43%) were connected to one. In 50% of cases, patients had the correct body part exposed for examination before the provider’s arrival.CONCLUSIONThis study highlights significant inefficiencies in patient preparation in the ED, specifically related to gowning and cardiac monitoring. While 89% of patients required a gown, only 69% had one before the provider’s arrival. Similarly, only 43% of the patients who required monitoring were appropriately connected to a monitor. Additionally, only half of the patients had the correct body parts exposed for examination. These gaps in preparation force providers to complete these tasks themselves, contributing to delays, increasing provider workload, and potentially leading to burnout. To address this, we recommend shifting from task-oriented to goal-oriented patient rooming, revising protocols, and implementing checklists. These changes could help optimize resource use, reduce delays, and improve overall efficiency.
Interrogating the complex relationship between Alzheimer’s disease and blood pressure: two instrumental variable approaches to focus on pre-clinical stages of Alzheimer’s disease in UK Biobank
Authors: Palmer Jennifer C , Hart Emma , Anderson Emma , Love Seth , Lawlor Deborah A 
Published: October 2024

AbstractBackground and AimsEvidence suggests there may be a bidirectional relationship between high blood pressure (BP) and Alzheimer’s disease (AD). It is hypothesised that this is due to cerebral changes during pre-clinical AD that cause elevation of systemic BP. We aimed to test this by exploring the effect of risk of pre-clinical AD on blood pressure.MethodsWe used data from the UK Biobank, including adults without prevalent or incident (within first 5-years of follow-up) clinical AD (N = 501,420, mean age 56.6, SD 8 years). We used two instrumental variables, an age-weighted parental dementia instrument score and a participant genetic instrument score, that are vulnerable to differing biases, to instrument risk of pre-clinical AD (the exposure). We tested the association of both instrument scores with systolic BP (SBP), diastolic BP (DBP) and hypertension. Sensitivity analyses were undertaken to explore different biases.ResultsBoth the higher parental dementia instrument and participant genetic instrument score were associated with higher mean SBP (difference in mean SBP mmHg per 1SD higher score: 0.12, 95% CI: 0.06 to 0.17, and 0.07, 95% CI: 0.00 to 0.13, respectively) but not DBP. Sensitivity analyses were largely consistent with these findings.ConclusionsOur findings provide preliminary evidence that pre-clinical AD increases SBP. Further research is required to determine whether this increase in SBP is due to increased cerebrovascular resistance in pre-clinical AD. Obtaining a better understanding of the changing relationship with BP at different stages of AD may enable effective optimisation and targeting of therapies.
Estimated prevalence of multiple chronic conditions throughout adulthood using data from theAll of UsResearch Program
Authors: Li Xintong , Dreisbach Caitlin , Gustafson Carolina M. , Murali Komal Patel , Koleck Theresa A. 
Published: October 2024

AbstractEstimation of multiple chronic condition (MCC) prevalence throughout adulthood provides a critical reflection of MCC burden. We analyzed electronic health record codes for 58 conditions to estimate MCC prevalence forAll of Us(AoU) Research Program adult participants (N=242,828). Approximately 76% ofAoUparticipants were diagnosed with MCCs, with over 40% having 6 or more conditions and prevalence increasing with age; the most frequently occurring MCC combinations varied by age category (i.e., mental health conditions in early adulthood and physical health conditions in middle adulthood through advanced old age). We report notable prevalence of MCC throughout adulthood and variability in MCC condition combinations by age category inAoUparticipants. These findings highlight the need for targeted, innovative care modalities and population health initiatives to address MCC burden throughout adulthood.
Multi-Cancer PRS Constellation Model for Cancer Risk Prediction
Authors: Moragas Núria , Díez-Villanueva Anna , Moratalla-Navarro Ferran , Fernández-Navarro Pablo , Pérez-Gómez Beatriz , Suárez-Varela María Morales , Molina-Barceló Ana , Castaño-Vinyals Gemma , Rius-Sansalvador Blanca , Riobó-Mayo Lois , Olmedo-Requena Rocío , Jiménez-Moleón José-Juan , Marcos-Gragera Rafael , Guevara Marcela , Fernandez-Tardon Guillermo , Amiano Exezarreta Pilar , Huerta José M. , Fernández-Villa Tania , Molina de la Torre Antonio José , Martín-Sánchez Vicente , Gómez-Acebo Inés , Dierssen Trinidad , Alguacil Juan , Guinó Elisabet , Kogevinas Manolis , Pollán Marina , Obón-Santacana Mireia , Moreno Victor 
Published: October 2024

AbstractCancer development is influenced by genetic factors and modifiable exposures. GWAS has identified genetic variants and developed of prediction models through Polygenic Risk Scores (PRS), but PRS alone has limitations for estimating cancer risk.This study assesses a novel PRS constellation approach that integrates Polygenic Risk Scores (PRS) from both lifestyle and genetic traits to enhance prediction models for colorectal, breast, and prostate cancers. The approach was developed using the UK Biobank dataset and validated in the independent GenRisk cohort.The model, incorporating sex and age, achieved AUCs of 0.74 for CRC, 0.65 for BC, and 0.75 for PC in the UK Biobank. Including tumor-related PRSs improved PC prediction but had limited impact on CRC and BC. Age and sex inclusion boosted CRC and PC model accuracy. However, GenRisk validation showed reduced AUCs and limited utility of lifestyle PRSs, with CRC and BC models achieving 0.62 and PC 0.56.Integrating lifestyle-related characteristics into PRS does not significantly enhance cancer-specific PRS prediction. However, PRSs for these traits show independent predictive power, highlighting the importance of considering lifestyle in cancer risk and the need for precision medicine to improve early detection.
Transcriptome analysis inC. elegansearly embryos upon depletion of the Topoisomerase 2/condensin II axis
Authors: Belew Mezmur D. , Michael W. Matthew 
Published: October 2024

AbstractInC. elegans, the chromosome compaction factors topoisomerase 2 (TOP-2) and condensin II have been shown to globally repress transcription in multiple contexts. Our group has previously reported that TOP-2 and condensin II repress transcription in theC. elegansgermline during larval starvation, oocyte maturation, and in germline progenitor cells of the early embryo. Here, we assess the transcriptome of early embryos treated with RNAi against TOP-2 and the condensin II subunit CAPG-2. We found 144 upregulated and 172 downregulated genes. Further analysis showed that the upregulated genes are mostly somatic, with a host of neuronal cells present in our tissue enrichment analysis.
Social benefits of facial experssion in a cichlid fish: Testing the face concentration hypothesis
Authors: Satoh Shun , Fukuda Kazuya , Matsui Hiroshi , Kawasaka Kento , Matsuo Sayaka , Banda Takezo , Kanbe Kota , Konno Alu , Takei Shiro , Kohda Masanori , Kutsukake Nobuyuki 
Published: October 2024

AbstractThe face is a uniquely distinctive stimulus, encapsulating a wealth of information. Among the myriad of social cues conveyed by the face, emotional signals, known as facial expressions, are paramount not only for humans but also for numerous social animals. The evolution of facial expressions in these animals can also manifest in taxa other than mammals, as suggested by various studies highlighting the socio-ecological benefits of facial expressions. In this study, we elucidated the social function of facial coloration, determined by melanophores, in the neotropical social cichlidSymphysodon aequifasciatus. In this species, facial coloration exhibits instantaneous changes in response to varying social contexts. Through behavioral observations and experimental manipulation, we confirmed that facial coloration inS. aequifasciatusserves to attenuate unnecessary aggressive competition among conspecifics. Furthermore, we observed that the facial area subjected to coloration in this species is innervated by the adenosine triphosphate- and noradrenaline-ergic nervous system. These findings indicated that facial expression inS. aequifasciatusdepends on the sympathetic nervous system and has evolved independently of mammalian facial expressions. Our study highlights teleost fishes as valuable animal models for exploring the universality of facial expressions and their underlying cognitive mechanisms in vertebrates.
Physics-Informed Ellipsoidal Coordinate Encoding Implicit Neural Representation for high-resolution volumetric wide-field microscopy
Authors: Zhou You , Xu Chenyu , Jin Zhouyu , Chen Yanqin , Zheng Bei , Wang Meiyue , Xiong Bo , Cao Xun , Gu Ning 
Published: October 2024

AbstractWide-field fluorescence microscopy through axial scanning provides a simple way for volumetric imaging of cellular and intracellular activities, but the optical transfer function (OTF) of wide-field microscopy suffers from axial frequency deficiencies, leading to strong interference from out-of-focus fluorescence signals and reduced imaging quality. Richardson-Lucy (RL) deconvolution and its variants are commonly employed to reduce inter-plane signal interference of wide-field microscopy. However, these methods are still affected by the “missing cone” issue inherent in the OTF, compromising both the axial resolution and optical sectioning capability. Existing deep learning methods could realize high-fidelity 3D image stack restoration, but relying on high-quality paired datasets or specific assumptions about sample distributions. Here, we propose a novel method named physics-informed ellipsoidal coordinate encoding implicit neural representation (PIECE-INR), to tackle the challenges of background signal interference and resolution loss in axial scanning image stacks using the wide-field microscopy. In PIECE-INR, we integrate the wide-field fluorescence imaging model with the self-supervised INR network for high-fidelity reconstruction of 3D fluorescence data without the need of additional ground truth data for training. We further design a novel ellipsoidal coordinate encoding based on the system’s OTF constraints and incorporate implicit priors derived from the physical model as the loss function into the reconstruction process. Our approach enables block-wise reconstruction of large-scale images by using localized physical information. We demonstrate state-of-the-art performance of our PIECE-INR method in volumetric imaging of live HeLa cells, large-volumeC. eleganswhole-embryo, and mitochondrial dynamics.
Cell-to-cell mobility of the stem cell inducing WUSCHEL transcription factor is controlled by a balance of transport and retention
Authors: Fuchs Michael , Stiehl Thomas , Marciniak-Czochra Anna , Lohmann Jan U. 
Published: October 2024

AbstractNon-cell autonomous induction of stem cell fate is a shared feature across multicellular organisms, however the underlying mechanisms diverge substantially between the kingdoms of live. In plants, cell to cell mobility of transcription factors has emerged as a key paradigm. For the shoot apical meristem of the reference plantArabidopsis thalianait has been described that the translocation of the WUSCHEL homeodomain transcription factor from niche cells to stem cells is essential for their maintenance. Here we systematically investigate the function of diverse WUS alleles and leverage multispectral live cell imaging coupled to computational analysis and mechanistic mathematical modelling to show that WUSCHEL protein mobility is the result of balance between active transport and retention in niche cells and likely independent of the stem cell signal CLAVATA3. Importantly, we show that diffusion across cell layers of the meristem is not symmetrical, suggesting that there is unexpected complexity in cellular connections.
Primary cilia shape postnatal astrocyte development through Sonic Hedgehog signaling
Authors: Bear Rachel , Sloan Steven A. , Caspary Tamara 
Published: October 2024

ABSTRACTPrimary cilia function as specialized signaling centers that regulate many cellular processes including neuron and glia development. Astrocytes possess cilia, but the function of cilia in astrocyte development remains largely unexplored. Critically, dysfunction of either astrocytes or cilia contributes to molecular changes observed in neurodevelopmental disorders. Here, we show that a sub-population of developing astrocytes in the prefrontal cortex are ciliated. This population corresponds to proliferating astrocytes and largely expresses the ciliary protein ARL13B. Genetic ablation of astrocyte ciliain vivoat two distinct stages of astrocyte development results in changes to Sonic Hedgehog (Shh) transcriptional targets. We show that Shh activity is decreased in immature and mature astrocytes upon loss of cilia. Furthermore, loss of cilia in immature astrocytes results in decreased astrocyte proliferation and loss of cilia in mature astrocytes causes enlarged astrocyte morphology. Together, these results indicate that astrocytes require cilia for Shh signaling throughout development and uncover functions for astrocyte cilia in regulating astrocyte proliferation and maturation. This expands our fundamental knowledge of astrocyte development and cilia function to advance our understanding of neurodevelopmental disorders.
Role of CCK1 receptor in metabolic benefits of intestinal enteropeptidase inhibition in mice
Authors: Albarazanji Kamal , Hinke Simon A. , Cavanaugh Cassandre , Liu Jianying , Beck Stephen , Shukla Neetu , Meng Rong , Ho George , Camacho Raul C. , Leonard James , Nawrocki Andrea R. 
Published: October 2024

AbstractEnteropeptidase (EP; enterokinase) is a serine protease that regulates intestinal protein digestion by converting trypsinogen into active trypsin, and thus initiates activation of the pancreatic zymogen cascade. Chronic inhibition of EP and trypsin (EP/T) with camostat (Foipan, FOY-305) or its active metabolite (FOY-251) causes weight loss in obese mice by reducing intestinal protein absorption and suppression of food intake, however, the mechanisms leading to appetite suppression are not well understood. We tested the hypothesis that cholecystokinin (CCK) signaling mediates the anorectic effects of EP/T inhibition using a CCK1R inhibitor (loxiglumide) or CCK1R knockout (KO) mice. Acute treatment with loxiglumide was able to partially reverse FOY-251-induced gallbladder contraction and delayed gastric emptying in mice. Chronic co-administration of loxiglumide reversed FOY-251 mediated effects on food intake and metabolism in diet-induced obese (DIO) mice. Chronic dosing of FOY-251 caused similar reductions in food intake but greater weight loss in CCK1R KO mice compared to wildtype (WT) mice, primarily due to fat mass loss. Pair fed (PF) groups revealed food intake-dependent and -independent mechanisms of weight loss by FOY-251. Notably, FOY-251 treatment induced sustained weight loss, whereas body weight loss rebounded in PF animals. In CCKR1 KO mice, FOY-251 caused greater weight loss, and increased protein calorie loss relative to that in WT mice, while having no effect on glycemic control or FGF21. Hence, CCK1R-dependent and - independent mechanisms modulate the metabolic effects of EP/T inhibition and may play a role in maintaining weight loss by this mechanism.
Two conserved arginine residues facilitate C-S bond cleavage and persulfide transfer in Suf family cysteine desulfurases
Authors: Gogar Rajleen K. , Conte Juliana V. , Dunkle Jack A. , Frantom Patrick A. 
Published: October 2024

AbstractUnder conditions of oxidative stress or iron starvation, iron-sulfur cluster biogenesis inE. coliis initiated by the cysteine desulfurase, SufS, via the SUF pathway. SufS is a type II cysteine desulfurase that catalyzes the PLP-dependent breakage of an L-cysteine C-S bond to generate L-alanine and a covalent active site persulfide as products. The persulfide is transferred from SufS to SufE and then to the SufBC2D complex, which utilizes it in iron-sulfur cluster biogenesis. Several lines of evidence suggest two conserved arginine residues that line the solvent side of the SufS active site could be important for function. To investigate the mechanistic roles of R56 and R359, the residues were substituted using site-directed mutagenesis to obtain R56A/K and R359A/K SufS variants. Steady state kinetics indicated R56 and R359 have moderate defects in the desulfurase half reaction but major defects in the transpersulfurase step. Fluorescence polarization binding assays showed that the loss of activity was not due to a defect in forming the SufS/SufE complex. Structural characterization of R56A SufS shows loss of electron density for the α3-α4 loop at the R56/G57 positions, consistent with a requirement of R56 for proper loop conformation. The structure of R359A SufS exhibits a conformational change in the α3-α4 loop allowing R56 to enter the active site and mimics the residue’s position in the PLP-cysteine aldimine structure. Taken together, the kinetic, binding, and structural data support a mechanism where R359 plays a role in linking SufS catalysis with modulation of the α3-α4 loop to promote a close-approach interaction of SufS and SufE conducive to persulfide transfer.
Post-transcriptional regulation ofcyclin Aandcyclin BmRNAs is mediated by Bruno 1 and Cup, and further fine-tuned within P-bodies
Authors: Bayer Livia V. , Milano Samantha N. , Kaur Harpreet , Bratu Diana P. 
Published: October 2024

AbstractCell cycle progression is tightly controlled by the regulated synthesis and degradation of Cyclins, such as Cyclin A and Cyclin B, which activate CDK1 to trigger mitosis. Mutations affecting Cyclin regulation are often linked to tumorigenesis, making the study of cyclin mRNA regulation critical for identifying new cancer therapies. In this study, we demonstrate via super-resolution microscopy thatcyclin Aandcyclin BmRNAs associate with Bruno 1 and Cup in nurse cells. The depletion of either protein leads to abnormal Cyclin A and Cyclin B protein expression and a reduction in mRNA levels for both Cyclins. We further reveal that bothcyclin Aandcyclin BmRNAs accumulate in P-bodies marked by Me31B. Interestingly, Me31B is not involved in regulatingcyclin AmRNA, as no changes incyclin AmRNA levels or repression are observed upon Me31B depletion. However,cyclin BmRNA shows stage-specific derepression and reduced levels when Me31B is absent. Notably, the association betweencyclin Band Cup is strengthened in the absence of Me31B, indicating that this interaction occurs independently of P-bodies. These results highlight the nuanced, mRNA-specific roles of P-body condensates in post-transcriptional regulation, challenging the idea of a uniform, binary mechanism of mRNA repression in P-bodies.