bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fibroblast growth factor 21: update on genetics and molecular biology
Authors: Barros Daniel R. , Hegele Robert A. 
Published: October 2024

Purpose of review
Since its discovery, most research on fibroblast growth factor 21 (FGF21) has focused on its antihyperglycemia properties. However, attention has recently shifted towards elucidating the ability of FGF21 to lower circulating lipid levels and ameliorate liver inflammation and steatosis. We here discuss the physiology of FGF21 and its role in lipid metabolism, with a focus on genetics, which has up until now not been fully appreciated.

Recent findings
New developments have uncovered associations of common small-effect variants of the FGF21 gene, such as the single nucleotide polymorphisms rs2548957 and rs838133, with numerous physiological, biochemical and behavioural phenotypes linked to energy metabolism and liver function. In addition, rare loss-of-function variants of the cellular receptors for FGF21 have been recently associated with severe endocrine and metabolic phenotypes. These associations corroborate the findings from basic studies and preliminary clinical investigations into the therapeutic potential of FGF21 for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) and hypertriglyceridemia. Furthermore, recent breakthrough research has begun to dissect mechanisms of a potential FGF21 brain-adipose axis. Such inter-organ communication would be comparable to that seen with other potent metabolic hormones. A deeper understanding of FGF21 could prove to be further beneficial for drug development.

Summary
FGF21 is a potent regulator of lipid and energy homeostasis and its physiology is currently at the centre of investigative efforts to develop agents targeting hypertriglyceridemia and MASLD.
Health Promotion and Physical Wellness in Pediatric Physical Therapy
Authors: Wengrovius Carissa , Miles Cindy , Fragala-Pinkham Maria , O’Neil Margaret E. 
Published: October 2024

Purpose:
A health promotion and physical wellness (HPPW) life course approach for pediatric physical therapy (PT) is recommended to improve children’s health outcomes across the lifespan.

Summary of Key Points:
A life course approach describes how a child’s individual responses to environmental factors influence health outcomes. Using HPPW strategies, pediatric physical therapists can identify health risks and promote positive outcomes. Outcome measures and intervention recommendations are outlined to assist therapists in integrating HPPW strategies to ensure a longitudinal plan of care and optimal health outcomes for children.

Conclusions and Recommendations for Clinical Practice:
A child’s health trajectory begins in the prenatal period and is influenced by individual and environmental factors. Pediatric PT uses child- and family-centered approaches and environmental assessments to design plans of care that address child and family HPPW goals. Incorporating HPPW strategies into pediatric PT facilitates positive health and physical wellness across a child’s lifespan.
See the video abstract for insights from the authors.

Video Abstract:
Supplemental digital content available at https://www.dropbox.com/scl/fi/3g468hj1rpxrrivbeses0/HPPW-Video-Abstract_1080.mp4?rlkey=4p1i8z1gynroz064zpx3alijz&st=8u0gqemz&dl=0.
HOUSING TEMPERATURE ALTERS BURN-INDUCED HYPERMETABOLISM IN MICE
Authors: Kingren Meagan Scott , Hall Jaycelyn Starr , Ross Taylor Joseph , Barre Mary Claire , Barlow Abigail , Morales Martin , Treas Lillie Danielle , Maxson Robert Todd , Teo Esther , Porter Craig 
Published: October 2024

ABSTRACT
Mice used in biomedical research are typically housed at ambient temperatures (22°C–24°C) below thermoneutrality (26°C–31°C). This chronic cold stress triggers a hypermetabolic response that may limit the utility of mice in modeling hypermetabolism in response to burns. To evaluate the effect of housing temperature on burn-induced hypermetabolism, mice were randomly assigned to receive sham, small, or large scald burns. Mice recovered for 21 days in metabolic phenotyping cages at 24°C or 30°C. Regardless of sex or sham/burn treatment, mice housed at 24°C had greater total energy expenditure (P < 0.001), which was largely attributable to greater basal energy expenditure when compared to mice housed at 30°C (P < 0.001). Thermoneutral housing (30°C) altered adipose tissue mass in a sex-dependent manner. Compared to sham and small burn groups, large burns resulted in greater water vapor loss, regardless of housing temperature (P < 0.01). Compared to sham, large burns resulted in greater basal energy expenditure and total energy expenditure in mice housed at 24°C; however, this hypermetabolic response to large burns was blunted in female mice housed at 30°C, and absent in male mice housed at 30°C. Locomotion was significantly reduced in mice with large burns compared to sham and small burn groups, irrespective of sex or housing temperature (P < 0.05). Housing at 30°C revealed sexual dimorphism in terms of the impact of burns on body mass and composition, where males with large burns displayed marked cachexia, whereas females did not. Collectively, this study demonstrates a sex-dependent role for housing temperature in influencing energetics and body composition in a rodent model of burn trauma.
Prognostic Implications of Changes in Platelet Trajectories in Patients With Sepsis: A Retrospective Analysis Using the Medical Information Mart for Intensive Care-IV Database
Authors: Wang Yingxin , Wu Jiaqian , Shao Tenghao , Su Dan , Ma Xin , Yu Zhanbiao , Li Ning 
Published: October 2024

Abstract

Objective
Patients with sepsis often experience reductions or increases in platelet counts, but the implications of these temporal patterns on prognosis remain unclear. The aim of this study was to investigate the impact of changes in platelet trajectories on the clinical prognosis of sepsis.

Methods
This study was a retrospective analysis using data from the Medical Information Mart for Intensive Care (MIMIC)-IV database. Patients with sepsis were identified from the database, and their platelet trajectories were categorized into four distinct models based on the changes in platelet counts over a period of 14 days post-diagnosis of sepsis. The effect of these trajectories on patient prognosis was subsequently evaluated.

Results
A total of 15,250 patients with sepsis were included to construct a model, and the following four distinct platelet count trajectories were identified: normal platelet levels (phenotype 1); persistently low platelet levels (phenotype 2); gradually increasing platelet levels exceeding the normal range (phenotype 3); and consistently significantly elevated platelet levels (phenotype 4). Statistically significant differences were found in the 28-day mortality, in-hospital mortality, and 90-day mortality among the four phenotypes. Multivariate regression analysis showed that compared to the group with normal platelet levels (phenotype 1), the group with persistently low platelet levels (phenotype 2) had higher in-hospital mortality (odds ratio [OR] = 1.34, 95% confidence interval [CI]: 1.16-1.54), 28-day mortality (OR = 1.69, 95% CI: 1.47-1.94), and 90-day mortality (OR = 1.50, 95% CI: 1.32-1.69). There was no difference in in-hospital mortality between phenotypes 3 and 4 compared to phenotype 1, although phenotype 4 showed an increase in 28-day mortality (p < 0.05), and phenotype 3 showed a decreasing trend in 90-day mortality (p < 0.05). The results of inverse probability weighting adjusted by regression were basically consistent with the above findings, except that there was no statistical difference in 28-day mortality between phenotype 4 and phenotype 1. In the subgroups based on age, weight, and antiplatelet drugs or therapies, there was an interaction between platelet levels and these factors.

Conclusion
In patients with sepsis, a decrease in platelet count is associated with increased mortality, while a moderate increase in platelet count can reduce 90-day mortality. However, for patients with persistently elevated platelet counts, caution is advised when using antiplatelet drugs or therapies, as it may increase mortality.
CIRCTMCO3 ALLEVIATES SEPSIS-INDUCED ACUTE KIDNEY INJURY VIA REGULATING MIR-218-5P/ZEB2 AXIS
Authors: Gong Yingfeng , Wei Na , Shi Peipei , Zhu Gang 
Published: October 2024

ABSTRACT

Background: Growing evidence has found the critical role of circular RNAs (circRNAs) in sepsis-induced acute kidney injury (S-AKI). CircTMCO3 has been found to be involved in tumor microenvironment changes of ovarian cancer. This study aimed to explore whether circTMCO3 functions in S-AKI, and if so, to elucidate the molecular mechanism. Methods: CircTMCO3 expression was analyzed in lipopolysaccharide (LPS)-induced HK-2 cells and in the kidney tissues of mice treated with cecal ligation and puncture (CLP), respectively. Furthermore, the effects of circTMCO3 on S-AKI and the related mechanisms were evaluated in both models through gain- and/or loss-of-function strategies. Results: CircTMCO3 expression was suppressed in both S-AKI models. Upregulation of circTMCO3 mitigated LPS-induced apoptosis, oxidative stress, and inflammation in HK-2 cells. In contrast, circTMCO3 downregulation exacerbated LPS-induced injuries in HK-2 cells. Intravenous injection of circTMCO3 lentivirus to increase circTMCO3 expression improved renal function and attenuated kidney injury in S-AKI mice, as evidenced by the decrease in serum creatinine and blood urea nitrogen concentrations, amelioration of tubular pathological injury, reduction of renal cell apoptosis, and mitigation of oxidative stress and proinflammatory cytokines (TNF-α, IL-1β, and IL-6). Moreover, circTMCO3 directly targeted miR-218-5p, and the mimic of which abolished the protective effect of circTMCO3 in cell models. ZEB2 was identified to be a target of miR-218-5p; its downregulation not only reversed the impacts of miR-218-5p inhibitor on S-AKI, but also mitigated the effects mediated by circTMCO3 upregulation in vitro. Conclusions: CircTMCO3 protects against S-AKI by regulating miR-218-5p/ZEB2 axis, thereby mediating antiapoptotic, antioxidant, and anti-inflammatory activities. This indicates that increasing circTMCO3 expression might be a future therapeutic method for S-AKI.
Assessment of absorbed dose in the hematopoietic stem cell layer of the bone marrow, assuming non-uniform distribution around the vascular endothelium of the bone marrow
Authors: Kobayashi Noriko 
Published: October 2024

AbstractRecent studies have shown that hematopoietic stem cells (HSCs) are concentrated around the endothelium of the sinusoidal capillaries. However, the current International Commission on Radiological Protection (ICRP) dosimetry model does not take into account the heterogeneity of the bone marrow tissue and stem cell distribution. In this study, the absorbed doses to the stem cell layer in the perivascular HSC layer in the bone marrow from radionuclides inhaled into the body were estimated for the major beta- and alpha-nuclides and noble gases and compared with the absorbed dose based on the ICRP 60 and ICRP 103 recommendations. The absorbed doses to the bone marrow obtained from the model calculations were not significantly different from ICRP60 and ICRP103 for beta-nuclides but were much lower than previously estimated for alpha-nuclides, and the contribution of red bone marrow and blood sources was greater than that of trabecular bone for alpha-nuclides. Noble gases in the red bone marrow may also affect the bone marrow stem cell layer. The bone marrow dose assessment for alpha nuclides and noble gases should be re-examined using a precise model based on CT images from the perspective of occupational and public radiation protection.
Fungal spore seasons advanced across the US over two decades of climate change
Authors: Wu Ruoyu , Song Yiluan , Head Jennifer R. , Katz Daniel S. W. , Peay Kabir G. , Shedden Kerby , Zhu Kai 
Published: October 2024

AbstractPhenological shifts due to climate change have been extensively studied in plants and animals. Yet, the responses of fungal spores—crucial organisms that play important roles in ecosystems and act as airborne allergens—remain understudied. This knowledge gap in global change biology hinders our understanding of its ecological and public health implications. To bridge this gap, we acquired a long-term (2003 ∼ 2022), large-scale (the continental US) dataset of airborne fungal spores collected by the US National Allergy Bureau. We first pre-processed the spore data by gap-filling and smoothing. Afterward, we extracted ten metrics describing the phenology (e.g., start and end of season) and intensity (e.g., peak concentration and integral) of fungal spore seasons. These metrics were derived using two complementary but not mutually exclusive approaches—ecological and public health approaches, defined as percentiles of total spore concentration and allergenic thresholds of spore concentration, respectively. Using linear mixed effects models, we quantified annual temporal shifts in these metrics across the continental US. We revealed a significant advancement in the onset of the spore seasons defined in both ecological (11 days, 95% confidence interval: 0.4 ∼ 23 days) and public health (22 days, 6 ∼ 38 days) approaches over two decades. Nevertheless, the total spore concentration in an annual cycle and in a spore allergy season tended to decrease over time. The earlier start of the spore season was significantly correlated with climatic variables, such as warmer temperatures and altered precipitations. Overall, our findings suggest possible climate-driven advanced fungal spore seasons, highlighting the importance of climate change mitigation and adaptation in public health decision-making.
Chromosomal instability promotes cell migration and invasion via EFEMP1 secretion into extracellular vesicles
Authors: Zheng Siqi , Tian Ruifang , Liu Yuanyuan , Wardenaar Rene , Shirzai Marjan , Kempe Laura , Dijkstra Emma , Warszawik Eliza , Suarez Peredo Rodriguez Maria , Sjollema Klaas , Bakker Petra L. , van Rijn Patrick , Borghesan Michaela , Paridaen Judith , Santaguida Stefano , Foijer Floris 
Published: October 2024

AbstractTriple-negative breast cancer (TNBC) is characterised by high rates of chromosomal instability (CIN) and a tumour microenvironment (TME) modulated by extracellular vesicles (EVs). To assess how CIN might affect the TME in TNBC, we studied the EV landscape of TNBC cell lines with induced CIN. We find that CIN leads to increased secretion of EVs and that these EVs promote cell migration of recipient cells. EVs are enriched for extracellular matrix (ECM) proteins, including EFEMP1. Indeed, modulation of EFEMP1 levels in EVs significantly alters migration behaviour of EV-treated cells. We show that EFEMP1 expression is regulated by STAT1, and that EVs from STAT1-deficient cells no longer promote migration, which can be rescued by overexpression of EFEMP1 in STAT1-null cells. Xenografting TNBC cells with EFEMP1 enriched cells promotes migration in zebrafish embryos, suggesting that EFEMP1 expression is a factor that promotes metastasis. Together our results uncover a novel role for CIN in shaping the TME of TNBC and identify EFEMP1 as a potential therapeutic target to prevent cell migration within the TME.
WRAD core perturbation impairs DNA replication fidelity promoting immunoediting in pancreatic cancer
Authors: Citron Francesca , Ho I-Lin , Balestrieri Chiara , Liu Zhaoliang , Yen Er-Yen , Cecchetto Luca , Perelli Luigi , Zhang Li , Montanez Luis Castillo , Blazanin Nicholas , Dyke Charles A. , Shah Rutvi , Attanasio Sergio , Srinivasan Sanjana , Chen Ko-Chien , Chen Ziheng , Scognamiglio Iolanda , Pham Nhung , Khan Hania , Jiang Shan , Pan Jing , Vanderkruk Ben , Leung Cecilia S. , Mattohti Mahinur , Rai Kunal , Chu Yanshuo , Wang Linghua , Gao Sisi , Deem Angela K. , Carugo Alessandro , Wang Huamin , Yao Wantong , Tonon Giovanni , Xiong Yun , Lorenzi Philip L. , Bonini Chiara , Zal M. Anna , Hoffman Brad G. , Heffernan Tim , Giuliani Virginia , Jeter Collene R. , Lissanu Yonathan , Genovese Giannicola , Di Pilato Mauro , Viale Andrea , Draetta Giulio F. 
Published: October 2024

AbstractIt is unclear how cells counteract the potentially harmful effects of uncoordinated DNA replication in the context of oncogenic stress. Here, we identify the WRAD (WDR5/RBBP5/ASH2L/DPY30) core as a modulator of DNA replication in pancreatic ductal adenocarcinoma (PDAC) models. Molecular analyses demonstrated that the WRAD core interacts with the replisome complex, with disruption of DPY30 resulting in DNA re-replication, DNA damage, and chromosomal instability (CIN) without affecting cancer cell proliferation. Consequently, in immunocompetent models, DPY30 loss induced T cell infiltration and immune-mediated clearance of highly proliferating cancer cells with complex karyotypes, thus improving anti-tumor efficacy upon anti-PD-1 treatment. In PDAC patients, DPY30 expression was associated with high tumor grade, worse prognosis, and limited response to immune checkpoint blockade. Together, our findings indicate that the WRAD core sustains genome stability and suggest that low intratumor DPY30 levels may identify PDAC patients who will benefit from immune checkpoint inhibitors.
Maintenance of parasite species diversity: Spatiotemporal niche partitioning and aggregation facilitate species coexistence
Authors: Ramesh Ashwini , McDermott-Sipe Olivia , Bashey-Visser Farrah 
Published: October 2024

ABSTRACTThe maintenance of parasite diversity has historically taken a host-centric approach. Yet, many parasites are host generalists, and most parasites spend at least some time outside of their hosts. So, what mechanisms besides host-associated niche partitioning allow parasites to coexist? Using a year-long field survey and lab mesocosms, we examined whether environmental niche partitioning or aggregation could enable coexistence among soil-dwelling entomopathogenic nematodes. Field patterns along an elevational gradient reveal that species abundances differentiate with soil structure and moisture levels. Yet, most species strongly overlap within-sites throughout the year. Thus, niche partitioning alone is not sufficient to explain the coexistence of these species and other mechanisms are necessary to explain their coexistence. Aggregation at the within-site scale provides evidence for such a mechanism. Each species showed significant intraspecific clumping and largely random associations with other species. A mesocosm test of the consequences of intraspecific aggregation found that parasites at low or high densities limit their own population growth. Aggregation can promote negative feedback facilitating species coexistence. Our findings offer field-based evidence that spatiotemporal niche partitioning and aggregation both play a critical role in maintaining parasite species diversity, illustrating the importance of extending out view of parasites beyond their hosts.
Single-chain nanobody inhibition of Notch and avidity enhancement utilizing the β-pore forming toxin Aerolysin
Authors: Lemmex Andrew C.D. , Allred Jeremy , Ostergard Jason , Trask Jake , Bui Hannah N. , Anderson Michael J. M. , Kopp Benjamin , Streeter Oakley , Smiley Adam T. , Babilonia-Díaz Natalia S. , Blazar Bruce R. , Higgins LeAnn , Gordon Peter M. , Muretta Joseph M. , Gordon Wendy R. 
Published: October 2024

AbstractNotch plays critical roles in developmental processes and disease pathogenesis, which has led to numerous efforts to modulate its function with small molecules and antibodies. Here we present a nanobody inhibitor of Notch signaling, derived from a synthetic phage-display library targeting the notch Negative Regulatory Region (NRR). The nanobody inhibits Notch signaling in a luciferase reporter assay and in Notch-dependent hematopoietic progenitor cell differentiation assay, despite a modest 19uM affinity for Notch. We addressed the low affinity by fusion to a membrane-associating domain derived from the β-Pore forming toxin Aerolysin, resulting in a significantly improved IC50 for Notch inhibition. The nanobody-aerolysin fusion inhibits proliferation of T-ALL cell lines with similar efficacy to other Notch pathway inhibitors. Overall, this study reports the development of a Notch inhibitory antibody, and demonstrates a proof-of-concept for a generalizable strategy to increase the efficacy and potency of low-affinity antibody binders.
Inhibition of UBE2N in regulatory T-cells boosts immunity against cancer
Authors: Miao Wanying , Jain Vaibhav , Han Madison , Jin Yingai J. , Beasley Georgia M. , Starczysnowski Daniel T. , Gregory Simon G. , Zhang Jennifer Y. 
Published: October 2024

AbstractRegulatory T (Treg) cells prevent autoimmunity and facilitate cancer immune evasion. Depletion of Tregs is a promising cancer therapy, but risks of autoimmune reactions hamper its clinical translation. Here, we demonstrate that temporally induced deletion of Ube2n in Tregs (Ube2nTreg-KO) of adult mice results in a robust expansion and activation of cytotoxic CD8+T-cells in response to cancer cell challenges, producing a long-lasting survival benefit without autoimmune complications. The anti-tumor effect persists following adoptive T-cell transfer to T-cell-deficient Rag1-knockout mice. Single-cell transcriptomic analysis revealed that UBE2N deletion shifted immunosuppressive Tregs to effector-like T-cells. This shift is characterized by the downregulation of c-Myc target genes, resembling that observed in tumor-infiltrating Tregs of melanoma patients. Further analyses confirm that UBE2N maintains c-Myc protein stability via suppression of K48-Ubiquitin-mediated proteasomal degradation. Taken together, our studies uncover a hitherto unexplored and potentially druggable UBE2N/c-Myc signaling axis to eradicate Treg-enabled cancer immune escape.