bluuebunny/crossref_metadata_2025_split huggingface dataset:
ACETYL-COA PRODUCTION BY OCTANOIC ACID ALLEVIATES ACUTE COMPARTMENT SYNDROME–INDUCED SKELETAL MUSCLE INJURY THROUGH REGULATING MITOPHAGY
Authors: Jiang Xiangkang , Liu Shaoyun , Yang Jingyuan , Lin Yao , Zhang Wenbin , Tao Jiawei , Zhong Huiming , Xu Jiefeng , Zhang Mao 
Published: February 2024

ABSTRACT

Background: Treatment of acute compartment syndrome (ACS)–induced skeletal muscle injury remains a challenge. Previous studies have shown that octanoic acid is a promising treatment for ACS owing to its potential ability to regulate metabolic/epigenetic pathways in ischemic injury. The present study was designed to investigate the efficacy and underlying mechanism of octanoic acid in ACS-induced skeletal muscle injury. Methods: In this study, we established a saline infusion ACS rat model. Subsequently, we assessed the protective effects of sodium octanoate (NaO, sodium salt of octanoic acid) on ACS-induced skeletal muscle injury. Afterward, the level of acetyl-coenzyme A and histone acetylation in the skeletal muscle tissue were quantified. Moreover, we investigated the activation of the AMP-activated protein kinas pathway and the occurrence of mitophagy in the skeletal muscle tissue. Lastly, we scrutinized the expression of proteins associated with mitochondrial dynamics in the skeletal muscle tissue. Results: The administration of NaO attenuated muscle inflammation, alleviating oxidative stress and muscle edema. Moreover, NaO treatment enhanced muscle blood perfusion, leading to the inhibition of apoptosis-related skeletal muscle cell death after ACS. In addition, NaO demonstrated the ability to halt skeletal muscle fibrosis and enhance the functional recovery of muscle post-ACS. Further analysis indicates that NaO treatment increases the acetyl-CoA level in muscle and the process of histone acetylation by acetyl-CoA. Lastly, we found NaO treatment exerts a stimulatory impact on the activation of the AMPK pathway, thus promoting mitophagy and improving mitochondrial dynamics. Conclusion: Our findings indicate that octanoic acid may ameliorate skeletal muscle injury induced by ACS. Its protective effects may be attributed to the promotion of acetyl-CoA synthesis and histone acetylation within the muscular tissue, as well as its activation of the AMPK-related mitophagy pathway.
Focusing on Earlier Management of Alzheimer Disease
Authors: Frederiksen Kristian Steen , Morató Xavier , Zetterberg Henrik , Gauthier Serge , Boada Mercè , Pytel Vanesa , Mattke Soeren 
Published: February 2024

Background:
Despite the number of people living with Alzheimer disease (AD), awareness of the early stages of this condition, including mild cognitive impairment due to AD—which poses management challenges—continues to be low. To identify areas for improvement in early AD management, dementia specialists convened in a virtual roundtable meeting.

Methodology:
A modified version of the nominal group technique was followed to prioritize specific topics and allow experts to provide their opinions. The overarching topics prioritized and discussed were (1) education and support for primary care physicians on cognitive assessment, detection of mild cognitive impairment, and patient monitoring; (2) nonpharmacological interventions; (3) and the introduction of disease-modifying therapies.

Conclusions:
Consensus was achieved regarding the need for educating primary care physicians on identifying people with cognitive impairment and for better diagnostic tools for its detection and early management. Management of mild cognitive impairment due to AD should encompass an adequate follow-up schedule aiming to maintain function for as long as possible, and primary care physicians and patients should be aware of the benefits of nonpharmacological interventions.
Utility of Circulating Tumor DNA Assessment in Characterizing Recurrence Sites after Optimal Resection for Metastatic Colorectal Cancer
Authors: Bansal Varun V , Belmont Erika , Godley Frederick , Dhiman Ankit , Witmer Hunter D , Li Shen , Liao Andy , Eng Oliver S , Turaga Kiran K , Shergill Ardaman 
Published: February 2024

BACKGROUND:
Plasma circulating tumor DNA (ctDNA) is a promising biomarker for metastatic colorectal cancer (mCRC); however, its role in characterizing recurrence sites after mCRC resection remains poorly understood. This single-institution study investigated the timing of ctDNA detection and its levels in the context of recurrence at different sites after mCRC resection.

STUDY DESIGN:
Patients who underwent optimal resection of CRC metastases involving the peritoneum, distant lymph nodes, or liver, with serial postoperative tumor-informed ctDNA assessments (Signatera) were included. Recurrence sites, as defined by surveillance imaging or laparoscopy, were categorized as peritoneal-only and other distant sites (liver, lung, lymph nodes, or body wall).

RESULTS:
Among the 31 included patients, ctDNA was detected in all 26 (83.4%) patients with postoperative recurrence and was persistently undetectable in 5 patients who did not experience recurrence. At 3 months postsurgery, ctDNA was detected in 2 (25%) of 8 patients with peritoneal-only recurrence and 17 (94.4%) of 18 patients with distant recurrence (p < 0.001). Beyond 3 months, ctDNA was detected in the remaining 6 patients with peritoneal-only disease and 1 patient with distant disease. ctDNA detection preceded the clinical diagnosis of recurrence by a median of 9 weeks in both groups. At recurrence, peritoneal-only recurrent cases exhibited lower ctDNA levels (median 0.4 mean tumor molecules/mL, interquartile range 0.1 to 0.8) compared with distant recurrence (median 5.5 mean tumor molecules/mL, interquartile range 0.8 to 33.3, p = 0.004).

CONCLUSIONS:
Peritoneal-only recurrence was associated with delayed ctDNA detection and low levels of ctDNA after optimal resection for mCRC. ctDNA testing may effectively characterize recurrence sites and may help guide subsequent treatments specific to the disease sites involved.
Accelerated Hematopoietic Stem Cell Aging in Space
Authors: Pham Jessica , Isquith Jane , Balaian Larisa , Ladel Luisa , Nandi Shuvro P. , Mack Karla , van der Werf Inge , Klacking Emma , Ruiz Antonio , Mays David , Gamble Paul , Giza Shelby , Janowitz Jiya , Nienaber Trevor , Mishra Tejaswini , Kulidjian Anna , Stoudemire Jana , Snyder Michael P. , Clements Twyman , Muotri Alysson R. , Morris Sheldon R. , Whisenant Thomas , Alexandrov Ludmil B. , Jamieson Catriona H.M. 
Published: February 2024

AbstractStem cell aging is accelerated by macroenvironmental and microenvironmental stressors, including inflammation. Previously, the NASA Twins study revealed inflammatory cytokine upregulation, chromosomal alterations, and telomere changes suggestive of accelerated aging in low-Earth orbit (LEO). To investigate the effects of spaceflight on human hematopoietic stem and progenitor cell (HSPC) aging, the NASA-supported Integrated Space Stem Cell Orbital Research team performed four independent 30- to 45-day NASA missions with matched flight and ground HSPC nanobioreactors in automated CubeLabs. These experiments revealed loss of HSPC dormancy, reduced self-renewal capacity, mitochondrial DNA amplification, APOBEC3-induced C-to-T mutagenesis, reduced ADAR1p150 expression, and alterations in the expression of repetitive elements. These molecular changes are indicative of accelerated HSPC aging and pre-leukemia stem cell generation in space and may be predictable and preventable.
Impact of inter-species hybridisation on antifungal drug response in theSaccharomycesgenus
Authors: Visinoni Federico , Royle William , Scholey Rachel , Hu Yue , Timouma Soukaina , Zeef Leo , Louis Edward J , Delneri Daniela 
Published: February 2024

AbstractAntifungal drug resistance across fungal and yeast pathogens presents one of the major concerns for global public health. Understanding the interactions between genetic background and environment is important for the development of new, effective treatments of infections. Allelic variation within populations of Ascomycota as well as hybridisation impacts the phenotype in response to stressful conditions, including to antifungal drugs. We exploited recent advances in multigenerational breeding ofSaccharomycesinterspecies hybrids to study the impact of hybridisation on antifungal resistance and identify quantitative trait loci (QTL) responsible for the phenotypes observed. A library ofSaccharomyces cerevisiaexS. kudriavzeviihybrid offspring was screened in the presence of sub-lethal concentrations of six antifungal drugs and revealed a broad phenotypic diversity across the progeny. QTL analysis was carried out comparing alleles between the pools of high and low fitness offspring, identifying hybrid-specific genetic regions involved in resistance to fluconazole, micafungin and flucytosine. We found both drug specific and pleiotropic regions, and through gene ontology and SIFT analysis we identify potential causal genes, such asBCK2andDNF1that were validated via reciprocal hemizygosity analysis. We highlight 41 regions that contain genes not previously associated with resistance phenotypes in the literature. The results of this screening will help identify new pathways contributing to drug resistance, and lead to greater understanding of how allelic variation, hybridisation and evolution affect antifungal drug resistance in yeast and fungi.
The ESCRT protein CHMP5 promotes T cell leukemia by controlling BRD4-p300-dependent transcription
Authors: Umphred-Wilson Katharine , Ratnayake Shashikala , Tang Qianzi , Wang Rui , Devaiah Ballachanda N. , Zhou Lan , Chen Qingrong , Meerzaman Daoud , Singer Dinah S , Adoro Stanley 
Published: February 2024

SummaryOncogene activity rewires cellular transcription, creating new transcription networks to which cancer cells become addicted, by mechanisms that are still poorly understood. Using human and mouse models of T cell acute lymphoblastic leukemia (T-ALL), we identify an essential nuclear role for CHMP5, a cytoplasmic endosomal sorting complex required for transport (ESCRT) protein, in establishing and maintaining the T-ALL transcriptional program. Nuclear CHMP5 promoted the T-ALL gene program by augmenting recruitment of the co-activator BRD4 by the histone acetyl transferase p300 selectively at enhancers and super-enhancers, an interaction that potentiated H3K27 acetylation at these regulatory enhancers. Consequently, loss of CHMP5 diminished BRD4 occupancy at enhancers and super-enhancers and impaired RNA polymerase II pause release, which resulted in downregulation of key T-ALL genes, notablyMYC. Reinforcing its importance in T-ALL pathogenesis, CHMP5 deficiency mitigated chemoresistance in human T-ALL cells and abrogated T-ALL induction by oncogenic NOTCH1in vivo. Thus, the ESCRT protein CHMP5 is an essential positive regulator of the transcriptional machinery promoting T-ALL disease.Graphical abstractHighlightsIdentification of a nuclear role for the cytosolic ESCRT protein CHMP5 in transcriptionCHMP5 mediates BRD4-dependent Pol II pause release and transcription of T-ALL genesP300-BRD4 induced enhancer and super-enhancer H3K27 acetylation requires CHMP5CHMP5 depletion mitigates chemoresistance and abrogates T-ALL initiationin vivo
PlasmodiumRON11 triggers biogenesis of the merozoite rhoptry pair and is essential for erythrocyte invasion
Authors: Anaguano David , Adewale-Fasoro Opeoluwa , Vick Grace S. , Yanik Sean , Blauwkamp James , Fierro Manuel A. , Absalon Sabrina , Srinivasan Prakash , Muralidharan Vasant 
Published: February 2024

ABSTRACTMalaria is a global and deadly human disease caused by the apicomplexan parasites of the genusPlasmodium. Parasite proliferation within human red blood cells (RBC) is associated with the clinical manifestations of the disease. This asexual expansion within human RBCs, begins with the invasion of RBCs byP. falciparum, which is mediated by the secretion of effectors from two specialized club-shaped secretory organelles in merozoite-stage parasites known as rhoptries. We investigated the function of the Rhoptry Neck Protein 11 (RON11), which contains seven transmembrane domains and calcium-binding EF-hand domains. We generated conditional mutants of theP. falciparumRON11. Knockdown of RON11 inhibits parasite growth by preventing merozoite invasion. The loss of RON11 did not lead to any defects in processing of rhoptry proteins but instead led to a decrease in the amount of rhoptry proteins. We utilized ultrastructure expansion microscopy (U-ExM) to determine the effect of RON11 knockdown on rhoptry biogenesis. Surprisingly, in the absence of RON11, fully developed merozoites had only one rhoptry each. The single rhoptry in RON11 deficient merozoites were morphologically typical with a bulb and a neck oriented into the apical polar ring. Moreover, rhoptry proteins are trafficked accurately to the single rhoptry in RON11 deficient parasites. These data show that in the absence of RON11, the first rhoptry is generated during schizogony but upon the start of cytokinesis, the second rhoptry never forms. Interestingly, these single-rhoptry merozoites were able to attach to host RBCs but are unable to invade RBCs. Instead, RON11 deficient merozoites continue to engage with RBC for prolonged periods eventually resulting in echinocytosis, a result of secreting the contents from the single rhoptry into the RBC. Together, our data show that RON11 triggers thede novobiogenesis of the second rhoptry and functions in RBC invasion.
An AhR-Ovol1-Id1 regulatory axis in keratinocytes promotes skin homeostasis against atopic dermatitis
Authors: Chen Zeyu , Dragan Morgan , Sun Peng , Haensel Daniel , Vu Remy , Cui Lian , Shi Yuling , Dai Xing 
Published: February 2024

ABSTRACTSkin is our outer permeability and immune defense barrier against myriad external assaults. Aryl hydrocarbon receptor (AhR) senses environmental factors and regulates barrier robustness and immune homeostasis. AhR agonist is in clinical trial for atopic dermatitis (AD) treatment, but the underlying mechanism of action remains ill-defined. Here we reportOVOL1/Ovol1as a conserved and direct transcriptional target of AhR in epidermal keratinocytes. We show that OVOL1/Ovol1 impacts AhR regulation of keratinocyte gene expression, andOvol1deletion in keratinocytes hampers AhR’s barrier promotion function and worsens AD-like inflammation. Mechanistically, we identify Ovol1’s direct downstream targets genome-wide, and providein vivoevidence for Id1’s critical role in barrier maintenance and disease suppression. Furthermore, our findings reveal an IL-1/dermal γδT cell axis exacerbating both type 2 and type 3 immune responses downstream of barrier perturbation inOvol1-deficient AD skin. Finally, we present data suggesting the clinical relevance of OVOL1 and ID1 function in human AD. Our study highlights a keratinocyte-intrinsic AhR-Ovol1-Id1 regulatory axis that promotes both epidermal and immune homeostasis against AD-like inflammation, implicating new therapeutic targets for AD.
Cryo-EM structures of the tubulin cofactors reveal the molecular basis for the biogenesis of alpha/beta-tubulin
Authors: Taheri Aryan , Wang Zhoaqian , Singal Bharti , Guo Fei , Al-Bassam Jawdat 
Published: February 2024

AbstractMicrotubule polarity and dynamic polymerization originate from the self-association properties of the a-tubulin heterodimer. For decades, it has remained poorly understood how the tubulin cofactors, TBCD, TBCE, TBCC, and the Arl2 GTPase mediate a-tubulin biogenesis from α- and β-tubulins. Here, we use cryogenic electron microscopy to determine structures of tubulin cofactors bound to αβ-tubulin. These structures show that TBCD, TBCE, and Arl2 form a heterotrimeric cage-like TBC-DEG assembly around the a-tubulin heterodimer. TBCD wraps around Arl2 and almost entirely encircles -tubulin, while TBCE forms a lever arm that anchors along the other end of TBCD and rotates α-tubulin. Structures of the TBC-DEG-αβ-tubulin assemblies bound to TBCC reveal the clockwise rotation of the TBCE lever that twists a-tubulin by pulling its C-terminal tail while TBCD holds -tubulin in place. Altogether, these structures uncover transition states in αβ-tubulin biogenesis, suggesting a vise-like mechanism for the GTP-hydrolysis dependent a-tubulin biogenesis mediated by TBC-DEG and TBCC. These structures provide the first evidence of the critical functions of the tubulin cofactors as enzymes that regulate the invariant organization of αβ-tubulin, by catalyzing α- and β-tubulin assembly, disassembly, and subunit exchange which are crucial for regulating the polymerization capacities of αβ-tubulins into microtubules.
Robust thalamic nuclei segmentation from T1-weighted MRI using polynomial intensity transformation
Authors: Vidal Julie P. , Danet Lola , Péran Patrice , Pariente Jérémie , Cuadra Meritxell Bach , Zahr Natalie M. , Barbeau Emmanuel J. , Saranathan Manojkumar 
Published: February 2024

AbstractAccurate segmentation of thalamic nuclei, crucial for understanding their role in healthy cognition and in pathologies, is challenging to achieve on standard T1-weighted (T1w) magnetic resonance imaging (MRI) due to poor image contrast. White-matter-nulled (WMn) MRI sequences improve intrathalamic contrast but are not part of clinical protocols or extant databases. In this study, we introduce histogram-based polynomial synthesis (HIPS), a fast preprocessing transform step that synthesizes WMn-like image contrast from standard T1w MRI using a polynomial approximation for intensity transformation. HIPS was incorporated into THalamus Optimized Multi-Atlas Segmentation (THOMAS) pipeline, a method developed and optimized for WMn MRI. HIPS-THOMAS was compared to a convolutional neural network (CNN)-based segmentation method and THOMAS modified for T1w images (T1w-THOMAS). The robustness and accuracy of the three methods were tested across different image contrasts (MPRAGE, SPGR, and MP2RAGE), scanner manufacturers (PHILIPS, GE, and Siemens), and field strengths (3T and 7T). HIPS-transformed images improved intra-thalamic contrast and thalamic boundaries, and HIPS-THOMAS yielded significantly higher mean Dice coefficients and reduced volume errors compared to both the CNN method and T1w-THOMAS. Finally, all three methods were compared using the frequently travelling human phantom MRI dataset for inter- and intra-scanner variability, with HIPS displaying the least inter-scanner variability and performing comparably with T1w-THOMAS for intra-scanner variability. In conclusion, our findings highlight the efficacy and robustness of HIPS in enhancing thalamic nuclei segmentation from standard T1w MRI.
Time to Eat - A Personalized Circadian Eating Schedule Leads to Weight Loss Without Imposing Calorie Restriction: A Randomized Controlled Pilot Study
Authors: Wilming Isabell , Tuschewski Jana , Osterhaus Jessie M , Bringmann Theresa JG , Hühne-Landgraf Anisja , Landgraf Dominic 
Published: February 2024

AbstractObjectiveMany weight loss strategies are based on the restriction of calories or certain foods. In this pilot study, we preliminary tested a weight loss intervention based solely on increasing the regularity of meals. The assumption is based on the evidence that eating at fixed times allows the circadian system to optimally prepare the food metabolism for these times.Participants & MethodsIn a two-group, single center randomized-controlled single-blind pilot study (pre-registration DRKS00021419) with participants aged 18-65 years and BMI ≥ 22 kg/m2, we used a smartphone application to identify the times at which each participant eats particularly frequently and asked participants of the experimental group to restrict their meals to only these times for six weeks. Control participants received sham treatment. Primary outcome was body weight/BMI and secondary outcome the well-being of participants.ResultsOf 148 participants taking part in the pilot study, 121 were randomized, of whom 100 (control: 33, experimental: 67) completed the study. Our results show that the more regular the meals of participants of the experimental group became, the more weight/BMI they lost, averaging 2.62 kg (0.87 kg/m2); p < 0.0001 (BMI: p < 0.0001) compared to an insignificant weight loss of 0.56 kg (0.20 kg/m2) in the control group; p = 0.0918 (BMI: p = 0.0658). Strikingly, weight loss was not related to self-reported changes in calories, food composition, and other food-related factors. Additionally, physical and mental well-being improved significantly.ConclusionIn summary, increasing the regularity of meals may cause participants to lose excess body weight and improve overall well-being. These promising results justify a larger-scale study, albeit with a more rigorous study design.HighlightsIndividual optimal times for meals are determined via an app-based meal diary.Generation of a structure plan for mealtimes are adjusted to individual circadian clocks.Following this plan, participants lost an average body weight of 2.6 kg over six weeks.Weight loss does not correlate with self-reported changes in food quantity or composition.Regular mealtimes contribute to the improvement of general well-being.
Pan-cancer analyses reveal molecular and clinical characteristics of TET family members and suggests that TET3 maybe a potential therapeutic target
Authors: Zhang Chunyan , Zheng Jie , Liu Jin , Xing Guoqiang , Zhang Shupeng , Chen Hekai , Wang Jian , Shao Zhijiang , Li Yongyuan , Jiang Zhongmin , Pan Yingzi , Liu Xiaozhi , Xu Ping , Wu Wenhan 
Published: February 2024

ABSTRACTThe ten eleven translation (TET) family genes involve a wide range of biological functions in human cancers. However, few studies have comprehensively analyzed the correlation between TET family members and the molecular phenotypes and clinical characteristics of different cancers. Based on updated public databases and integrated several bioinformatics analysis methods, we evaluated expression level, somatic variation, methylation level, prognostic values of TET family gene and explore the association between expression of TET family genes and pathway activity, TME, stemness score, immune subtype, clinical staging, drug sensitivity in pan-cancer. Molecular biology and cytology experiments were used to validate the potential role of TET3 in tumor progression. Each TET family gene exhibits differentiated expression in at least ten detected tumors. The frequency of single nucleotide variation (SNV) of TETs gene was 91.24%, with most missense mutation type, and the main types of copy number variation (CNV) are heterozygous amplification and deletion. The TET1 gene is highly methylated, while the TET2 and TET3 genes are hypomethylated in most cancers, and that closely related to patient prognosis. Pathway activity analysis shows that the TET family genes are involved in multiple signaling pathways such as cell cycle, apoptosis, DNA damage response, hormone AR, PI3K/AKT, and RTK. In addition, the expression level of TET family genes also affects the clinical stage of tumor patients, increases or inhibits the sensitivity of chemotherapy drugs, and then affects the prognosis of patients by participating in the regulation of tumor microenvironment (TME), cellular stemness potential, and the immune subtype. It is particularly pointed out that TET3 plays a role in promoting cancer progression in various tumors, and silencing TET3 can inhibit tumor malignancy and increase chemotherapy sensitivity. These findings may elucidate the role of TET family genes in cancer progression and provide insights for further research on TET3 as a potential target for pan-cancer.