bluuebunny/crossref_metadata_2025 huggingface dataset:
Machine learning algorithm to predict postoperative bleeding complications after lateral decubitus percutaneous nephrolithotomy
Authors: Meng Rui , Wang Weining , Zhai Zhipeng , Zuo Chao
Published: February 2024

Bleeding is a serious complication following percutaneous nephrolithotomy (PCNL). This study establishes a predictive model based on machine learning algorithms to forecast the occurrence of postoperative bleeding complications in patients with renal and upper ureteral stones undergoing lateral decubitus PCNL. We retrospectively collected data from 356 patients with renal stones and upper ureteral stones who underwent lateral decubitus PCNL in the Department of Urology at Peking University First Hospital-Miyun Hospital, between January 2015 and August 2022. Among them, 290 patients had complete baseline data. The data was randomly divided into a training group (n = 232) and a test group (n = 58) in an 8:2 ratio. Predictive models were constructed using Logistic Regression, Random Forest, and Extreme Gradient Boosting (XGBoost). The performance of each model was evaluated using Accuracy, Precision, F1-Score, Receiver Operating Characteristic curves, and Area Under the Curve (AUC). Among the 290 patients, 35 (12.07%) experienced postoperative bleeding complications after lateral decubitus PCNL. Using postoperative bleeding as the outcome, the Logistic model achieved an accuracy of 73.2%, AUC of 0.605, and F1 score of 0.732. The Random Forest model achieved an accuracy of 74.5%, AUC of 0.679, and F1 score of 0.732. The XGBoost model achieved an accuracy of 68.3%, AUC of 0.513, and F1 score of 0.644. The predictive model for postoperative bleeding after lateral decubitus PCNL, established based on machine learning algorithms, is reasonably accurate. It can be utilized to predict postoperative stone residue and recurrence, aiding urologists in making appropriate treatment decisions.
Self-Chiropractic Cervical Spinal Manipulation Resulting in Fatal Vertebral Artery Dissection
Authors: Fink Cameron , Bryce Clare H. , Knight Laura D.
Published: February 2024

Chiropractic cervical spinal manipulations have several complications and can result in vascular injury, including traumatic dissection of the vertebral arteries. A 43-year-old woman was admitted to the emergency department after performing a self-chiropractic spinal manipulation. She experienced headache and vomiting and was unresponsive with severe hypertension at the time of hospital admission. Clinical computerized tomography angiography showed narrowing of the right vertebral artery but was inconclusive for dissection or thrombosis. At autopsy, subacute dissection of the right vertebral artery was identified along with cerebral edema and herniation. A small peripheral pulmonary thromboembolism in the right lung was also seen. Neuropathology consultation confirmed the presence of diffuse cerebral edema and acute hypoxic-ischemic changes, with multifocal acute subarachnoid and intraparenchymal hemorrhage of the brain and spinal cord. This case presents a unique circumstance of a fatal vertebral artery dissection after self-chiropractic manipulation that, to the best of our knowledge, has not been previously described in the medical literature.
Th-Cell Subsets of Submandibular Lymph Nodes in Peri-Implantitis
Authors: Zhang Hongming , Sun Mengzhe , Xu Haisong , Huang Hui
Published: February 2024

Background:

Implant surgery is a popular operation in craniomaxillofacial surgery, but the occurrence of peri-implantitis affects the success and survival rate of the implant. Research has found that Th-cell–related cytokines are associated with peri-implantitis. However, the distribution and proportions of Th-cell subsets in submandibular lymph nodes’ immune environments during the progression of peri-implantitis remain unclear.

Methods:

Forty-eight rats were randomly divided into 4 groups: the control group, the 1-week ligation peri-implantitis induction (Lig 1w) group, the Lig 2w group, and the Lig 4w group (n=12). Ligation was maintained for different times to induce peri-implantitis 4 weeks after implantation. Inflammation and bone resorption were examined by clinical probing and micro-CT. The submandibular lymph nodes were harvested for quantitative real-time polymerase chain reaction and flow cytometry to obtain the Th-cell profiles.

Results:

With increasing ligation time, more redness and swelling in the gingiva and more bone resorption around the implant were observed (P<0.05). The proportions of Th1 and Th17 cells increased, the proportion of Th2 cells decreased, and the proportion of Treg cells first increased and then decreased in the lymph nodes (P<0.05).

Conclusions:

This study provided a preliminary characterization of the temporal distribution of Th cells in lymph nodes of peri-implantitis. Persistent elevation of Th1 and Th17 proportions and decrease of Treg proportion may be the cause of bone resorption in peri-implantitis. Lymphatic drainage may be a bridge between craniomaxillofacial diseases and systemic diseases. Early immune support against T cells may be a potential therapeutic idea for the prevention of implant failure and the potential risk of systemic disease.
Primary Failure of Dental Eruption Due to Variants Parathyroid Hormone Receptor 1: Retrospective Study and Proposal of Guidelines Treatment
Authors: Thuaire Antoine , Delebarre Hélène , Marsili Luisa , Colson Cindy , Vanlerberghe Clemence , Lauwers Ludovic , Raoul Gwenael , Touzet-Roumazeille Sandrine , Ferri Joël
Published: February 2024

Objective:

Primary failure of eruption is characterized by a nonsyndromic defect in tooth eruption in the absence of mechanical obstruction. It is correlated to rare heterozygous variants in the parathyroid hormone receptor 1 gene. The management of primary failure of eruption is complex because many therapies are ineffective. The present study aimed to compare the clinical outcomes of our patients with the findings reported in the literature, and to propose a treatment guideline based on the literature and our experience.

Methods:

Retrospective study of patients affected by primary dental eruption failure in the department and analyse of the results and compare with those of the litterature.

Results:

Twelve patients belonging to 5 families (9 males, 3 females; 13–52 y old) diagnosed and treated in the maxillofacial surgery and stomatology department of the Lille University Hospital were included. All patients showed posterior tooth involvement, and most patients showed bilateral defects. None of the affected teeth had coronal alveolar bone, whereas 6 patients showed root resorption in the affected teeth. Genetic analyses, performed on 11 patients, identified a parathyroid hormone receptor 1 disease-causing variant in 7 of them (63%). Multidisciplinary treatment was required to rehabilitate these patients. Orthodontic interventions, even at an early age, are difficult in affected teeth, which are often blocked or have internal resorption. Moreover, retention of these affected teeth during growth leads to dentoskeletal malocclusions, requiring difficult surgical management in the long term. Therefore, early extraction of these teeth is frequently recommended once the diagnosis has been confirmed. An implant-borne prosthetic rehabilitation can then be achieved at the end of growth after correction of the jaw discrepancy. In case of a late diagnosis, other surgical or noninvasive techniques may be used depending on the clinical situation. Distraction osteogenesis or segmental osteotomy could be discussed for patients with mild phenotypes.

Conclusions:

Early diagnosis of primary eruption defects is crucial to offer appropriate management as early as possible, and so to avoid late complicated treatments.
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

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.
UK Medical Cannabis Registry: a case series analyzing clinical outcomes of medical cannabis therapy for generalized anxiety disorder patients
Authors: Li Adam , Erridge Simon , Holvey Carl , Coomber Ross , Barros Daniela , Bhoskar Urmila , Crews Matthieu , Donnelly Lorna , Imran Muhammad , Korb Laura , Mwimba Gracia , Sachdeva-Mohan Simmi , Rucker James J. , Sodergren Mikael H.
Published: February 2024

This study aims to analyze changes in health-related quality of life (HRQoL) and safety in patients with generalized anxiety disorder (GAD) prescribed a homogenous selection of cannabis-based medicinal products (CBMPs). Patients prescribed Adven CBMPs (Curaleaf International, UK) for GAD were identified from the UK Medical Cannabis Registry. Primary outcomes were changes in patient-reported outcome measures (PROMs) from baseline up to 12 months, including GAD-7, Single-Item Sleep Quality Scale (SQS), and EQ-5D-5L. Adverse events were recorded using CTCAE version 4.0. A total of 120 patients were identified for inclusion, of which 38 (31.67%), 52 (43.33%), and 30 (25.00%) were prescribed oils, dried flower, and both formulations of CBMP. Associated improvements in GAD-7, SQS, and EQ-5D-5L at 1, 3, 6, and 12 months were observed compared to baseline (P < 0.010). There were 24 (20.00%) patients who reported 442 (368.33%) adverse events, most of which were mild (n = 184, 41.63%) and moderate (n = 197, 44.57%). This study reports an association between initiation of a homogeneous CBMP therapy and improvements in anxiety severity and HRQoL in individuals with GAD. Moreover, therapy was well-tolerated at 12 months follow-up. Further investigation through randomized controlled trials will ultimately be required to determine causation.
A conserved methyltransferase active site residue of Zika virus NS5 is required for the restriction of STING activation and interferon expression
Authors: Li Yuting , Li Zhaoxin , Zou Haimei , Zhou Peiwen , Huo Yuhang , Fan Yaohua , Liu Xiaohong , Wu Jianguo , Li Geng , Wang Xiao
Published: February 2024

Zika virus (ZIKV) is a re-emerging RNA virus and causes major public health events due to its link to severe neurological complications in foetuses and neonates. The cGAS–STING signalling pathway regulates innate immunity and plays an important role in the invasion of DNA and RNA viruses. This study reveals a distinct mechanism by which ZIKV restricts the cGAS–STING signalling to repress IFN-β expression. ZIKV attenuates IFN-β expression induced by DNA viruses (herpes simplex virus type 1, HSV-1) or two double-stranded DNAs (dsDNA90 and HSV120) in mouse embryonic fibroblasts (MEFs). Notably, ZIKV NS5, the viral RNA-dependent RNA polymerase, was responsible for the repression of IFN-β. NS5 interacts with STING in the cytoplasm, suppresses IRF3 phosphorylation and nucleus localization and promotes the cleavage of STING K48-linked polyubiquitination. Furthermore, the NS5 methyltransferase (MTase) domain interacts with STING to restrict STING-induced IFN-β expression. Interestingly, point mutation analyses of conserved methyltransferase active site residue D146 indicate that it is critical for repressing IFN-β expression induced by STING stimulation in cGAS–STING signalling.
Identification of consensus head and neck cancer-associated microbiota signatures: a systematic review and meta-analysis of 16S rRNA and The Cancer Microbiome Atlas datasets
Authors: Yeo Kenny , Li Runhao , Wu Fangmeinuo , Bouras George , Mai Linh T.H. , Smith Eric , Wormald Peter-John , Valentine Rowan , Psaltis Alkis James , Vreugde Sarah , Fenix Kevin
Published: February 2024

Introduction. Multiple reports have attempted to describe the tumour microbiota in head and neck cancer (HNSC).

Gap statement. However, these have failed to produce a consistent microbiota signature, which may undermine understanding the importance of bacterial-mediated effects in HNSC.

Aim. The aim of this study is to consolidate these datasets and identify a consensus microbiota signature in HNSC.

Methodology. We analysed 12 published HNSC 16S rRNA microbial datasets collected from cancer, cancer-adjacent and non-cancer tissues to generate a consensus microbiota signature. These signatures were then validated using The Cancer Microbiome Atlas (TCMA) database and correlated with the tumour microenvironment phenotypes and patient’s clinical outcome.

Results. We identified a consensus microbial signature at the genus level to differentiate between HNSC sample types, with cancer and cancer-adjacent tissues sharing more similarity than non-cancer tissues. Univariate analysis on 16S rRNA datasets identified significant differences in the abundance of 34 bacterial genera among the tissue types. Paired cancer and cancer-adjacent tissue analyses in 16S rRNA and TCMA datasets identified increased abundance in Fusobacterium in cancer tissues and decreased abundance of Atopobium, Rothia and Actinomyces in cancer-adjacent tissues. Furthermore, these bacteria were associated with different tumour microenvironment phenotypes. Notably, high Fusobacterium signature was associated with high neutrophil (r=0.37, P<0.0001), angiogenesis (r=0.38, P<0.0001) and granulocyte signatures (r=0.38, P<0.0001) and better overall patient survival [continuous: HR 0.8482, 95 % confidence interval (CI) 0.7758–0.9273, P=0.0003].

Conclusion. Our meta-analysis demonstrates a consensus microbiota signature for HNSC, highlighting its potential importance in this disease.
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

Stem 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

Antifungal 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

Oncogene 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 abstract

Highlights

Identification of a nuclear role for the cytosolic ESCRT protein CHMP5 in transcription

CHMP5 mediates BRD4-dependent Pol II pause release and transcription of T-ALL genes

P300-BRD4 induced enhancer and super-enhancer H3K27 acetylation requires CHMP5

CHMP5 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

Malaria 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

Skin 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

Microtubule 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

Accurate 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

Objective

Many 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 & Methods

In 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.

Results

Of 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.

Conclusion

In 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.

Highlights

Individual 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

The 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.
Creating an automated tool for a consistent and repeatable evaluation of disability progression in clinical studies for Multiple Sclerosis
Authors: Montobbio Noemi , Carmisciano Luca , Signori Alessio , Ponzano Marta , Schiavetti Irene , Bovis Francesca , Sormani Maria Pia
Published: February 2024

Background

The lack of standardized disability progression evaluation in multiple sclerosis (MS) hinders reproducibility of clinical study results, due to heterogeneous and poorly reported criteria.

Objectives

To demonstrate the impact of using different parameters when evaluating MS progression, and to introduce an automated tool for reproducible outcome computation.

Methods

Re-analyzing BRAVO clinical trial data (NCT00605215), we examined the fluctuations in computed treatment effect on confirmed disability progression (CDP) and progression independent of relapse activity (PIRA) when varying different parameters. These analyses were conducted using themsprogpackage for R, which we developed as a tool for CDP assessment from longitudinal data, given a set of criteria that can be specified by the user.

Results

The BRAVO study reported a hazard ratio (HR) of 0.69 (95%CI:0.46-1.02) for CDP. Using the different parameter configurations, the resulting treatment effect on CDP varied considerably, with HRs ranging from 0.59 (95%CI:0.41-0.86) to 0.72 (95%CI:0.48-1.07). The treatment effect on PIRA varied from an HR=0.62 (95%CI:0.41-0.93) to an HR=0.65 (95%CI:0.40-1.04).

Conclusions

The adoption of an open-access tool validated by the research community, with clear parameter specification and standardized output, could greatly reduce heterogeneity in CDP estimation and promote repeatability of study results.
Structural covariance networks in the fetal brain reveal altered neurodevelopment for specific subtypes of congenital heart disease
Authors: Wilson Siân , Cromb Daniel , Bonthrone Alexandra F. , Uus Alena , Price Anthony , Egloff Alexia , Van Poppe Milou P.M , Steinweg Johannes K , Pushparajah Kuberan , Simpson John , Lloyd David FA , Razavi Reza , O’Muircheartaigh Jonathan , Edwards A. David , Hajnal Joseph V. , Rutherford Mary , Counsell Serena J.
Published: February 2024

Background

Altered structural brain development has been identified in fetuses with Congenital Heart Disease (CHD), suggesting that the neurodevelopmental impairment observed later in life might originate in utero. There are many interacting factors that may perturb neurodevelopment during the fetal period and manifest as structural brain alterations, such as altered cerebral substrate delivery and aberrant fetal hemodynamics.

Methods

We extracted structural covariance networks (SCNs) from the log Jacobian determinants of 429 in utero T2w MRI scans, (n = 67 controls, 362 CHD) acquired during the third trimester. We fit general linear models to test whether age, sex, expected cerebral substrate delivery and CHD diagnosis were significant predictors of structural covariance.

Results

We identified significant effects of age, sex, cerebral substrate delivery, and specific CHD diagnosis across a variety of SCNs, including primary motor and sensory cortices, cerebellar regions, frontal cortex, extra-axial CSF, thalamus, brainstem, and insula, consistent with widespread coordinated aberrant maturation of specific brain regions over the third trimester.

Conclusions

SCNs offer a sensitive, data-driven approach to explore whole-brain structural changes without anatomical priors. We used them to stratify a heterogenous CHD patient cohort, highlighting similarities and differences between diagnoses during fetal neurodevelopment. Although there was a clear effect of abnormal fetal hemodynamics on structural brain maturation, our results suggest that this alone does not explain all the variation in brain development between individuals with CHD.
Cryo-EM structures of human cone visual pigments
Authors: Peng Qi , Li Jian , Jiang Haihai , Cheng Xinyu , Lu Qiuyuan , Zhou Sili , Zhang Yuting , Lv Sijia , Wan Shuangyan , Yang Tingting , Chen Yixiang , Zhang Wei , Nan Weiwei , Che Tong , Li Yanyan , Liao Hongfei , Zhang Jin
Published: February 2024

Trichromatic color vision in humans constitutes a pivotal evolutionary adaptation, endowing individuals with the capacity to discern and discriminate a diverse spectrum of colors. This unique visual capability confers a selective advantage crucial for successful adaptation, survival, and reproductive success in the natural environment. Color vision in humans is facilitated by the red, green, and blue cone visual pigments within cone photoreceptor cells. These pigments consist of a G-protein-coupled receptor opsin apoprotein and a chromophore covalently linked to opsins. Despite the elucidated structure of rhodopsin, the structures of cone visual pigments have yet to be determined. Here, we present the cryo-EM structures of three human cone visual pigments in complex with G proteins. Our structural analysis reveals detailed interactions between cone opsins, all-trans-retinal, and G proteins, indicating their active state. We also provide a concise summary and analysis of mutations in human cone opsins, elucidating potential relationships between residue substitutions and spectral tuning. Notably, S1162.67Y, A2335.52S, Y2776.44F were found to induce a blue shift in the absorption spectrum of the red-pigment, while the substitutions W2816.48Y and K3127.43A resulted in the absence of the absorption spectrum. The structural elucidation of human cone visual pigments significantly contributes to our understanding of how distinct types of cone cells perceive light across varying wavelengths. Furthermore, it provides a deeper insight into the functioning of the human trichromatic vision system, probing the mechanisms enabling humans to perceive a broad spectrum of colors.
Upregulated cholesterol biosynthesis facilitates the survival of methylation-retaining AML cells following decitabine treatment
Authors: Bond Danielle R , Burnard Sean M , Uddipto Kumar , Hunt Kooper V , Harvey Brooke M , Reinhardt Luiza Steffens , Lawlor-O’Neill Charley , Roper Ellise A , Humphries Sam , Murray Heather C. , Bowden Nikola A , Enjeti Anoop K , Verrills Nicole M , Riveros Carlos , Cao Kim-Anh Lê , Lee Heather J
Published: February 2024

DNA hypomethylating agents (HMAs) are used to treat acute myeloid leukaemia (AML) and myelodysplasia patients who are unsuitable for intensive chemotherapy, but low response rates and therapy-resistant relapse remain significant challenges. To optimise HMA efficacy, we must understand how resistance and relapse arise from cells that survive treatment. Here we combine single-cell multi-omic analysis with parallel colony-forming assays to link HMA-induced molecular heterogeneity with functional consequences in AML cells. HMAs, azacytidine (AZA) and decitabine (DAC), induced global epigenetic heterogeneity associated with upregulation of inflammatory responses and cell death pathways in a subset of hypomethylated cells. Some AML cells maintained high DNA methylation during treatment, and these methylation-retaining cells had increased self-renewal capacity following DAC, but not AZA. Molecular profiling of individual colonies revealed upregulated cholesterol biosynthesis as an adaptation to HMA treatment, and inhibition by rosuvastatin enhanced DAC effectsin vitroandin vivo. Thus, HMA-induced heterogeneity has important implications for AML cell growth and statins are a candidate co-treatment strategy to delay or prevent HMA-resistant relapse.
Simultaneous Identification of Changepoints and Model Parameters in Switching Dynamical Systems
Authors: Fu Xiaoming , Fan Kai , Zozmann Heinrich , Schüler Lennart , Calabrese Justin M.
Published: February 2024

Many complex natural systems undergo shifts in dynamics at particular points in time. Examples include phase transitions in gene expression during the cell cycle, introduced species affecting predator-prey interactions, and disease outbreaks responding to intervention measures. Such changepoints partition timeseries into different dynamical regimes characterized by distinct parameter sets, and inference on both the changepoints and regime-specific dynamical parameters is of primary interest. Conventional approaches to analyzing switching dynamical systems first estimate changepoints, and then estimate dynamical parameters assuming the changepoints are fixed and known. Such two-stage approaches are ad-hoc, can introduce biases in the analysis, and do not fully account for uncertainty. Here, we introduce a rigorous, simulation-based inference framework that simultaneously estimates changepoints and model parameters from noisy data while admitting full uncertainty. We use simulation studies of oscillatory predator-prey dynamics and stochastic gene expression to demonstrate that our method yields accurate estimates of changepoints and model parameters together with appropriate uncertainty bounds. We then apply our approach to a real-world case study of COVID-19 intervention effects, and show that our inferred changepoints aligned closely with the actual dates of intervention implementation. Taken together, these results suggest that our framework will have broad utility in diverse scientific domains.
ENT3C: an entropy-based similarity measure for Hi-C and micro-C derived contact matrices
Authors: Lainscsek Xenia , Taher Leila
Published: February 2024

Hi-C and micro-C sequencing have shed light on the profound importance of 3D genome organization in cellular function by probing 3D contact frequencies across the linear genome. The resulting contact matrices are extremely sparse and susceptible to technical- and sequence-based biases, making their comparison challenging. The development of reliable, robust and efficient methods for quantifying similarity between contact matrix is crucial for investigating variations in the 3D genome organization between different cell types or under different conditions, as well as evaluating experimental reproducibility. We present a novel method, ENT3C, which measures the change in pattern complexity in the vicinity of contact matrix diagonals to quantify their similarity. ENT3C provides a robust, user-friendly Hi-C or micro-C contact matrix similarity metric and a characteristic entropy signal that can be used to gain detailed biological insights into 3D genome organization.

Availability

https://github.com/xX3N1A/ENT3C
Sequence, Structure and Functional space ofDrosophila de novoproteins
Authors: Middendorf Lasse , Iyengar Bharat Ravi , Eicholt Lars A.
Published: February 2024

Duringde novoemergence, new protein coding genes emerge from previously non-genic sequences. Thede novoproteins they encode are dissimilar in composition and predicted biochemical properties to conserved proteins. However, many functionalde novoproteins indeed exist. Both identification of functionalde novoproteins and their structural characterisation are experimentally laborious. To identify functional and structuredde novoproteinsin silico, we applied recently developed machine learning based tools and refined the results forde novoproteins. We found that mostde novoproteins are indeed different from conserved proteins both in their structure and sequence. However, somede novoproteins are predicted to adopt known protein folds, participate in cellular reactions, and to form biomolecular condensates. Apart from broadening our understanding ofde novoprotein evolution, our study also provides a large set of testable hypotheses for focused experimental studies on structure and function ofde novoproteins inDrosophila.