tbuckley/cabot-search huggingface dataset:
SIRT1 improves lactate homeostasis in the brain to alleviate parkinsonism via deacetylation and inhibition of PKM2
Authors: Bolin Lian, Jing Zhang, Xiang Yin, Jiayan Wang, Li Li, Qianqian Ju, Yuejun Wang, Yuhui Jiang, Xiaoyu Liu, Yu Chen, Xin Tang, Cheng Sun
Journal: Cell Reports Medicine (2024)

Sirtuin 1 (SIRT1) is a histone deacetylase and plays diverse functions in various physiological events, from development to lifespan regulation. Here, in Parkinson's disease (PD) model mice, we demonstrated that SIRT1 ameliorates parkinsonism, while SIRT1 knockdown further aggravates PD phenotypes. Mechanistically, SIRT1 interacts with and deacetylates pyruvate kinase M2 (PKM2) at K135 and K206, thus leading to reduced PKM2 enzyme activity and lactate production, which eventually results in decreased glial activation in the brain. Administration of lactate in the brain recapitulates PD-like phenotypes. Furthermore, increased expression of PKM2 worsens PD symptoms, and, on the contrary, inhibition of PKM2 by shikonin or PKM2-IN-1 alleviates parkinsonism in mice. Collectively, our data indicate that excessive lactate in the brain might be involved in the progression of PD. By improving lactate homeostasis, SIRT1, together with PKM2, are likely drug targets for developing agents for the treatment of neurodegeneration in PD.
Disparities in clinical studies of AI enabled applications from a global perspective
Authors: Rui Yang, Sabarinath Vinod Nair, Yuhe Ke, Danny D’Agostino, Mingxuan Liu, Yilin Ning, Nan Liu
Journal: npj Digital Medicine (2024)

Artificial intelligence (AI) has been extensively researched in medicine, but its practical application remains limited. Meanwhile, there are various disparities in existing AI-enabled clinical studies, which pose a challenge to global health equity. In this study, we conducted an in-depth analysis of the geo-economic distribution of 159 AI-enabled clinical studies, as well as the gender disparities among these studies. We aim to reveal these disparities from a global literature perspective, thus highlighting the need for equitable access to medical AI technologies.
Experiences of menopause among non-binary and trans people
Authors: Michael Toze, Sue Westwood
Journal: International Journal of Transgender Health (2024)

Conventional categorizations of menopause can be difficult to apply to trans, gender non-conforming and non-binary (TGNB) populations. Menopause has biological, psychological and social meanings that may be hard to clearly apply within a context of diverse experiences of sex and gender. Nonetheless, some TGNB people do experience menopause, and their experiences may be different from those of other groups due to those diverse biopsychosocial understandings and experiences. This paper thematically analyses the responses of 15 TGNB respondents who responded to a larger survey about LGBTQ+ experiences of menopause. Two key themes were identified: Menopause and embodied identities, and Navigating gender normativity and gender binarism. The first of these contains two sub-themes, shifting and (un)settled gender identities, and embodied dis/connections with femaleness. These findings appear to be comparatively novel within the published academic literature but potentially have some parallels with prior observations regarding interactions between puberty and gender identity, and also regarding TGNB people's experiences of challenges in navigating other health and life experiences normatively understood as female. These explorations raise a number of potentially sensitive questions, given the current debate and controversies around gender, sex and identity. Nonetheless, they point to a need for further research and practice into menopause that is inclusive and supportive of a range of gender and sexual identities.
A Small‐Molecule NIR‐II Probe for the Diagnosis of Hemorrhagic Diseases
Authors: Jinwei Li, Tongtong Xu, Jiabei Chen, Xiaoyan He, Renwei Ma, Xiuhong Lu, Jialu Yuan, Minghua Yao, Yaohui Tang, Jianfeng Li
Journal: Advanced Healthcare Materials (2024)

Numerous hemorrhagic disorders, particularly those presenting deep hemorrhage, pose diagnostic challenges, often leading to delayed treatment and severe outcomes. Near-infrared (NIR)-II fluorescence imaging offers advantages such as deep tissue penetration, real-time visualization, and a high signal-to-background ratio, making it highly suitable for diagnosing hemorrhagic diseases. In this study, an NIR-II fluorescent probe LJ-2P carrying carboxylic and phosphoric acid groups is successfully applied for imaging hemorrhagic diseases. LJ-2P demonstrates a strong affinity for fibrinogen and fibrin clots both computationally and experimentally, thus exhibiting increased brightness upon coagulation. As compared to Indocyanine Green, LJ-2P provides a longer imaging window, higher imaging specificity, and signal-to-background ratio, as well as superior photobleaching resistance in three disease models: gastric, pulmonary, and cerebral hemorrhages. These results reveal that LJ-2P demonstrates enhanced imaging capabilities, enabling precise identification of hemorrhagic sites.
Discovery of FeP/Carbon Dots Nanozymes for Enhanced Peroxidase‐Like Catalytic and Antibacterial Activity
Authors: Jiaxin Dong, Guanxiong Liu, Yuri V. Petrov, Yujie Feng, Dechang Jia, Vladimir E Baulin, Aslan Yu Tsivadze, Yu Zhou, Baoqiang Li
Journal: Advanced Healthcare Materials (2024)

Iron phosphide/carbon (FeP/C) serving as electrocatalysts exhibit excellent activity in oxygen reduction reaction (ORR) process. H
Microbial intestinal dysbiosis drives long-term allergic susceptibility by sculpting an ILC2-B1 cell–innate IgE axis.
Authors: Ahmed Kabil, Natalia Nayyar, Julyanne Brassard, Yicong Li, Sameeksha Chopra, Michael R. Hughes, Kelly M. McNagny
Journal: Journal of Allergy and Clinical Immunology (2024)

Graphical abstractAbstractBackgroundThe abundance and diversity of intestinal commensal bacteria influence systemic immunity with impact on disease susceptibility and severity. For example, loss of short chain fatty acid (SCFA)-fermenting bacteria in early life (humans and mice) is associated with enhanced type 2 immune responses in peripheral tissues including the lung.ObjectiveOur goal was to reveal the microbiome-dependent cellular and molecular mechanisms driving enhanced susceptibility to type 2 allergic lung disease.MethodsWe used low-dose vancomycin to selectively deplete SCFA-fermenting bacteria in wild-type mice. We then examined the frequency and activation status of innate and adaptive immune cell lineages with and without SCFA supplementation. Finally, we used ILC2-deficient and signal transducer and activator of transcription 6 (STAT6)-deficient transgenic mouse strains to delineate the cellular and cytokine pathways leading to enhanced allergic disease susceptibility.ResultsMice with vancomycin-induced dysbiosis exhibited a 2-fold increase in lung ILC2 primed to produce elevated levels of IL-2, -5, and -13. In addition, upon IL-33 inhalation, mouse lung ILC2 displayed a novel ability to produce high levels of IL-4. These expanded and primed ILC2s drove B1 cell expansion and IL-4–dependent production of IgE that in turn led to exacerbated allergic inflammation. Importantly, these enhanced lung inflammatory phenotypes in mice with vancomycin-induced dysbiosis were reversed by administration of dietary SCFA (specifically butyrate).ConclusionSCFAs regulate an ILC2–B1 cell–IgE axis. Early-life administration of vancomycin, an antibiotic known to deplete SCFA-fermenting gut bacteria, primes and amplifies this axis and leads to lifelong enhanced susceptibility to type 2 allergic lung disease.
Engineering Lipid‐Based Pop‐up Conductive Interfaces with PEDOT:PSS and Light‐Responsive Azopolymer Films
Authors: Luca Terenzi, Ziyu Gao, Mehdi Ravandeh, Chiara Fedele, Lasse Hyldgaard Klausen, Claudia Latte Bovio, Arri Priimagi, Francesca Santoro
Journal: Advanced Healthcare Materials (2024)

Significant challenges have emerged in the development of biomimetic electronic interfaces capable of dynamic interaction with living organisms and biological systems, including neurons, muscles, and sensory organs. Yet, there remains a need for interfaces that can function on demand, facilitating communication and biorecognition with living cells in bioelectronic systems. In this study, the design and engineering of a responsive and conductive material with cell-instructive properties, allowing for the modification of its topography through light irradiation, resulting in the formation of "pop-up structures", is presented. A deformable substrate, composed of a bilayer comprising a light-responsive, azobenzene-containing polymer, pDR1m, and a conductive polymer, PEDOT:PSS, is fabricated and characterized. Moreover, the successful formation of supported lipid bilayers (SLBs) and the maintenance of integrity while deforming the pDR1m/PEDOT:PSS films represent promising advancements for future applications in responsive bioelectronics and neuroelectronic interfaces.
A Microfluidic 3D‐Tumor‐Spheroid Model for the Evaluation of Targeted Therapies from Angiogenesis‐Related Cytokines at the Single Spheroid Level
Authors: Mengqi Liu, Yihe Wang, Chao Wang, Ping Li, Jiaoyan Qiu, Ningkai Yang, Mingyuan Sun, Lin Han
Journal: Advanced Healthcare Materials (2024)

Angiogenesis is a key player in drug resistance to targeted therapies for breast cancer. The average expression of angiogenesis-related cytokines is widely associated with the treatments of target therapies for a population of cells or spheroids, overlooking the distinct responses for individuals. In this work, a highly integrated microfluidic platform is developed for the generation of monodisperse multicellular tumor spheroids (MTSs), drug treatments, and the measurement of cytokines for individual MTSs in a single chip. The platform allows the correlation evaluation between cytokine secretion and drug treatment at the level of individual spheroids. For validation, quantities of six representative proangiogenic cytokines are tested against treatments with four model drugs at varying times and concentrations. By applying a linear regression model, significant correlations are established between cytokine secretion and the treated drug concentration for individual spheroids. The proposed platform provides a high-throughput method for the investigation of the molecular mechanism of the cytokine response to targeted therapies and paves the way for future drug screening using predictive regression models at the single-spheroid level.
White matter damage and degeneration in traumatic brain injury
Authors: Regina C. Armstrong, Genevieve M. Sullivan, Daniel P. Perl, Jessica D. Rosarda, Kryslaine L. Radomski
Journal: Trends in Neurosciences (2024)

Traumatic brain injury (TBI) is a complex condition that can resolve over time but all too often leads to persistent symptoms, and the risk of poor patient outcomes increases with aging. TBI damages neurons and long axons within white matter tracts that are critical for communication between brain regions; this causes slowed information processing and neuronal circuit dysfunction. This review focuses on white matter injury after TBI and the multifactorial processes that underlie white matter damage, potential for recovery, and progression of degeneration. A multiscale perspective across clinical and preclinical advances is presented to encourage interdisciplinary insights from whole-brain neuroimaging of white matter tracts down to cellular and molecular responses of axons, myelin, and glial cells within white matter tissue.
Effective knockdown - replace gene therapy in a novel mouse model of DNM1 developmental and epileptic encephalopathy
Authors: Devin J. Jones, Divya Soundararajan, Noah K. Taylor, Osasumwen V. Aimiuwu, Pranav Mathkar, Amy Shore, Jia Jie Teoh, Wanqi Wang, Tristan T. Sands, Matthew C. Weston, Scott Q. Harper, Wayne N. Frankel
Journal: Molecular Therapy (2024)

Effective gene therapy for gain-of-function or dominant-negative disease mutations may require eliminating expression of the mutant copy together with wild-type replacement. We evaluated such a knockdown-replace strategy in a mouse model of DNM1 disease, a debilitating and intractable neurodevelopmental epilepsy. To challenge the approach robustly, we expressed a patient-based variant in GABAergic neurons-which resulted in growth delay and lethal seizures evident by postnatal week three-and delivered to newborn pups an AAV9-based vector encoding a ubiquitously expressed, Dnm1-specific interfering RNA (RNAi) bivalently in tail-to-tail configuration with a neuron-specific, RNAi-resistant, codon-optimized Dnm1 cDNA. Pups receiving RNAi or cDNA alone fared no better than untreated pups, whereas the vast majority of mutants receiving modest doses survived with almost full growth recovery. Synaptic recordings of cortical neurons derived from treated pups revealed that significant alterations in transmission from inhibitory to excitatory neurons were rectified by bivalent vector application. To examine the mutant transcriptome and impact of treatment, we used RNA sequencing and functional annotation clustering. Mutants displayed abnormal expression of more than 1,000 genes in highly significant and relevant functional clusters, clusters that were abrogated by treatment. Together these results suggest knockdown-replace as a potentially effective strategy for treating DNM1 and related genetic neurodevelopmental disease.
Corrigendum to “Cascade-targeting polymeric particles eliminate intracellular C. neoformans in fungal infection therapy” [Journal of Controlled Release 373 (2024) 399–409]
Authors: Yinglan Yu, Xuefeng Tang, Liya Zhou, Fanshu Xu, Ying Zhang, Linggao Zeng, Jun Li, Guojian Liao, Lei Luo
Journal: Journal of Controlled Release (2024)
Salpingectomy versus tubal occlusion in laparoscopic sterilisation (SALSTER): a national register-based randomised non-inferiority trial
Authors: Annika Strandell, Leonidas Magarakis, Karin Sundfeldt, Mathias Pålsson, Per Liv, Annika Idahl
Journal: The Lancet Regional Health - Europe (2024)

Opportunistic salpingectomy to reduce ovarian cancer incidence has become increasingly common despite the lack of randomised trials investigating its safety. In SALSTER, we tested whether salpingectomy for laparoscopic sterilisation is non-inferior to tubal occlusion regarding complications up to eight weeks postoperatively. SALSTER is a register-based randomised non-inferiority trial in which 41 gynaecological departments in Sweden participated. After being reported to The Swedish National Quality Register of Gynaecological Surgery (GynOp) for laparoscopic sterilisation, women aged <50 years received study information and could consent to participation online. If eligible, randomisation was performed by the examining/operating gynaecologist before surgery, with stratification for centre, and allocation 1:1 to salpingectomy or tubal occlusion. Blinding was attempted for patients but was impossible for surgeons. The first primary outcome, any complication up to eight weeks postoperatively, was routinely reported in GynOp through physician assessment of patient questionnaires, medical records and personal contact. Complications up to eight weeks postoperatively, a primary safety outcome, were analysed in the per-protocol population. The non-inferiority margin for the difference in the absolute risk of complications was defined as ten percentage points. Missing data were handled using multiple imputation. SALSTER was registered at ClinicalTrials.gov (NCT03860805). Between April 4, 2019, and March 31, 2023, 539 women were randomised to salpingectomy and 527 to tubal occlusion. In the salpingectomy and tubal occlusion arms, 40 and 18 women discontinued their participation in the trial and another 26 and 10 did not receive the allocated surgery, respectively. Calculated on imputed data, any complication up to eight weeks postoperatively occurred in 8.1% (38.5/473) of patients after salpingectomy and in 6.2% (31.0/499) of patients after tubal occlusion. The risk difference was 1.9 percentage points (95% confidence interval -1.4 to 5.3). Laparoscopic salpingectomy is non-inferior to tubal occlusion regarding complication rates up to eight weeks postoperatively. This research was funded by the Swedish Cancer Society, the Lena Wäppling foundation, the Swedish state under the ALF-agreement, Umeå University, County of Värmland, and Gothenburg Society of Medicine.
Species‐level, metagenomic and proteomic analysis of microbe‐immune interactions in severe asthma
Authors: Maisha F. Jabeen, Nicholas D. Sanderson, Mariaenrica Tinè, Gillian Donachie, Clair Barber, Adnan Azim, Laurie C. K. Lau, Thomas Brown, Ian D. Pavord, Anoop Chauhan, Paul Klenerman, Teresa L. Street, Emanuele Marchi, Peter H. Howarth, Timothy S. C. Hinks
Journal: Allergy (2024)

Abstract Background The airway microbiome in severe asthma has not been characterised at species‐level by metagenomic sequencing, nor have the relationships between specific species and mucosal immune responses in ‘type‐2 low’, neutrophilic asthma been defined. We performed an integrated species‐level metagenomic data with inflammatory mediators to characterise prevalence of dominant potentially pathogenic organisms and host immune responses. Methods Sputum and nasal lavage samples were analysed using long‐read metagenomic sequencing with Nanopore and qPCR in two cross‐sectional adult severe asthma cohorts, Wessex ( n = 66) and Oxford ( n = 30). We integrated species‐level data with clinical parameters and 39 selected airway proteins measured by immunoassay and O‐link. Results The sputum microbiome in health and mild asthma displayed comparable microbial diversity. By contrast, 23% (19/81) of severe asthma microbiomes were dominated by a single respiratory pathogen, namely H. influenzae ( n = 10), M. catarrhalis ( n = 4), S. pneumoniae ( n = 4) and P. aeruginosa ( n = 1). Neutrophilic asthma was associated with H. influenzae, M. catarrhalis, S. pneumoniae and T. whipplei with elevated type‐1 cytokines and proteases; eosinophilic asthma with higher M. catarrhalis , but lower H. influenzae , and S. pneumoniae abundance. H. influenzae load correlated with Eosinophil Cationic Protein, elastase and IL‐10. R. mucilaginosa associated positively with IL‐6 and negatively with FGF. Bayesian network analysis also revealed close and distinct relationships of H. influenzae and M. catarrhalis with type‐1 airway inflammation. The microbiomes and cytokine milieu were distinct between upper and lower airways. Conclusions This species‐level integrated analysis reveals central, but distinct associations between potentially pathogenic bacteria and airways inflammation in severe asthma.
An autoantibody profile identified by human genome‐wide protein arrays in rheumatoid arthritis
Authors: Xu Liu, Xiaoying Zhang, Yu‐Jian Kang, Fei Huang, Shuang Liu, Yixue Guo, Yingni Li, Changcheng Yin, Mingling Liu, Qimao Han, Qingwen Wang, Hua Ye, Haihong Yao, Chun Li, Jiahe Li, Wangzha Pingcuo, Yan Zhang, Yin Su, Ge Gao, Zhanguo Li, Xiaolin Sun
Journal: MedComm (2024)

Abstract Precise diagnostic biomarkers of anticitrullination protein antibody (ACPA)‐negative and early‐stage RA are still to be improved. We aimed to screen autoantibodies in ACPA‐negative patients and evaluated their diagnostic performance. The human genome‐wide protein arrays (HuProt arrays) were used to define specific autoantibodies from the sera of 182 RA patients and 261 disease and healthy controls. Statistical analysis was performed with SPSS 17.0. In Phase I study, 51 out of 19,275 recombinant proteins covering the whole human genome were selected. In Phase II validation study, anti‐ANAPC15 (anaphase promoting complex subunit 15) exhibited 41.8% sensitivity and 91.5% specificity among total RA patients. There were five autoantibodies increased in ACPA‐negative RA, including anti‐ANAPC15, anti‐LSP1, anti‐APBB1, anti‐parathymosin, and anti‐UBL7. Anti‐ parathymosin showed the highest prevalence of 46.2% ( p = 0.016) in ACPA‐negative early stage (&lt;2 years) RA. To further improve the diagnostic efficacy, a prediction model was constructed with 44 autoantibodies. With increased threshold for RA calling, the specificity of the model is 90.8%, while the sensitivity is 66.1% (87.8% in ACPA‐positive RA and 23.8% in ACPA‐negative RA) in independent testing patients. Therefore, HuProt arrays identified RA‐associated autoantibodies that might become possible diagnostic markers, especially in early stage ACPA‐negative RA.
PITX2 deficiency leads to atrial mitochondrial dysfunction
Authors: Jasmeet S Reyat, Laura C Sommerfeld, Molly O’Reilly, Victor Roth Cardoso, Ellen Thiemann, Abdullah O Khan, Christopher O’Shea, Sönke Harder, Christian Müller, Jonathan Barlow, Rachel J Stapley, Winnie Chua, S Nashitha Kabir, Olivia Grech, Oliver Hummel, Norbert Hübner, Stefan Kääb, Lluis Mont, Stéphane N Hatem, Joris Winters, Stef Zeemering, Neil V Morgan, Julie Rayes, Katja Gehmlich, Monika Stoll, Theresa Brand, Michaela Schweizer, Angelika Piasecki, Ulrich Schotten, Georgios V Gkoutos, Kristina Lorenz, Friederike Cuello, Paulus Kirchhof, Larissa Fabritz
Journal: Cardiovascular Research (2024)

Abstract Aims Reduced left atrial PITX2 is associated with atrial cardiomyopathy and atrial fibrillation (AF). PITX2 is restricted to left atrial cardiomyocytes (aCMs) in the adult heart. The links between PITX2 deficiency, atrial cardiomyopathy, and AF are not fully understood. Methods and results To identify mechanisms linking PITX2 deficiency to AF, we generated and characterized PITX2-deficient human aCMs derived from human induced pluripotent stem cells (hiPSC) and their controls. PITX2-deficient hiPSC-derived atrial cardiomyocytes showed shorter and disorganized sarcomeres and increased mononucleation. Electron microscopy found an increased number of smaller mitochondria compared with isogenic controls. Mitochondrial protein expression was altered in PITX2-deficient hiPSC-derived atrial cardiomyocytes. Single-nuclear RNA-sequencing found differences in cellular respiration pathways and differentially expressed mitochondrial and ion channel genes in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2 repression in hiPSC-derived atrial cardiomyocytes replicated dysregulation of cellular respiration. Mitochondrial respiration was shifted to increased glycolysis in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2-deficient human hiPSC-derived atrial cardiomyocytes showed higher spontaneous beating rates. Action potential duration was more variable with an overall prolongation of early repolarization, consistent with metabolic defects. Gene expression analyses confirmed changes in mitochondrial genes in left atria from 42 patients with AF compared with 43 patients with sinus rhythm. Dysregulation of left atrial mitochondrial (COX7C) and metabolic (FOXO1) genes was associated with PITX2 expression in human left atria. Conclusion PITX2 deficiency causes atrial mitochondrial dysfunction and a metabolic shift to glycolysis in human aCMs. PITX2-dependent metabolic changes can contribute to the structural and functional defects found in PITX2-deficient atria.
Ce<sub>12</sub>V<sub>6</sub> Clusters with Multi‐Enzymatic Activities for Sepsis Treatment
Authors: Di Liu, Si Sun, Huanhuan Qiao, Qi Xin, Sufei Zhou, Lingxia Li, Nan Song, Lijie Zhang, Qi Chen, Fangzhen Tian, Xiaoyu Mu, Shaofang Zhang, Jing Zhang, Meili Guo, Hao Wang, Xiao‐Dong Zhang, Ruiping Zhang
Journal: Advanced Healthcare Materials (2024)

Artificial enzymes, especially nanozymes, have attracted wide attention due to their controlled catalytic activity, selectivity, and stability. The rising Cerium-based nanozymes exhibit unique SOD-like activity, and Vanadium-based nanozymes always hold excellent GPx-like activity. However, most inflammatory diseases involve polymerase biocatalytic processes that require multi-enzyme activities. The nanocomposite can fulfill multi-enzymatic activity simultaneously, but large nanoparticles (>10 nm) cannot be excreted rapidly, leading to biosafety challenges. Herein, atomically precise Ce