bluuebunny/crossref_metadata_2025 huggingface dataset:
Dysfunctional endocannabinoid CB1 receptor expression and signaling contribute to skeletal muscle cell toxicity induced by simvastatin
Authors: Kalkan Hilal , Panza Elisabetta , Pagano Ester , Ercolano Giuseppe , Moriello Claudia , Piscitelli Fabiana , Sztretye Mónika , Capasso Raffaele , Di Marzo Vincenzo , Iannotti Fabio Arturo
Published: August 2023

Statins are the most prescribed lipid-lowering agents worldwide. Their use is generally safe, although muscular toxicity occurs in about 1 in 10.000 patients. In this study, we explored the role of the endocannabinoid system (ECS) during muscle toxicity induced by simvastatin. In murine C2C12 myoblasts exposed to simvastatin, levels of the endocannabinoids AEA and 2-AG as well the expression of specific miRNAs (in particular miR-152) targeting the endocannabinoid CB1 gene were increased in a time-dependent manner. Rimonabant, a selective CB1 antagonist, exacerbated simvastatin-induced toxicity in myoblasts, while only a weak opposite effect was observed with ACEA and GAT211, selective orthosteric and allosteric agonists of CB1 receptor, respectively. In antagomiR152-transfected myoblasts, simvastatin toxicity was in part prevented together with the functional rescue of CB1. Further analyses revealed that simvastatin in C2C12 cells also suppresses PKC and ERK signaling pathways, which are instead activated downstream of CB1 receptor stimulation, thus adding more insight into the mechanism causing CB1 functional inactivation. Importantly, simvastatin induced similar alterations in skeletal muscles of C57BL/6 J mice and primary human myoblasts. In sum, we identified the dysregulated expression of the endocannabinoid CB1 receptor as well as the impairment of its downstream signaling pathways as a novel pathological mechanism involved in statin-induced myopathy.
Haspin balances the ratio of asymmetric cell division through Wnt5a and regulates cell fate decisions in mouse embryonic stem cells
Authors: Gao Yingying , Ma Bin , Li Yifan , Wu Xiangyu , Zhao Shifeng , Guo Huiping , Wang Yiwei , Sun Lihua , Xie Jing
Published: August 2023

Many different types of stem cells utilize asymmetric cell division (ACD) to produce two daughter cells with distinct fates. Haspin-catalyzed phosphorylation of histone H3 at Thr3 (H3T3ph) plays important roles during mitosis, including ACD in stem cells. However, whether and how Haspin functions in ACD regulation remains unclear. Here, we report that Haspin knockout (Haspin-KO) mouse embryonic stem cells (mESCs) had increased ratio of ACD, which cumulatively regulates cell fate decisions. Furthermore, Wnt5a is significantly downregulated due to decreased Pax2 in Haspin-KO mESCs. Wnt5a knockdown mESCs phenocopied Haspin-KO cells while overexpression of Wnt5a in Haspin-KO cells rescued disproportionated ACD. Collectively, Haspin is indispensable for mESCs to maintain a balanced ratio of ACD, which is essential for normal development and homeostasis.
Persistent symptoms after COVID-19 are not associated with differential SARS-CoV-2 antibody or T cell immunity
Authors: Altmann Daniel M. , Reynolds Catherine J. , Joy George , Otter Ashley D. , Gibbons Joseph M. , Pade Corinna , Swadling Leo , Maini Mala K. , Brooks Tim , Semper Amanda , McKnight Áine , Noursadeghi Mahdad , Manisty Charlotte , Treibel Thomas A. , Moon James C. ,   COVIDsortium investigators, Boyton Rosemary J.
Published: August 2023

Among the unknowns in decoding the pathogenesis of SARS-CoV-2 persistent symptoms in Long Covid is whether there is a contributory role of abnormal immunity during acute infection. It has been proposed that Long Covid is a consequence of either an excessive or inadequate initial immune response. Here, we analyze SARS-CoV-2 humoral and cellular immunity in 86 healthcare workers with laboratory confirmed mild or asymptomatic SARS-CoV-2 infection during the first wave. Symptom questionnaires allow stratification into those with persistent symptoms and those without for comparison. During the period up to 18-weeks post-infection, we observe no difference in antibody responses to spike RBD or nucleoprotein, virus neutralization, or T cell responses. Also, there is no difference in the profile of antibody waning. Analysis at 1-year, after two vaccine doses, comparing those with persistent symptoms to those without, again shows similar SARS-CoV-2 immunity. Thus, quantitative differences in these measured parameters of SARS-CoV-2 adaptive immunity following mild or asymptomatic acute infection are unlikely to have contributed to Long Covid causality. ClinicalTrials.gov (NCT04318314).
A circuit suppressing retinal drive to the optokinetic system during fast image motion
Authors: Mani Adam , Yang Xinzhu , Zhao Tiffany A. , Leyrer Megan L. , Schreck Daniel , Berson David M.
Published: August 2023

Optokinetic nystagmus (OKN) assists stabilization of the retinal image during head rotation. OKN is driven by ON direction selective retinal ganglion cells (ON DSGCs), which encode both the direction and speed of global retinal slip. The synaptic circuits responsible for the direction selectivity of ON DSGCs are well understood, but those sculpting their slow-speed preference remain enigmatic. Here, we probe this mechanism in mouse retina through patch clamp recordings, functional imaging, genetic manipulation, and electron microscopic reconstructions. We confirm earlier evidence that feedforward glycinergic inhibition is the main suppressor of ON DSGC responses to fast motion, and reveal the source for this inhibition—the VGluT3 amacrine cell, a dual neurotransmitter, excitatory/inhibitory interneuron. Together, our results identify a role for VGluT3 cells in limiting the speed range of OKN. More broadly, they suggest VGluT3 cells shape the response of many retinal cell types to fast motion, suppressing it in some while enhancing it in others.
Data-mining unveils structure–property–activity correlation of viral infectivity enhancing self-assembling peptides
Authors: Kaygisiz Kübra , Rauch-Wirth Lena , Dutta Arghya , Yu Xiaoqing , Nagata Yuki , Bereau Tristan , Münch Jan , Synatschke Christopher V. , Weil Tanja
Published: August 2023

Gene therapy via retroviral vectors holds great promise for treating a variety of serious diseases. It requires the use of additives to boost infectivity. Amyloid-like peptide nanofibers (PNFs) were shown to efficiently enhance retroviral gene transfer. However, the underlying mode of action of these peptides remains largely unknown. Data-mining is an efficient method to systematically study structure–function relationship and unveil patterns in a database. This data-mining study elucidates the multi-scale structure–property–activity relationship of transduction enhancing peptides for retroviral gene transfer. In contrast to previous reports, we find that not the amyloid fibrils themselves, but rather µm-sized β-sheet rich aggregates enhance infectivity. Specifically, microscopic aggregation of β-sheet rich amyloid structures with a hydrophobic surface pattern and positive surface charge are identified as key material properties. We validate the reliability of the amphiphilic sequence pattern and the general applicability of the key properties by rationally creating new active sequences and identifying short amyloidal peptides from various pathogenic and functional origin. Data-mining—even for small datasets—enables the development of new efficient retroviral transduction enhancers and provides important insights into the diverse bioactivity of the functional material class of amyloids.
Effect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer’s disease
Authors: Langella Stephanie , Barksdale N. Gil , Vasquez Daniel , Aguillon David , Chen Yinghua , Su Yi , Acosta-Baena Natalia , Acosta-Uribe Juliana , Baena Ana Y. , Garcia-Ospina Gloria , Giraldo-Chica Margarita , Tirado Victoria , Muñoz Claudia , Ríos-Romenets Silvia , Guzman-Martínez Claudia , Oliveira Gabriel , Yang Hyun-Sik , Vila-Castelar Clara , Pruzin Jeremy J. , Ghisays Valentina , Arboleda-Velasquez Joseph F. , Kosik Kenneth S. , Reiman Eric M. , Lopera Francisco , Quiroz Yakeel T.
Published: August 2023

Autosomal dominant Alzheimer’s disease (ADAD) is genetically determined, but variability in age of symptom onset suggests additional factors may influence cognitive trajectories. Although apolipoprotein E (APOE) genotype and educational attainment both influence dementia onset in sporadic AD, evidence for these effects in ADAD is limited. To investigate the effects ofAPOEand educational attainment on age-related cognitive trajectories in ADAD, we analyzed data from 675 Presenilin-1 E280A mutation carriers and 594 non-carriers. Here we show that age-related cognitive decline is accelerated in ADAD mutation carriers who also have anAPOEe4 allele compared to those who do not and delayed in mutation carriers who also have anAPOEe2 allele compared to those who do not. Educational attainment is protective and moderates the effect ofAPOEon cognition. Despite ADAD mutation carriers being genetically determined to develop dementia, age-related cognitive decline may be influenced by other genetic and environmental factors.
Cell type-specific delivery by modular envelope design
Authors: Strebinger Daniel , Frangieh Chris J. , Friedrich Mirco J. , Faure Guilhem , Macrae Rhiannon K. , Zhang Feng
Published: August 2023

The delivery of genetic cargo remains one of the largest obstacles to the successful translation of experimental therapies, in large part due to the absence of targetable delivery vectors. Enveloped delivery modalities use viral envelope proteins, which determine tropism and induce membrane fusion. Here we develop DIRECTED (Delivery to Intended REcipient Cells Through Envelope Design), a modular platform that consists of separate fusion and targeting components. To achieve high modularity and programmable cell type specificity, we develop multiple strategies to recruit or immobilize antibodies on the viral envelope, including a chimeric antibody binding protein and a SNAP-tag enabling the use of antibodies or other proteins as targeting molecules. Moreover, we show that fusogens from multiple viral families are compatible with DIRECTED and that DIRECTED components can target multiple delivery chassis (e.g., lentivirus and MMLV gag) to specific cell types, including primary human T cells in PBMCs and whole blood.
Type-2 CD8+ T-cell formation relies on interleukin-33 and is linked to asthma exacerbations
Authors: van der Ploeg Esmee K. , Krabbendam Lisette , Vroman Heleen , van Nimwegen Menno , de Bruijn Marjolein J. W. , de Boer Geertje M. , Bergen Ingrid M. , Kool Mirjam , Tramper-Standers Gerdien A. , Braunstahl Gert-Jan , Huylebroeck Danny , Hendriks Rudi W. , Stadhouders Ralph
Published: August 2023

CD4+ T helper 2 (Th2) cells and group 2 innate lymphoid cells are considered the main producers of type-2 cytokines that fuel chronic airway inflammation in allergic asthma. However, CD8+ cytotoxic T (Tc) cells - critical for anti-viral defense - can also produce type-2 cytokines (referred to as ‘Tc2’ cells). The role of Tc cells in asthma and virus-induced disease exacerbations remains poorly understood, including which micro-environmental signals and cell types promote Tc2 cell formation. Here we show increased circulating Tc2 cell abundance in severe asthma patients, reaching peak levels during exacerbations and likely emerging from canonical IFNγ+ Tc cells through plasticity. Tc2 cell abundance is associated with increased disease burden, higher exacerbations rates and steroid insensitivity. Mouse models of asthma recapitulate the human disease by showing extensive type-2 skewing of lung Tc cells, which is controlled by conventional type-1 dendritic cells and IFNγ. Importantly, we demonstrate that the alarmin interleukin-33 (IL-33) critically promotes type-2 cytokine production by lung Tc cells in experimental allergic airway inflammation. Our data identify Tc cells as major producers of type-2 cytokines in severe asthma and during exacerbations that are remarkably sensitive to alterations in their inflammatory tissue micro-environment, with IL-33 emerging as an important regulator of Tc2 formation.
Trim33 masks a non-transcriptional function of E2f4 in replication fork progression
Authors: Rousseau Vanessa , Einig Elias , Jin Chao , Horn Julia , Riebold Mathias , Poth Tanja , Jarboui Mohamed-Ali , Flentje Michael , Popov Nikita
Published: August 2023

Replicative stress promotes genomic instability and tumorigenesis but also presents an effective therapeutic endpoint, rationalizing detailed analysis of pathways that control DNA replication. We show here that the transcription factor E2f4 recruits the DNA helicase Recql to facilitate progression of DNA replication forks upon drug- or oncogene-induced replicative stress. In unperturbed cells, the Trim33 ubiquitin ligase targets E2f4 for degradation, limiting its genomic binding and interactions with Recql. Replicative stress blunts Trim33-dependent ubiquitination of E2f4, which stimulates transient Recql recruitment to chromatin and facilitates recovery of DNA synthesis. In contrast, deletion of Trim33 induces chronic genome-wide recruitment of Recql and strongly accelerates DNA replication under stress, compromising checkpoint signaling and DNA repair. Depletion of Trim33 in Myc-overexpressing cells leads to accumulation of replication-associated DNA damage and delays Myc-driven tumorigenesis. We propose that the Trim33-E2f4-Recql axis controls progression of DNA replication forks along transcriptionally active chromatin to maintain genome integrity.
Hypothermal opto-thermophoretic tweezers
Authors: Kollipara Pavana Siddhartha , Li Xiuying , Li Jingang , Chen Zhihan , Ding Hongru , Kim Youngsun , Huang Suichu , Qin Zhenpeng , Zheng Yuebing
Published: August 2023

Optical tweezers have profound importance across fields ranging from manufacturing to biotechnology. However, the requirement of refractive index contrast and high laser power results in potential photon and thermal damage to the trapped objects, such as nanoparticles and biological cells. Optothermal tweezers have been developed to trap particles and biological cells via opto-thermophoresis with much lower laser powers. However, the intense laser heating and stringent requirement of the solution environment prevent their use for general biological applications. Here, we propose hypothermal opto-thermophoretic tweezers (HOTTs) to achieve low-power trapping of diverse colloids and biological cells in their native fluids. HOTTs exploit an environmental cooling strategy to simultaneously enhance the thermophoretic trapping force at sub-ambient temperatures and suppress the thermal damage to target objects. We further apply HOTTs to demonstrate the three-dimensional manipulation of functional plasmonic vesicles for controlled cargo delivery. With their noninvasiveness and versatile capabilities, HOTTs present a promising tool for fundamental studies and practical applications in materials science and biotechnology.
Stable trapping of multiple proteins at physiological conditions using nanoscale chambers with macromolecular gates
Authors: Svirelis Justas , Adali Zeynep , Emilsson Gustav , Medin Jesper , Andersson John , Vattikunta Radhika , Hulander Mats , Järlebark Julia , Kolman Krzysztof , Olsson Oliver , Sakiyama Yusuke , Lim Roderick Y. H. , Dahlin Andreas
Published: August 2023

The possibility to detect and analyze single or few biological molecules is very important for understanding interactions and reaction mechanisms. Ideally, the molecules should be confined to a nanoscale volume so that the observation time by optical methods can be extended. However, it has proven difficult to develop reliable, non-invasive trapping techniques for biomolecules under physiological conditions. Here we present a platform for long-term tether-free (solution phase) trapping of proteins without exposing them to any field gradient forces. We show that a responsive polymer brush can make solid state nanopores switch between a fully open and a fully closed state with respect to proteins, while always allowing the passage of solvent, ions and small molecules. This makes it possible to trap a very high number of proteins (500-1000) inside nanoscale chambers as small as one attoliter, reaching concentrations up to 60 gL−1. Our method is fully compatible with parallelization by imaging arrays of nanochambers. Additionally, we show that enzymatic cascade reactions can be performed with multiple native enzymes under full nanoscale confinement and steady supply of reactants. This platform will greatly extend the possibilities to optically analyze interactions involving multiple proteins, such as the dynamics of oligomerization events.
Biology-guided deep learning predicts prognosis and cancer immunotherapy response
Authors: Jiang Yuming , Zhang Zhicheng , Wang Wei , Huang Weicai , Chen Chuanli , Xi Sujuan , Ahmad M. Usman , Ren Yulan , Sang Shengtian , Xie Jingjing , Wang Jen-Yeu , Xiong Wenjun , Li Tuanjie , Han Zhen , Yuan Qingyu , Xu Yikai , Xing Lei , Poultsides George A. , Li Guoxin , Li Ruijiang
Published: August 2023

Substantial progress has been made in using deep learning for cancer detection and diagnosis in medical images. Yet, there is limited success on prediction of treatment response and outcomes, which has important implications for personalized treatment strategies. A significant hurdle for clinical translation of current data-driven deep learning models is lack of interpretability, often attributable to a disconnect from the underlying pathobiology. Here, we present a biology-guided deep learning approach that enables simultaneous prediction of the tumor immune and stromal microenvironment status as well as treatment outcomes from medical images. We validate the model for predicting prognosis of gastric cancer and the benefit from adjuvant chemotherapy in a multi-center international study. Further, the model predicts response to immune checkpoint inhibitors and complements clinically approved biomarkers. Importantly, our model identifies a subset of mismatch repair-deficient tumors that are non-responsive to immunotherapy and may inform the selection of patients for combination treatments.
Mimicking reductive dehalogenases for efficient electrocatalytic water dechlorination
Authors: Min Yuan , Mei Shu-Chuan , Pan Xiao-Qiang , Chen Jie-Jie , Yu Han-Qing , Xiong Yujie
Published: August 2023

Electrochemical technology is a robust approach to removing toxic and persistent chlorinated organic pollutants from water; however, it remains a challenge to design electrocatalysts with high activity and selectivity as elaborately as natural reductive dehalogenases. Here we report the design of high-performance electrocatalysts toward water dechlorination by mimicking the binding pocket configuration and catalytic center of reductive dehalogenases. Specifically, our designed electrocatalyst is an assembled heterostructure by sandwiching a molecular catalyst into the interlayers of two-dimensional graphene oxide. The electrocatalyst exhibits excellent dechlorination performance, which enhances reduction of intermediate dichloroacetic acid by 7.8 folds against that without sandwich configuration and can selectively generate monochloro-groups from trichloro-groups. Molecular simulations suggest that the sandwiched inner space plays an essential role in tuning solvation shell, altering protonation state and facilitating carbon−chlorine bond cleavage. This work demonstrates the concept of mimicking natural reductive dehalogenases toward the sustainable treatment of organohalogen-contaminated water and wastewater.
Nano-metal diborides-supported anode catalyst with strongly coupled TaOx/IrO2 catalytic layer for low-iridium-loading proton exchange membrane electrolyzer
Authors: Wang Yuannan , Zhang Mingcheng , Kang Zhenye , Shi Lei , Shen Yucheng , Tian Boyuan , Zou Yongcun , Chen Hui , Zou Xiaoxin
Published: August 2023

The sluggish kinetics of oxygen evolution reaction (OER) and high iridium loading in catalyst coated membrane (CCM) are the key challenges for practical proton exchange membrane water electrolyzer (PEMWE). Herein, we demonstrate high-surface-area nano-metal diborides as promising supports of iridium-based OER nanocatalysts for realizing efficient, low-iridium-loading PEMWE. Nano-metal diborides are prepared by a novel disulphide-to-diboride transition route, in which the entropy contribution to the Gibbs free energy by generation of gaseous sulfur-containing products plays a crucial role. The nano-metal diborides, TaB2 in particular, are investigated as the support of IrO2 nanocatalysts, which finally forms a TaOx/IrO2 heterojunction catalytic layer on TaB2 surface. Multiple advantageous properties are achieved simultaneously by the resulting composite material (denoted as IrO2@TaB2), including high electrical conductivity, improved iridium mass activity and enhanced corrosion resistance. As a consequence, the IrO2@TaB2 can be used to fabricate the membrane electrode with a low iridium loading of 0.15 mg cm−2, and to give an excellent catalytic performance (3.06 A cm−2@2.0 V@80 oC) in PEMWE―the one that is usually inaccessible by unsupported Ir-based nanocatalysts and the vast majority of existing supported Ir-based catalysts at such a low iridium loading.
Self-triggered thermoelectric nanoheterojunction for cancer catalytic and immunotherapy
Authors: Yuan Xue , Kang Yong , Dong Jinrui , Li Ruiyan , Ye Jiamin , Fan Yueyue , Han Jingwen , Yu Junhui , Ni Guangjian , Ji Xiaoyuan , Ming Dong
Published: August 2023

The exogenous excitation requirement and electron-hole recombination are the key elements limiting the application of catalytic therapies. Here a tumor microenvironment (TME)-specific self-triggered thermoelectric nanoheterojunction (Bi0.5Sb1.5Te3/CaO2 nanosheets, BST/CaO2 NSs) with self-built-in electric field facilitated charge separation is fabricated. Upon exposure to TME, the CaO2 coating undergoes rapid hydrolysis, releasing Ca2+, H2O2, and heat. The resulting temperature difference on the BST NSs initiates a thermoelectric effect, driving reactive oxygen species production. H2O2 not only serves as a substrate supplement for ROS generation but also dysregulates Ca2+ channels, preventing Ca2+ efflux. This further exacerbates calcium overload-mediated therapy. Additionally, Ca2+ promotes DC maturation and tumor antigen presentation, facilitating immunotherapy. It is worth noting that the CaO2 NP coating hydrolyzes very slowly in normal cells, releasing Ca2+ and O2 without causing any adverse effects. Tumor-specific self-triggered thermoelectric nanoheterojunction combined catalytic therapy, ion interference therapy, and immunotherapy exhibit excellent antitumor performance in female mice.
Non-cell-autonomous cancer progression from chromosomal instability
Authors: Li Jun , Hubisz Melissa J. , Earlie Ethan M. , Duran Mercedes A. , Hong Christy , Varela Austin A. , Lettera Emanuele , Deyell Matthew , Tavora Bernardo , Havel Jonathan J. , Phyu Su M. , Amin Amit Dipak , Budre Karolina , Kamiya Erina , Cavallo Julie-Ann , Garris Christopher , Powell Simon , Reis-Filho Jorge S. , Wen Hannah , Bettigole Sarah , Khan Atif J. , Izar Benjamin , Parkes Eileen E. , Laughney Ashley M. , Bakhoum Samuel F.
Published: August 2023

Chromosomal instability (CIN) is a driver of cancer metastasis1–4, yet the extent to which this effect depends on the immune system remains unknown. Using ContactTracing—a newly developed, validated and benchmarked tool to infer the nature and conditional dependence of cell–cell interactions from single-cell transcriptomic data—we show that CIN-induced chronic activation of the cGAS–STING pathway promotes downstream signal re-wiring in cancer cells, leading to a pro-metastatic tumour microenvironment. This re-wiring is manifested by type I interferon tachyphylaxis selectively downstream of STING and a corresponding increase in cancer cell-derived endoplasmic reticulum (ER) stress response. Reversal of CIN, depletion of cancer cell STING or inhibition of ER stress response signalling abrogates CIN-dependent effects on the tumour microenvironment and suppresses metastasis in immune competent, but not severely immune compromised, settings. Treatment with STING inhibitors reduces CIN-driven metastasis in melanoma, breast and colorectal cancers in a manner dependent on tumour cell-intrinsic STING. Finally, we show that CIN and pervasive cGAS activation in micronuclei are associated with ER stress signalling, immune suppression and metastasis in human triple-negative breast cancer, highlighting a viable strategy to identify and therapeutically intervene in tumours spurred by CIN-induced inflammation.
A natural language fMRI dataset for voxelwise encoding models
Authors: LeBel Amanda , Wagner Lauren , Jain Shailee , Adhikari-Desai Aneesh , Gupta Bhavin , Morgenthal Allyson , Tang Jerry , Xu Lixiang , Huth Alexander G.
Published: August 2023

Speech comprehension is a complex process that draws on humans’ abilities to extract lexical information, parse syntax, and form semantic understanding. These sub-processes have traditionally been studied using separate neuroimaging experiments that attempt to isolate specific effects of interest. More recently it has become possible to study all stages of language comprehension in a single neuroimaging experiment using narrative natural language stimuli. The resulting data are richly varied at every level, enabling analyses that can probe everything from spectral representations to high-level representations of semantic meaning. We provide a dataset containing BOLD fMRI responses recorded while 8 participants each listened to 27 complete, natural, narrative stories (~6 hours). This dataset includes pre-processed and raw MRIs, as well as hand-constructed 3D cortical surfaces for each participant. To address the challenges of analyzing naturalistic data, this dataset is accompanied by a python library containing basic code for creating voxelwise encoding models. Altogether, this dataset provides a large and novel resource for understanding speech and language processing in the human brain.
DiaTrend: A dataset from advanced diabetes technology to enable development of novel analytic solutions
Authors: Prioleau Temiloluwa , Bartolome Abigail , Comi Richard , Stanger Catherine
Published: August 2023

Objective digital data is scarce yet needed in many domains to enable research that can transform the standard of healthcare. While data from consumer-grade wearables and smartphones is more accessible, there is critical need for similar data from clinical-grade devices used by patients with a diagnosed condition. The prevalence of wearable medical devices in the diabetes domain sets the stage for unique research and development within this field and beyond. However, the scarcity of open-source datasets presents a major barrier to progress. To facilitate broader research on diabetes-relevant problems and accelerate development of robust computational solutions, we provide the DiaTrend dataset. The DiaTrend dataset is composed of intensive longitudinal data from wearable medical devices, including a total of 27,561 days of continuous glucose monitor data and 8,220 days of insulin pump data from 54 patients with diabetes. This dataset is useful for developing novel analytic solutions that can reduce the disease burden for people living with diabetes and increase knowledge on chronic condition management in outpatient settings.
A module classification method for light industrial equipment based on improved NSGA2-FCM algorithm
Authors: Zheng Hui , Guo Hanwen , Pang Tonglin , Guo Zijian , Guo Xiao
Published: August 2023

In response to the problem that it is easy to fall into local optimum when using the traditional clustering algorithm to divide the modules, this paper improves the initialisation strategy of the NSGA2 algorithm and combines it with the FCM algorithm to propose an improved NSGA2-FCM algorithm for clustering analysis. Firstly, the FBS mapping is used to model the functional structure of the product system and identify the relationship between the product functional structures. Secondly, a correlation synthesis matrix is constructed based on the relationships between the module division drivers. Finally, the improved NSGA2-FCM algorithm is applied to cluster analysis of the product to derive the best module division scheme. The algorithm avoids falling into local optima by optimising the initialisation strategy of the NSGA2 algorithm, while using the FCM algorithm to improve the accuracy of the clustering. This allows the algorithm to explore the solution space more effectively when finding the best module partitioning solution. Finally, the effectiveness of the algorithm for module classification of light industrial equipment is verified using beer fermenters as a case study.
Integration of plasma and CSF metabolomics with CSF proteomic reveals novel associations between lipid mediators and central nervous system vascular and energy metabolism
Authors: Borkowski Kamil , Seyfried Nicholas T. , Arnold Matthias , Lah James J. , Levey Allan I. , Hales Chadwick M. , Dammer Eric B. , Blach Colette , Louie Gregory , Kaddurah-Daouk Rima , Newman John W.
Published: August 2023

Integration of the omics data, including metabolomics and proteomics, provides a unique opportunity to search for new associations within metabolic disorders, including Alzheimer’s disease. Using metabolomics, we have previously profiled oxylipins, endocannabinoids, bile acids, and steroids in 293 CSF and 202 matched plasma samples from AD cases and healthy controls and identified both central and peripheral markers of AD pathology within inflammation-regulating cytochrome p450/soluble epoxide hydrolase pathway. Additionally, using proteomics, we have identified five cerebrospinal fluid protein panels, involved in the regulation of energy metabolism, vasculature, myelin/oligodendrocyte, glia/inflammation, and synapses/neurons, affected in AD, and reflective of AD-related changes in the brain. In the current manuscript, using metabolomics-proteomics data integration, we describe new associations between peripheral and central lipid mediators, with the above-described CSF protein panels. Particularly strong associations were observed between cytochrome p450/soluble epoxide hydrolase metabolites, bile acids, and proteins involved in glycolysis, blood coagulation, and vascular inflammation and the regulators of extracellular matrix. Those metabolic associations were not observed at the gene-co-expression level in the central nervous system. In summary, this manuscript provides new information regarding Alzheimer’s disease, linking both central and peripheral metabolism, and illustrates the necessity for the “omics” data integration to uncover associations beyond gene co-expression.
A population-based longitudinal study on glycated hemoglobin levels and new-onset chronic kidney disease among non-diabetic Japanese adults
Authors: Okawa Yukari , Suzuki Etsuji , Mitsuhashi Toshiharu , Tsuda Toshihide , Yorifuji Takashi
Published: August 2023

Chronic kidney disease (CKD) is a major global public health problem. Recent studies reported that diabetes and prediabetes are risk factors for developing CKD; however, the exact glycated hemoglobin (HbA1c) cut-off value for prediabetes remains controversial. In this study, we aimed to examine the relationship between HbA1c levels and subsequent CKD development in greater detail than previous studies. Longitudinal data of annual checkups of 7176 Japanese non-diabetic people (male: 40.4%) from 1998 to 2022 was analyzed. HbA1c values were categorized into < 5.0%, 5.0–5.4%, 5.5–5.9%, and 6.0–6.4%. CKD was defined as an estimated glomerular filtration rate < 60 ml/min/1.73 m2. The descriptive statistics at study entry showed that higher HbA1c values were associated with male, older, overweight or obese, hypertensive, or dyslipidemic people. During a mean follow-up of 7.75 person-years, 2374 participants (male: 40.0%) developed CKD. The Weibull accelerated failure time model was selected because the proportional hazards assumption was violated. The adjusted time ratios of developing CKD for HbA1c levels of 5.5–5.9% and 6.0–6.4% compared with 5.0–5.4% were 0.97 (95% confidence interval: 0.92–1.03) and 1.01 (95% confidence interval: 0.90–1.13), respectively. There was no association between HbA1c in the prediabetic range and subsequent CKD development.
Acute effects of caffeine supplementation on taekwondo performance: the influence of competition level and sex
Authors: Ouergui Ibrahim , Delleli Slaheddine , Bridge Craig Alan , Messaoudi Hamdi , Chtourou Hamdi , Ballmann Christopher Garrett , Ardigò Luca Paolo , Franchini Emerson
Published: August 2023

The purpose of this study was to assess the effects of acute caffeine supplementation on physical performance and perceived exertion during taekwondo-specific tasks in male and female athletes with varying expertise. In a double-blinded, randomized, placebo-controlled crossover study design, 52 young athletes from elite (n = 32; 16 males and 16 females) and sub-elite competitive level (n = 20; 10 males and 10 females) participated. Athletes performed taekwondo-specific tasks including the taekwondo-specific agility test (TSAT), 10 s frequency speed of kick test (FSKT-10 s) and multi-bout FSKT (FSKT-multi) under the following conditions: (1) Caffeine (CAF; 3 mg kg−1), placebo (PLA), and no supplement control (CON). Session rating of perceived exertion (s-RPE) was determined after the tests. Findings show that regardless of condition, males performed better than females (p < 0.05) and elite athletes had superior performance compared to their sub-elite counterparts (p < 0.05). For the TSAT (p < 0.001), FSKT-10s (p < 0.001), and FSKT-multi (p < 0.001), CAF enhanced performance in elite female athletes compared to sub-elite females. Likewise, CAF ingestion resulted in superior performance in elite males compared to sub-elite males for FSKT-10s (p = 0.003) and FSKT-multi (p < 0.01). The ergogenic potential of CAF during taekwondo-specific tasks appears to be related to a competitive level, with greater benefits in elite than sub-elite athletes.
M1 transcranial direct current stimulation augments laparoscopic surgical skill acquisition
Authors: Galvin Daniel , Toth Adam J. , O’Reilly Barry , O’Sullivan Ray , Campbell Mark J.
Published: August 2023

The acquisition of basic surgical skills is a key component of medical education and trainees in laparoscopic surgery typically begin developing their skills using simulation box trainers. However, despite the advantages of simulation surgical training, access can be difficult for many trainees. One technique that has shown promise to enhance the deliberate practice of motor skills is transcranial electric stimulation (tES). The purpose of this study was to assess the impact of transcranial direct current stimulation (tDCS) on training induced improvements and retention of traditional time and kinematic based laparoscopic surgical skill metrics. Forty-nine medical students were randomly allocated to a neurostimulation or sham group and completed 5 training sessions of a bead transfer and threading laparoscopic task. Participants in both the sham and stimulation groups significantly improved their time and kinematic performance on both tasks following training. Although we did find that participants who received M1 tDCS saw greater performance benefits in response to training on a bead transfer task compared to those receiving sham stimulation no effect of neurostimulation was found for the threading task. This finding raises new questions regarding the effect that motor task complexity has on the efficacy of neurostimulation to augment training induced improvement and contributes to a growing body of research investigating the effects of neurostimulation on the sensory-motor performance of laparoscopic surgical skill.
Exploiting individual differences to assess the role of place and phase locking cues in auditory frequency discrimination at 2 kHz
Authors: Vinay  , Moore Brian C. J.
Published: August 2023

The relative role of place and temporal mechanisms in auditory frequency discrimination was assessed for a centre frequency of 2 kHz. Four measures of frequency discrimination were obtained for 63 normal-hearing participants: detection of frequency modulation using modulation rates of 2 Hz (FM2) and 20 Hz (FM20); detection of a change in frequency across successive pure tones (difference limen for frequency, DLF); and detection of changes in the temporal fine structure of bandpass filtered complex tones centred at 2 kHz (TFS). Previous work has suggested that: FM2 depends on the use of both temporal and place cues; FM20 depends primarily on the use of place cues because the temporal mechanism cannot track rapid changes in frequency; DLF depends primarily on temporal cues; TFS depends exclusively on temporal cues. This led to the following predicted patterns of the correlations of scores across participants: DLF and TFS should be highly correlated; FM2 should be correlated with DLF and TFS; FM20 should not be correlated with DLF or TFS. The results were broadly consistent with these predictions and with the idea that frequency discrimination at 2 kHz depends partly or primarily on temporal cues except for frequency modulation detection at a high rate.
Implementing automated 3D measurements to quantify reference values and side-to-side differences in the ankle syndesmosis
Authors: Peiffer Matthias , Van Den Borre Ide , Segers Tanguy , Ashkani-Esfahani Soheil , Guss Daniel , De Cesar Netto Cesar , DiGiovanni Christopher W. , Victor Jan , Audenaert Emmanuel , Burssens Arne
Published: August 2023

Detection of syndesmotic ankle instability remains challenging in clinical practice due to the limitations of two-dimensional (2D) measurements. The transition to automated three-dimensional (3D) measurement techniques is on the verge of a breakthrough but normative and side-to-side comparative data are missing. Therefore, our study aim was two-fold: (1) to establish 3D anatomical reference values of the ankle syndesmosis based on automated measurements and (2) to determine to what extent the ankle syndesmosis is symmetric across all 3D measurements. Patients without syndesmotic pathology with a non-weight-bearing CT scan (NWBCT; N = 38; Age = 51.6 ± 17.43 years) and weight-bearing CT scan (WBCT; N = 43; Age = 48.9 ± 14.3 years) were retrospectively included. After training and validation of a neural network to automate the segmentation of 3D ankle models, an iterative closest point registration was performed to superimpose the left on the right ankle. Subsequently, 3D measurements were manually and automatically computed using a custom-made algorithm and side-to-side comparison of these landmarks allowed one to investigate symmetry. Intra-observer analysis showed excellent agreements for all manual measurements (ICC range 0.85–0.99) and good (i.e. < 2.7° for the angles and < 0.5 mm for the distances) accuracy was found between the automated and manual measurements. A mean Dice coefficient of 0.99 was found for the automated segmentation framework. The established mean, standard deviation and range were provided for each 3D measurement. From these data, reference values were derived to differ physiological from pathological syndesmotic alignment. Furthermore, side-to-side symmetry was revealed when comparing left to right measurements (P > 0.05). In clinical practice, our novel algorithm could surmount the current limitations of manual 2D measurements and distinguish patients with a syndesmotic ankle lesion from normal variance.
Hierarchical based classification method based on fusion of Gaussian map descriptors for Alzheimer diagnosis using T1-weighted magnetic resonance imaging
Authors: Morsy Shereen E. , Zayed Nourhan , Yassine Inas A.
Published: August 2023

Alzheimer’s disease (AD) is considered one of the most spouting elderly diseases. In 2015, AD is reported the US’s sixth cause of death. Substantially, non-invasive imaging is widely employed to provide biomarkers supporting AD screening, diagnosis, and progression. In this study, Gaussian descriptors-based features are proposed to be efficient new biomarkers using Magnetic Resonance Imaging (MRI) T1-weighted images to differentiate between Alzheimer’s disease (AD), Mild Cognitive Impairment (MCI), and Normal controls (NC). Several Gaussian map-based features are extracted such as Gaussian shape operator, Gaussian curvature, and mean curvature. The aforementioned features are then introduced to the Support Vector Machine (SVM). They were, first, calculated separately for the Hippocampus and Amygdala. Followed by the fusion of the features. Moreover, Fusion of the regions before feature extraction was also employed. Alzheimer's disease Neuroimaging Initiative (ADNI) dataset, formed of 45, 55, and 65 cases for AD, MCI, and NC respectively, is appointed in this study. The shape operator feature outperformed the other features, with 74.6%, and 98.9% accuracy in the case of normal vs. abnormal, and AD vs. MCI classification respectively.
A solvable model for symmetry-breaking phase transitions
Authors: Kumar Shatrughna , Li Pengfei , Zeng Liangwei , He Jingsong , Malomed Boris A.
Published: August 2023

Analytically solvable models are benchmarks in studies of phase transitions and pattern-forming bifurcations. Such models are known for phase transitions of the second kind in uniform media, but not for localized states (solitons), as integrable equations which produce solitons do not admit intrinsic transitions in them. We introduce a solvable model for symmetry-breaking phase transitions of both the first and second kinds (alias sub- and supercritical bifurcations) for solitons pinned to a combined linear-nonlinear double-well potential, represented by a symmetric pair of delta-functions. Both self-focusing and defocusing signs of the nonlinearity are considered. In the former case, exact solutions are produced for symmetric and asymmetric solitons. The solutions explicitly demonstrate a switch between the symmetry-breaking transitions of the first and second kinds (i.e., sub- and supercritical bifurcations, respectively). In the self-defocusing model, the solution demonstrates the transition of the second kind which breaks antisymmetry of the first excited state.
Wolbachia has subtle effects on thermal preference in highly inbred Drosophila melanogaster which vary with life stage and environmental conditions
Authors: Strunov Anton , Schoenherr Charlotte , Kapun Martin
Published: August 2023

Temperature fluctuations are challenging for ectotherms which are not able to regulate body temperature by physiological means and thus have to adjust their thermal environment via behavior. However, little is yet known about whether microbial symbionts influence thermal preference (Tp) in ectotherms by modulating their physiology. Several recent studies have demonstrated substantial effects of Wolbachia infections on host Tp in different Drosophila species. These data indicate that the direction and strength of thermal preference variation is strongly dependent on host and symbiont genotypes and highly variable among studies. By employing highly controlled experiments, we investigated the impact of several environmental factors including humidity, food quality, light exposure, and experimental setup that may influence Tp measurements in adult Drosophila melanogaster flies. Additionally, we assessed the effects of Wolbachia infection on Tp of Drosophila at different developmental stages, which has not been done before. We find only subtle effects of Wolbachia on host Tp which are strongly affected by experimental variation in adult, but not during juvenile life stages. Our in-depth analyses show that environmental variation has a substantial influence on Tp which demonstrates the necessity of careful experimental design and cautious interpretations of Tp measurements together with a thorough description of the methods and equipment used to conduct behavioral studies.
Cocaine hydrochloride, cocaine methiodide and methylenedioxypyrovalerone (MDPV) cause distinct alterations in the structure and composition of the gut microbiota
Authors: Angoa-Pérez Mariana , Zagorac Branislava , Francescutti Dina M. , Shaffer Zachary D. , Theis Kevin R. , Kuhn Donald M.
Published: August 2023

Cocaine is a highly addictive psychostimulant drug of abuse that constitutes an ongoing public health threat. Emerging research is revealing that numerous peripheral effects of this drug may serve as conditioned stimuli for its central reinforcing properties. The gut microbiota is emerging as one of these peripheral sources of input to cocaine reward. The primary objective of the present study was to determine how cocaine HCl and methylenedioxypyrovalerone, both of which powerfully activate central reward pathways, alter the gut microbiota. Cocaine methiodide, a quaternary derivative of cocaine that does not enter the brain, was included to assess peripheral influences on the gut microbiota. Both cocaine congeners caused significant and similar alterations of the gut microbiota after a 10-day course of treatment. Contrary to expectations, the effects of cocaine HCl and MDPV on the gut microbiota were most dissimilar. Functional predictions of metabolic alterations caused by the treatment drugs reaffirmed that the cocaine congeners were similar whereas MDPV was most dissimilar from the other two drugs and controls. It appears that the monoamine transporters in the gut mediate the effects of the treatment drugs. The effects of the cocaine congeners and MDPV on the gut microbiome may form the basis of interoceptive cues that can influence their abuse properties.
Advancing prostate cancer detection: a comparative analysis of PCLDA-SVM and PCLDA-KNN classifiers for enhanced diagnostic accuracy
Authors: Dubey Priya , Kumar Surendra
Published: August 2023

This investigation aimed to assess the effectiveness of different classification models in diagnosing prostate cancer using a screening dataset obtained from the National Cancer Institute’s Cancer Data Access System. The dataset was first reduced using the PCLDA method, which combines Principal Component Analysis and Linear Discriminant Analysis. Two classifiers, Support Vector Machine (SVM) and k-Nearest Neighbour (KNN), were then applied to compare their performance. The results showed that the PCLDA-SVM model achieved an impressive accuracy rate of 97.99%, with a precision of 0.92, sensitivity of 92.83%, specificity of 97.65%, and F1 score of 0.93. Additionally, it demonstrated a low error rate of 0.016 and a Matthews Correlation Coefficient (MCC) and Kappa coefficient of 0.946. On the other hand, the PCLDA-KNN model also performed well, achieving an accuracy of 97.8%, precision of 0.93, sensitivity of 93.39%, specificity of 97.86%, an F1 score of 0.92, a high MCC and Kappa coefficient of 0.98, and an error rate of 0.006. In conclusion, the PCLDA-SVM method exhibited improved efficacy in diagnosing prostate cancer compared to the PCLDA-KNN model. Both models, however, showed promising results, suggesting the potential of these classifiers in prostate cancer diagnosis.