bluuebunny/crossref_metadata_2025_split huggingface dataset:
Where are we in the implementation of tissue-specific epigenetic clocks?
Authors: Sala Claudia , Di Lena Pietro , Fernandes Durso Danielle , Faria do Valle Italo , Bacalini Maria Giulia , Dall’Olio Daniele , Franceschi Claudio , Castellani Gastone , Garagnani Paolo , Nardini Christine 
Published: March 2024

Introduction: DNA methylation clocks presents advantageous characteristics with respect to the ambitious goal of identifying very early markers of disease, based on the concept that accelerated ageing is a reliable predictor in this sense.Methods: Such tools, being epigenomic based, are expected to be conditioned by sex and tissue specificities, and this work is about quantifying this dependency as well as that from the regression model and the size of the training set.Results: Our quantitative results indicate that elastic-net penalization is the best performing strategy, and better so when—unsurprisingly—the data set is bigger; sex does not appear to condition clocks performances and tissue specific clocks appear to perform better than generic blood clocks. Finally, when considering all trained clocks, we identified a subset of genes that, to the best of our knowledge, have not been presented yet and might deserve further investigation: CPT1A, MMP15, SHROOM3, SLIT3, and SYNGR.Conclusion: These factual starting points can be useful for the future medical translation of clocks and in particular in the debate between multi-tissue clocks, generally trained on a large majority of blood samples, and tissue-specific clocks.
Optimization of doping design for planar P-N homologous junction perovskite solar cells
Authors: Liu Wenfeng , Zhou Ziyou , Zhou Jicheng 
Published: March 2024

In this study, we used the solar cell capacitance simulator (SCAPS) to analyse numerically the performance of perovskite solar cells (PSCs) containing CH3NH3PbI3. The findings indicate that P-N homologous junction processing based on traditional P-I-N PSCs can enhance the photoelectric conversion efficiency (PCE). Furthermore, the authors analyzed the effect of uniform P-N doping of CH3NH3PbI3, concluding that the photoelectric efficiency can be improved from 16.10% to 19.03% after doping. In addition, the optical properties of PSCs under solar irradiation are simulated using finite difference time-domain (FDTD) software under AM1.5. This method is applied to investigate the effect of the P-N uniform junction on the internal electric field generated within the cell. The generation of this electric field promotes carrier separation and transmission, ultimately increasing the open circuit voltage (VOC) of the solar cell from 1.03 to 1.12 V. The usage of P-N junctions enhances PSCs performance and exhibits vast potential for designing and developing PSCs.
Serum klotho as a novel biomarker for metabolic syndrome: findings from a large national cohort
Authors: Yuguang Li , Chang Yu , Chen Naifei , Zhao Yixin , Zhang Xinwei , Song Wei , Lu Jin , Liu Xiangliang 
Published: March 2024

BackgroundMetabolic syndrome is a cluster of metabolic abnormalities that significantly increase the risk of cardiovascular disease and mortality. The identification of novel biomarkers associated with mortality in patients with metabolic syndrome could facilitate early risk stratification and targeted interventions.MethodsWe conducted a large prospective cohort study using data from five cycles (2009-2016) of the National Health and Nutrition Examination Survey (NHANES) database, including a total of 40,439 participants. Logistic regression analysis was used to assess the association between serum klotho protein levels and metabolic syndrome, while Cox regression analysis was employed to examine the correlation between serum klotho levels and all-cause mortality. Mortality data were updated until December 31, 2019.ResultsAfter adjusting for demographic and socioeconomic confounders, the logistic regression model demonstrated that higher serum klotho levels were significantly associated with a decreased prevalence of metabolic syndrome (OR [95% CI] Highest vs. lowest quartile: 0.84 [0.70-0.99], P=0.038). In the Cox regression model, elevated klotho levels were found to significantly reduce the risk of all-cause mortality among individuals with metabolic syndrome (HR [95% CI] Highest vs. lowest quartile: 0.68 [0.51-0.90], P=0.006).ConclusionSerum klotho levels were found to be inversely associated with the prevalence of metabolic syndrome, independent of potential confounding factors such as demographics, socioeconomic status, and lifestyle factors. Furthermore, higher klotho levels strongly indicated a lower risk of all-cause mortality in individuals with metabolic syndrome.
A two-sample bidirectional Mendelian randomization analysis investigates associations between gut microbiota and type 2 diabetes mellitus
Authors: Song Siyuan , Zhang Qiling , Zhang Li , Zhou Xiqiao , Yu Jiangyi 
Published: March 2024

ObjectiveThis study sought to elucidate the causal association between gut microbiota (GM) composition and type 2 diabetes mellitus (T2DM) through a comprehensive two-sample bidirectional Mendelian randomization analysis.MethodT2DM data were sourced from the IEU OpenGWAS Project database, complemented by 211 gut microbiota (GM) datasets from the MiBioGen Federation. The primary analytical approach employed was inverse variance weighted (IVW), supplemented by MR-Egger regression and weighted median (WME) methods to investigate their potential interplay. Results were assessed using odds ratios (OR) and 95% confidence intervals (CI). The robustness and reliability of the findings were confirmed through leave-one-out analysis, heterogeneity testing, and assessment of horizontal pleiotropy. Furthermore, we explored the potential mediating role of metabolites in the pathway linking GM to T2DM.ResultA set of 11 Single Nucleotide Polymorphisms (SNPs) linked to GM were identified as instrumental variables (IVs). The IVW analysis revealed that increased abundance of the genus Actinomyces, genus Bilophila, genus Lachnoclostridium, genus Ruminococcus gnavus group, and genus Streptococcus corresponded to a heightened risk of T2DM. Conversely, higher levels of genus Eubacterium oxidoreducens group, genus Oscillospira, genus Ruminococcaceae UCG003, genus Ruminococcaceae UCG010, and genus Sellimonas were associated with a reduced risk of T2DM. However, following false discovery rate (FDR) correction, only the abundance of genus Lachnoclostridium retained a significant positive correlation with T2DM risk (OR = 1.22, q value = 0.09), while the other ten GM showed suggestive associations with T2DM. Reverse MR analysis did not reveal any causal relationship between T2DM and the increased risk associated with the identified GM. Additionally, metabolites did not exhibit mediating effects in this context.ConclusionThis study effectively pinpointed specific GM associated with T2DM, potentially paving the way for novel biomarkers in the prevention and treatment of this condition. The findings suggested that probiotics could emerge as a promising avenue for managing T2DM in the future. Furthermore, the analysis indicated that metabolites do not appear to act as mediators in the pathway from GM to T2DM.
Finding potential lncRNA–disease associations using a boosting-based ensemble learning model
Authors: Zhou Liqian , Peng Xinhuai , Zeng Lijun , Peng Lihong 
Published: March 2024

Introduction: Long non-coding RNAs (lncRNAs) have been in the clinical use as potential prognostic biomarkers of various types of cancer. Identifying associations between lncRNAs and diseases helps capture the potential biomarkers and design efficient therapeutic options for diseases. Wet experiments for identifying these associations are costly and laborious.Methods: We developed LDA-SABC, a novel boosting-based framework for lncRNA–disease association (LDA) prediction. LDA-SABC extracts LDA features based on singular value decomposition (SVD) and classifies lncRNA–disease pairs (LDPs) by incorporating LightGBM and AdaBoost into the convolutional neural network.Results: The LDA-SABC performance was evaluated under five-fold cross validations (CVs) on lncRNAs, diseases, and LDPs. It obviously outperformed four other classical LDA inference methods (SDLDA, LDNFSGB, LDASR, and IPCAF) through precision, recall, accuracy, F1 score, AUC, and AUPR. Based on the accurate LDA prediction performance of LDA-SABC, we used it to find potential lncRNA biomarkers for lung cancer. The results elucidated that 7SK and HULC could have a relationship with non-small-cell lung cancer (NSCLC) and lung adenocarcinoma (LUAD), respectively.Conclusion: We hope that our proposed LDA-SABC method can help improve the LDA identification.
Associations of perchlorate, nitrate, and thiocyanate exposure with arthritis and inflammation indicators in young and middle-aged adults, NHANES 2005-2016
Authors: Zhao Hui , Chen Xuyang , Ni Jianping , Fang Lanlan , Chen Yuting , Ma Yubo , Cai Guoqi , Pan Faming 
Published: March 2024

BackgroundPerchlorates, nitrates, and thiocyanates are prevalent environmental chemicals. Their potential association with arthritis remains unexplored. This study aimed to investigate the link between perchlorate, nitrate, and thiocyanate exposure and arthritis, as well as the potential role of inflammation in this context.MethodsUtilizing the National Health and Nutrition Examination Survey (NHANES) data spanning from 2005 to 2016, the study enrolled 6597 participants aged 20-59 (young and middle-aged), of which 1045 had arthritis. Employing multivariate logistic regression modeling, multiple linear regression models, restricted cubic spline analysis, Bayesian kernel machine regression (BKMR) modeling, and mediation analysis, we assessed these relationships.ResultsThere was a significant positive association between elevated urinary thiocyanate levels and arthritis risk [1.19 (1.11, 1.28)]. This association held true across subgroups of osteoarthritis (OA) [1.24 (1.10, 1.40)] and rheumatoid arthritis (RA) [1.33 (1.15, 1.55)]. Thiocyanate levels displayed a dose-dependent relationship with arthritis risk, showing a linear trend (nonlinear P &gt; 0.05). Conversely, perchlorate and nitrate did not exhibit associations with arthritis risk. BKMR outcomes highlighted a positive correlation between a mixture of perchlorate, nitrate, and thiocyanate and arthritis risk, with thiocyanate being the predominant predictors. Moreover, BKMR and generalized linear model analyses unveiled no significant synergistic effect of urinary perchlorate, nitrate, and thiocyanate on arthritis risk. Furthermore, thiocyanate exposure has been linked to elevated levels of inflammatory indicators (white blood cell, neutrophils, lymphocytes, and systemic immune-inflammatory index (SII)).ConclusionHeightened thiocyanate exposure may be linked to elevated arthritis risk, either single or in combined effects. Additionally, thiocyanate exposure is associated with heightened inflammation levels.
Case report: Rapidly progressive neurocognitive disorder with a fatal outcome in a patient with PU.1 mutated agammaglobulinemia
Authors: Miskovic Rada , Ljubicic Jelena , Bonaci-Nikolic Branka , Petkovic Ana , Markovic Vladana , Rankovic Ivan , Djordjevic Jelena , Stankovic Ana , Klaassen Kristel , Pavlovic Sonja , Stojanovic Maja 
Published: March 2024

IntroductionPU.1-mutated agammaglobulinemia (PU.MA) represents a recently described autosomal-dominant form of agammaglobulinemia caused by mutation of the SPI1 gene. This gene codes for PU.1 pioneer transcription factor important for the maturation of monocytes, B lymphocytes, and conventional dendritic cells. Only six cases with PU.MA, presenting with chronic sinopulmonary and systemic enteroviral infections, have been previously described. Accumulating literature evidence suggests a possible relationship between SPI1 mutation, microglial phagocytic dysfunction, and the development of Alzheimer’s disease (AD).Case descriptionWe present a Caucasian female patient born from a non-consanguineous marriage, who was diagnosed with agammaglobulinemia at the age of 15 years when the immunoglobulin replacement therapy was started. During the following seventeen years, she was treated for recurrent respiratory and intestinal infections. At the age of 33 years, the diagnosis of celiac-like disease was established. Five years later progressive cognitive deterioration, unstable gait, speech disturbances, and behavioral changes developed. Comprehensive microbiological investigations were negative, excluding possible infective etiology. Brain MRI, 18FDG-PET-CT, and neuropsychological testing were suggestive for a diagnosis of a frontal variant of AD. Clinical exome sequencing revealed the presence of a novel frameshift heterozygous variant c.441dup in exon 4 of the SPI1 gene. Despite intensive therapy, the patient passed away a few months after the onset of the first neurological symptoms.ConclusionWe describe the first case of PU.MA patient presenting with a rapidly progressive neurocognitive deterioration. The possible role of microglial dysfunction in patients with SPI1 mutation could explain their susceptibility to neurodegenerative diseases thus highlighting the importance of genetic testing in patients with inborn errors of immunity. Since PU.MA represents a newly described form of agammaglobulinemia, our case expands the spectrum of manifestations associated with SPI1 mutation.
B-cell-depleted patients with persistent SARS-CoV-2 infection: combination therapy or monotherapy? A real-world experience
Authors: D’Abramo Alessandra , Vita Serena , Beccacece Alessia , Navarra Assunta , Pisapia Raffaella , Fusco Francesco Maria , Matusali Giulia , Girardi Enrico , Maggi Fabrizio , Goletti Delia , Nicastri Emanuele ,   ImmunoCOVID team
Published: March 2024

ObjectivesThe aim of the study was to describe a cohort of B-cell-depleted immunocompromised (IC) patients with prolonged or relapsing COVID-19 treated with monotherapy or combination therapy.MethodsThis is a multicenter observational retrospective study conducted on IC patients consecutively hospitalized with a prolonged or relapsing SARS-CoV-2 infection from November 2020 to January 2023. IC COVID-19 subjects were stratified according to the monotherapy or combination anti-SARS-CoV-2 therapy received.ResultsEighty-eight patients were enrolled, 19 under monotherapy and 69 under combination therapy. The study population had a history of immunosuppression (median of 2 B-cells/mm3, IQR 1–24 cells), and residual hypogammaglobulinemia was observed in 55 patients. A reduced length of hospitalization and time to negative SARS-CoV-2 molecular nasopharyngeal swab (NPS) in the combination versus monotherapy group was observed. In the univariable and multivariable analyses, the percentage change in the rate of days to NPS negativity showed a significant reduction in patients receiving combination therapy compared to those receiving monotherapy.ConclusionIn IC persistent COVID-19 patients, it is essential to explore new therapeutic strategies such as combination multi-target therapy (antiviral or double antiviral plus antibody-based therapies) to avoid persistent viral shedding and/or severe SARS-CoV-2 infection.
Primary hepatic malignant triton tumor mimicking hepatocellular carcinoma by demonstrating arterial-phase hypervascularity and subsequent washout on dynamic contrast-enhanced imaging: a case report and literature review
Authors: Zhou Bo , Zhan Canyang , Tian Yang , Gao Zhenzhen , Yan Sheng 
Published: March 2024

BackgroundMalignant Triton tumor (MTT) is a relatively rare subtype of malignant peripheral nerve sheath tumor (MPNST) characterized by rhabdomyosarcoma differentiation. There are no distinct features of MTT, and it is easy to misdiagnose preoperatively.Case presentationHere, we describe a rare case of primary hepatic MTT in a 56-year-old male who presented with nonspecific abdominal pain for 1 day. Magnetic resonance imaging and abdominal computed tomography revealed an extremely large mass located in the right liver with intratumoral hemorrhage, arterial-phase hypervascularity and subsequent washout on dynamic contrast-enhanced imaging and the possibility of intrahepatic metastasis. Tumor marker levels revealed only an elevated level of alpha-fetoprotein (AFP: 5304.0 ng/mL). Then, he received transcatheter arterial chemoembolization combined with lenvatinib and pembrolizumab, and he was diagnosed with hepatocellular carcinoma. After 3 months of neoadjuvant therapy, we resected the hepatic cancer and adherent diaphragmatic pleura. MTT was confirmed by postoperative pathology and immunohistochemistry.ConclusionDespite the preoperative diagnosis of hepatocellular carcinoma with a rising serum AFP level, typical CT and MRI findings, histopathology assessment showing MPNST with rhabdomyosarcoma differentiation confirms the diagnosis of primary hepatic MTT.
Diagnosis of pulmonary hemorrhagic leptospirosis complicated by invasive pulmonary aspergillosis complemented by metagenomic next-generation sequencing: a case report
Authors: Yang Qiong-Fang , Shu Cai-Min , Ji Qiao-Ying 
Published: March 2024

BackgroundLeptospirosis is a bacterial zoonosis with variable clinical manifestations. Pulmonary diffuse hemorrhagic leptospirosis often occurs rapidly and, when not promptly diagnosed and treated, it can be life-threatening. Aspergillus flavus is an opportunistic fungus that is commonly seen in immunosuppressed patients. Invasive pulmonary aspergillosis also progresses rapidly. This case study describes a patient with severe pneumonia caused by pulmonary hemorrhagic leptospirosis combined with invasive pulmonary aspergillosis. We have found almost no clinical reports to date on these two diseases occurring in the same patient.Case presentationA 73-year-old male arrived at our hospital complaining of fever, general malaise, and hemoptysis that had lasted 4 days. The patient was initially diagnosed with severe pneumonia in the emergency department, but he did not respond well to empiric antibiotics. Subsequently, the patient’s condition worsened and was transferred to the ICU ward after emergency tracheal intubation and invasive ventilator. In the ICU, antibacterial drugs were adjusted to treat bacteria and fungi extensively. Although the inflammatory indices decreased, the patient still had recurrent fever, and a series of etiological tests were negative. Finally, metagenomic next-generation sequencing (mNGS) of bronchial alveolar lavage fluid detected Leptospira interrogans and Aspergillus flavus. After targeted treatment with penicillin G and voriconazole, the patient’s condition improved rapidly, and he was eventually transferred out of the ICU and recovered.ConclusionEarly recognition and diagnosis of leptospirosis is difficult, especially when a patient is co-infected with other pathogens. The use of mNGS to detect pathogens in bronchial alveolar lavage fluid is conducive to early diagnosis and treatment of the disease, and may significantly improve the prognosis in severe cases.
Rapid detection of multidrug resistance in tuberculosis using nanopore-based targeted next-generation sequencing: a multicenter, double-blind study
Authors: Liu Aimei , Liu Sang , Lv Kangyan , Zhu Qingdong , Wen Jun , Li Jianpeng , Liang Chengyuan , Huang Xuegang , Gong Chunming , Sun Qingfeng , Gu Hongcang 
Published: March 2024

BackgroundResistance to anti-tuberculous drugs is a major challenge in the treatment of tuberculosis (TB). We aimed to evaluate the clinical availability of nanopore-based targeted next-generation sequencing (NanoTNGS) for the diagnosis of drug-resistant tuberculosis (DR-TB).MethodsThis study enrolled 253 patients with suspected DR-TB from six hospitals. The diagnostic efficacy of NanoTNGS for detecting Mycobacterium tuberculosis and its susceptibility or resistance to first- and second-line anti-tuberculosis drugs was assessed by comparing conventional phenotypic drug susceptibility testing (pDST) and Xpert MTB/RIF assays. NanoTNGS can be performed within 12 hours from DNA extraction to the result delivery.ResultsNanoTNGS showed a remarkable concordance rate of 99.44% (179/180) with the culture assay for identifying the Mycobacterium tuberculosis complex. The sensitivity of NanoTNGS for detecting drug resistance was 93.53% for rifampicin, 89.72% for isoniazid, 85.45% for ethambutol, 74.00% for streptomycin, and 88.89% for fluoroquinolones. Specificities ranged from 83.33% to 100% for all drugs tested. Sensitivity for rifampicin-resistant tuberculosis using NanoTNGS increased by 9.73% compared to Xpert MTB/RIF. The most common mutations were S531L (codon in E. coli) in the rpoB gene, S315T in the katG gene, and M306V in the embB gene, conferring resistance to rifampicin, isoniazid, and ethambutol, respectively. In addition, mutations in the pncA gene, potentially contributing to pyrazinamide resistance, were detected in 32 patients. Other prevalent variants, including D94G in the gyrA gene and K43R in the rpsL gene, conferred resistance to fluoroquinolones and streptomycin, respectively. Furthermore, the rv0678 R94Q mutation was detected in one sample, indicating potential resistance to bedaquiline.ConclusionNanoTNGS rapidly and accurately identifies resistance or susceptibility to anti-TB drugs, outperforming traditional methods. Clinical implementation of the technique can recognize DR-TB in time and provide guidance for choosing appropriate antituberculosis agents.
Population pharmacokinetic model for oral ORIN1001 in Chinese patients with advanced solid tumors
Authors: Li Xiaoqing , Bo Yunhai , Zeng Qingping , Diao Lei , Greene Stephanie , Patterson John , Liu Lu , Yang Fen 
Published: March 2024

Background: ORIN1001, a first-in-class oral IRE1-α endoribonuclease inhibitor to block the activation of XBP1, is currently in clinical development for inhibiting tumor growth and enhancing the effect of chemical or targeted therapy. Early establishment of a population pharmacokinetic (PopPK) model could characterize the pharmacokinetics (PK) of ORIN1001 and evaluate the effects of individual-specific factors on PK, which will facilitate the future development of this investigational drug.Methods: Non-linear mixed effect model was constructed by Phoenix NLME software, utilizing the information from Chinese patients with advanced solid tumors in a phase I clinical trial (Register No. NCT05154201). Statistically significant PK covariates were screened out by a stepwise process. The final model, after validating by the goodness-of-fit plots, non-parametric bootstrap, visual predictive check and test of normalized prediction distribution errors, was further applied to simulate and evaluate the impact of covariates on ORIN1001 exposure at steady state up to 900 mg per day as a single agent.Results: A two-compartment model with first-order absorption (with lag-time)/elimination was selected as the best structural model. Total bilirubin (TBIL) and lean body weight (LBW) were considered as the statistically significant covariates on clearance (CL/F) of ORIN1001. They were also confirmed to exert clinically significant effects on ORIN1001 steady-state exposure after model simulation. The necessity of dose adjustments based on these two covariates remains to be validated in a larger population.Conclusion: The first PopPK model of ORIN1001 was successfully constructed, which may provide some important references for future research.