bluuebunny/crossref_metadata_2025_split huggingface dataset:
Machine learning and molecular docking prediction of potential inhibitors against dengue virus
Authors: Hanson George , Adams Joseph , Kepgang Daveson I. B. , Zondagh Luke S. , Tem Bueh Lewis , Asante Andy , Shirolkar Soham A. , Kisaakye Maureen , Bondarwad Hem , Awe Olaitan I. 
Published: December 2024

IntroductionDengue Fever continues to pose a global threat due to the widespread distribution of its vector mosquitoes, Aedes aegypti and Aedes albopictus. While the WHO-approved vaccine, Dengvaxia, and antiviral treatments like Balapiravir and Celgosivir are available, challenges such as drug resistance, reduced efficacy, and high treatment costs persist. This study aims to identify novel potential inhibitors of the Dengue virus (DENV) using an integrative drug discovery approach encompassing machine learning and molecular docking techniques.MethodUtilizing a dataset of 21,250 bioactive compounds from PubChem (AID: 651640), alongside a total of 1,444 descriptors generated using PaDEL, we trained various models such as Support Vector Machine, Random Forest, k-nearest neighbors, Logistic Regression, and Gaussian Naïve Bayes. The top-performing model was used to predict active compounds, followed by molecular docking performed using AutoDock Vina. The detailed interactions, toxicity, stability, and conformational changes of selected compounds were assessed through protein-ligand interaction studies, molecular dynamics (MD) simulations, and binding free energy calculations.ResultsWe implemented a robust three-dataset splitting strategy, employing the Logistic Regression algorithm, which achieved an accuracy of 94%. The model successfully predicted 18 known DENV inhibitors, with 11 identified as active, paving the way for further exploration of 2683 new compounds from the ZINC and EANPDB databases. Subsequent molecular docking studies were performed on the NS2B/NS3 protease, an enzyme essential in viral replication. ZINC95485940, ZINC38628344, 2′,4′-dihydroxychalcone and ZINC14441502 demonstrated a high binding affinity of −8.1, −8.5, −8.6, and −8.0 kcal/mol, respectively, exhibiting stable interactions with His51, Ser135, Leu128, Pro132, Ser131, Tyr161, and Asp75 within the active site, which are critical residues involved in inhibition. Molecular dynamics simulations coupled with MMPBSA further elucidated the stability, making it a promising candidate for drug development.ConclusionOverall, this integrative approach, combining machine learning, molecular docking, and dynamics simulations, highlights the strength and utility of computational tools in drug discovery. It suggests a promising pathway for the rapid identification and development of novel antiviral drugs against DENV. These in silico findings provide a strong foundation for future experimental validations and in-vitro studies aimed at fighting DENV.
Metagenomic next-generation sequencing of cerebrospinal fluid: a diagnostic approach for varicella zoster virus-related encephalitis
Authors: Tang Jin , Wang Kaimeng , Xu Haoming , Han Jingzhe 
Published: December 2024

PurposeVaricella zoster virus-related encephalitis (VZV-RE) is a rare and often misdiagnosed condition caused by an infection with the VZV. It leads to meningitis or encephalitis, with patients frequently experiencing poor prognosis. In this study, we used metagenomic next-generation sequencing (mNGS) to rapidly and accurately detect and identify the VZV pathogen directly from cerebrospinal fluid (CSF) samples, aiming to achieve a definitive diagnosis for encephalitis patients.MethodsIn this retrospective study, we analyzed the clinical characteristics and laboratory evaluations of 28 patients at the Harrison International Peace Hospital in Hebei, China, between 2018 and 2024. These patients were diagnosed with neurological disorders using mNGS techniques applied to CSF.ResultsIn this cohort of 28 patients, 11 were females and 17 males, with a median age of 65 (IQR: 42.3-70). VZV-RE presented with a range of clinical manifestations, the most common being headaches (81.2%), fever&gt;38°C (42.9%), and vomiting (42.9%). Less frequent symptoms include personality changes (10.7%), speech impairments (21.4%), cranial nerve involvement (21.4%), altered consciousness (17.9%) and convulsions (3.6%). Herpes zoster rash was observed in 35.7% of the cases. Neurological examination revealed nuchal rigidity in only 5 patients. CSF analysis indicated mild pressure and protein levels increase, with all patients having negative bacterial cultures. Abnormal electroencephalogram (EEG) findings were noted in 10.7% (N=3), and encephalorrhagia on Magnetic Resonance Imaging (MRI) was observed in 3.6%. VZV-RE was confirmed through mNGS analysis of CSF within three days of admission. All patients received empiric treatment with acyclovir or valacyclovir, with 21.4% receiving hormonotherapy, and 7.14% receiving immunoglobulin therapy. At the three-month follow-up, 10.7% of the patients had persistent neurologic sequelae, and the mortality rate was 3.6%.ConclusionsPerforming mNGS on CSF offers a rapidly and precisely diagnostic method for identifying causative pathogens in patients with VZV central nervous system (CNS) infections, especially when traditional CNS examination results are negative. Furthermore, the cases reported highlight the positive therapeutic effect of ganciclovir in treating VZV infections.
Malignant hypertension: current challenges, prevention strategies, and future perspectives
Authors: Tsige Abate Wondesen , Ayele Siraye Genzeb 
Published: December 2024

IntroductionBased on office blood pressure (BP) values, hypertension is categorized into three stages: stage 1 (140–159/90–99 mmHg), stage 2 (160–179/100–109 mmHg), and stage 3 (≥180/≥110 mmHg). Malignant hypertension (MHT) is characterized by extreme BP elevation (systolic blood pressure above 200 mmHg and diastolic blood pressure above 130 mmHg) and acute microvascular damage affecting various organs, particularly the retinas, brain, and kidneys.ObjectivesThe pathogenesis, predisposing variables, therapy, and preventive strategies for MHT were examined in this review.Conclusions and recommendationsMalignant hypertension requires prompt and efficient treatment because it is the most severe kind of hypertension that affects target organs. At the same time, there are a number of alternatives available for treating MHT. The International Society of Hypertension 2020 and European Society of Cardiology/European Society of Hypertension 2018 recommendations suggest using labetalol and nicardipine as the first-line choice, with urapidil and nitroprusside serving as alternative medications. Elevated risk of MHT has been linked to many socio-demographic and genetic factors.
Comparison of volumetric analysis between conventional and rotary files in the preparation of root canals in primary molars—an in vitro study
Authors: Vishwanathaiah Satish 
Published: December 2024

BackgroundTo compare and evaluate the efficacy of canal preparation and volumetric filling of primary molars instrumented by conventional hand K-file, ProAF baby rotary file and Kedo-S square file using cone beam computed tomography.Materials and methodsThirty freshly extracted human primary second molars were randomly divided into 3 groups of 10 teeth each. After access opening and working length determination, preoperative volume analysis was done using cone beam computed tomography (CBCT). The canals were then instrumented by either hand K-files, Pro AF Baby rotary files and Kedo-S square rotary files. Post operative volume analysis was performed using CBCT. All the canals were obturated using Metapex and scanned again using CBCT. Mean values of the pre- and post-operative canal volumes were analyzed using one-way ANOVA. Inter- and intra- group volumetric changes were analyzed statistically by post hoc test.ResultsThe mean difference in volume after canal preparation and obturation was the highest in the hand K-file group, followed by Pro AF Baby Gold group and the least in the Kedo-S square group. Inter and intra group comparison showed statistically significant differences for all the file groups used.ConclusionKedo- S square showed the least difference in preparation volume and better obturating volume compared to Pro AF baby gold file systems.
How do immune cells shape type 1 diabetes? Insights from Mendelian randomization
Authors: Yu Yunfeng , Yang Xinyu , Deng Juan , Wu Jingyi , Bai Siyang , Yu Rong 
Published: December 2024

ObjectiveThe role of immune cells in type 1 diabetes (T1D) is unclear. The aim of this study was to assess the causal effect of different immune cells on T1D using Mendelian randomization (MR).MethodsA dataset of immune cell phenotypes (numbered from GCST0001391 to GCST0002121) was obtained from the European Bioinformatics Institute, while a T1D dataset (numbered finngen_R10_T1D) was obtained from FinnGen. Single nucleotide polymorphisms meeting the conditions were screened stepwise according to the assumptions of association, independence, and exclusivity. Inverse variance weighted was used as the main method for the MR analysis. MR-Egger was used to assess the horizontal pleiotropy of the results. Cochran’s Q and the leave-one-out method were respectively used for the heterogeneity analysis and the sensitivity analysis of the results.ResultsMR analysis showed that effector memory (EM) double-negative (DN) (CD4−CD8−) %T cells [odds ratio (OR) = 1.157, 95% confidence interval (95% CI) = 1.016–1.318, p = 0.028, false discovery rate (FDR) = 0.899], EM CD8br %T cells (OR = 1.049, 95% CI = 1.003–1.098, p = 0.037, FDR = 0.902), CD28 on CD28+CD45RA+CD8br (OR = 1.334, 95% CI = 1.132–1.571, p = 0.001, FDR = 0.044), IgD+CD38dim %lymphocytes (OR = 1.045, 95% CI = 1.002–1.089, p = 0.039, FDR = 0.902), CD80 on monocytes (OR = 1.084, 95% CI = 1.013–1.161, p = 0.020, FDR = 0.834), SSC-A on plasmacytoid dendritic cells (pDCs) (OR = 1.174, 95% CI = 1.004–1.372, p = 0.044, FDR = 0.902), and FSC-A on pDCs (OR = 1.182, 95% CI = 1.011–1.382, p = 0.036, FDR = 0.902) were associated with an increased genetic susceptibility to T1D. Cochran’s Q showed that there was heterogeneity for CD28 on the CD28+CD45RA+CD8br results (p = 0.043), whereas there was no heterogeneity for the other results (p ≥ 0.05). The sensitivity analysis showed that the MR analysis results were robust.ConclusionThe MR analysis demonstrated that seven immune cell phenotypes were associated with an increased genetic susceptibility to T1D. These findings provide a new direction for the pathogenesis of and the drug development for T1D.
Association and function analysis of genetic variants and the risk of gestational diabetes mellitus in a southern Chinese population
Authors: Liang Qiulian , Sun Yan , Li Ming , Li Ruiqi , Nie Lijie , Lin Lin , Yu Xiangyuan 
Published: December 2024

BackgroundGestational diabetes mellitus (GDM) is a complex metabolic disease that has short-term and long-term adverse effects on mothers and infants. However, the specific pathogenic mechanism has not been elucidated.ObjectiveThe aim of this study was to confirm the associations between candidate genetic variants (rs4134819, rs720918, rs2034410, rs11109509, and rs12524768) and GDM risk and prediction in a southern Chinese population.MethodsCandidate variants were genotyped in 538 GDM cases and 626 healthy controls. The odds ratio (OR) and its corresponding 95% confidence interval (CI) were calculated to assess the associations between genotypes and GDM risk. Then, the false-positive report probability (FPRP) analysis was adopted to confirm the significant associations, and bioinformatics tools were used to explore the potential biological function of studied variants. Finally, risk factors of genetic variants and clinical indicators identified by logistics regression were used to construct a nomogram model for GDM prediction.ResultsIt was shown that the XAB2 gene rs4134819 was significantly associated with GDM susceptibility (CT vs. CC: adjusted OR = 1.38, 95% CI: 1.01–1.87, p = 0.044; CT/TT vs. CC: crude OR = 1.42, 95% CI: 1.08–1.86, p = 0.013). Functional analysis suggested that rs4134819 can alter the specific transcription factors (CPE bind and GATE-1) binding to the promoter of the XAB2 gene, regulating the transcription of XAB2. The nomogram established with factors such as age, FPG, HbA1c, 1hPG, 2hPG, TG, and rs4134819 showed a good discriminated and calibrated ability with an area under the curve (AUC) = 0.931 and a Hosmer–Lemeshow test p-value &gt; 0.05.ConclusionThe variant rs4134819 can significantly alter the susceptibility of the Chinese population to GDM possibly by regulating the transcription of functional genes. The nomogram prediction model constructed with genetic variants and clinical factors can help distinguish high-risk GDM individuals.
Suitability, acceptability, feasibility of modern menstrual methods: a qualitative study in Coimbatore district, Tamil Nadu, India
Authors: Aparnavi P. , Ramanathan Rashmi , Shanmugam Jeevithan , Narayanan Seetharaman , Kumar Mohan , Ramya V. , Rathinamoorthy Ramesh , Vignesh Sakthivel 
Published: December 2024

ObjectiveTo examine women's perceptions of modern menstrual hygiene methods (MMHM), such as tampons and menstrual cups, focusing on socio-demographic variations and special groups in the Coimbatore district of Tamil Nadu.MethodsA qualitative study among women of reproductive age (15–49 years) group was conducted using Focus Group Discussions (FGDs) among twelve women subgroups independently in 2023.ResultsThe present study involved 23 focus group discussions (FGDs) across various groups of women, including those in formal and informal sectors, urban and rural areas, school and college students, healthcare workers, women in sports, tribal women, transgender women, and female sex workers (FSW), with a total of 188 participants. The age range varied across groups, from 15 to 45 years. Over half of the participants were married (51.1%), and 68.7% were literate, though illiteracy was higher in the informal sector, rural, tribal areas, transgender women, and FSW groups. Sanitary pads were the most used menstrual hygiene method (88.3%), followed by cloth (4.8%), and modern methods like menstrual cups or tampons (1.6%). Notably, 70% of FSW and 28.6% of tribal women still used cloths. Menstrual hygiene choices were often influenced by family recommendations, school-based menstrual hygiene sessions, institutional policies, and social media. Regarding satisfaction, 27.1% were content with their menstrual hygiene method, citing accessibility, affordability, and leakage prevention. However, issues with pads included heat, rashes, and discomfort. A significant number (31.4%) shifted from cloth to pads recently, mainly due to leakage and lack of adequate washing facilities. Only 6.1% had tried modern menstrual methods, with tampons and menstrual cups being considered more suitable but less feasible, especially among tribal women. Participant concerns ranged from the potential health risks of sanitary pads to waste disposal challenges. Recommendations included public menstrual hygiene management (MHM) dispensers, better waste collection practices, and increased awareness through advertisements. Some participants advocated for the concept of free menstruation, emphasizing informed choices and accessibility for all.ConclusionThe findings suggest that increasing access to modern menstrual hygiene products, coupled with comprehensive education and support, could improve acceptance and feasibility, especially for marginalized and underrepresented women.
Case report: Complete response in TMB-H advanced uterine clear cell carcinoma: a case analysis of paclitaxel albumin-bound combined with PD-1/CTLA-4 bispecific antibody
Authors: Chen Yue , Zhou Wenting , Wang Yili 
Published: December 2024

BackgroundUterine clear cell carcinoma (UCCC) is a rare and aggressive subtype of endometrial cancer, often presenting at an advanced stage with poor prognosis. Treatment options for advanced or recurrent UCCC are currently limited, especially after platinum-based chemotherapy has failed.Case presentationWe present the case of a 49-year-old female diagnosed with stage IV uterine clear cell carcinoma. The patient had a history of atrial fibrillation and initially received several surgical interventions and platinum-based chemotherapy, but these treatments resulted in poor outcomes and rapid tumor progression. Genetic testing showed a high tumor mutation burden (TMB-H, 42.24 mutations/Mb) with stable microsatellites and a suspected harmful mutation in the PMS2 gene. After conventional therapies failed, the patient received a combination treatment of cadonilimab (375 mg) and albumin-bound paclitaxel (380 mg) for six cycles. This was followed by cadonilimab monotherapy for maintenance. This treatment regimen led to a complete response (CR), with no detectable abdominal fluid or enlarged lymph nodes by January 4, 2023. The CR status was maintained during a follow-up on April 07, 2024. The adverse effects included severe myelosuppression, mild skin reactions, hypothyroidism, and Grade 3 hyperglycemia, all of which were managed symptomatically.ConclusionThis case illustrates how effective AK104/Cadonilimab (a PD-1/CTLA-4 bispecific) can be when combined with albumin-bound paclitaxel for treating advanced UCCC, especially in patients who have not responded to standard therapies. The patient’s complete and lasting response shows the potential of PD-1/CTLA-4 bispecific immunotherapy. This suggests that cadonilimab could provide important clinical benefits for patients with advanced or recurrent UCCC.
Single-cell Atlas reveals core function of CPVL/MSR1 expressing macrophages in the prognosis of triple-negative breast cancer
Authors: Wang Xinan , Lin Li , Zhang Xue , Zhang Minghui , Sun Zhuo , Yang Yichen , Zhang Xiuna , Yuan Yonghui , Zhang Yong , Chen Hao , Wen Ti 
Published: December 2024

BackgroundTriple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with the worst prognosis among all subtypes. The impact of distinct cell subpopulations within the tumor microenvironment (TME) on TNBC patient prognosis has yet to be clarified.MethodsUtilizing single-cell RNA sequencing (scRNA-seq) integrated with bulk RNA sequencing (bulk RNA-seq), we applied Cox regression models to compute hazard ratios, and cross-validated prognostic scoring using a GLMNET-based Cox model. Cell communication analysis was used to elucidate the potential mechanisms of CPVL and MSR1. Ultimately, RNA interference-mediated gene knockdown was utilized to validate the impact of specific genes on the polarization of tumor-associated macrophages (TAMs).ResultsOur findings revealed that the function of immune cells is more pivotal in prognosis, with TAMs showing the strongest correlation with TNBC patient outcomes, compared with other immune cells. Additionally, we identified CPVL and MSR1 as critical prognostic genes within TAMs, with CPVL expression positively correlated with favorable outcomes and MSR1 expression associated with poorer prognosis. Mechanistically, CPVL may contribute to favorable prognosis by inhibiting the SPP1-CD44 ligand-receptor and promoting CXCL9-CXCR3, C3-C3AR1 ligand-receptor, through which TAMs interact with other cells such as monocytes, neutrophils, and T cells. Moreover, cytokines including IL-18, IFNγR1, CCL20, and CCL2, along with complement-related gene like TREM2 and complement component CFD, may participate in the process of CPVL or MSR1 regulating macrophage polarization. Furthermore, RT-PCR experiments confirmed that CPVL is positively associated with M1-like TAM polarization, while MSR1 is linked to M2-like TAM polarization. Finally, the prognostic significance of these two genes is also validated in HER2-positive breast cancer subtypes.ConclusionsCPVL and MSR1 are potential biomarkers for macrophage-mediated TNBC prognosis, suggesting the therapeutic potential of macrophage targeting in TNBC.
Immune complexes-mediated activation of neutrophils in systemic lupus erythematosus is dependent on RNA recognition by toll-like receptor 8
Authors: Wang Ting , Kuley Runa , Hermanson Payton , Chu Peirou , Pohlmeyer Christopher , Ravichandar Jayamary Divya , Lopez David , Min-Oo Gundula , Crellin Natasha , Shang Ching , Lood Christian 
Published: December 2024

IntroductionNeutrophil activation is important in systemic lupus erythematosus (SLE). We previously demonstrated that ribonucleoprotein (RNP) immune complexes (ICs) promoted neutrophil activation in a TLR7/8-dependent manner. However, it remains unclear if this mechanism occurs in patients. Here, we investigated the role of RNA recognition by evaluating TLR7/8 in plasma-mediated neutrophil activation in SLE.MethodsPlasma levels of neutrophil activation markers and ICs were measured by ELISA and flow cytometry in SLE patients (n=151) and healthy controls (HCs, n=31). Neutrophils were incubated with plasma and assessed for CD66b and CD11b up-regulation by flow cytometry in the presence of select inhibitors to define the mechanisms of neutrophil activation by SLE plasma.ResultsSLE plasma induced higher levels of CD66b (p=0.0002) and CD11b (p=0.01) expression than plasma from HCs. Blocking FcγRIIA, targeting RNA sensing by adding RNase, or blocking TLR7/8, TLR8 only, or IRAK4, decreased plasma-mediated neutrophil activation (p&lt;0.05). Consistent with the ability of selective TLR8 inhibitor to block plasma-mediated neutrophil activation, TLR8 agonists, but not TLR7 agonists induced robust neutrophil activation. Further, neutrophil mRNA expression of TLR8 was higher than TLR7. Finally, patients with plasma samples inducing neutrophil activation in RNA-dependent manner had increased levels of interferon alpha, IP-10 (p&lt;0.05), ICs (p&lt;0.05), and reduced complement C3 levels (p&lt;0.01), indicative of IC-driven disease.ConclusionThe data support IC-driven RNA-sensing by TLR8 in neutrophils is a key mechanism of neutrophil activation in SLE. Patients with elevated neutrophil activation and presence of RNA-containing ICs, may benefit from TLR8 inhibition and other strategies targeting RNA removal.
Fecal microbiota transplantation in severe pneumonia: a case report on overcoming pan-drug resistant Klebsiella pneumoniae infection
Authors: Zhuang Liying , You Yanjing , Zeng Shenyuan , Yu Zongyang , Wang Huijuan , Chen Meiyan , Wen Wen 
Published: December 2024

ObjectiveTo evaluate the therapeutic potential of fecal microbiota transplantation (FMT) in treating severe pneumonia patients with concurrent pan-drug resistant Klebsiella pneumoniae infection.MethodsA case report of a 95-year-old female patient with severe pneumonia, complicated by pan-resistant bacterial infections, is presented. The patient was diagnosed with severe pneumonia caused by COVID-19, along with co-infections of Staphylococcus hominis, Enterococcus faecalis, Candida tropicalis, Pseudomonas aeruginosa, ESBL-producing pan-drug resistant Klebsiella pneumoniae and pan-resistant Acinetobacter baumannii. During hospitalization, the patient underwent comprehensive treatments, including antimicrobials, mechanical ventilation, and fiberoptic bronchoscopic alveolar lavage. FMT was administered following the failure of conventional treatments to resolve recurrent diarrhea, increased sputum production, and persistent pan-drug resistant Klebsiella pneumoniae infection.ResultsPost-FMT, the patient exhibited significant clinical improvement, including reduced sputum production, cessation of diarrhea, and the normalization of respiratory symptoms. Gut microbiota analysis revealed that FMT enhanced the abundance of beneficial microbiota and suppressed Klebsiella pneumoniae, and the patient was successfully discharged after 133 days of hospitalization.ConclusionFMT emerged as a pivotal intervention in the management of this severe pneumonia case, suggesting its efficacy in restoring gut microbiota balance and aiding recovery from multi-drug-resistant infections. This case underscores the potential of FMT as a therapeutic option in severe pulmonary infections, especially in the context of antibiotic resistance in severe pneumonia patients.