bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating methods for integrating single-cell data and genetics to understand inflammatory disease complexity
Authors: Townsend Hope A. , Rosenberger Kaylee J. , Vanderlinden Lauren A. , Inamo Jun , Zhang Fan 
Published: December 2024

BackgroundUnderstanding genetic underpinnings of immune-mediated inflammatory diseases is crucial to improve treatments. Single-cell RNA sequencing (scRNA-seq) identifies cell states expanded in disease, but often overlooks genetic causality due to cost and small genotyping cohorts. Conversely, large genome-wide association studies (GWAS) are commonly accessible.MethodsWe present a 3-step robust benchmarking analysis of integrating GWAS and scRNA-seq to identify genetically relevant cell states and genes in inflammatory diseases. First, we applied and compared the results of three recent algorithms, based on pathways (scGWAS), single-cell disease scores (scDRS), or both (scPagwas), according to accuracy/sensitivity and interpretability. While previous studies focused on coarse cell types, we used disease-specific, fine-grained single-cell atlases (183,742 and 228,211 cells) and GWAS data (Ns of 97,173 and 45,975) for rheumatoid arthritis (RA) and ulcerative colitis (UC). Second, given the lack of scRNA-seq for many diseases with GWAS, we further tested the tools’ resolution limits by differentiating between similar diseases with only one fine-grained scRNA-seq atlas. Lastly, we provide a novel evaluation of noncoding SNP incorporation methods by testing which enabled the highest sensitivity/accuracy of known cell-state calls.ResultsWe first found that single-cell based tools scDRS and scPagwas called superior numbers of supported cell states that were overlooked by scGWAS. While scGWAS and scPagwas were advantageous for gene exploration, scDRS effectively accounted for batch effect and captured cellular heterogeneity of disease-relevance without single-cell genotyping. For noncoding SNP integration, we found a key trade-off between statistical power and confidence with positional (e.g. MAGMA) and non-positional approaches (e.g. chromatin-interaction, eQTL). Even when directly incorporating noncoding SNPs through 5’ scRNA-seq measures of regulatory elements, non disease-specific atlases gave misleading results by not containing disease-tissue specific transcriptomic patterns. Despite this criticality of tissue-specific scRNA-seq, we showed that scDRS enabled deconvolution of two similar diseases with a single fine-grained scRNA-seq atlas and separate GWAS. Indeed, we identified supported and novel genetic-phenotype linkages separating RA and ankylosing spondylitis, and UC and crohn’s disease. Overall, while noting evolving single-cell technologies, our study provides key findings for integrating expanding fine-grained scRNA-seq, GWAS, and noncoding SNP resources to unravel the complexities of inflammatory diseases.
Complications of the Bacillus Calmette-Guerin vaccine as an early warning sign of inborn errors of immunity: a report of 197 patients
Authors: Fazlollahi Mohammad Reza , Goudarzi Ali , Nourizadeh Maryam , Alizadeh Zahra , Tajik Shaghayegh , Badalzadeh Mohsen , Sarafzadeh Shokouh Azam , Mahlooji Rad Maryam , Adab Zeinab , Moradi Leila , Razaghian Anahita , Sabetkish Nastaran , Pourpak Zahra , Moin Mostafa 
Published: December 2024

BackgroundAccording to the WHO’s recommendation for developing countries, Bacillus Calmette-Guerin (BCG) vaccination has been implemented in some countries as part of national vaccination programs at birth. Although it is generally considered safe, some complications may occur; including BCGitis (local) or BCGosis (systemic), ranging from mild like local abscesses to fatal impediments like osteomyelitis and disseminated BCG infection. This study aimed to determine the spectrum of inborn errors of immunity (IEI) in BCG-vaccinated neonates experiencing local or systemic complications.MethodsIn this cross-sectional study, we investigated Iranian children referred to the Immunology, Asthma, and Allergy Research Institute (IAARI) between 2007-2023 for suspected immunodeficiency. Medical history was recorded, and primary screening tests for immunodeficiency were conducted for all cases. For suspected cases, more advanced immunologic investigations were performed to reach a definitive diagnosis. Furthermore, the study incorporated the documented genetic findings of the patients under investigation. All patients with inborn error of immunity who had a history of BCG vaccine complications within the first year of vaccination were enrolled in the study.ResultsWe investigated 3,275 cases suspected of IEI, identifying197 patients with both IEI and BCG vaccine complications. Among these, 127 (64.5%) were male. Symptoms began at or before 3 months of age in 64.8% of the cases, and parental consanguinity was reported in 79.2%. Genetic diagnoses were confirmed in 108 patients. Of the 197 patients, 108 (54.8%) had BCGitis, while 89 (45.2%) experienced systemic complications (BCGosis). A family history of IEI, BCG-related complications, and unexplained deaths were observed in 20.3%, 12.2%, and 29.9% of cases, respectively. Furthermore, 46.2% had at least one of these three risk factors in their history.ConclusionsEarly BCG vaccine complications may indicate an underlying immunodeficiency, particularly when there is a positive family history of BCG complications, immunodeficiency, or unexplained deaths. Nation-wide vaccination protocols should address this issue by delaying inoculation to allow for immunological screening of suspected immunodeficient patients, thereby preventing BCG vaccine-related morbidity and mortality.
Pan-cancer single cell and spatial transcriptomics analysis deciphers the molecular landscapes of senescence related cancer-associated fibroblasts and reveals its predictive value in neuroblastoma via integrated multi-omics analysis and machine learning
Authors: Li Shan , Luo Junyi , Liu Junhong , He Dawei 
Published: December 2024

IntroductionCancer-associated fibroblasts (CAFs) are a diverse group of cells that significantly contribute to reshaping the tumor microenvironment (TME), and no research has systematically explored the molecular landscapes of senescence related CAFs (senes CAF) in NB.MethodsWe utilized pan-cancer single cell and spatial transcriptomics analysis to identify the subpopulation of senes CAFs via senescence related genes, exploring its spatial distribution characteristics. Harnessing the maker genes with prognostic significance, we delineated the molecular landscapes of senes CAFs in bulk-seq data. We established the senes CAFs related signature (SCRS) by amalgamating 12 and 10 distinct machine learning (ML) algorithms to precisely diagnose stage 4 NB and to predict prognosis in NB. Based on risk scores calculated by prognostic SCRS, patients were categorized into high and low risk groups according to median risk score. We conducted comprehensive analysis between two risk groups, in terms of clinical applications, immune microenvironment, somatic mutations, immunotherapy, chemotherapy and single cell level. Ultimately, we explore the biological function of the hub gene JAK1 in pan-cancer multi-omics landscape.ResultsThrough integrated analysis of pan-cancer spatial and single-cell transcriptomics data, we identified distinct functional subgroups of CAFs and characterized their spatial distribution patterns. With marker genes of senes CAF and leave-one-out cross-validation, we selected RF algorithm to establish diagnostic SCRS, and SuperPC algorithm to develop prognostic SCRS. SCRS demonstrated a stable predictive capability, outperforming the previously published NB signatures and clinic variables. We stratified NB patients into high and low risk group, which showed the low-risk group with a superior survival outcome, an abundant immune infiltration, a different mutation landscape, and an enhanced sensitivity to immunotherapy. Single cell analysis reveals biologically cellular variations underlying model genes of SCRS. Spatial transcriptomics delineated the molecular variant expressions of hub gene JAK1 in malignant cells across cancers, while immunohistochemistry validated the differential protein levels of JAK1 in NB.ConclusionBased on multi-omics analysis and ML algorithms, we successfully developed the SCRS to enable accurate diagnosis and prognostic stratification in NB, which shed light on molecular landscapes of senes CAF and clinical utilization of SCRS.
Comparison of metabolism, gut histology, and microbiota between Schizothorax lissolabiatus and Schizothorax griseus under identical farming conditions
Authors: Zhong Chuanyan , Chen Li , Huang Zhengwei , Hu Yuan , Jiang Yujie , Zhou Jun , Long Xiaowen 
Published: December 2024

Schizothorax lissolabiatus and Schizothorax griseus are native Chinese fish species with significant ecological and economic importance. We wanted to support sustainable aquaculture practices by exploring the differences in metabolic, histological, and microbiota between the two Schizothorax species. This study analyzed and compared the digestive enzyme activities, metabolic indicators, gut histology, and microbiota composition of S. lissolabiatus and S. griseus under identical farming conditions. Our comparative analysis reveals both shared characteristics and species-specific differences. While a-amylase and trypsin activities showed no significant differences between species, a consistent trend was observed, with enzyme activity highest in the hindgut, followed by the midgut, foregut, esophagus, and liver. In terms of specific metabolic markers, S. griseus shows higher lipase activity in the liver and foregut, as well as higher aspartate aminotransferase and catalase levels in the liver, along with an increased serum glucose content compared to S. lissolabiatus. Serum metabolomics analysis revealed 21 differentially abundant metabolites linked to glycerophospholipid metabolism, autophagy, purine metabolism, and necroptosis, reflecting distinct metabolic adaptations and nutritional needs for each species. These metabolic differences provide a basis for optimizing feed composition and aquaculture practices tailored to each species. Notably, S. lissolabiatus displays a significantly higher goblet cell count in the hindgut compared to S. griseus. Additionally, both species exhibit greater villi number, length, width, crypt depth, and muscle thickness in the esophagus than in the foregut, midgut, and hindgut. S. griseus also has a higher number of operational taxonomic units (OTUs) and greater microbial diversity in its intestinal microbiota, which may enhance its nutrient utilization capabilities. While both species’ dominant microbial phyla include Fusobacteria, Firmicutes, Proteobacteria, and Bacteroidetes, S. griseus demonstrated superior lipid digestion capabilities. Furthermore, the midgut and hindgut in both species display higher starch and protein digestive enzyme activities than other digestive tissues. These findings highlight the physiological differences between the two Schizothorax species, suggesting targeted strategies to improve health, growth, and sustainability in aquaculture.
Predictive value of serum neurofilament light chain for cognitive impairment in Parkinson’s disease
Authors: Gu Lihua , Zhang Pengcheng , Gao Rui , Shu Hao , Wang Pan 
Published: December 2024

BackgroundNeurofilament light chain (NfL) has recently emerged as a key indicator of neurodegeneration. In this study, our hypothesis is that the levels of blood-derived NfL and its accumulation during the Parkinson’s disease (PD) progression could serve as a potential biomarker for predicting subsequent cognitive decline. To investigate this, we conducted a study utilizing a large single-center cohort.MethodsThe study included 193 participants, consisting of 106 cognitively normal PD (PD-CN) patients and 87 normal controls (NC) individuals. Serum NfL concentrations were measured. PD patients were followed up for clinical assessment at an average of 2 ± 0.6 years.ResultsThe serum NfL levels were significantly higher in PD-CN patients compared to NC. PD-CN patients and NC at follow-up time exhibited higher serum NfL levels compared to those at baseline. PD patients with high serum NfL levels were found to have a higher likelihood of transitioning from normal cognition to mild cognitive impairment (MCI) or dementia (Hazard ratio (HR) 1.107, 95% confidence intervals (CI) 1.010–1.213, p = 0.030). The area under the curve (AUC) for PD-CN conversion to MCI or dementia at follow-up time was determined to be 0.684 (95% CI 0.569–0.799).ConclusionIn conclusion, our study found that PD patients have significantly higher levels of serum NfL compared to individuals without PD. Furthermore, serum NfL levels increase as PD progresses and can predict cognitive impairment within a 2-year timeframe. Serum NfL may serve as a feasible, non-invasive biomarker of cognitive progression in PD. However, further studies and functional experiments are needed to validate these findings.
Aging of visual word perception is related to decreased segregation within and beyond the word network in the brain
Authors: Xue Licheng , Qing Tianying , Lv Yating , Zhao Jing 
Published: December 2024

IntroductionWe investigated the neural correlates of cognitive decline in visual word perception from the perspective of intrinsic brain networks.MethodsA total of 19 healthy older adults and 22 young adults were recruited to participate in two functional magnetic resonance imaging (fMRI) sessions (one resting-state session and one for localizer tasks), along with a visual word perceptual processing task. We examined age-related alterations in resting-state functional connectivity (FC) within the word network, as well as between the word network and other networks. We tested their associations with behavioral performance in word and symbol-form processing.ResultsWe found that, compared to young adults, older adults exhibited increased FC between the two word-selective regions in the left and right ventral occipitotemporal cortex (vOT). Additionally, older adults exhibited increased FC between these two word-selective regions and non-word-selective regions. Notably, these FC alterations correlated with individual differences in behavioral performance in visual word perception.DiscussionThese results suggest that cognitive decline in visual word perception is associated with decreased segregation within and beyond the word network in the aging brain. Our findings support the neural dedifferentiation hypothesis for cognitive decline in visual word processing and improve our understanding of interactive neural specialization theory.
Action observation treatment may improve daily living activities and verb recovery in Parkinson’s disease-dementia: findings from a preliminary randomized controlled trial
Authors: Paciaroni Lucia , Mastrosanti Elena , Biscetti Leonardo , Paolini Susy , Mauri Sara , Fabbietti Paolo , Riccardi Giovanni Renato , Rocchi Marco Bruno Luigi , Pelliccioni Giuseppe 
Published: December 2024

Background and objectivesAction observation treatment (AOT) is a novel rehabilitation approach aimed to the recovery of both motor and linguistic deficits in subjects with brain lesions. The aim of the present randomized controlled study was to assess the benefits of AOT treatment in the activities of daily living (ADLs) and in the linguistic abilities of the patients with Parkinson’s disease dementia (PDD) at mild–moderate stage (Hoehn &amp; Yahr’s stage scale: 2–3).MethodsTwenty patients were enrolled and randomly assigned to an experimental group (submitted to AOT) or to a control group. The experimental group (AOT-group) underwent the vision of a video containing 6 complex ADLs, while the control group (C-group) was subjected to a video-clip regarding semantic information of a geographical-naturalistic type without motor content. The treatment duration was 4 weeks. All patients underwent assessment before and after the treatment by the following tools: Unified Parkinson’s Disease Rating Scale Part III (UPDRS-Part III), Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL), Direct Assessment of Functional Status (DAFS) and subtest Verb Naming of Analysis of Aphasic Deficit Battery (BADA). Paired samples t test was performed to compare all the variables of interest in the time, dividing by groups. p-value&lt;0.05 was considered significant in all analyses.ResultsAOT-group showed an improvement from baseline to the end of study in ADCS-ADL (p = 0.001), BADA (p = 0.011) and DAFS (p = 0.005), while C-group did not change significantly in the time.ConclusionThese preliminary results suggest the potential efficacy of AOT in rehabilitation of ADLs and verb retrieval in people with PD. Further studies will be necessary to verify these findings.
Comorbidity of physical illnesses and mental disorders in outpatients with tic disorders: a retrospective study using the outpatient case system
Authors: Yu Liping , Xu Hui , Jiang Zhongliang , Yang Hanxue , Cui Yonghua , Li Ying 
Published: December 2024

BackgroundTic disorder, a chronic neurodevelopmental disorder that typically onsets during childhood, is characterized by sudden, involuntary, rapid, and non-rhythmic motor and vocal tics. Individuals with tic disorders often experience physical health issues. The purpose of our retrospective analysis was to elucidate the common comorbid physical diseases and mental disorders and their characteristics of outpatient children with tic disorders in a large public children’s hospital in China over the past 5 years.MethodsParticipants were outpatients with tic disorders who visited Beijing Children’s Hospital, from January 1, 2018 to December 31, 2022. After the inclusion screening, a total of 523,462 patient visits were included in the analysis. Based on the International Classification of Diseases, 10th Revision (ICD-10) diagnostic system, we employed descriptive statistical analysis to examine the frequently co-occurring somatic diseases in patients with tic disorders, as well as the influence of variables such as age and seasonal variation on these comorbidities.ResultsThe top five diseases of total outpatient visits were as follows: Respiratory diseases, Mental and behavioral disorders, Diseases of the eye and adnexal, Digestive disorders, Diseases of the skin and subcutaneous tissue. Among the top five comorbid disease system, the most commonly third- level classification of diseases were upper respiratory tract infections, attention deficit and hyperactivity disorder, conjunctivitis, dyspepsia, dermatitis. Respiratory system diseases experienced a peak in April, while the other four types of diseases reached their peak in August. Additionally, each disease system showed the lowest number of patient visits in February. Additional to the mental and behavioral disorders, the other four disease systems would experience a peak in medical visits between the ages of 4 and 6.ConclusionOur study highlighted the most common physical diseases and mental disorders in tic disorders, namely the respiratory diseases, specifically upper respiratory tract infections, and mental and behavioral disorders, with ADHD being the most common co-occurring condition.
Polyphenol-rich extracts enhance growth, immune function, and antioxidant defense in juvenile rainbow trout (Oncorhynchus mykiss)
Authors: Mansoori Aghil , Allaf Noveirian Hamid , Hoseinifar Seyed Hossein , Sajjadi Mirmasoud , Ashouri Ghasem , Imperatore Roberta , Paolucci Marina 
Published: December 2024

IntroductionThe present study was conducted to investigate the effects of PMIX, a polyphenol-rich extract mixture from chestnut wood and olive, on growth performance, hematological parameters, immunity in serum and skin mucus, hepatic antioxidant enzymes, and intestinal cytokine expression in rainbow trout (Oncorhynchus mykiss).MethodsFour experimental diets containing 0 g PMIX kg−1 diet (control, C), 0.5 g PMIX kg−1 diet (P0.5), 1 g PMIX kg−1 diet (P1), and 2 g PMIX kg−1 diet (P2) were fed to rainbow trout in an eight-week feeding trial. Triplicate groups of fish received each treatment. Growth performance, feed conversion ratio, protein efficiency, hepatosomatic and viscerosomatic indices, hematological parameters, immunity markers, hepatic antioxidant enzyme activities, and intestinal cytokine expression were determined.ResultsPMIX supplementation significantly improved feed conversion ratios, while groups P0.5 and P1 evidenced an increase in growth performance along with protein efficiency ratios. It also showed decreased hepatosomatic and viscerosomatic indices in the P1 group. Except for higher percentages of monocytes in P0.5 and P1, most hematological parameters of the fish did not differ from that of the control. Serum lysozyme and respiratory burst activities were heightened in all PMIX-treated groups, and the skin mucus lysozyme activity was enhanced in P1. The blood phagocytic activity and phagocytic index, serum immunoglobulin, total protein, and bactericidal activity against A. hydrophila did not change. Hepatic superoxide dismutase activity significantly increased in P1 and P2, even though catalase activity did not change. Intestinal interleukin-6 expression was upregulated in all PMIX-treated groups, while tumor necrosis factor-alpha and interleukin-1 beta were upregulated in P1, P2, and P0.5 respectively.DiscussionThe present results evidence that dietary polyphenols from chestnut wood and olive extracts enhance growth performance, antioxidant capacity, and several immunological parameters in the blood, skin mucus, and intestine of rainbow trout. A suitable supplementation level was 1 g PMIX kg−1 diet to separate these improvements.
Case report: HSV lymphadenitis in immunocompromised patient with CLL
Authors: Al-Assil Talal , Handelsman Shane , Ansari Faisal , Flatley Ellen , Stone Steven , Omaira Mohammad 
Published: December 2024

BackgroundRichter’s transformation (RT) in chronic lymphocytic leukemia (CLL) is associated with poor prognosis and requires prompt modifications in patient care. CLL patients are susceptible to severe infections due to immune dysregulation induced by their malignancy and immunosuppressive therapies.Case presentationWe present a case of a 63-year-old man with CLL who previously achieved remission and presented with a right inguinal mass. He was diagnosed with Rai Stage I CLL with del6q, without TP53 mutation, and treated with 6 cycles of fludarabine, cyclophosphamide, and rituximab (FCR) 6 years prior. Transformed CLL was suspected based on his lymphadenopathy, elevated lactate dehydrogenase, and constitutional symptoms, but excisional biopsy unexpectedly revealed herpes simplex virus (HSV)-1 and HSV-2, indicating a diagnosis of HSV lymphadenitis concurrent with CLL relapse with no transformation but acquisition of 17p deletion consistent with clonal evolution. The patient received three courses of dexamethasone and acyclovir, leading to successful clearance of the infection, evidenced by the resolution of his B symptoms. Subsequently, he was treated for the CLL recurrence with rituximab and venetoclax, demonstrating a favorable response with significant improvement in adenopathy and resolution of lymphocytosis.DiscussionThis case highlights the possibility of reactivated dormant viral infections in the context of CLL relapse, underscoring the importance of comprehensive evaluation in CLL patients presenting with lymphadenopathy. Due to immunosuppressive defects and iatrogenic hypogammaglobulinemia, patients with CLL face an increased risk of viral infections, with HSV reactivation occurring more frequently and severely in the setting of hematologic malignancies and dysregulated T-cell immunity. Timely administration of antiviral therapy is crucial for HSV lymphadenitis to prevent rapid progression and debilitating symptoms. This case demonstrates the importance of considering atypical viral infection presentations in CLL patients and emphasizes the necessity of timely and adequate biopsies to differentiate between CLL transformation, HSV lymphadenopathy, and other causes of lymphadenopathy while avoiding unnecessarily aggressive lymphoma therapy.