bluuebunny/crossref_metadata_2025_split huggingface dataset:
A de Novo ZMIZ1 Pathogenic Variant for Neurodevelopmental Disorder With Dysmorphic Facies and Distal Skeletal Anomalies
Authors: Lu Guanting , Ma Liya , Xu Pei , Xian Binqiang , Wu Lianying , Ding Jianying , He Xiaoyan , Xia Huiyun , Ding Wuwu , Yang Zhirong , Peng Qiongling 
Published: March 2022

Background: Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA) is a rare syndromic disorder characterized by global neurodevelopmental delay, early-onset hypotonia, poor overall growth, poor speech/language ability, and additional common phenotypes such as eye anomalies, joint hypermobility, and skeletal anomalies of the hands and feet. NEDDFSA is caused by heterozygous pathogenic variants in the ZMIZ1 gene on chromosome 10q22.3 with autosomal dominant (AD) mode of inheritance. All the 32 reported cases with variants in ZMIZ1 gene had a genetic background in Caucasian, Hispanic, North African, and Southeastern Asian. Until now, there are no reports of Chinese patients with ZMIZ1 pathogenic variants.Methods: A 5-year-old girl was found to have the characteristic phenotypes of NEDDFSA. Array-Comparative Genomic Hybridization (array-CGH) and whole exome sequencing (WES) were applied for the trio of this female patient. Sanger sequencing was used to verify the selected variants. A comprehensive molecular analysis was carried out by protein structure prediction, evolutionary conservation, motif scanning, tissue-specific expression, and protein interaction network to elucidate pathogenicity of the identified ZMIZ1 variants.Results: The karyotype was 46, XX with no micro-chromosomal abnormalities identified by array-CGH. There were 20 variants detected in the female patient by WES. A de novo heterozygous missense variant (c.2330G &gt; A, p.Gly777Glu, G777E) was identified in the exon 20 of ZMIZ1. No variants of ZMIZ1 were identified in the non-consanguineous parents and her healthy elder sister. It was predicted that G777E was pathogenic and detrimental to the spatial conformation of the MIZ/SP-RING zinc finger domain of ZMIZ1.Conclusion: Thus far, only four scientific articles reported deleterious variants in ZMIZ1 and most of the cases were from Western countries. This is the first report about a Chinese patient with ZMIZ1 variant. It will broaden the current knowledge of ZMIZ1 variants and variable clinical presentations for clinicians and genetic counselors.
Mutation Analysis of the RPGR Gene in a Chinese Cohort
Authors: Liu Hong-Li , Gao Feng-Guan , Wang Dan-Dan , Hu Fang-Yuan , Xu Ping , Chang Qing , Xu Ge-Zhi , Wu Ji-Hong 
Published: March 2022

Purpose: The purpose of this study was to investigate the clinical and genetic characteristics of the retinitis pigmentosa GTPase regulatory factor gene (RPGR) in a Chinese cohort.Methods: A retrospective analysis was performed on 80 subjects with RPGR-retinal dystrophy (RPGR-RD) for detailed genetic and clinical characterization. The panel-based next-generation sequencing of 792 causative genes involved in common genetic eye diseases was conducted in all individuals, followed by clinical variant interpretation. Information, including age, sex, geographic distribution, family history, consanguineous marriage, age at symptom onset, disease duration, best corrected visual acuity (BCVA), and complete ophthalmologic examination results, was collected.Results: This cohort (41 men and 39 women) included 26 families (26 probands and their available family members) and 13 sporadic cases. The average age of these participants was 36.35 ± 17.68 years, and the majority of the families were from eastern China (28 families, 71.79%). The average duration of disease in the probands was 22.68 ± 15.80 years. In addition, the average BCVA values of the right and left eyes in the probands were 0.96 ± 0.77 and 1.00 ± 0.77, respectively. A total of 34 RPGR variants were identified, including 6 reported variants and 28 novel variants. Among these variants, NM_001034853.1: c.2899_2902delGAAG and c.2744_2745ins24 were considered de novo variants. The majority of the RPGR variants were classified as likely pathogenic, accounting for 70.59% of the variants (24 variants). The most common nucleotide and amino acid changes identified in this study were deletions (16 variants, 45.06%) and frameshifts (17 variants, 50.00%), respectively. Genetic analysis revealed that these RPGR variants were distributed in 10 different subregions of RPGR, and 70.59% of the RPGR variants (24 variants) were located in exon 15. Four RPGR variants, NM_001034853.1: c.2405_2406delAG, c.1345C &gt; T, c.2218G &gt; T and c.2236_2237delGA, occurred at a very high frequency of 28.21% (11 families) among 39 unrelated families.Conclusion: This study expands the known mutational spectrum of RPGR, and we provide a new reference for the genetic diagnosis of RPGR variants.
Chromosome-Level Genome Assembly of Bupleurum chinense DC Provides Insights Into the Saikosaponin Biosynthesis
Authors: Zhang Quanfang , Li Min , Chen Xueyan , Liu Guoxia , Zhang Zhe , Tan Qingqing , Hu Yue , Fan Yangyang , Liu Yanyan , Zhu Tongshan , Yang Xue , Yue Mingming , Bu Xun , Zhang Yongqing 
Published: March 2022

Bupleurum chinense DC is a plant widely used in Chinese traditional medicine. Saikosaponins are the major bioactive constituents of B. chinense DC. Saikosaponins biosynthesis in Bupleurum has been more intensively studied than any other metabolic processes or bioactive constituents. However, whole-genome sequencing and chromosome-level assembly for Bupleurum genus have not been reported yet. Here, we report a high-quality chromosome-level genome of B. chinense DC. through the integration of PacBio long-read sequencing, Illumina short-read sequencing, and Hi-C sequencing. The genome was phased into haplotype 0 (621.27 Mb with a contig N50 of 16.86 Mb and a scaffold N50 of 92.25 Mb) and haplotype 1 (600.48 Mb with a contig N50 of 23.90 Mb and a scaffold N50 of 102.68 Mb). A total of 45,909 and 35,805 protein-coding genes were predicted in haplotypes 0 and 1, respectively. The enrichment analyses suggested that the gene families that expanded during the evolution of B. chinense DC are involved in the biosynthesis of isoquinoline alkaloid, tyrosine, and anthocyanin. Furthermore, we analyzed the genes involved in saikosaponin biosynthesis and determined the candidate P450 and UGT genes in the third stage of saikosaponins biosynthetic, which provided new insight into the saikosaponins biosynthetic. The genomic data provide a valuable resource for future investigations of the molecular mechanisms, biological functions, and evolutionary adaptations of B. chinense DC.
Humoral and Cellular Immunogenicity and Safety of Five Different SARS-CoV-2 Vaccines in Patients With Autoimmune Rheumatic and Musculoskeletal Diseases in Remission or With Low Disease Activity and in Healthy Controls: A Single Center Study
Authors: Szebeni Gábor J. , Gémes Nikolett , Honfi Dániel , Szabó Enikő , Neuperger Patrícia , Balog József Á. , Nagy Lajos I. , Szekanecz Zoltán , Puskás László G. , Toldi Gergely , Balog Attila 
Published: March 2022

BackgroundVaccine-induced immunity is essential for controlling the COVID-19 pandemic. Data on humoral and cellular immunogenicity and safety of different SARS-CoV-2 vaccines in patients with autoimmune rheumatic and musculoskeletal diseases (RMDs) are limited.MethodsA single center observational study evaluated the immunogenicity and safety of the two-dose regimen of the BBIBP-CorV inactivated, Gam-COVID-Vac and AZD1222 adenovirus-based, and BNT162b2 and mRNA-1273 mRNA-based vaccines in patients with RMDs (n = 89) compared with healthy controls (n = 74). Neutralizing anti-RBD (receptor binding domain) specific antibodies and SARS-CoV-2 specific T-cell response were measured one and four months after the second vaccine dose in parallel with vaccination efficacy and safety.ResultsDisease-specific comparison showed that antibody response at four months was higher in spondylarthropathies compared to rheumatoid arthritis and autoimmune RMDs. Risk factors for reduced immunogenicity included longer disease duration, positive immunoserological profile and anti-CD20 therapy of patients. The rate of positive anti-RBD antibody response for healthy controls versus patients after 4 months post vaccination was 69% vs. 55% for the inactivated viral vaccine BBIBP-CorV, 97% vs. 53% for the pooled data of adenovirus vector-based vaccines Gam-COVID-Vac and AZD1222, or 100% vs. 81% for the pooled data of mRNA vaccines BNT162b2 and mRNA-1273, respectively. Patients who received the Gam-COVID-Vac or mRNA-1273 vaccines had a higher proportion of TNF-α producing CD4+ T-cells upon SARS-CoV-2 antigen stimulation compared to the inactivated viral vaccine.ConclusionAll five investigated vaccines were immunogenic in the majority of patients and healthy controls with variable antibody and T-cell response and an acceptable safety profile.
Early-Life Antibiotic Exposure Associated With Varicella Occurrence and Breakthrough Infections: Evidence From Nationwide Pre-Vaccination and Post-Vaccination Cohorts
Authors: Lin Teng-Li , Fan Yi-Hsuan , Chang Yi-Ling , Ho Hsiu J. , Liang Li-Lin , Chen Yi-Ju , Wu Chun-Ying 
Published: March 2022

BackgroundAntibiotic-driven dysbiosis may impair immune function and reduce vaccine-induced antibody titers.ObjectivesThis study aims to investigate the impacts of early-life antibiotic exposure on subsequent varicella and breakthrough infections.MethodsThis is a nationwide matched cohort study. From Taiwan’s National Health Insurance Research Database, we initially enrolled 187,921 children born from 1997 to 2010. Since 2003, the Taiwan government has implemented a one-dose universal varicella vaccination program for children aged 1 year. We identified 82,716 children born during the period 1997 to 2003 (pre-vaccination era) and 48,254 children born from July 1, 2004, to 2009 (vaccination era). In the pre-vaccination era, 4,246 children exposed to antibiotics for at least 7 days within the first 2 years of life (Unvaccinated A-cohort) were compared with reference children not exposed to antibiotics (Unvaccinated R-cohort), with 1:1 matching for gender, propensity score, and non-antibiotic microbiota-altering medications. Using the same process, 9,531 children in the Vaccinated A-cohort and Vaccinated R-cohort were enrolled from the vaccination era and compared. The primary outcome was varicella. In each era, demographic characteristics were compared, and cumulative incidences of varicella were calculated. Cox proportional hazards model was used to examine associations.ResultsIn the pre-vaccination era, the 5-year cumulative incidence of varicella in the Unvaccinated A-cohort (23.45%, 95% CI 22.20% to 24.70%) was significantly higher than in the Unvaccinated R-cohort (16.72%, 95% CI 15.62% to 17.82%) (p&lt;.001). In the vaccination era, a significantly higher 5-year cumulative incidence of varicella was observed in the Vaccinated A-cohort (1.63%, 95% 1.32% to 1.93%) than in the Vaccinated R-cohort (1.19%, 95% CI 0.90% to 0.45%) (p=0.006). On multivariate analyses, early-life antibiotic exposure was an independent risk factor for varicella occurrence in the pre-vaccination (adjusted hazard ratio [aHR] 1.92, 95% CI 1.74 to 2.12) and vaccination eras (aHR 1.66, 95% CI 1.24 to 2.23). The use of penicillins, cephalosporins, macrolides, or sulfonamides in infancy was all positively associated with childhood varicella regardless of vaccine administration.ConclusionsAntibiotic exposure in early life is associated with varicella occurrence and breakthrough infections.
Similar CD4/CD8 Ratio Recovery After Initiation of Dolutegravir Plus Lamivudine Versus Dolutegravir or Bictegravir-Based Three-Drug Regimens in Naive Adults With HIV
Authors: Martínez-Sanz Javier , Ron Raquel , Moreno Elena , Sánchez-Conde Matilde , Muriel Alfonso , López Cortés Luis Fernando , Blanco José Ramón , Pineda Juan Antonio , Mena Álvaro , Calzado Isbert Sonia , Moreno Santiago , Serrano-Villar Sergio 
Published: March 2022

BackgroundThe initiation of antiretroviral treatment based on a 2-drug regimen (2DR) with dolutegravir plus lamivudine has demonstrated non-inferior efficacy than dolutegravir-based three-drug regimens (3DR). We aimed to assess whether the treatment initiation with this 2DR has a different impact on the CD4/CD8 ratio recovery than INSTI-based 3DR.MethodsWe emulated a target trial using observational data from the Spanish HIV Research Network cohort (CoRIS). The outcomes of interest were the normalization of the CD4/CD8 ratio at 48 weeks using three different cutoffs: 0.5, 1.0, and 1.5. We matched each participant who started 2DR with up to four participants who received 3DR. Subsequently, we fitted generalized estimating equation (GEE) models and used the Kaplan–Meier method for survival curves.ResultsWe included 485, 805, and 924 participants for cutoffs of 0.5, 1.0, and 1.5, respectively. At 48 weeks, 45% of participants achieved a CD4/CD8 ratio &gt;0.5, 15% achieved a ratio &gt;1.0, and 6% achieved a ratio &gt;1.5. GEE models yielded a similar risk of reaching a CD4/CD8 ratio &gt;0.5 (OR 1.00, 95% CI 0.67 - 1.50), CD4/CD8 &gt;1.0 (OR 1.03, 95% CI 0.68 - 1.58), and CD4/CD8 &gt;1.5 (OR 0.86, 95% CI 0.48 - 1.54) between both treatment strategies. There were no differences between 2DR and 3DR in the incidence ratio of CD4/CD8 ratio normalization at 0.5, 1.0 and 1.5 cut-offs.ConclusionsIn this large cohort study in people with HIV, ART initiation with dolutegravir plus lamivudine vs. dolutegravir or bictegravir-based triple antiretroviral therapy showed no difference in the rates of CD4/CD8 normalization at 48 weeks.
Neuromyelitis Optica Spectrum Disorder With Anti-Aquaporin-4 Antibody: Outcome Prediction Models
Authors: Wang Liang , Du Lei , Li Qinying , Li Fang , Wang Bei , Zhao Yuanqi , Meng Qiang , Li Wenyu , Pan Juyuan , Xia Junhui , Wu Shitao , Yang Jie , Li Heng , Ma Jianhua , ZhangBao Jingzi , Huang Wenjuan , Chang Xuechun , Tan Hongmei , Yu Jian , Zhou Lei , Lu Chuanzhen , Wang Min , Dong Qiang , Lu Jiahong , Zhao Chongbo , Quan Chao 
Published: March 2022

BackgroundRecognizing the predictors of disease relapses in patients with anti-aquaporin-4 antibody (AQP4-ab)-positive neuromyelitis optica spectrum disorder (NMOSD) is essential for individualized treatment strategy. We aimed to identify the factors that predicted relapses among patients with AQP4-ab-positive NMOSD, develop outcome prediction models, and validate them in a multicenter validation cohort.MethodsBetween January 2015 and December 2020, 820 patients with NMOSD were registered at Huashan Hospital. We retrospectively reviewed their medical records, and included 358 AQP4-ab-positive patients with 1135 treatment episodes. Univariate and multivariate analyses were used to explore the predictors of relapse, severe visual or motor disability during follow-up. A model predicting the 1- and 2-year relapse-free probability was developed and validated in an external validation cohort of 92 patients with 213 treatment episodes.ResultsLower serum AQP4-ab titer (&lt; 1:100), higher Expanded Disability Status Scale (EDSS) score at onset (≥ 2.5), and use of intravenous methylprednisolone (IVMP) at the first attack predicted an overall lower annualized relapse rate. Older age (&gt; 48 years), optic neuritis at onset, and higher onset EDSS score (≥ 2.5) significantly increased the risk for blindness, while IVMP at the first attack and maintenance therapy reduced the risk for blindness. Myelitis at onset increased the possibility of motor disability (EDSS ≥ 6.0), severe motor disability or death (EDSS ≥ 8.0), while maintenance therapy reduced these possibilities. Anderson and Gill model identified that the risk factors predicting recurrent relapses under certain treatment status were female gender, high AQP4-ab titer (≥ 1:100), previous attack under same therapy, lower EDSS score at treatment initiation (&lt; 2.5), and no maintenance therapy or oral prednisone lasting less than 6 months. A nomogram using the above factors showed good discrimination and calibration abilities. The concordance indexes in the primary and validation cohort were 0.66 and 0.65, respectively.ConclusionThis study reports the demographic, clinical and therapeutic predictors of relapse, and severe visual or motor disability in NMOSD. Early identification of patients at risk of unfavorable outcomes is of paramount importance to inform treatment decisions.
Investigation of Serum and Macular Carotenoids in Central Serous Chorioretinopathy
Authors: Ji Yuying , Gan Yuhong , Su Yongyue , Zhang Yining , Li Miaoling , Mi Lan , Zuo Chengguo , Wen Feng 
Published: April 2022

PurposeThis study aimed to evaluate serum lutein and zeaxanthin levels and macular pigment optical density (MPOD) in central serous chorioretinopathy (CSC).MethodsFifty-four patients with acute CSC (28–56 years old; 44 men and 10 women) and 62 matched controls were enrolled. Serum lutein and zeaxanthin were measured using the high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS) method. MPOD was measured at 7° of eccentricity and reported in parameters as “max” and “mean” optical density (OD) (Visucam 200; Carl Zeiss Meditec). MPOD was re-measured in 9 patients whose subretinal fluid was absorbed.ResultsThe average max OD and the mean OD in CSC were 0.275 ± 0.047 d.u. and 0.098 ± 0.018 d.u., respectively, which were significantly lower than the control (p &lt; 0.001). The average MPOD value in the unaffected eyes of patients with CSC was 0.298 ± 0.045 for max OD, 0.106 ± 0.017 for mean OD, and both were significantly lower compared with the affected eyes (p &lt; 0.001 for max OD, p = 0.01 for mean OD). In the 9 follow-up patients, the decrease in MPOD was partially recovered. The mean serum level was 409.80 ± 182.52 ng/ml for lutein and 22.97 ± 12.23 ng/ml for zeaxanthin in patients with CSC. In controls, the mean serum level was 393.38 ± 202.44 ng/ml for lutein and 22.16 ± 10.12 ng/ml for zeaxanthin. The difference was not statistically significant (p = 0.649, p = 0.698, respectively).ConclusionMPOD decreased within 7° of eccentricity in CSC without serum lutein and zeaxanthin changes. The decrease may be due to the subretinal fluid. Whether local oxidative stress is involved in CSC and the supplementation with lutein and zeaxanthin is helpful for CSC requires further investigation.
Network Pharmacology and Experimental Validation to Reveal the Pharmacological Mechanisms of Chongcaoyishen Decoction Against Chronic Kidney Disease
Authors: Fan Zhenliang , Chen Jingjing , Yang Qiaorui , He Jiabei 
Published: March 2022

Objective: To explore the pharmacological mechanisms of Chongcaoyishen decoction (CCYSD) against chronic kidney disease (CKD) via network pharmacology analysis combined with experimental validation.Methods: The bioactive components and potential regulatory targets of CCYSD were extracted from the TCMSP database, and the putative CKD-related target proteins were collected from the GeneCards and OMIM database. We matched the active ingredients with gene targets and conducted regulatory networks through Perl5 and R 3.6.1. The network visualization analysis was performed by Cytoscape 3.7.1, which contains ClueGO plug-in for GO and KEGG analysis. In vivo experiments were performed on 40 male SD rats, which were randomly divided into the control group (n = 10), sham group (n = 10), UUO group (n = 10), and CCYSD group (n = 10). A tubulointerstitial fibrosis model was constructed by unilateral ureteral obstruction through surgery and treated for seven consecutive days with CCYSD (0.00657 g/g/d). At the end of treatment, the rats were euthanized and the serum and kidney were collected for further detection.Results: In total, 53 chemical compounds from CCYSD were identified and 12,348 CKD-related targets were collected from the OMIM and GeneCards. A total of 130 shared targets of CCYSD and CKD were acquired by Venn diagram analysis. Functional enrichment analysis suggested that CCYSD might exert its pharmacological effects in multiple biological processes, including oxidative stress, apoptosis, inflammatory response, autophagy, and fiber synthesis, and the potential targets might be associated with JAK-STAT and PI3K-AKT, as well as other signaling pathways. The results of the experiments revealed that the oxidative stress in the UUO group was significantly higher than that in normal state and was accompanied by severe tubulointerstitial fibrosis (TIF), which could be effectively reversed by CCYSD (p &lt; 0.05). Meanwhile, aggravated mitochondrial injury and autophagy was observed in the epithelial cells of the renal tubule in the UUO group, compared to the normal ones (p &lt; 0.05), while the intervention of CCYSD could further activate the autophagy and reduce the mitochondrial injury (p &lt; 0.05).Conclusion: We provide an integrative network pharmacology approach combined with in vivo experiments to explore the underlying mechanisms governing the CCYSD treatment of CKD, which indicates that the relationship between CCYSD and CKD is related to its activation of autophagy, promotion of mitochondrial degradation, and reduction of tissue oxidative stress injury, promoting the explanation and understanding of the biological mechanism of CCYSD in the treatment of CKD.
Therapy-Induced Electrophysiological Changes in Primary Progressive Aphasia: A Preliminary Study
Authors: Stalpaert Jara , Standaert Sofie , D’Helft Lien , Miatton Marijke , Sieben Anne , Van Langenhove Tim , Duyck Wouter , van Mierlo Pieter , De Letter Miet 
Published: March 2022

AimsThis preliminary study aimed to investigate therapy-induced electrophysiological changes in persons with primary progressive aphasia (PPA). The investigated event-related potential (ERP) components associated with language processing were the mismatch negativity, P300, N400, and P600.MethodsA linguistic ERP test battery and standardized language assessment were administered in four patients with PPA of which two received speech-language therapy (SLT) and two did not receive therapy. The battery was administered twice with approximately 6 months in between in each patient. The results of the follow-up assessments were compared to the results of the initial assessments.ResultsAlthough the results of the behavioral language assessment remained relatively stable between the initial and follow-up assessments, changes in the mean amplitudes, onset latencies, and duration of the ERP components were found in the four patients. In the two patients that did not receive SLT, an increased delay in 50% and a decreased mean amplitude in 25% of the measured ERP components were found. The electrophysiological changes found in the patients that received SLT were variable. Interestingly, the mismatch negativity and the N400 effect elicited by the categorical priming paradigm were less delayed and had an increased mean amplitude at the follow-up assessment in the patient with the non-fluent variant who received SLT. In this patient, the P600 component was absent at the initial assessment but present at the follow-up assessment.ConclusionAlthough no clear patterns in electrophysiological changes between patients who received SLT and patients who did not receive SLT were found by our preliminary study, it seems like the SLT induced improvements or compensation mechanisms in some specific language comprehension processes in the patient with the NFV. The results of this study are still preliminary because only four heterogeneous patients were included. Future studies should include larger patient groups of the three clinical variants because the therapy-induced electrophysiological changes might differ depending on the clinical variant and the underlying pathology.