bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dupilumab improves clinical symptoms in children with Netherton syndrome by suppressing Th2-mediated inflammation
Authors: Yan Shi , Wu Xuege , Jiang Jinqiu , Yu Shijuan , Fang Xiao , Yang Huan , Bai Xiaoming , Wang Hua , Luo Xiaoyan 
Published: December 2022

BackgroundNetherton syndrome is a rare, life-threatening autosomal recessive genetic disorder with no effective treatment yet. Skin barrier dysfunction caused by SPINK5 gene mutations is a hallmark of the disease. Antigen penetration through the defective skin and nonspecific inflammation provide a pro-T helper 2 (Th2) immune microenvironment in the disease. Therefore, Th2 cytokines are considered to be candidate therapeutic targets.ObjectiveTo evaluate the clinical responses of patients with Netherton syndrome to dupilumab, an IL-4Rα antagonist, and identify changes in the Th1/2/17 pathway activity, skin barrier defect protein LEKTI expression after treatment.MethodsFour children with severe Netherton syndrome (aged 2 y to 4 y and 6 m) who were treated with dupilumab from January to June 2022 were evaluated at baseline, and at 4, 8, 12, 16, and 20 weeks after the start of dupilumab administration. Treatment response was assessed using the Eczema Area and Severity Index (EASI), the Numerical Rating Scale (NRS), the Dermatology Life Quality Index (CDLQI), and the Dermatitis Family Impact-questionnaire (DFI). Blood eosinophil counts, serum IgE levels and inflammatory cytokines were measured. The immunotyping of Th1/2/17 cells was performed by flow cytometry and cytokine expressions in T cell subsets were analyzed by single-cell RNA sequencing. In addition, expression of the LEKTI in skin lesions was evaluated by immunohistochemical analysis.ResultsAll four patients experienced clinical improvement, with significantly reduced EASI scores (by 75.0–83.9%) and NRS (by 87.5–90.0%) from baseline to 20 weeks of treatment. Improved quality of life scores were also seen for all patients, as measured by CDLQI and DFI. Serum IgE levels also fell by 75.6–86.9%. The serum Th2 cytokines IL-4, IL-5 and IL-13 were found at low level, with no significant changes during the treatment. However, Th2 cytokines expressed by T cells, especially IL-4, decreased at single-cell level after treatment (P = 0.029). The baseline percentage of Th2 cells (among total CD3+CD4+ T cells) was significantly higher in patients than that in healthy controls (HC) (P &lt; 0.0001); this percentage fell from 8.25% ± 0.75% to 4.02% ± 0.62% after 20 weeks dupilumab treatment. There was no noticeable change in LEKTI protein expression in skin lesions pre- and post-treatment. Two patients reported mild ocular adverse effects, but there were no severe adverse events.ConclusionDupilumab may be an effective and safe treatment option in a subset of pediatric patients with Netherton syndrome, especially in improving itch and the quality of life. These effects were achieved in part by suppression of the Th2-mediated inflammation.
Causal association between systemic lupus erythematosus and the risk of dementia: A Mendelian randomization study
Authors: Jin Tianyu , Huang Wei , Cao Fangzheng , Yu Xinyue , Guo Shunyuan , Ying Zhenhua , Xu Chao 
Published: December 2022

IntroductionIt is well-documented that systemic lupus erythematosus (SLE) is associated with dementia. However, the genetic causality of this association remains unclear. Mendelian randomization (MR) was used to investigate the potential causal relationship between SLE and dementia risk in the current study.MethodsWe selected 45 single nucleotide polymorphisms (SNPs) associated with SLE from publicly available genome-wide association studies (GWAS). Summary level statistics were obtained from the dementia GWAS database. MR estimates were performed using the inverse variance weighted (IVW) method, MR-Egger method and weighted median (WM) method. Cochran’s Q test, the intercept of MR-Egger, MR-Pleiotropy Residual Sum and Outlier method, leave-one-out analysis and funnel plot were applied for sensitivity analyses.ResultsNo significant causal association was found between SLE and any type of dementia, including Alzheimer’s disease, vascular dementia, frontotemporal dementia, and dementia with Lewy bodies. These findings were robust across several sensitivity analyses.ConclusionOverall, our findings do not support a causal association between SLE and dementia risk.
Myomedin replicas of gp120 V3 loop glycan epitopes recognized by PGT121 and PGT126 antibodies as non-cognate antigens for stimulation of HIV-1 broadly neutralizing antibodies
Authors: Daniel Lišková Veronika , Kosztyu Petr , Kuchař Milan , Černý Jiří , Bharadwaj Shiv , Petroková Hana , Vroblová Eliška , Křupka Michal , Malý Michal , Zosinčuková Tereza , Šulc Josef , Rašková Kafková Leona , Raška Milan , Malý Petr 
Published: December 2022

IntroductionImprinting broadly neutralizing antibody (bNAb) paratopes by shape complementary protein mimotopes represents a potential alternative for developing vaccine immunogens. This approach, designated as a Non-Cognate Ligand Strategy (NCLS), has recently been used for the identification of protein variants mimicking CD4 binding region epitope or membrane proximal external region (MPER) epitope of HIV-1 envelope (Env) glycoprotein. However, the potential of small binding proteins to mimic viral glycan-containing epitopes has not yet been verified.MethodsIn this work, we employed a highly complex combinatorial Myomedin scaffold library to identify variants recognizing paratopes of super candidate bNAbs, PGT121 and PGT126, specific for HIV-1 V3 loop epitopes.ResultsIn the collection of Myomedins called MLD variants targeted to PGT121, three candidates competed with gp120 for binding to this bNAb in ELISA, thus suggesting an overlapping binding site and epitope-mimicking potential. Myomedins targeted to PGT126 designated MLB also provided variants that competed with gp120. Immunization of mice with MLB or MLD binders resulted in the production of anti-gp120 and -Env serum antibodies. Mouse hyper-immune sera elicited with MLB036, MLB041, MLB049, and MLD108 moderately neutralized 8-to-10 of 22 tested HIV-1-pseudotyped viruses of A, B, and C clades in vitro.DiscussionOur data demonstrate that Myomedin-derived variants can mimic particular V3 glycan epitopes of prominent anti-HIV-1 bNAbs, ascertain the potential of particular glycans controlling neutralizing sensitivity of individual HIV-1 pseudoviruses, and represent promising prophylactic candidates for HIV-1 vaccine development.
The ER Aminopeptidases, ERAP1 and ERAP2, synergize to self-modulate their respective activities
Authors: Martín-Esteban Adrian , Rodriguez Jesus Contreras , Peske David , Lopez de Castro Jose A. , Shastri Nilabh , Sadegh-Nasseri Scheherazade 
Published: December 2022

IntroductionCritical steps in Major Histocompatibility Complex Class I (MHC-I) antigen presentation occur in the endoplasmic reticulum (ER). In general, peptides that enter the ER are longer than the optimal length for MHC-I binding. The final trimming of MHC-I epitopes is performed by two related aminopeptidases, ERAP1 and ERAP2 in humans that possess unique and complementary substrate trimming specificities. While ERAP1 efficiently trims peptides longer than 9 residues, ERAP2 preferentially trims peptides shorter than 9 residues.Materials and MethodsUsing a combination of biochemical and proteomic studies followed by biological verification.ResultsWe demonstrate that the optimal ligands for either enzyme act as inhibitors of the other enzyme. Specifically, the presence of octamers reduced the trimming of long peptides by ERAP1, while peptides longer than nonomers inhibit ERAP2 activity.DiscussionWe propose a mechanism for how ERAP1 and ERAP2 synergize to modulate their respective activities and shape the MHC-I peptidome by generating optimal peptides for presentation.
The single-cell landscape of cystic echinococcosis in different stages provided insights into endothelial and immune cell heterogeneity
Authors: Jiang Xiaofeng , Zhang Xiaofan , Jiang Nan , Sun Yeting , Li Teng , Zhang Jing , Shen Yujuan , Cao Jianping 
Published: December 2022

IntroductionHydatid cysts and angiogenesis are the key characteristics of cystic echinococcosis, with immune cells and endothelial cells mediating essential roles in disease progression. Recent single-cell analysis studies demonstrated immune cell infiltration after Echinococcus granulosus infection, highlighting the diagnostic and therapeutic potential of targeting certain cell types in the lesion microenvironment. However, more detailed immune mechanisms during different periods of E. granulosus infection were not elucidated.MethodsHerein, we characterized immune and endothelial cells from the liver samples of mice in different stages by single-cell RNA sequencing.ResultsWe profiled the transcriptomes of 45,199 cells from the liver samples of mice at 1, 3, and 6 months after infection (two replicates) and uninfected wild-type mice. The cells were categorized into 26 clusters with four distinct cell types: natural killer (NK)/T cells, B cells, myeloid cells, and endothelial cells. An SPP1+ macrophage subset with immunosuppressive and pro-angiogenic functions was identified in the late infection stage. Single-cell regulatory network inference and clustering (SCENIC) analysis suggested that Cebpe, Runx3, and Rora were the key regulators of the SPP1+ macrophages. Cell communication analysis revealed that the SPP1+ macrophages interacted with endothelial cells and had pro-angiogenic functions. There was an obvious communicative relationship between SPP1+ macrophages and endothelial cells via Vegfa–Vegfr1/Vegfr2, and SPP1+ macrophages interacted with other immune cells via specific ligand–receptor pairs, which might have contributed to their immunosuppressive function.DiscussionOur comprehensive exploration of the cystic echinococcosis ecosystem and the first discovery of SPP1+ macrophages with infection period specificity provide deeper insights into angiogenesis and the immune evasion mechanisms associated with later stages of infection.
Comparison between Lactobacillus rhamnosus GG and LuxS-deficient strain in regulating gut barrier function and inflammation in early-weaned piglets
Authors: Deng Zhaoxi , Dai Jinyan , Wei Yusen , Ma Yanfei , Mao Yingying , Zhang Jinzhi , Hua Weidong , Wang Haifeng 
Published: December 2022

BackgroundEarly weaning-induced stress impairs the intestinal barrier function and adversely affects the health of piglet. Probiotics can be used to prevent and treat various intestinal diseases. Lactobacillus rhamnosus GG (LGG) has an LuxS/AI-2 quorum sensing (QS) system that senses environmental changes through chemical signaling molecules. The aim of the study was to explore whether luxS mutant affects the protective role of LGG in the gut barrier of weaned piglets by comparing the luxS mutant (ΔluxS) with its wild-type (WT).MethodsNewborn piglets were orally administered with WT and ΔluxS at dosage of 109 CFU, respectively. Accordingly, newborn piglets in the Con group were orally administered with PBS. Piglets were weaned on day 21 and euthanized on day 24, three days following weaning.ResultsSupplementation of ΔluxS in advance significantly boosted the relative abundances of healthy microbes (including Catenibacterium, Eubacterium, Lachnospiraceae and Bifidobacterium). WT and ΔluxS maintain intestinal barrier function mainly by promoting intestinal villus to crypt ratio (VCR), occludin protein expression and mucus secretion (P&lt;0.05). Furthermore, LGG reduces pro-inflammatory mediators by inhibiting TLR4 and MAPK signal transduction (P&lt;0.05).ConclusionBoth WT and ΔluxS were shown to resist weaning stress by enhancing the intestinal barrier function of piglets. It has to be said that the ability of ΔluxS to maintain intestinal tissue morphology and promote mucus secretion significantly decreased compared with that of WT.
Plasma cell subtypes analyzed using artificial intelligence algorithm for predicting biochemical recurrence, immune escape potential, and immunotherapy response of prostate cancer
Authors: Xie Xiao , Dou Chun-Xia , Luo Ming-Rui , Zhang Ke , Liu Yang , Zhou Jia-Wei , Huang Zhi-Peng , Xue Kang-Yi , Liang Hao-Yu , Ouyang Ao-Rong , Ma Sheng-Xiao , Yang Jian-Kun , Zhou Qi-Zhao , Guo Wen-Bing , Liu Cun-Dong , Zhao Shan-Chao , Chen Ming-Kun 
Published: December 2022

BackgroundPlasma cells as an important component of immune microenvironment plays a crucial role in immune escape and are closely related to immune therapy response. However, its role for prostate cancer is rarely understood. In this study, we intend to investigate the value of a new plasma cell molecular subtype for predicting the biochemical recurrence, immune escape and immunotherapy response in prostate cancer.MethodsGene expression and clinicopathological data were collected from 481 prostate cancer patients in the Cancer Genome Atlas. Then, the immune characteristics of the patients were analyzed based on plasma cell infiltration fractions. The unsupervised clustering based machine learning algorithm was used to identify the molecular subtypes of the plasma cell. And the characteristic genes of plasma cell subtypes were screened out by three types of machine learning models to establish an artificial neural network for predicting plasma cell subtypes. Finally, the prediction artificial neural network of plasma cell infiltration subtypes was validated in an independent cohort of 449 prostate cancer patients from the Gene Expression Omnibus.ResultsThe plasma cell fraction in prostate cancer was significantly decreased in tumors with high T stage, high Gleason score and lymph node metastasis. In addition, low plasma cell fraction patients had a higher risk of biochemical recurrence. Based on the differential genes of plasma cells, plasma cell infiltration status of PCa patients were divided into two independent molecular subtypes(subtype 1 and subtype 2). Subtype 1 tends to be immunosuppressive plasma cells infiltrating to the PCa region, with a higher likelihood of biochemical recurrence, more active immune microenvironment, and stronger immune escape potential, leading to a poor response to immunotherapy. Subsequently, 10 characteristic genes of plasma cell subtype were screened out by three machine learning algorithms. Finally, an artificial neural network was constructed by those 10 genes to predict the plasma cell subtype of new patients. This artificial neural network was validated in an independent validation set, and the similar results were gained.ConclusionsPlasma cell infiltration subtypes could provide a potent prognostic predictor for prostate cancer and be an option for potential responders to prostate cancer immunotherapy.
Both N- and C-terminal domains of galectin-9 are capable of inducing HIV reactivation despite mediating differential immunomodulatory functionalities
Authors: Shete Ashwini , Bhat Mahalakshmi , Sawant Jyoti , Deshpande Supriya 
Published: December 2022

BackgroundThe shock-and-kill strategy for HIV cure requires the reactivation of latent HIV followed by the killing of the reactivated cellular reservoir. Galectin-9, an immunomodulatory protein, is shown to induce HIV reactivation as well as contribute to non-AIDS- and AIDS-defining events. The protein is prone to cleavage by inflammatory proteases at its linker region separating the N- and C-terminal carbohydrate-binding domains (N- and C-CRDs) which differ in their binding specificities. It is important to study the activity of its cleaved as well as uncleaved forms in mediating HIV reactivation and immunomodulation in order to understand their role in HIV pathogenesis and their further utilization for the shock-and-kill strategy.MethodologyThe PBMCs of HIV patients on virally suppressive ART (n = 11) were stimulated using 350 nM of the full-length protein and N- and C-CRDs of Gal-9. HIV reactivation was determined by analyzing gag RNA copies using qPCR using isolated CD4 cells and intracellular P24 staining of PBMCs by flow cytometry. Cytokine responses induced by the full-length protein and N- and C-CRDs of Gal-9 were also assessed by flow cytometry, Luminex, and gene expression assays. Changes in T helper cell gene expression pattern after the stimulation were also determined by real-time PCR array.ResultsBoth N- and C-CRDs of galectin-9 induced HIV reactivation in addition to the full-length galectin-9 protein. The two domains elicited higher cytokine responses than the full-length protein, possibly capable of mediating higher perturbations in the immune system if used for HIV reactivation. N-CRD was found to induce the development of Treg cells, whereas C-CRD inhibited the induction of Treg cells. Despite this, both domains elicited IL-10 secretory response although targeting different CD4 cell phenotypes.ConclusionN- and C-CRDs were found to induce HIV reactivation similar to that of the full-length protein, indicating their possible usefulness in the shock-and-kill strategy. The study indicated an anti-inflammatory role of N-CRD versus the proinflammatory properties of C-CRD of galectin-9 in HIV infection.
A socio-ecological assessment of land-based contamination and pollution: The Magdalena delta, Colombia
Authors: Gallo-Vélez David , Restrepo Juan Camilo , Newton Alice 
Published: December 2022

River mouth systems, such as estuaries and deltas are important earth system transitional zones linking the land and coastal marine systems. They funnel anthropogenic contaminants and pollutants from the activities in the river catchment into the marine environment. The present study is focused on the Magdalena River-mouth at Bocas de Ceniza where land-based contamination and pollution are important issues. These were subsequently analysed using an expanded DPSIR framework (Drivers Pressures, State, Impacts Responses). Based on export coefficients and secondary information, the loads of BOD, TSS, Nutrients and solid waste from different sources were identified and compared to prioritize their management within the study area. Findings suggest that contaminants generated in the study area may be insignificant compared to the inputs from the Magdalena River, but they can have a significant impact on the state of local ecosystems. Of all the sources analysed, agriculture and livestock are theoretically the largest contributors of nitrogen (i.e., 14.84 t d-1 and 48.99 t d-1) and phosphorus (i.e., 5.90 t d-1 and 19.46 t d-1) in the basin ‘Direct to the Caribbean’ and ‘Cienaga de Mallorquín’ (that altogether are identified as DtC+) and the ‘Western bank of the lower Magdalena’ (DtM-LM), respectively. In the case of BOD, domestic and industrial wastewaters contribute about 5.10 t d-1 and 98.43 t d-1 in the same basins. Contributions of faecal coliforms were more than 4 orders of magnitude higher in untreated wastewater, being 4.86 x1016 NMP d-1 and 1.78 x1016 NMP d-1 in the lower Magdalena and Caribbean catchments, respectively. Inadequately managed waste and plastic represent a serious problem for the Caribbean Basin. Solid waste generated within the study area and coming from the Magdalena basin and the Caribbean Sea, reaches the coast and deteriorates its visual quality, affects mangrove ecosystems, and generates impacts on coastal populations. By basin, the DtM-LM is where the greatest pollutant loads are generated. However, in terms of impact on human well-being, it is the DtC+ that bears the brunt where pressures are translated in impacts such as increased maintenance and cleaning cost of beaches, reduction or loss of tourism revenue, adverse health effects to vulnerable groups, reduce protection against natural hazards, increased living costs and loss of cultural values.
Severity of frailty using modified Thai frailty index, social factors, and prediction of mortality among community-dwelling older adults in a middle-income country
Authors: Morkphrom Ekkaphop , Srinonprasert Varalak , Sura-amonrattana Unchana , Siriussawakul Arunotai , Sainimnuan Supawadee , Preedachitkun Rinrada , Aekplakorn Wichai 
Published: December 2022

BackgroundFrailty has been increasingly recognized as a public health problem for aging populations with significant social impact, particularly in low- and middle-income countries. We aimed to develop a modified version of the Thai Frailty Index (TFI) and explore the association between different frailty statuses, socioeconomic factors, and mortality in community-dwelling older people from a middle-income country.MethodsThe data from participants aged ≥60 years in the Fourth Thai National Health Examination Survey were used to construct the 30-item TFI. Cutoff points were created based on stratum-specific likelihood ratio. TFI ≤ 0.10 was categorized as fit, 0.10–0.25 as pre-frail, 0.25–0.45 as mildly frail, and &gt;0.45 as severely frail. The association of frailty status with mortality was examined using Cox proportional hazard models.FindingsAmong 8,195 older adults with a mean age of 69.2 years, 1,284 died during the 7-year follow-up. The prevalence of frailty was 16.6%. The adjusted hazard ratio (aHR) for mortality in pre-frail was 1.76 (95% CI = 1.50–2.07), mildly frail 2.79 (95% CI = 2.33–3.35), and severely frail 6.34 (95% CI = 4.60–8.73). Having a caretaker in the same household alleviated mortality risk for severely frail participants with an aHR of 2.93 (95% CI = 1.92–4.46) compared with an aHR of 6.89 (95% CI = 3.87–12.26) among those living without a caretaker.InterpretationThe severity of frailty classified by the modified TFI can predict long-term mortality risk for community-dwelling older adults. Identification of severely frail older people to provide appropriate care might alleviate mortality risk. Our findings can inform policymakers to appropriately allocate services in a resource-limited setting.
Prevotella genus and its related NOD-like receptor signaling pathway in young males with stage III periodontitis
Authors: Zhao Yaqiong , Ye Qin , Feng Yao , Chen Yun , Tan Li , Ouyang Zeyue , Zhao Jie , Hu Jing , Chen Ningxin , Su Xiaolin , Dusenge Marie Aimee , Feng Yunzhi , Guo Yue 
Published: December 2022

BackgroundAs periodontitis progresses, the oral microbiota community changes dynamically. In this study, we evaluated the dominant bacteria and their roles in the potential pathway in young males with stage III periodontitis.Methods16S rRNA sequencing was performed to evaluate variations in the composition of oral bacteria between males with stage I and III periodontitis and identify the dominant bacteria of each group. Function prediction was obtained based on 16S rRNA sequencing data. The inhibitor of the predominant pathway for stage III periodontitis was used to investigate the role of the dominant bacteria in periodontitis in vivo and in vitro.ResultsChao1 index, Observed Species and Phylogenetic Diversity (PD) whole tree values were significantly higher in the stage III periodontitis group. β-diversity suggested that samples could be divided according to the stages of periodontitis. The dominant bacteria in stage III periodontitis were Prevotella, Prevotella_7, and Dialister, whereas that in stage I periodontitis was Cardiobacterium. KEGG analysis predicted that variations in the oral microbiome may be related to the NOD-like receptor signaling pathway. The inhibitor of this pathway, NOD-IN-1, decreased P. intermedia -induced Tnf-α mRNA expression and increased P. intermedia -induced Il-6 mRNA expression, consistent with the ELISA results. Immunohistochemistry confirmed the down-regulation of TNF-α and IL-6 expressions by NOD-IN-1 in P. intermedia–induced periodontitis.ConclusionThe composition of the oral bacteria in young males varied according to the stage of periodontitis. The species richness of oral microtia was greater in young males with stage III periodontitis than those with stage I periodontitis. Prevotella was the dominant bacteria in young males with stage III periodontitis, and inhibition of the NOD-like receptor signaling pathway can decrease the periodontal inflammation induced by P. intermedia.