bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-27-containing exosomes secreted by innate B-1a cells suppress and ameliorate uveitis
Authors: Kang Minkyung , Yadav Manoj Kumar , Mbanefo Evaristus C. , Yu Cheng-Rong , Egwuagu Charles E. 
Published: June 2023

IntroductionIL-27 is a heterodimeric cytokine composed of Ebi3 and IL-27p28 and can exert proinflammatory or immune suppressive effects depending on the physiological context. Ebi3 does not contain membrane-anchoring motifs, suggesting that it is a secreted protein while IL-27p28 is poorly secreted. How IL-27p28 and Ebi3 dimerize in-vivo to form biologically active IL-27 is unknown. Major impediment to clinical use of IL-27 derives from difficulty of determining exact amount of bioavailable heterodimeric IL-27 needed for therapy.MethodsTo understand how IL-27 mediates immune suppression, we characterized an innate IL-27-producing B-1a regulatory B cell population (i27-Breg) and mechanisms i27-Bregs utilize to suppress neuroinflammation in mouse model of uveitis. We also investigated biosynthesis of IL-27 and i27-Breg immunobiology by FACS, immunohistochemical and confocal microscopy.ResultsContrary to prevailing view that IL-27 is a soluble cytokine, we show that i27-Bregs express membrane-bound IL-27. Immunohistochemical and confocal analyses co-localized expression of IL-27p28 at the plasma membrane in association with CD81 tetraspanin, a BCR-coreceptor protein and revealed that IL-27p28 is a transmembrane protein in B cells. Most surprising, we found that i27-Bregs secrete IL-27-containing exosomes (i27-exosomes) and adoptive transfer of i27-exosomes suppressed uveitis by antagonizing Th1/Th17 cells, up-regulating inhibitory-receptors associated with T-cell exhaustion while inducing Treg expansion.DiscussionUse of i27-exosomes thus obviates the IL-27 dosing problem, making it possible to determine bioavailable heterodimeric IL-27 needed for therapy. Moreover, as exosomes readily cross the blood-retina-barrier and no adverse effects were observed in mice treated with i27-exosome, results of this study suggest that i27-exosomes might be a promising therapeutic approach for CNS autoimmune diseases.
Frequent IgE recognition of Blomia tropicalis allergen molecules in asthmatic children and young adults in equatorial Africa
Authors: Pauli Gabrielle , Wurmser Carole , Roos Antoine , Kokou Cosme , Huang Huey-Jy , D’souza Nishelle , Lupinek Christian , Zakzuk Josefina , Regino Ronald , Acevedo Nathalie , Caraballo Luis , Vrtala Susanne , Valenta Rudolf 
Published: June 2023

BackgroundAsthma is not well investigated in equatorial Africa and little is known about the disease-associated allergen molecules recognized by IgE from patients in this area. The aim was to study the molecular IgE sensitization profile of asthmatic children and young adults in a semi-rural area (Lambaréné) of an equatorial African country (Gabon), to identify the most important allergen molecules associated with allergic asthma in equatorial Africa.MethodsFifty-nine asthmatic patients, mainly children and few young adults, were studied by skin prick testing to Dermatophagoides pteronyssinus (Der p), D. farinae (Der f), cat, dog, cockroach, grass, Alternaria and peanut. Sera were obtained from a subset of 35 patients, 32 with positive and 3 with negative skin reaction to Der p and tested for IgE reactivity to 176 allergen molecules from different allergen sources by ImmunoCAP ISAC microarray technology and to seven recombinant Blomia tropicalis (Blo t) allergens by IgE dot blot assay.ResultsThirty-three of the 59 patients (56%) were sensitized to Der p and 23 of them (39%) were also sensitized to other allergen sources, whereas 9 patients (15%) were only sensitized to allergen sources other than Der p. IgE serology analyses (n=35) showed high IgE-binding frequencies to the Blo t allergens Blo t 5 (43%), Blo t 21 (43%) and Blo t 2 (40%), whereas the Der p allergens rDer p 2, rDer p 21 and rDer p 5 (34%, 29% and 26%) were less frequently recognized. Only few patients showed IgE reactivity to allergens from other allergen sources, except to allergens containing carbohydrate determinants (CCDs) or to wasp venom allergens (i.e., antigen 5).ConclusionOur results thus demonstrate that IgE sensitization to mite allergens is very prevalent in asthmatics in Equatorial Africa with B. tropicalis allergen molecules representing the most important ones associated with allergic asthma.
Schlafen4+-MDSC in Helicobacter-induced gastric metaplasia reveals role for GTPases
Authors: Ding Lin , Sheriff Sulaiman , Sontz Ricky A. , Merchant Juanita L. 
Published: June 2023

IntroductionMDSCs express SCHLAFEN 4 (SLFN4) in Helicobacter-infected stomachs coincident with spasmolytic polypeptide-expressing metaplasia (SPEM), a precursor of gastric cancer. We aimed to characterize SLFN4+ cell identity and the role of Slfn4 in these cells.MethodsSingle-cell RNA sequencing was performed on immune cells sorted from PBMCs and stomachs prepared from uninfected and 6-month H. felis-infected mice. Knockdown of Slfn4 by siRNA or PDE5/6 inhibition by sildenafil were performed in vitro. Intracellular ATP/GTP levels and GTPase activity of immunoprecipitated Slfn4 complexes were measured using the GTPase-Glo assay kit. The intracellular level of ROS was quantified by the DCF-DA fluorescent staining, and apoptosis was determined by cleaved Caspase-3 and Annexin V expression. Gli1CreERT2 x Slfn4fl/fl mice were generated and infected with H. felis. Sildenafil was administered twice over 2 weeks by gavaging H. felis infected mice ~4 months after inoculation once SPEM had developed.ResultsSlfn4 was highly induced in both monocytic and granulocytic MDSCs from infected stomachs. Both Slfn4+-MDSC populations exhibited strong transcriptional signatures for type-I interferon responsive GTPases and exhibited T cell suppressor function. SLFN4-containing protein complexes immunoprecipitated from myeloid cell cultures treated with IFNa exhibited GTPase activity. Knocking down Slfn4 or PDE5/6 inhibition with sildenafil blocked IFNa induction of GTP, SLFN4 and NOS2. Moreover, IFNa induction of Slfn+-MDSC function was inhibited by inducing their reactive oxygen species (ROS) production and apoptosis through protein kinase G activation. Accordingly, in vivo disruption of Slfn4 in Gli1CreERT2 x Slfn4fl/fl mice or pharmacologic inhibition by sildenafil after Helicobacter infection also suppressed SLFN4 and NOS2, reversed T cell suppression and mitigated SPEM development.ConclusionTaken together, SLFN4 regulates the activity of the GTPase pathway in MDSCs and precludes these cells from succumbing to the massive ROS generation when they acquire MDSC function.
Case Report: Localized bullous pemphigoid induced by local triggers: a case series and a proposal for diagnostic criteria based on a literature review
Authors: Corbella-Bagot Lluís , Gil-Lianes Javier , Fernández-Vela Javier , Martí-Martí Ignasi , Alegre-Fernández Marta , Fuertes Irene , Garbayo-Salmons Patricia , Bosch-Amate Xavier , Guilabert Antonio , Mascaró José M. 
Published: June 2023

IntroductionLocalized bullous pemphigoid (LBP) is an infrequent bullous pemphigoid (BP) variant restricted to a body region. According to the most compelling evidence, LBP occurs in patients with pre-existent serum antibodies against the basement membrane zone, which occasionally acquire the capacity to induce disease after the influence of different local factors acting as triggers.MethodsWe hereby present a multicenter cohort of 7 patients with LBP developed after local triggers: radiotherapy, thermal burns, surgery, rosacea, edema and a paretic leg. In addition, we conducted a review of the literature, and we propose a set of diagnostic criteria for LBP, also based on our case series and the 2022 BP guidelines from the European Academy of Dermatology and Venereology.ResultsDuring follow-up, three of the patients from our series evolved to a generalized BP, with only one requiring hospitalization. Our literature search retrieved 47 articles including a total of 108 patients with LBP, with a 63% with a potential local precipitating factor previous to their diagnosis. LBP mostly affected older females, and a subsequent generalized progression occurred in 16.7% of the cases. The most frequently involved areas were the lower limbs. Radiation therapy and surgery were responsible for the inducement of nearly 2 in 3 cases of LBP. We observed a significantly higher risk of generalization in cases where the trigger led to the developing of LBP earlier (p=0.016). Our statistical analysis did not detect any other prognosis factor for generalization when assessing direct immunofluorescence, histological and serological results, or other patient related factors.ConclusionLBP should be suspected in patients with recurrent localized bullous eruptions. The presence of a trauma history in the same anatomic area is reported in most cases.
Identification of heterogeneous subtypes and a prognostic model for gliomas based on mitochondrial dysfunction and oxidative stress-related genes
Authors: Li Junsheng , Wang Siyu , Chi Xiaojing , He Qiheng , Tao Chuming , Ding Yaowei , Wang Jia , Zhao Jizong , Wang Wen 
Published: June 2023

ObjectiveMitochondrial dysfunction and oxidative stress are known to involved in tumor occurrence and progression. This study aimed to explore the molecular subtypes of lower-grade gliomas (LGGs) based on oxidative stress-related and mitochondrial-related genes (OMRGs) and construct a prognostic model for predicting prognosis and therapeutic response in LGG patients.MethodsA total of 223 OMRGs were identified by the overlap of oxidative stress-related genes (ORGs) and mitochondrial-related genes (MRGs). Using consensus clustering analysis, we identified molecular subtypes of LGG samples from TCGA database and confirmed the differentially expressed genes (DEGs) between clusters. We constructed a risk score model using LASSO regression and analyzed the immune-related profiles and drug sensitivity of different risk groups. The prognostic role of the risk score was confirmed using Cox regression and Kaplan-Meier curves, and a nomogram model was constructed to predict OS rates. We validated the prognostic role of OMRG-related risk score in three external datasets. Quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) staining confirmed the expression of selected genes. Furthermore, wound healing and transwell assays were performed to confirm the gene function in glioma.ResultsWe identified two OMRG-related clusters and cluster 1 was significantly associated with poor outcomes (P&lt;0.001). The mutant frequencies of IDH were significantly lower in cluster 1 (P&lt;0.05). We found that the OMRG-related risk scores were significantly correlated to the levels of immune infiltration and immune checkpoint expression. High-risk samples were more sensitive to most chemotherapeutic agents. We identified the prognostic role of OMRG-related risk score in LGG patients (HR=2.665, 95%CI=1.626-4.369, P&lt;0.001) and observed that patients with high-risk scores were significantly associated with poor prognosis (P&lt;0.001). We validated our findings in three external datasets. The results of qRT-PCR and IHC staining verified the expression levels of the selected genes. The functional experiments showed a significant decrease in the migration of glioma after knockdown of SCNN1B.ConclusionWe identified two molecular subtypes and constructed a prognostic model, which provided a novel insight into the potential biological function and prognostic significance of mitochondrial dysfunction and oxidative stress in LGG. Our study might help in the development of more precise treatments for gliomas.
miR-10a-3p modulates adiposity and suppresses adipose inflammation through TGF-β1/Smad3 signaling pathway
Authors: Kiran Sonia , Mandal Mousumi , Rakib Ahmed , Bajwa Amandeep , Singh Udai P. 
Published: June 2023

BackgroundObesity is a multifactorial disease characterized by an enhanced amount of fat and energy storage in adipose tissue (AT). Obesity appears to promote and maintain low-grade chronic inflammation by activating a subset of inflammatory T cells, macrophages, and other immune cells that infiltrate the AT. Maintenance of AT inflammation during obesity involves regulation by microRNAs (miRs), which also regulate the expression of genes implicated in adipocyte differentiation. This study aims to use ex vivo and in vitro approaches to evaluate the role and mechanism of miR-10a-3p in adipose inflammation and adipogenesis.MethodsWild-type BL/6 mice were placed on normal (ND) and high-fat diet (HFD) for 12 weeks and their obesity phenotype, inflammatory genes, and miRs expression were examined in the AT. We also used differentiated 3T3-L1 adipocytes for mechanistic in vitro studies.ResultsMicroarray analysis allowed us to identify an altered set of miRs in the AT immune cells and Ingenuity pathway analysis (IPA) prediction demonstrated that miR-10a-3p expression was downregulated in AT immune cells in the HFD group as compared to ND. A molecular mimic of miR-10a-3p reduced expression of inflammatory M1 macrophages, cytokines, and chemokines, including transforming growth factor-beta 1 (TGF-β1), transcription factor Krüppel-like factor 4 (KLF4), and interleukin 17F (IL-17F) and induced expression of forkhead box P3 (FoxP3) in the immune cells isolated from AT of HFD-fed mice as compared to ND. In differentiated 3T3-L1 adipocytes, the miR-10a-3p mimics also reduced expression of proinflammatory genes and lipid accumulation, which plays a role in the dysregulation of AT function. In these cells, overexpression of miR-10a-3p reduced the expression of TGF-β1, Smad3, CHOP-10, and fatty acid synthase (FASN), relative to the control scramble miRs.ConclusionOur findings suggest that miR-10a-3p mimic mediates the TGF-β1/Smad3 signaling to improve metabolic markers and adipose inflammation. This study provides a new opportunity for the development of miR-10a-3p as a novel therapeutic for adipose inflammation, and its associated metabolic disorders.
Expression of Human ACE2 N-terminal Domain, Part of the Receptor for SARS-CoV-2, in Fusion With Maltose-Binding Protein, E. coli Ribonuclease I and Human RNase A
Authors: Xu Shuang-yong , Fomenkov Alexey , Chen Tien-Hao , Yigit Erbay 
Published: June 2023

Graphical AbstractCartoon illustration part of this work (Human ACE2 N-terminal domain tethered to RNase A and RNA degradation by the fusion enzyme).
BrevicidineB, a New Member of the Brevicidine Family, Displays an Extended Target Specificity
Authors: Zhao Xinghong , Kuipers Oscar P. 
Published: June 2023

Graphical AbstractThe antimicrobial mode of action of brevicidines. Brevicidines are potent antimicrobial cyclic lipopeptides active against Gram-negative pathogens. They have low hemolytic activity and cytotoxicity. BrevicidineB, a single amino acid residue mutant of brevicidine, displays an altered antimicrobial spectrum, showing also antimicrobial activity against Gram-positive pathogens. Due to disruption of the proton motive force of Gram-negative pathogens, brevicidines act as bactericidal antibiotics. In addition, brevicidineB acts as a bactericidal antibiotic against Gram-positive pathogens, because of its disruption capacity of the cellular membrane.
Whole-genome sequencing and phylogenetic analysis capture the emergence of a multi-drug resistant Salmonella enterica serovar Infantis clone from diagnostic animal samples in the United States
Authors: Srednik Mariela E. , Morningstar-Shaw Brenda R. , Hicks Jessica A. , Tong Christopher , Mackie Tonya A. , Schlater Linda K. 
Published: June 2023

IntroductionSalmonella enterica is a major cause of foodborne illness in the United States. A multi-drug resistant (MDR) emergent Salmonella Infantis (ESI) with a megaplasmid (pESI) was first identified in Israel and Italy and subsequently reported worldwide. The ESI clone carrying an extended spectrum β-lactamase blaCTX-M-65 on a pESI-like plasmid and a mutation in the gyrA gene has recently been found in the United States in poultry meat.MethodsWe analyzed the phenotypic and genotypic antimicrobial resistance, genomics and phylogeny of 200 S. infantis isolates from animal diagnostic samples.ResultsOf these, 33.5% were resistant to at least one antimicrobial and 19.5% were multi-drug resistant (MDR). Eleven isolates from different animal sources were phenotypically and genetically similar to the ESI clone. These isolates had a D87Y mutation in the gyrA gene conferring reduced susceptibility to ciprofloxacin and harbored a combination of 6–10 resistance genes: blaCTX-M-65, aac(3)-IVa, aadA1, aph(4)-Ia, aph(3′)-Ia, floR, sul1, dfrA14, tetA, and fosA. These 11 isolates carried class I and class II integrons and three virulence genes: sinH, involved in adhesion and invasion, ybtQ and ybtP, associated with iron transport. These isolates were also closely related to each other (separated by 7 to 27 SNPs) and phylogenetically related to the ESI clone recently found in the U.S.DiscussionThis dataset captured the emergence of the MDR ESI clone in multiple animal species and the first report of a pESI-like plasmid in isolates from horses in the U.S.
Classification of Parkinson's disease stages with a two-stage deep neural network
Authors: Pedrero-Sánchez José Francisco , Belda-Lois Juan Manuel , Serra-Añó Pilar , Mollà-Casanova Sara , López-Pascual Juan 
Published: June 2023

IntroductionParkinson's disease is one of the most prevalent neurodegenerative diseases. In the most advanced stages, PD produces motor dysfunction that impairs basic activities of daily living such as balance, gait, sitting, or standing. Early identification allows healthcare personnel to intervene more effectively in rehabilitation. Understanding the altered aspects and impact on the progression of the disease is important for improving the quality of life. This study proposes a two-stage neural network model for the classifying the initial stages of PD using data recorded with smartphone sensors during a modified Timed Up &amp; Go test.MethodsThe proposed model consists on two stages: in the first stage, a semantic segmentation of the raw sensor signals classifies the activities included in the test and obtains biomechanical variables that are considered clinically relevant parameters for functional assessment. The second stage is a neural network with three input branches: one with the biomechanical variables, one with the spectrogram image of the sensor signals, and the third with the raw sensor signals.ResultsThis stage employs convolutional layers and long short-term memory. The results show a mean accuracy of 99.64% for the stratified k-fold training/validation process and 100% success rate of participants in the test phase.DiscussionThe proposed model is capable of identifying the three initial stages of Parkinson's disease using a 2-min functional test. The test easy instrumentation requirements and short duration make it feasible for use feasible in the clinical context.
The correlation between changes in gray matter microstructure and cerebral blood flow in Alzheimer’s disease
Authors: Niu Xiaoxi , Guo Ying , Chang Zhongyu , Li Tongtong , Chen Yuanyuan , Zhang Xianchang , Ni Hongyan 
Published: June 2023

ObjectiveTo investigate the relationship between changes in cerebral blood flow (CBF) and gray matter (GM) microstructure in Alzheimer’s disease (AD) and mild cognitive impairment (MCI).MethodsA recruited cohort of 23 AD patients, 40 MCI patients, and 37 normal controls (NCs) underwent diffusional kurtosis imaging (DKI) for microstructure evaluation and pseudo-continuous arterial spin labeling (pCASL) for CBF assessment. We investigated the differences in diffusion- and perfusion-related parameters across the three groups, including CBF, mean diffusivity (MD), mean kurtosis (MK), and fractional anisotropy (FA). These quantitative parameters were compared using volume-based analyses for the deep GM and surface-based analyses for the cortical GM. The correlation between CBF, diffusion parameters, and cognitive scores was assessed using Spearman coefficients, respectively. The diagnostic performance of different parameters was investigated with k-nearest neighbor (KNN) analysis, using fivefold cross-validation to generate the mean accuracy (mAcc), mean precision (mPre), and mean area under the curve (mAuc).ResultsIn the cortical GM, CBF reduction primarily occurred in the parietal and temporal lobes. Microstructural abnormalities were predominantly noted in the parietal, temporal, and frontal lobes. In the deep GM, more regions showed DKI and CBF parametric changes at the MCI stage. MD showed most of the significant abnormalities among all the DKI metrics. The MD, FA, MK, and CBF values of many GM regions were significantly correlated with cognitive scores. In the whole sample, the MD, FA, and MK were associated with CBF in most evaluated regions, with lower CBF values associated with higher MD, lower FA, or lower MK values in the left occipital lobe, left frontal lobe, and right parietal lobe. CBF values performed best (mAuc = 0.876) for distinguishing the MCI from the NC group. Last, MD values performed best (mAuc = 0.939) for distinguishing the AD from the NC group.ConclusionGray matter microstructure and CBF are closely related in AD. Increased MD, decreased FA, and MK are accompanied by decreased blood perfusion throughout the AD course. Furthermore, CBF values are valuable for the predictive diagnosis of MCI and AD. GM microstructural changes are promising as novel neuroimaging biomarkers of AD.
A brain CT-based approach for predicting and analyzing stroke-associated pneumonia from intracerebral hemorrhage
Authors: Yang Guangtong , Xu Min , Chen Wei , Qiao Xu , Shi Hongfeng , Hu Yongmei 
Published: June 2023

IntroductionStroke-associated pneumonia (SAP) is a common complication of stroke that can increase the mortality rate of patients and the burden on their families. In contrast to prior clinical scoring models that rely on baseline data, we propose constructing models based on brain CT scans due to their accessibility and clinical universality.MethodsOur study aims to explore the mechanism behind the distribution and lesion areas of intracerebral hemorrhage (ICH) in relation to pneumonia, we utilized an MRI atlas that could present brain structures and a registration method in our program to extract features that may represent this relationship. We developed three machine learning models to predict the occurrence of SAP using these features. Ten-fold cross-validation was applied to evaluate the performance of models. Additionally, we constructed a probability map through statistical analysis that could display which brain regions are more frequently impacted by hematoma in patients with SAP based on four types of pneumonia.ResultsOur study included a cohort of 244 patients, and we extracted 35 features that captured the invasion of ICH to different brain regions for model development. We evaluated the performance of three machine learning models, namely, logistic regression, support vector machine, and random forest, in predicting SAP, and the AUCs for these models ranged from 0.77 to 0.82. The probability map revealed that the distribution of ICH varied between the left and right brain hemispheres in patients with moderate and severe SAP, and we identified several brain structures, including the left-choroid-plexus, right-choroid-plexus, right-hippocampus, and left-hippocampus, that were more closely related to SAP based on feature selection. Additionally, we observed that some statistical indicators of ICH volume, such as mean and maximum values, were proportional to the severity of SAP.DiscussionOur findings suggest that our method is effective in classifying the development of pneumonia based on brain CT scans. Furthermore, we identified distinct characteristics, such as volume and distribution, of ICH in four different types of SAP.