TIGER: technical variation elimination for metabolomics data using ensemble learning architecture.

Large metabolomics datasets inevitably contain unwanted technical variations which can obscure meaningful biological signals and affect how this information is applied to personalized healthcare. Many methods have been developed to handle unwanted variations. However, the underlying assumptions of many existing methods only hold for a few specific scenarios. Some tools remove technical variations with models trained on quality control (QC) samples which may not generalize well on subject samples. Additionally, almost none of the existing methods supports datasets with multiple types of QC samples, which greatly limits their performance and flexibility. To address these issues, a non-parametric method TIGER (Technical variation elImination with ensemble learninG architEctuRe) is developed in this study and released as an R package (https://CRAN.R-project.org/package=TIGERr). TIGER integrates the random forest algorithm into an adaptable ensemble learning architecture. Evaluation results show that TIGER outperforms four popular methods with respect to robustness and reliability on three human cohort datasets constructed with targeted or untargeted metabolomics data. Additionally, a case study aiming to identify age-associated metabolites is performed to illustrate how TIGER can be used for cross-kit adjustment in a longitudinal analysis with experimental data of three time-points generated by different analytical kits. A dynamic website is developed to help evaluate the performance of TIGER and examine the patterns revealed in our longitudinal analysis (https://han-siyu.github.io/TIGER_web/). Overall, TIGER is expected to be a powerful tool for metabolomics data analysis.

Bidirectional modulation of TCA cycle metabolites and anaplerosis by metformin and its combination with SGLT2i.

BACKGROUND: Metformin and sodium-glucose-cotransporter-2 inhibitors (SGLT2i) are cornerstone therapies for managing hyperglycemia in diabetes. However, their detailed impacts on metabolic processes, particularly within the citric acid (TCA) cycle and its anaplerotic pathways, remain unclear. This study investigates the tissue-specific metabolic effects of metformin, both as a monotherapy and in combination with SGLT2i, on the TCA cycle and associated anaplerotic reactions in both mice and humans. METHODS: Metformin-specific metabolic changes were initially identified by comparing metformin-treated diabetic mice (MET) with vehicle-treated db/db mice (VG). These findings were then assessed in two human cohorts (KORA and QBB) and a longitudinal KORA study of metformin-naïve patients with Type 2 Diabetes (T2D). We also compared MET with db/db mice on combination therapy (SGLT2i + MET). Metabolic profiling analyzed 716 metabolites from plasma, liver, and kidney tissues post-treatment, using linear regression and Bonferroni correction for statistical analysis, complemented by pathway analyses to explore the pathophysiological implications. RESULTS: Metformin monotherapy significantly upregulated TCA cycle intermediates such as malate, fumarate, and α-ketoglutarate (α-KG) in plasma, and anaplerotic substrates including hepatic glutamate and renal 2-hydroxyglutarate (2-HG) in diabetic mice. Downregulated hepatic taurine was also observed. The addition of SGLT2i, however, reversed these effects, such as downregulating circulating malate and α-KG, and hepatic glutamate and renal 2-HG, but upregulated hepatic taurine. In human T2D patients on metformin therapy, significant systemic alterations in metabolites were observed, including increased malate but decreased citrulline. The bidirectional modulation of TCA cycle intermediates in mice influenced key anaplerotic pathways linked to glutaminolysis, tumorigenesis, immune regulation, and antioxidative responses. CONCLUSION: This study elucidates the specific metabolic consequences of metformin and SGLT2i on the TCA cycle, reflecting potential impacts on the immune system. Metformin shows promise for its anti-inflammatory properties, while the addition of SGLT2i may provide liver protection in conditions like metabolic dysfunction-associated steatotic liver disease (MASLD). These observations underscore the importance of personalized treatment strategies.

Sarcomatoid renal cell tumor harboring a novel BYSL::TFEB fusion with concurrent TFEB amplification.

Transcription factor EB (TFEB)-rearranged renal cell carcinoma (RCC) exhibits diverse gene fusion patterns and heterogeneous clinicopathologic features. Rare TFEB-amplified RCCs have been described recently and are associated with a more aggressive clinical course. Herein, we report a case of an 86-year-old man with a solid 9.2-cm kidney tumor that showed a diffuse high-grade sarcomatoid morphology. The tumor demonstrated a novel BYSL::TFEB fusion containing exons 1-2 of the BYSL gene fused to exons 3-10 of TFEB via next-generation sequencing by using NextSeq sequencer. Fluorescence in situ hybridization (FISH) studies displayed concurrent high-copy number TFEB amplification in two distinct patterns, a balanced increase of 5' and 3' copies, and solely increased 5' copies, and mouse double minute 2 (MDM2) gene amplification by using TFEB (6p21.1) dual-color break-apart probe and MDM2 FISH probe. Notably, the tumor showed a distinctive immunoprofile with overexpressions of TFEB, epithelial membrane antigen, Cathepsin K, and PDL-1 (SP263). FISH test for transcription factor binding to IGHM enhancer 3 (TFE3) was negative for rearrangement and corresponding immunonegativity of TFE3. These findings not only expand the repertoire of known TFEB fusion partners implicated in tumorigenesis, but also may provide novel information for target therapy.

Ubiquitous WiFi and Acoustic Sensing: Principles, Technologies, and Applications.

With the increasing pervasiveness of mobile devices such as smartphones, smart TVs, and wearables, smart sensing, transforming the physical world into digital information based on various sensing medias, has drawn researchers' great attention. Among different sensing medias, WiFi and acoustic signals stand out due to their ubiquity and zero hardware cost. Based on different basic principles, researchers have proposed different technologies for sensing applications with WiFi and acoustic signals covering human activity recognition, motion tracking, indoor localization, health monitoring, and the like. To enable readers to get a comprehensive understanding of ubiquitous wireless sensing, we conduct a survey of existing work to introduce their underlying principles, proposed technologies, and practical applications. Besides we also discuss some open issues of this research area. Our survey reals that as a promising research direction, WiFi and acoustic sensing technologies can bring about fancy applications, but still have limitations in hardware restriction, robustness, and applicability. Supplementary Information: The online version contains supplementary material available at 10.1007/s11390-023-3073-5.

Marital status and survival in laryngeal squamous cell carcinoma patients: a multinomial propensity scores matched study.

OBJECTIVE: To explore the correlation between the marital status and prognosis of patients with laryngeal squamous cell carcinoma (LSCC). STUDY DESIGN: MPSM was adopted to minimize the maximum standardized average difference of the covariates among the four groups with different marital status. SETTING: Multinomial propensity scores matching (MPSM) based on data from the surveillance, epidemiology, and end results (SEER) database. METHODS: The Kaplan-Meier method and log-rank test were used to compare the survival outcomes of these groups with different marital status. RESULTS: Totally, 16,981 LSCC patients (median [IQR] age 62 [55-69] years; 829 [76.41%] males) from 2004 to 2016 were included in this study. Among them, 9112 (53.66%) were married, 2708 (15.95%) divorced or separated, 1709 (10.06%) widowed, and 3452 (20.33%) single. After MPSM, the weights make the characteristics of four groups with different marital status sufficient balance. The Kaplan-Meier method and log-rank test showed widowed patients may lead to the highest mortality rate while married patients have a higher survival rate than the other three groups. Single and divorced or separated patients had no significant difference in the survival rate. In addition, multivariate analysis by controlling for confounding factors showed that in male, well-differentiated, and early stage patients, compared with married, unmarried was an independent risk factor for CSS (P < 0.05). CONCLUSION: Marital status showed a significant association with the survival status of LSCC patients. Importantly, the outcome of married patients was better, while widowed patients tended to have worse prognosis.

Refined diagnosis of hydatidiform moles with p57 immunohistochemistry and molecular genotyping: updated analysis of a prospective series of 2217 cases.

Immunohistochemical analysis of p57 expression and molecular genotyping accurately subclassify molar specimens into complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM) and distinguish these from nonmolar specimens. Characteristics of a prospective series of potentially molar specimens analyzed in a large gynecologic pathology practice are summarized. Of 2217 cases (2160 uterine, 57 ectopic), 2080 (94%) were successfully classified: 571 CHMs (570 uterine, 1 ectopic), 498 PHMs (497 uterine, 1 ectopic), 900 nonmolar (including 147 trisomies, 19 digynic triploids, and 4 donor egg conceptions), and 56 androgenetic/biparental mosaics; 137 were complex or unsatisfactory and not definitively classified. CHMs dominated in patients aged < 21 and >45 years and were the only kind of molar conception found in the latter group. Of 564 successfully immunostained CHMs, 563 (99.8%) were p57-negative (1 p57-positive [retained maternal chromosome 11] androgenetic by genotyping). Of 153 genotyped CHMs, 148 (96.7%) were androgenetic (85% monospermic) and 5 were biparental, the latter likely familial biparental hydatidiform moles. Of 486 successfully immunostained PHMs, 481 (99%) were p57-positive (3 p57-negative [loss of maternal chromosome 11], 2 unknown mechanism). Of 497 genotyped PHMs, 484 (97%) were diandric triploid (99% dispermic) and 13 were triandric tetraploid (all at least dispermic). Of 56 androgenetic/biparental mosaics, 37 had a p57-negative complete molar component (16 confirmed as androgenetic by genotyping). p57 expression is highly correlated with genotyping, serving as a reliable marker for CHMs, and identifies molar components and androgenetic cell lines in mosaic conceptions. Correlation of morphology, p57 expression, genotyping data, and history are required to recognize familial biparental hydatidiform moles and donor egg conceptions, as the former can be misclassified as nonmolar and the latter can be misclassified as dispermic CHM on the basis of isolated genotyping results.

Integrated Proteomics and Metabolomics Assessment Indicated Metabolic Alterations in Hypothalamus of Mice Exposed to Triclosan.

Triclosan (TCS) is a ubiquitous antimicrobial used in many daily consumer products. It has been reported to induce endocrine disrupting effects at low doses in mammals, disturbing sex hormone function and thyroid function. The hypothalamus plays a crucial role in the maintenance of neuroendocrine function and energy homeostasis. We speculated that the adverse effects of TCS might be related to the disturbance of metabolic processes in hypothalamus. The present study aimed at investigating the effects of TCS exposure on the protein and metabolite profiles in hypothalamus of mice. Male C57BL/6 mice were orally exposed to TCS at the dosage of 10 mg/kg/d for 13 weeks. The hypothalamus was isolated and processed for mass spectrometry (MS)-based proteomics and metabolomics analyses. The results showed that a 10.6% decrease (P = 0.066) in body weight gain was observed in the TCS exposure group compared with vehicle control group. Differential analysis defined 52 proteins and 57 metabolites that delineated TCS exposed mice from vehicle controls. Among the differential features, multiple proteins and metabolites were found to play vital roles in neuronal signaling and function. Bioinformatics analysis revealed that these differentially expressed proteins and metabolites were involved in four major biological processes, including glucose metabolism, purine metabolism, neurotransmitter release, and neural plasticity, suggesting the disturbance of homeostasis in energy metabolism, mitochondria function, neurotransmitter system, and neuronal function. Our results may provide insights into the neurotoxicity of TCS and extend our understanding of the biological effects induced by TCS exposure.

Identification of two microRNA signatures in whole blood as novel biomarkers for diagnosis of nasopharyngeal carcinoma.

BACKGROUND: Early diagnosis is critical to reduce the mortality caused by nasopharyngeal carcinoma (NPC). MicroRNAs (miRNAs) are dysregulated and play important roles in carcinogenesis. Therefore, this study aimed to identify diagnostically relevant circulating miRNA signatures in patients with NPC. METHODS: Total RNA was extracted from whole blood samples obtained from 120 patients with NPC, 30 patients with head-neck tumors (HNT), and 30 healthy subjects (HSs), and examined by using a custom microarray. The expression levels of four miRNAs identified by using the microarray were validated with quantitative real-time reverse transcription polymerase chain reaction. The 120 patients with NPC and 30 HSs were randomly assigned to training group-1 and validation group-1, respectively. By using significance analysis of microarray (SAM), the specific miRNA expression profiles in whole blood from patients with NPC are obtained. By using lasso regression and adaptive boosting, a diagnostic signature was identified in training group-1, and its accuracy was verified in validation group-1. By using the same methods, another signature to distinguish patients with NPC from those with HNT and HSs was identified in training group-2 and confirmed in validation group-2. RESULTS: There were 117 differentially expressed miRNAs (upregulated and downregulated fold change ≥ 1.5) between the patients with NPC and HSs, among which an 8-miRNA signature was identified with 96.43% sensitivity and 100% specificity [area under the curve (AUC) = 0.995] to diagnose NPC in training group-1 and 86.11% sensitivity and 88.89% specificity (AUC = 0.941) in validation group-1. Compared with traditional Epstein-Barr virus (EBV) seromarkers, this signature was more specific for NPC. Furthermore, a 16-miRNA signature to differentiate NPC from HNT and HS (HNT-HS) was established from 164 differentially expressed miRNAs, which diagnosed NPC and HNT-HS with 100% accuracy (AUC = 1.000) in training group-2 and 87.04% (AUC = 0.924) in validation group-2. CONCLUSIONS: The present study identified two miRNA signatures for the highly accurate diagnosis and differential diagnosis of patients with NPC from HSs and patients with HNT. The identified miRNAs might represent novel serological biomarkers and potential therapeutic targets for NPC.

A novel approach to determine two optimal cut-points of a continuous predictor with a U-shaped relationship to hazard ratio in survival data: simulation and application.

BACKGROUND: In clinical and epidemiological researches, continuous predictors are often discretized into categorical variables for classification of patients. When the relationship between a continuous predictor and log relative hazards is U-shaped in survival data, there is a lack of a satisfying solution to find optimal cut-points to discretize the continuous predictor. In this study, we propose a novel approach named optimal equal-HR method to discretize a continuous variable that has a U-shaped relationship with log relative hazards in survival data. METHODS: The main idea of the optimal equal-HR method is to find two optimal cut-points that have equal log relative hazard values and result in Cox models with minimum AIC value. An R package 'CutpointsOEHR' has been developed for easy implementation of the optimal equal-HR method. A Monte Carlo simulation study was carried out to investigate the performance of the optimal equal-HR method. In the simulation process, different censoring proportions, baseline hazard functions and asymmetry levels of U-shaped relationships were chosen. To compare the optimal equal-HR method with other common approaches, the predictive performance of Cox models with variables discretized by different cut-points was assessed. RESULTS: Simulation results showed that in asymmetric U-shape scenarios the optimal equal-HR method had better performance than the median split method, the upper and lower quantiles method, and the minimum p-value method regarding discrimination ability and overall performance of Cox models. The optimal equal-HR method was applied to a real dataset of small cell lung cancer. The real data example demonstrated that the optimal equal-HR method could provide clinical meaningful cut-points and had good predictive performance in Cox models. CONCLUSIONS: In general, the optimal equal-HR method is recommended to discretize a continuous predictor with right-censored outcomes if the predictor has an asymmetric U-shaped relationship with log relative hazards based on Cox regression models.

The impact of an expressive writing intervention on quality of life among Chinese breast cancer patients undergoing chemotherapy.

BACKGROUND: Expressive writing interventions are shown to confer physical and psychological benefits for Caucasian cancer survivors. This study evaluated the health benefits of an expressive writing intervention among breast cancer patients in mainland China. METHODS: Stage I-III Chinese breast cancer survivors undergoing chemotherapy were recruited in Shanghai, China. They (n = 90) were randomly assigned to one of three conditions: a positive thinking group (PTC) to write about the positive aspects of their cancer experience; a self-regulation condition (SRC) to write about their stress and coping efforts, deepest feelings, and positive aspects of their cancer experience; or a cancer-fact group (CFC) to write about facts relevant to their cancer experience. All groups wrote for 30 min every week for 4 weeks. Quality of life (QOL) was assessed using the FACT-B at baseline and 1- and 2-month follow-ups. Linear mixed effects models were used to test the hypotheses that the SRC and PTC would improve QOL compared to the CFC. RESULTS: QOL improved overtime in the whole sample. Contrary to hypotheses, the CFC had increased QOL compared with the SRC from baseline to both the 1- and 2-month follow-ups (ΔQOL = 9.31, p = 0.01, d = 0.44; ΔQOL = 9.45, p = 0.025, d = 0.49). The PTC did not differ from cancer-fact writing but had increased QOL compared with the SRC from baseline to both the 1- and 2-month follow-ups (ΔQOL = 7.44, p = 0.04, d = 0.35; ΔQOL = 11.72, p = 0.06, d = 0.61). CONCLUSION: Interventions through expressive writing about positive experience and cancer facts are feasible and can benefit Chinese cancer patients undergoing chemotherapy.

[Identification of the Strain Which Highly Produces Protease and ß-D-glucosidase Isolated from Shuidouchi Produced in Sichuan and Evaluating Its Ability of Producing Protease].

OBJECTIVE: To select and identify the bacterium which highly produces protease and ß-D-glucosidase from 72 strains of Shuidouchi from Sichuan, and to provide evidence for further research on its nutritional value and fermentation strain exploiting. METHODS: Casein degradation test and pNPG chemical test were applied respectively to detect the capacity to produce protease and ß-D-glucosidase of each strain. Characteristics of morphology, biochemistry, 16S rRNA and MALDI-TOF-MS were used to identify the fermentation strain, which genetic stability, curves of growth and enzyme producing were also obtained. RESULTS: The strain with the highest enzyme activity of ß-D-glucosidase (0.084 U/L) among the top 10 strains for producing protease was selected as the fermentation strain and was identified as Bacillus subtilis, which curves of growth and enzyme producing conformed as well. The result of genetic stability showed that capacity of enzyme producing was stable until the 10th generation. CONCLUSIONS: The fermentation strain which highly produced protease and ß-D-glucosidase was selected from 72 strains of shuidouchi from Sichuan and was identified as Bacillus subtilis.

Prediction of myopia development among Chinese school-aged children using refraction data from electronic medical records: A retrospective, multicentre machine learning study.

BACKGROUND: Electronic medical records provide large-scale real-world clinical data for use in developing clinical decision systems. However, sophisticated methodology and analytical skills are required to handle the large-scale datasets necessary for the optimisation of prediction accuracy. Myopia is a common cause of vision loss. Current approaches to control myopia progression are effective but have significant side effects. Therefore, identifying those at greatest risk who should undergo targeted therapy is of great clinical importance. The objective of this study was to apply big data and machine learning technology to develop an algorithm that can predict the onset of high myopia, at specific future time points, among Chinese school-aged children. METHODS AND FINDINGS: Real-world clinical refraction data were derived from electronic medical record systems in 8 ophthalmic centres from January 1, 2005, to December 30, 2015. The variables of age, spherical equivalent (SE), and annual progression rate were used to develop an algorithm to predict SE and onset of high myopia (SE ≤ -6.0 dioptres) up to 10 years in the future. Random forest machine learning was used for algorithm training and validation. Electronic medical records from the Zhongshan Ophthalmic Centre (a major tertiary ophthalmic centre in China) were used as the training set. Ten-fold cross-validation and out-of-bag (OOB) methods were applied for internal validation. The remaining 7 independent datasets were used for external validation. Two population-based datasets, which had no participant overlap with the ophthalmic-centre-based datasets, were used for multi-resource validation testing. The main outcomes and measures were the area under the curve (AUC) values for predicting the onset of high myopia over 10 years and the presence of high myopia at 18 years of age. In total, 687,063 multiple visit records (≥3 records) of 129,242 individuals in the ophthalmic-centre-based electronic medical record databases and 17,113 follow-up records of 3,215 participants in population-based cohorts were included in the analysis. Our algorithm accurately predicted the presence of high myopia in internal validation (the AUC ranged from 0.903 to 0.986 for 3 years, 0.875 to 0.901 for 5 years, and 0.852 to 0.888 for 8 years), external validation (the AUC ranged from 0.874 to 0.976 for 3 years, 0.847 to 0.921 for 5 years, and 0.802 to 0.886 for 8 years), and multi-resource testing (the AUC ranged from 0.752 to 0.869 for 4 years). With respect to the prediction of high myopia development by 18 years of age, as a surrogate of high myopia in adulthood, the algorithm provided clinically acceptable accuracy over 3 years (the AUC ranged from 0.940 to 0.985), 5 years (the AUC ranged from 0.856 to 0.901), and even 8 years (the AUC ranged from 0.801 to 0.837). Meanwhile, our algorithm achieved clinically acceptable prediction of the actual refraction values at future time points, which is supported by the regressive performance and calibration curves. Although the algorithm achieved balanced and robust performance, concerns about the compromised quality of real-world clinical data and over-fitting issues should be cautiously considered. CONCLUSIONS: To our knowledge, this study, for the first time, used large-scale data collected from electronic health records to demonstrate the contribution of big data and machine learning approaches to improved prediction of myopia prognosis in Chinese school-aged children. This work provides evidence for transforming clinical practice, health policy-making, and precise individualised interventions regarding the practical control of school-aged myopia.

A Tumor Mitochondria Vaccine Protects against Experimental Renal Cell Carcinoma.

Mitochondria provide energy for cells via oxidative phosphorylation. Reactive oxygen species, a byproduct of this mitochondrial respiration, can damage mitochondrial DNA (mtDNA), and somatic mtDNA mutations have been found in all colorectal, ovarian, breast, urinary bladder, kidney, lung, and pancreatic tumors studied. The resulting altered mitochondrial proteins or tumor-associated mitochondrial Ags (TAMAs) are potentially immunogenic, suggesting that they may be targetable Ags for cancer immunotherapy. In this article, we show that the RENCA tumor cell line harbors TAMAs that can drive an antitumor immune response. We generated a cellular tumor vaccine by pulsing dendritic cells with enriched mitochondrial proteins from RENCA cells. Our dendritic cell-based RENCA mitochondrial lysate vaccine elicited a cytotoxic T cell response in vivo and conferred durable protection against challenge with RENCA cells when used in a prophylactic or therapeutic setting. By sequencing mtDNA from RENCA cells, we identified two mutated molecules: COX1 and ND5. Peptide vaccines generated from mitochondrial-encoded COX1 but not from ND5 had therapeutic properties similar to RENCA mitochondrial protein preparation. Thus, TAMAs can elicit effective antitumor immune responses, potentially providing a new immunotherapeutic strategy to treat cancer.

[Construction and Evaluation of a Novel TB Vaccine Candidate Based on inlB1 Gene Attenuated Listeria ivanovii].

OBJECTIVE: To construct a novel tuberculosis vaccine candidate LIΔinlB1-Ag85C by knocking out the inlB1 gene of Listeria ivanovii (LI) recombinant strain LI-Ag85C,and study the biological characteristics of the attenuated strain in vitro and in vivo. METHODS: Targeting plasmid carrying inlB1 upstream and downstream sequences was constructed and electroporated into LI-Ag85C competent cells. Afterward inlB1 gene was knocked out by homologous recombination. Recombinant attenuated strain LIΔinlB1-Ag85C and parental strain LI-Ag85C were tested in growth characteristics,hemolyticability,the adhesion and invasion tendency to HepG2 in vitro and the median lethal dose (LD50) for C57BL/6 mice in vivo. RESULTS: Genome sequence of the attenuated tuberculosis vaccine candidate LIΔinlB1-Ag85C was as expected. The attenuated strain and the parental strain showed the similar growth curve in vitro. The adhesion rates of the two strains were 6.66% and 7.46%,respectively,and the invasion rate of them were 0.031% and 0.042% respectively. LIΔinlB1-Ag85C seemed having a lower adhesion and invasion rates to HepG2 cells,however the difference had no significance. The hemolytic ability of recombinant strain was the same as to the parental strain. The LD50 of LIΔinlB1-Ag85C and LI-Ag85C for C57BL/6 mice were 3.2×108 CFU/per mouse and 6.7×107 CFU/per mouse,respectively. LIΔinlB1-Ag85C showed a significantly decrease in animal virulence. CONCLUSION: A novel tuberculosis vaccine candidate LIΔinlB1-Ag85C based on attenuated Listeria ivanovii was successfully constructed with a significant decrease in toxicity.

Blocking herpes simplex virus 2 glycoprotein E immune evasion as an approach to enhance efficacy of a trivalent subunit antigen vaccine for genital herpes.

UNLABELLED: Herpes simplex virus 2 (HSV-2) subunit antigen vaccines targeting virus entry molecules have failed to prevent genital herpes in human trials. Our approach is to include a virus entry molecule and add antigens that block HSV-2 immune evasion. HSV-2 glycoprotein C (gC2) is an immune evasion molecule that inhibits complement. We previously reported that adding gC2 to gD2 improved vaccine efficacy compared to the efficacy of either antigen alone in mice and guinea pigs. Here we demonstrate that HSV-2 glycoprotein E (gE2) functions as an immune evasion molecule by binding the IgG Fc domain. HSV-2 gE2 is synergistic with gC2 in protecting the virus from antibody and complement neutralization. Antibodies produced by immunization with gE2 blocked gE2-mediated IgG Fc binding and cell-to-cell spread. Mice immunized with gE2 were only partially protected against HSV-2 vaginal challenge in mice; however, when gE2 was added to gC2/gD2 to form a trivalent vaccine, neutralizing antibody titers with and without complement were significantly higher than those produced by gD2 alone. Importantly, the trivalent vaccine protected the dorsal root ganglia (DRG) of 32/33 (97%) mice between days 2 and 7 postchallenge, compared with 27/33 (82%) in the gD2 group. The HSV-2 DNA copy number was significantly lower in mice immunized with the trivalent vaccine than in those immunized with gD2 alone. The extent of DRG protection using the trivalent vaccine was better than what we previously reported for gC2/gD2 immunization. Therefore, gE2 is a candidate antigen for inclusion in a multivalent subunit vaccine that attempts to block HSV-2 immune evasion. IMPORTANCE: Herpes simplex virus is the most common cause of genital ulcer disease worldwide. Infection results in emotional distress for infected individuals and their partners, is life threatening for infants exposed to herpes during childbirth, and greatly increases the risk of individuals acquiring and transmitting HIV infection. A vaccine that prevents genital herpes infection will have major public health benefits. Our vaccine approach includes strategies to prevent the virus from evading immune attack. Mice were immunized with a trivalent vaccine containing an antigen that induces antibodies to block virus entry and two antigens that induce antibodies that block immune evasion from antibody and complement. Immunized mice demonstrated no genital disease, and 32/33 (97%) animals had no evidence of infection of dorsal root ganglia, suggesting that the vaccine may prevent the establishment of latency and recurrent infections.

[A Project to Reduce the Occlusion Rate in Hemodialysis Arteriovenous Access].

BACKGROUND & PROBLEMS: Vascular occlusions in patients frequently necessitate that duty nurses work overtime to manage related vascular problems. For patients, vascular occlusions require invasive treatments that are painful, take time to heal, and increase anxiety. Furthermore, vascular occlusions seriously influence the effectiveness of hemodialysis. PURPOSE: This project worked to reduce the rates of occlusion from 18.6% to < 15% for hemodialysis arteriovenous grafts (AVGs) and from 5.2% to < 2.6% for arteriovenous fistulas (AVFs). METHOD: This project was conducted between September 1st, 2012 and July 31th, 2013. Our approach used a retrospective study, literature review, meeting discussions, and data compilation. The four main problems identified as associated with occlusion were: (1) low blood pressure during hemodialysis; (2) successive fistula puncture sites were located too close to one another; (3) abnormal blood flow; and (4) poor moisture control. Our solutions included: 1) adjusting and creating forms; 2) adjusting related nursing procedures; and 3) organizing a related lecture for our department. RESULT: The occlusion rates of AVG and AVF decreased from 18.6% to 7.4% and 5.2% to 0.9%, respectively. CONCLUSION: We significantly reduced AVG and AVF occlusion rates by using simple methods such as using a tourniquet ruler, designing big-print, illustrated patient instruction sheets on preventing low blood pressure, creating a simplified fistula puncture site series chart, creating a moisture control card, and scheduling follow-up visits for patients with abnormal blood flow at the OPD. This project provides a reference for other hemodialysis departments.

Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes.

The latency of human immunodeficiency virus type 1 (HIV-1) in resting primary CD4+ T cells is the major barrier for the eradication of the virus in patients on suppressive highly active antiretroviral therapy (HAART). Even with optimal HAART treatment, replication-competent HIV-1 still exists in resting primary CD4+ T cells. Multiple restriction factors that act upon various steps of the viral life cycle could contribute to viral latency. Here we show that cellular microRNAs (miRNAs) potently inhibit HIV-1 production in resting primary CD4+ T cells. We have found that the 3' ends of HIV-1 messenger RNAs are targeted by a cluster of cellular miRNAs including miR-28, miR-125b, miR-150, miR-223 and miR-382, which are enriched in resting CD4+ T cells as compared to activated CD4+ T cells. Specific inhibitors of these miRNAs substantially counteracted their effects on the target mRNAs, measured either as HIV-1 protein translation in resting CD4+ T cells transfected with HIV-1 infectious clones, or as HIV-1 virus production from resting CD4+ T cells isolated from HIV-1-infected individuals on suppressive HAART. Our data indicate that cellular miRNAs are pivotal in HIV-1 latency and suggest that manipulation of cellular miRNAs could be a novel approach for purging the HIV-1 reservoir.

Deciphering Autoimmune Diseases: Unveiling the Diagnostic, Therapeutic, and Prognostic Potential of Immune Repertoire Sequencing.

Autoimmune diseases (AIDs) are immune system disorders where the body exhibits an immune response to its own antigens, causing damage to its own tissues and organs. The pathogenesis of AIDs is incompletely understood. However, recent advances in immune repertoire sequencing (IR-seq) technology have opened-up a new avenue to study the IR. These studies have revealed the prevalence in IR alterations, potentially inducing AIDs by disrupting immune tolerance and thereby contributing to our comprehension of AIDs. IR-seq harbors significant potential for the clinical diagnosis, personalized treatment, and prognosis of AIDs. This article reviews the application and progress of IR-seq in diseases, such as multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, and type 1 diabetes, to enhance our understanding of the pathogenesis of AIDs and offer valuable references for the diagnosis and treatment of AIDs.

Exosomes in Action: Unraveling Their Role in Autoimmune Diseases and Exploring Potential Therapeutic Applications.

Exosomes are double phospholipid membrane vesicles that are synthesized and secreted by a variety of cells, including T cells, B cells, dendritic cells, immune cells, are extracellular vesicles. Recent studies have revealed that exosomes can play a significant role in under both physiological and pathological conditions. They have been implicated in regulation of inflammatory responses, immune response, angiogenesis, tissue repair, and antioxidant activities, particularly in modulating immunity in autoimmune diseases (AIDs). Moreover, variations in the expression of exosome-related substances, such as miRNA and proteins, may not only offer valuable perspectives for the early warning, and prognostic assessment of various AIDs, but may also serve as novel markers for disease diagnosis. This article examines the impact of exosomes on the development of AIDs and explores their potential for therapeutic application.