Predicting amyloid-PET and clinical conversion in apolipoprotein E ε3/ε3 non-demented individuals with multidimensional factors.

The apolipoprotein E (APOE) ε4 is a well-established risk factor of amyloid-ß (Aß) in Alzheimer's disease (AD). However, because of the high prevalence of APOE ε3, there may be a large number of people with APOE ε3/ε3 who are non-demented and have Aß pathology. There are limited studies on assessing Aß status and clinical conversion in the APOE ε3/ε3 non-demented population. Two hundred and ninety-three non-demented individuals with APOE ε3/ε3 from ADNI database were divided into Aß-positron emission tomography (Aß-PET) positivity (+) and Aß-PET negativity (-) groups using cut-off value of >1.11. Stepwise regression searched for a single or multidimensional clinical variables for predicting Aß-PET (+), and the receiver operating characteristic curve (ROC) assessed the accuracy of the predictive models. The Cox regression model explored the risk factors associated with clinical conversion to mild cognitive impairment (MCI) or AD. The results showed that the combination of sex, education, ventricle and white matter hyperintensity (WMH) volume can accurately predict Aß-PET status in cognitively normal (CN), and the combination of everyday cognition study partner total (EcogSPTotal) score, age, plasma p-tau 181 and WMH can accurately predict Aß-PET status in MCI individuals. EcogSPTotal score were independent predictors of clinical conversion to MCI or AD. The findings may provide a non-invasive and effective tool to improve the efficiency of screening Aß-PET (+), accelerate and reduce costs of AD trial recruitment in future secondary prevention trials or help to select patients at high risk of disease progression in clinical trials.

The Spx stress regulator confers high-level ß-lactam resistance and decreases susceptibility to last-line antibiotics in methicillin-resistant Staphylococcus aureus.

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a leading cause of mortality worldwide. MRSA has acquired resistance to next-generation ß-lactam antibiotics through the horizontal acquisition of the mecA resistance gene. Development of high resistance is, however, often associated with additional mutations in a set of chromosomal core genes, known as potentiators, which, through poorly described mechanisms, enhance resistance. The yjbH gene was recently identified as a hot spot for adaptive mutations during severe infections. Here, we show that inactivation of yjbH increased ß-lactam MICs up to 16-fold and transformed MRSA cells with low levels of resistance to being homogenously highly resistant to ß-lactams. The yjbH gene encodes an adaptor protein that targets the transcriptional stress regulator Spx for degradation by the ClpXP protease. Using CRISPR interference (CRISPRi) to knock down spx transcription, we unambiguously linked hyper-resistance to the accumulation of Spx. Spx was previously proposed to be essential; however, our data suggest that Spx is dispensable for growth at 37°C but becomes essential in the presence of antibiotics with various targets. On the other hand, high Spx levels bypassed the role of PBP4 in ß-lactam resistance and broadly decreased MRSA susceptibility to compounds targeting the cell wall or the cell membrane, including vancomycin, daptomycin, and nisin. Strikingly, Spx potentiated resistance independently of its redox-sensing switch. Collectively, our study identifies a general stress pathway that, in addition to promoting the development of high-level, broad-spectrum ß-lactam resistance, also decreases MRSA susceptibility to critical antibiotics of last resort.

Effect of aromatase inhibitors for preventing ovarian hyperstimulation syndrome in infertile patients undergoing in vitro fertilization: a systematic review and meta-analysis.

PURPOSE: To summarize the findings of relevant randomized controlled trials (RCTs) and conduct a meta-analysis to investigate the potential effect of aromatase inhibitors on preventing moderate to severe ovarian hyperstimulation syndrome (OHSS) in infertile women undergoing in vitro fertilization (IVF). METHODS: We searched for relevant RCTs in electronic databases, including MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov (from inception to August 2023). In addition, we manually searched the related reviews and reference lists of included studies for further relevant studies. We included RCTs where aromatase inhibitors prescribed either during controlled ovarian stimulation (COS) or in early luteal phase. The meta-analysis was performed using RevMan 5.4.1 software. The primary outcome was the incidence of moderate to severe OHSS. A descriptive analysis was conducted in cases where a meta-analysis was not feasible due to heterogeneity or lack of comparable data. RESULTS: 2858 records were retrieved and 12 RCTs were finally included. Letrozole was administered in the treatment group during COS in seven RCTs, whereas in the early luteal phase in five RCTs. Compared with the control group, the risk of moderate to severe OHSS significantly reduced by 55% in the letrozole group (RR 0.45, 95% CI 0.32 to 0.64, I2 = 0%, 5 RCTs, 494 patients). Moreover, serum estradiol (E2) levels on hCG trigger day significantly decreased with the administration of letrozole during COS (MD -847.23, 95% CI -1398.00 to -296.47, I2 = 93%, 5 RCTs, 374 patients). And serum E2 levels on the 4th, 5th and 7th to 10th day after hCG trigger were also significantly lower than those in the control group when letrozole was administered in the early luteal phase. CONCLUSIONS: Patients with high risk of OHSS probably benefit from letrozole, which has been revealed to reduce the incidence of moderate to severe OHSS by this systematic review. However, the very limited number of participants and the quality of the included studies does not allow to recommend letrozole for the prevention of severe OHSS.

Nrf2 ameliorates atrial fibrosis during antithrombotic therapy for atrial fibrillation by modulating CYP2C9 activity.

Anticoagulant therapy can significantly reduce the incidence of stroke and peripheral embolism events in patients with atrial fibrillation (AF). Although warfarin is widely used as an anticoagulant drug, a wrong dose can lead to increased risks of bleeding or blood clots. This study aimed to assess whether nuclear factor-erythroid-2-related factor 2 (Nrf2) can improve the efficacy of warfarin through the regulation of cytochrome P450 family 2 Subfamily C Member 9 (CYP2C9) using a rat model of AF. Results showed that AF significantly reduced Nrf2 in myocardial tissue of sham-operated rats. Furthermore, Nrf2 overexpression effectively reduced AF-induced atrial fibrosis by reducing collagen in the left atrium, inhibiting the expression of the fibrosis-related genes collagen I and transforming growth factor-ß1 in rats with AF. Nrf2 overexpression can activate CYP2C9, decrease the serum concentration of warfarin, and decrease prothrombin time and international normalized ratio in AF rats. Herein, Nrf2 overexpression protects against fibrosis, increased survival in AF rats, and activated CYP2C9 expression, thus broadening the therapeutic range of warfarin in AF rats.

Analysis of Xp22.31q27.1 Region Variation Detection based on SNP Array Technology.

BACKGROUND: The aim of the study was to investigate the value of single nucleotide polymorphism array (SNP array) technology in the prenatal diagnosis. METHODS: The variants in Xp22.31q27.1 region of 13 fetuses were analyzed by SNP array technology. Chromosome karyotype analysis was also performed for these fetuses and their parents. RESULTS: Chromosome karyotype analysis found no obvious chromosomal abnormality at 400 bands resolution. Using SNP array technology, we found that all fetuses had mutations in Xp22.31q27.1 region, which was mainly Xp22.31 lesion (61.5%, 8/13) that contained 2 to 5 OMIM genes. Moreover, these mutations consisted of 7 cases of repetition and 6 cases of deletion. In addition, 9 variants were inherited from their mothers, 3 mutations were inherited from the father, and 1 variant was de novo. CONCLUSIONS: Compared to traditional analysis of chromosome karyotype, SNP-array technology can detect more chromosomal microdeletions and microduplications. SNP-array technology can act as a supplementary diagnostic method in clinical cytogenetic diagnosis.

Reliability, validity and minimal detectable change of the Chinese Version of the Assessment of Physical Activity in Frail Older People (APAFOP-C).

BACKGROUND: Physical activity (PA) is essential in mitigating frailty syndrome, and it is necessary to measure PA in older adults with frailty. Assessment of Physical Activity in Frail Older People (APAFOP) is a suitable patient-reported outcome measure (PROM) for assessing PA among older adults with frailty. This study aimed to determine the reliability, validity and minimal detectable change of the Chinese version of the APAFOP (APAFOP-C). METHODS: This cross-sectional validation study was designed to measure the reliability and criterion validity of the APAFOP-C with 124 frail community-residing older adults. APAFOP-C was completed twice within an interval of 7-17 days to determine test-retest reliability. The investigator triangulation method was used to investigate inter-rater reliability, and a pedometer was used as the reference measurement to assess the criterion validity. Reliability and criterion validity were assessed using the intraclass correlation coefficient (ICC2,1), Pearson correlation coefficient for normally distributed variables, Spearman correlation coefficient, Wilcoxon signed-rank test for skewed variables, and the minimal detectable change at 95% level of confidence (MDC95). Agreement assessment was conducted using Bland-Altman plots for inter-rater reliability and criterion validity. Kendall's W test assessed absolute agreement among three raters in inter-rater reliability. The Mann-Whitney U test was used to evaluate whether any particular day was more representative of certain daily activities. RESULTS: Total PA on any arbitrarily chosen day illustrates daily activity (Z= -0.84, p = 0.40). The APAFOP-C exhibited strong-to-very strong test-retest reliability (ICC2,1=0.73-0.97; Spearman ρ = 0.67-0.89), and the total PA score demonstrated MDC95 < 10%. Inter-rater reliability was also strong-to-very strong (ICC2,1=0.96-0.98; Spearman ρ = 0.88-1.00), and moderate criterion validity when compared with total PA score on pedometer readings (Spearman ρ = 0.61). Limits of agreement among different raters regarding the APAFOP-C and the pedometer were narrow. CONCLUSION: The APAFOP-C was found to have limited but acceptable psychometric properties for measuring PA among community-dwelling older adults with frailty in China. It was a feasible comparative PROM for assessing PA worldwide. Practitioners can develop individualized exercise programs for frail older adults and efficiently track changes in PA utilizing the APAFOP-C.

Sleep quality, frailty and overall health among community-dwelling older people: A longitudinal study.

AIMS: The aims of the study were to describe sleep quality among community-dwelling older people; determine the association between sleep quality (total and multidimensional), frailty and overall health; study frailty as a mediator in the association between sleep quality and overall health. DESIGN: This longitudinal, correlative study used data from 2020 to 2022. METHODS: A total of 181 community-dwelling older people in a city in Southeast China were assessed twice. Sleep quality was measured using the Pittsburgh Sleep Quality Index at Time 1 (year 2020); frailty was measured using the FRAIL scale, and overall health was measured using the EuroQol visual analogue scale at Time 1 and 2 (1 year later). Associations and indirect effects were examined using linear regression analyses using the PROCESS Macro (Model 4). RESULTS: Poor sleep quality (higher scores) was associated with increased frailty over time (total scale), as well as subjective sleep quality, sleep duration, sleep efficiency and daytime dysfunction. Mediation analyses indicated that frailty change had an indirect effect on the association between sleep quality total score Time (T) 1 and overall health T2 and between the dimensions subjective sleep quality, sleep duration, sleep efficiency and daytime dysfunction and overall health. All analyses were adjusted for age, multimorbidity and overall health T1. CONCLUSIONS: Poor sleep quality is a common problem associated with poor overall health after 1 year, and the progression of frailty mediates this association. IMPACT: The findings provide a better understanding of the association between sleep quality and overall health and elucidate the mediating effect of frailty. Regular screening and effective treatment by healthcare providers for sleep problems and frailty in older people are necessary to improve their overall health and enhance healthy ageing. PATIENT OR PUBLIC CONTRIBUTION: Participants in the study provided the data used for all data analysis in the manuscript. Patient or public were not involved in data analysis, interpretation or manuscript preparation. Staff in the community health centre helped with data collection.

Pulsed electric field-assisted extraction of hesperidin from tangerine peel and its technological optimization through response surface methodology.

BACKGROUND: Tangerine peel is rich in flavonoids, particularly hesperidin, which has anti-inflammatory, antioxidant and anticancer biological activities. However, it is often wasted during citrus processing. The current common extraction method for hesperidin is solvent extraction, which has the characteristics of low extraction rate and high contamination. The aim of this study was to investigate the effect of pulsed electric field-assisted alkali dissolution extraction, followed by an acidification precipitation method, on the extraction rate and structure of hesperidin from tangerine peel. RESULTS: The results showed that the selected factors (material/liquid ratio, electric field intensity and pulse number) had a significant effect on the extraction yield. An optimum condition of 66.00 mL g-1, 4.00 kV cm-1 and 35.00 pulses gave the maximum amount (669.38 µg mL-1), which was consistent with the theoretically predicted value by software (672.10 µg mL-1), indicating that the extraction process was feasible. In addition, the purified extract was further identified as hesperidin from UV and NMR spectra. CONCLUSION: An appropriate strength of pulsed electric field-assisted alkali dissolution extraction followed by an acidification precipitation method can effectively improve the extraction rate of orange peel, and the purity of the extracted orange peel is higher. Compared with the traditional extraction, the pulsed electric field-assisted extraction method may be a potential technology for hesperidin extraction, which is beneficial for the high-value utilization of citrus resources. © 2024 Society of Chemical Industry.

Profiling of small-molecule necroptosis inhibitors based on the subpockets of kinase-ligand interactions.

Necroptosis is a highly regulated cell death (RCD) form in various inflammatory diseases. Receptor-interacting protein kinase 1 (RIPK1) and RIPK3 are involved in the pathway. Targeting the kinase domains of RIPK1 and/or 3 is a drug design strategy for related diseases. It is generally accepted that essential reoccurring features are observed across the human kinase domains, including RIPK1 and RIPK3. They present common N- and C-terminal domains that are built up mostly by α-helices and ß-sheets, respectively. The current RIPK1/3 kinase inhibitors mainly interact with the kinase catalytic cleft. This article aims to present an in-depth profiling for ligand-kinase interactions in the crucial cleft areas by carefully aligning the kinase-ligand cocrystal complexes or molecular docking models. The similarity and differential structural segments of ligands are systematically evaluated. New insights on the adaption of the conserved and selective kinase domains to the diversity of chemical scaffolds are also provided. In a word, our analysis can provide a better structural requirement for RIPK1 and RIPK3 inhibition and a guide for inhibitor discovery and optimization of their potency and selectivity.

A Clinically Selected Staphylococcus aureus clpP Mutant Survives Daptomycin Treatment by Reducing Binding of the Antibiotic and Adapting a Rod-Shaped Morphology.

Daptomycin is a last-resort antibiotic used for the treatment of infections caused by Gram-positive antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). Treatment failure is commonly linked to accumulation of point mutations; however, the contribution of single mutations to resistance and the mechanisms underlying resistance remain incompletely understood. Here, we show that a single nucleotide polymorphism (SNP) selected during daptomycin therapy inactivates the highly conserved ClpP protease and is causing reduced susceptibility of MRSA to daptomycin, vancomycin, and ß-lactam antibiotics as well as decreased expression of virulence factors. Super-resolution microscopy demonstrated that inactivation of ClpP reduced binding of daptomycin to the septal site and diminished membrane damage. In both the parental strain and the clpP strain, daptomycin inhibited the inward progression of septum synthesis, eventually leading to lysis and death of the parental strain while surviving clpP cells were able to continue synthesis of the peripheral cell wall in the presence of 10× MIC daptomycin, resulting in a rod-shaped morphology. To our knowledge, this is the first demonstration that synthesis of the outer cell wall continues in the presence of daptomycin. Collectively, our data provide novel insight into the mechanisms behind bacterial killing and resistance to this important antibiotic. Also, the study emphasizes that treatment with last-line antibiotics is selective for mutations that, like the SNP in clpP, favor antibiotic resistance over virulence gene expression.

Engineered Cytokine-Primed Extracellular Vesicles with High PD-L1 Expression Ameliorate Type 1 Diabetes.

Type 1 diabetes (T1D), which is a chronic autoimmune disease, results from the destruction of insulin-producing ß cells targeted by autoreactive T cells. The recent discovery that mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) function as therapeutic tools for autoimmune conditions has attracted substantial attention. However, the in vivo distribution and therapeutic effects of MSC-EVs potentiated by pro-inflammatory cytokines in the context of T1D have yet to be established. Here, it is reported that hexyl 5-aminolevulinate hydrochloride (HAL)-loaded engineered cytokine-primed MSC-EVs (H@TI-EVs) with high expression of immune checkpoint molecule programmed death-legend 1 (PD-L1) exert excellent inflammatory targeting and immunosuppressive effects for T1D imaging and therapy. The accumulated H@TI-EVs in injured pancreas not only enabled the fluorescence imaging and tracking of TI-EVs through the intermediate product protoporphyrin (PpIX) generated by HAL, but also promoted the proliferative and anti-apoptotic effects of islet ß cells. Further analysis revealed that H@TI-EVs exhibited an impressive ability to reduce CD4+ T cell density and activation through the PD-L1/PD-1 axis, and induced M1-to-M2 macrophage transition to reshape the immune microenvironment, exhibiting high therapeutic efficiency in mice with T1D. This work identifies a novel strategy for the imaging and treatment of T1D with great potential for clinical application.

Analysis on benzothiazole necroptosis inhibitors with chiral substitutions in the solvent-accessible region of RIP kinase domain.

Receptor-interacting protein kinase 1 (RIPK1) and RIPK3, two imperative targets of the necroptosis pathway, are associated with various inflammatory-related diseases. Regulating kinase activity with inhibitors has been confirmed as a promising strategy for inflammation treatment. However, most of the reported type I and II kinase inhibitors of RIPK1 and RIPK3, including benzothiazole compounds discovered by our group, have selective limitations due to interaction with ATP-binding pockets. Fortunately, a solvent exposure E0 region of the kinase domain, which extends into the linker region, has been reported to be related to the potency and selectivity of inhibitors. Hence, based on our previous study, a series of benzothiazole necroptosis inhibitors with chiral substitutions in the linker region were developed to investigate RIPK1/3 inhibitory potency. The results showed a 2-to 6-fold increase in anti-necroptotic activity for these chiral compounds. The improved selectivity on RIPK1 or RIPK3 was demonstrated on different derivatives. Predicted binding conformations of enantiomers with RIPK1/3 gave an explanation for their activity differences, guiding further rational design of chiral necroptosis inhibitors.

Strepolyketide D, a new SEK15-derived polyketide compound from salt-lake-derived Streptomyces sp. DBC5.

A new SEK15-derived polyketide compound, strepolyketide D (1), was isolated from salt-lake-derived Streptomyces sp. DBC5, together with two known analogues (2-3). Their structures were elucidated based on spectroscopic analysis of IR, MS, 1 D and 2 D NMR. Compound 2 elicited moderate antioxidation with IC50 value of 39.26 µg/ml. The results of the study revealed that salt-lake actinomycetes of Lake Dabancheng appear to have immense potential as a source of polyketide compounds.

Translation and Linguistic Validation of the Assessment of Physical Activity in Frail Older People into Simplified Chinese Using Cognitive Interviewing Methodology.

The Assessment of Physical Activity in Frail Older People (APAFOP) is a patient-reported outcome measure assessing physical activity among community-dwelling older adults. However, this instrument has not been verified in the Chinese context. Thus, we translated the APAFOP into Chinese and then linguistically validated the Chinese version of APAFOP (APAFOP-C) by following the guidelines developed by Beaton and Willis. The translation process took 6 months. We identified nine translation issues in the translation process, of which experiential equivalence issues were the most frequent. It took three rounds of cognitive interviews to achieve linguistic validity, and the most significant issues were related to the layout of the questionnaire identified during the cognitive interview. In conclusion, the items of the APAFOP-C were considered comprehensive and relevant to assessing the physical activities of frail older adults in China. This study has laid the foundation for future evaluation of its measurement properties.

A Three-Dimensional ResNet and Transformer-Based Approach to Anomaly Detection in Multivariate Temporal-Spatial Data.

Anomaly detection in multivariate time series is an important problem with applications in several domains. However, the key limitation of the approaches that have been proposed so far lies in the lack of a highly parallel model that can fuse temporal and spatial features. In this paper, we propose TDRT, a three-dimensional ResNet and transformer-based anomaly detection method. TDRT can automatically learn the multi-dimensional features of temporal-spatial data to improve the accuracy of anomaly detection. Using the TDRT method, we were able to obtain temporal-spatial correlations from multi-dimensional industrial control temporal-spatial data and quickly mine long-term dependencies. We compared the performance of five state-of-the-art algorithms on three datasets (SWaT, WADI, and BATADAL). TDRT achieves an average anomaly detection F1 score higher than 0.98 and a recall of 0.98, significantly outperforming five state-of-the-art anomaly detection methods.

LRFN2 binding to NMDAR inhibits the progress of ESCC via regulating the Wnt/ß-Catenin and NF-κB signaling pathway.

As a neuronal transmembrane protein, leucine-rich repeat and fibronectin type-III domain-containing protein 2 (LRFN2) can recruit and combine with N-methyl-d-aspartate receptors (NMDARs) to promote nerve growth. Genetic studies suggest that mutations in LRFN2 are associated with various cancers. However, the role and mechanism of LRFN2 in the progression of ESCC have not been elucidated. In this study, we demonstrated that LRFN2 was significantly downregulated in ESCC tissues by qRT-PCR and immunohistochemistry. Low LRFN2 expression was an adverse prognostic factor in patients with ESCC. Overexpression of LRFN2 effectively suppressed the proliferation, migration, invasion, and epithelial-to-mesenchymal transition in vitro and tumor growth in vivo. Bioinformatics analysis indicated that Wnt/ß-catenin signaling regulation was one of the most potential mechanisms and studies confirmed that overexpression of LFRN2 obviously downregulated the expression of ß-catenin, c-Myc, and cyclin D1 in ESCC cells and tumor tissues. Further studies revealed that LRFN2 plays an anti-ESCC role by binding with NMDAR-GRIN2B and this effect can be weakened by NR2B-selective NMDA antagonist-NMDA-IN-1. Moreover, the bioinformatics analysis showed that the interaction of GRIN2B and GSK3ß affects the NF-κB pathway, which was demonstrated by western blot experiments. Collectively, our results indicate that LRFN2 binding to NMDARs inhibits the progression of ESCC by regulating the Wnt/ß-catenin and NF-κB pathway, which provides a new therapeutic target for improving the prognosis of patients with ESCC.

Altered follicular regulatory T (Tfr)- and helper T (Tfh)-cell subsets are associated with autoantibody levels in microscopic polyangiitis patients.

Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) is an autoimmune disease characterized by B cells-derived ANCAs, and ANCA was proved to be a key factor in its pathogenesis. Follicular regulatory T (Tfr) and follicular helper T (Tfh) cells were T-cell subsets that play important roles in B-cell maturation and antibody production. However, their significances in microscopic polyangiitis (MPA) patients, one type of AAV, has not been thoroughly studied. In this study, comprehensive pattern analyses of circulating Tfr and Tfh were performed in MPA patients and healthy controls (HCs), and we found Tfr levels and Tfr/Tfh ratios were significantly decreased in MPA patients. Compared with HCs, Helios+, CD45RA-FoxP3hi, and Ki-67+ Tfr were lower in MPA patients, while CD226+ Tfr cells were higher. These phenotypes suggest that function and proliferation ability of Tfr cells were relatively impaired. Tfh subsets, including ICOS+PD-1+ and Ki-67+ Tfh, were significantly increased, suggesting that the function of Tfh was enhanced in MPA although the total Tfh levels did not change significantly. Circulating memory B cells and plasmablasts were significantly elevated and negatively correlated with Tfr levels and Tfr/Tfh ratios in MPA patients. In addition, Tfr levels and Tfr/Tfh ratios were negatively while Tfh was positively correlated with serum myeloperoxidase (MPO)-ANCA levels. Furthermore, Tfr and Tfr/Tfh ratio were also reversely associated with SCr, BUN, IL-4, and IL-21 levels. Our results suggest that the imbalance of Tfr and Tfh functional subsets is related to increased level of autoantibodies in MPA patients, and we propose a new mechanism for the pathogenesis of MPA.

The altered HLA-DQ expression in peripheral blood T cells of chronic hepatitis B patients characterizes the function of T cells.

OBJECTIVE: This study aimed to clarify the expression of HLA-DQ and granulysin in peripheral blood T-cell subsets in patients with chronic hepatitis B virus (CHB) and to evaluate their significance in assisting CHB diagnosis and immune status assessment. METHODS: Peripheral blood from 34 CHB patients, 36 inactive HBsAg carriers and 33 healthy controls were collected, and HLA-DQ and granulysin in a series of T-cell subsets were analysed by flow cytometry. The ability to secrete IL-10 and IFN-γ and the functional T-cell subsets were measured in Treg and CD4 cells expressing HLA-DQ or not. Correlation analyses were further conducted between HLA-DQ/granulysin-related subsets and clinical indicators of HBV infection, and ROC curves were built to evaluate diagnosis efficiency of HLA-DQ-related subsets. RESULTS: HLA-DQ+ percentages in circulating CD4 T cells were downregulated in CHB patients. The proportions of HLA-DQ + Tfh in CHB were upregulated while HLA-DQ+ percentages in Treg were decreased. In terms of function, the IFN-γ secretion ability of CD4 + T cells and IL-10 secretion in Tregs were stronger in HLA-DQ+ than HLA-DQ- subsets. HLA-DQ + CD4 + T cells and HLA-DQ + Treg were negatively correlated with HBV-DNA, while HLA-DQ + Tfh and Tfc cells were positively correlated with HBV-DNA and ALT. HLA-DQ + Treg/Tfh/Tfc could help to distinguish CHB from inactive HBsAg carriers. CONCLUSION: HLA-DQ on T cells can characterize the function of T-cell subsets and analysis of HLA-DQ can help to evaluate immune status and assist in diagnosis of CHB.

Ubiquitin-specific protease 14 promotes radio-resistance and suppresses autophagy in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a common malignant tumor in the world. Radiotherapy is one of the standard therapies for patients with OSCC, but its clinical efficiency is limited due to radioresistance. In this study, we identified a mechanism of such resistance regulated by Ubiquitin-specific protease 14 (USP14). USP14 expression was significantly increased in clinical OSCC tissue samples and cell lines, and OSCC patients with high USP14 expression predicted poor overall survival rate. Additionally, a negative correlation between USP14 and LC3B was observed in patients with OSCC. We then found that irradiation (IR)-reduced cell survival of OSCC cells lines was further decreased when USP14 was knocked down. However, USP14 over-expression significantly promoted the cell viability of OSCC cells after IR treatment. Colony formation analysis confirmed thatafter IR treatment,USP14 knockdown markedly decreased the proliferation of OSCC cells, but over-expressing USP14 significantly up-regulated the proliferative activity of OSCC cells. Furthermore, DNA damage caused by IR was enhanced by USP14 knockdown, while been suppressed in OSCC cells with USP14 over-expression. Additionally, IR-inducedapoptosis was further promoted by USP14 knockdown in OSCC cells, which was, however, significantly abolished by USP14 over-expression.Moreover, our in vivo studies showed that IR-reduced tumor growth and tumor weight were further enhanced by USP14 knockdown in OSCC tumor-bearing nude mice. Finally, we found that USP14 knockdown could promote IR-induced autophagy by increasing LC3BII and γH2AX expression levels in IR-treated OSCC cells. However, this event was markedly abolished by ATG5 knockdown, subsequently restoring the cell proliferation in IR-incubated OSCC cells.Finally, we found that USP14-mediated apoptosis was autophagy-dependent in IR-treated OSCC cells. Taken together, these findings suggested that suppressing USP14 could alleviateradioresistancein OSCC both in vitro and in vivo by inducing apoptosis and autophagy, and thus could be served as a promising therapeutic strategy for OSCC treatment.

Quality of life of older people in nursing homes in China-evaluation and application of the Chinese version of the life satisfaction questionnaire.

BACKGROUND: Chinese and global populations are aging, and more older people are living in nursing homes in China. However, there is a lack of research measuring nursing home residents' quality of life (QOL), and especially associations with nursing home types (publicly versus privately run). Therefore, this study aimed to determine the construct validity and internal consistency of the Chinese version of the life satisfaction questionnaire (LSQ-Chinese) and determine the associations between nursing home types (publicly versus privately run), residents' sociodemographic characteristics, and their QOL. METHODS: A cross-sectional survey measuring QOL among older people living in nursing homes was conducted (n = 419). Confirmatory factor analysis and Cronbach's alpha were used to assess the construct validity and reliability of the LSQ-Chinese. In addition, multivariate regression analysis was used to examine these associations. RESULTS: Confirmatory factor analysis indicated acceptable goodness-of-fit statistics for the seven-factor LSQ solution. All factors and the total scale had good internal consistency, with Cronbach's alpha values > 0.70. The two factors with the highest QOL scores (higher scores indicate a more desirable state) were "physical symptoms" and "socioeconomic situation," and those with the lowest QOL scores were "quality of close-friend relationships" and "quality of daily activities fun". Residents living in privately run nursing homes had higher LSQ scores overall and for all factors except "physical symptoms" and "sickness impact" compared with publicly run nursing homes. Multivariate analyses indicated that marital status, number of chronic diseases, education level, main source of income, and nursing home type significantly contributed to the variance in the total LSQ scores. The associated sociodemographic variables differed between the factors, and the variable publicly versus privately run was significant for five of the seven factors. CONCLUSIONS: The LSQ is a suitable instrument for measuring the QOL of Chinese nursing home residents. The total LSQ score was higher among residents in privately run nursing homes than in publicly run ones. According to residents' needs, staff should work for person-centered activities, and facilitate residents' social interactions with friends, as both these aspects were scored relatively low.