Soybean RVE8a confers salt and drought tolerance in Arabidopsis.

Soybean is an economically important crop, which often suffers various abiotic stresses. REVEILLE (RVE) genes have been generally considered as circadian oscillators to mediate diverse developmental processes and plant response to environmental stresses. Addressing their roles is of significance for utilizing them to enhance agronomic traits in crops. However, our understanding of soybean RVEs is extremely limited. In the study, we investigated the expression patterns of soybean CCA1-like genes under salt stress using our RNA-Seq data. Subsequently, a salt stress-inducible gene, GmRVE8a, was chosen for further study. Phylogenetic analysis indicated that GmRVE8a is most closely related to Arabidopsis RVE4 and RVE8. Also, GmRVE8a showed circadian expression pattern with 24 h rhythmic period, suggesting that it might be a clock-regulated gene. Moreover, transgenic Arabidopsis lines over-expressing GmRVE8a were generated. It was observed that ectopic over-expression of GmRVE8a caused a significant delay in flowering. Further observation indicated that under salt and drought stress, transgenic seedlings were stronger than wild type. Consistently, three-week-old transgenic plants grew better than wild type under salt and drought conditions, and the MDA content in transgenic lines was significantly lower than wild type, suggesting that GmRVE8a might be a positive regulator in response to salt and drought stress. Intriguingly, Y2H assay indicated that GmRVE8a physically interacted with a drought-tolerant protein, GmNAC17. Overall, our findings provided preliminary information regarding the functional roles of GmRVE8a in response to salt and drought stress.

Integrative single-cell analysis reveals distinct adaptive immune signatures in the cutaneous lesions of pemphigus.

Pemphigus, an autoimmune bullous disease affecting the skin and mucosal membranes, is primarily driven by anti-desmoglein (Dsg) autoantibodies. However, the underlying immune mechanisms of this disease remain largely elusive. Here, we compile an unbiased atlas of immune cells in pemphigus cutaneous lesions at single-cell resolution. We reveal clonally expanded antibody-secreting cells (ASCs) that exhibit variable hypermutation and accumulation of IgG4 class-switching in their immunoglobulin genes. Importantly, pathogenic Dsg-specific ASCs are localized within pemphigus lesions and can evolve from both Dsg-autoreactive and non-binding precursors. We observe an altered distribution of CD4+ T cell subsets within pemphigus lesions, including an imbalance of Th17/Th2 cells. Significantly, we identify a distinct subpopulation of Th17 cells expressing CXCL13 and IL-21 within pemphigus lesions, implying its pivotal role in B cell recruitment and local production of autoantibodies. Furthermore, we characterize multiple clonally expanded CD8+ subpopulations, including effector GMZB+ and GMZK+ subsets with augmented cytotoxic activities, within pemphigus lesions. Chemokine-receptor mapping uncovers cell-type-specific signaling programs involved in the recruitment of T/B cells within pemphigus lesions. Our findings significantly contribute to advancing the understanding of the heterogeneous immune microenvironment and the pathogenesis of pemphigus cutaneous lesions, thereby providing valuable insights for potential therapeutic interventions in this disease.

Chirality induced spin selectivity in chiral hybrid organic-inorganic perovskites.

Chiral materials exhibit many interesting physical properties including circular dichroism, circularly polarized photoluminescence, and spin selectivity. Since its discovery, chirality-induced spin selectivity (CISS) has been demonstrated in many chiral material systems, which indicates promising applications in spintronic devices. Thus, searching for compounds that possess both sizable chirality and excellent spin transport properties is in order. Hybrid organic-inorganic perovskites have attracted intensive research interest due to their long carrier lifetime, high carrier mobility, chemically tunable electronic properties, and long spin lifetime, which make this emerging class of semiconductors promising candidate for spintronics. Moreover, hybrid perovskites integrate inorganic octahedral framework and organic ligands, which may introduce chirality into the materials, especially in quasi-two-dimensional structures. Recently, CISS has been observed in 2D chiral hybrid perovskites, showing the spin filtering effect. Studies of CISS in chiral hybrid perovskites not only help deepen our understanding of CISS mechanism but also shed new light on designing novel spintronic devices. In this review, we summarize the state-of-the-art studies of CISS effect in 2D chiral hybrid organic-inorganic perovskites system. We also discuss the remaining challenges and research opportunities of employing CISS in next-generation spintronic devices.

Silencing CircEIF3I/miR-526b-5p Axis Epigenetically Targets HGF/c-Met Signal to Hinder the Malignant Growth, Metastasis and Angiogenesis of Hepatocellular Carcinoma.

BACKGROUND: Hepatocyte growth factor (HGF)/c-mesenchymal-epithelial transition factor (c-Met) is important for the diagnosis and prognosis of hepatocellular carcinoma (HCC). Circular RNAs (circRNAs) are key regulators of HCC progression, and this study focused on circRNA eukaryotic translation initiation factor 3 subunit I (circEIF3I) with HGF/c-Met in HCC. METHODS: Levels of circEIF3I, microRNA (miR)-526b-5p, HGF, E-cadherin, N-cadherin, and Vimentin were detected by Gene Expression Omnibus database, quantitative PCR and western blotting. Cell functions were measured by detecting cell growth (cell proliferation assay with WST-1 and EdU, colony formation assay, flow cytometry, caspase 3 activity assay, and nude mouse tumorigenicity assay), metastasis (transwell assay and western blotting), angiogenesis (endothelial tube formation assay). Molecular interaction was determined dual-luciferase reporter assay, RNA immunoprecipitation, and Pearson correlation analysis. RESULTS: Expression of circEIF3I was upregulated in HCC tissues. Knockdown of circEIF3I suppressed cell proliferation epithelial-mesenchymal transition, migration, invasion and tube formation ability but promoted apoptosis of HCC cells. CircEIF3I could sponge miR-526b-5pto regulate downstream HGF. Functionally, circEIF3I regulation in HCC cell progression was associated with miR-526b-5p sponging function and HGF upregulation could attenuate tumor-inhibiting roles of miR-526b-5p. HCC tumor growth was delayed by interfering circEIF3I. CONCLUSION: CircEIF3I was an oncogenic circRNA in HCC-, and interfering circEIF3I exhibited anti-HCC activity via circEIF3I-miR-526b-5p-HGF/c-Met pathway.

Identification of ARF family in blueberry and its potential involvement of fruit development and pH stress response.

BACKGROUND: Auxin responsive factor (ARF) family is one of core components in auxin signalling pathway, which governs diverse developmental processes and stress responses. Blueberry is an economically important berry-bearing crop and prefers to acidic soil. However, the understandings of ARF family has not yet been reported in blueberry. RESULTS: In the present study, 60 ARF genes (VcARF) were identified in blueberry, and they showed diverse gene structures and motif compositions among the groups and similar within each group in the phylogenetic tree. Noticeably, 9 digenic, 5 trigenic and 6 tetragenic VcARF pairs exhibited more than 95% identity to each other. Computational analysis indicated that 23 VcARFs harbored the miRNA responsive element (MRE) of miR160 or miR167 like other plant ARF genes. Interestingly, the MRE of miR156d/h-3p was observed in the 5'UTR of 3 VcARFs, suggesting a potentially novel post-transcriptional control. Furthermore, the transcript accumulations of VcARFs were investigated during fruit development, and three categories of transcript profiles were observed, implying different functional roles. Meanwhile, the expressions of VcARFs to different pH conditions (pH4.5 and pH6.5) were surveyed in pH-sensitive and tolerant blueberry species, and a number of VcARFs showed different transcript accumulations. More importantly, distinct transcriptional response to pH stress (pH6.5) were observed for several VcARFs (such as VcARF6s and VcARF19-3/19-4) between pH-sensitive and tolerant species, suggesting their potential roles in adaption to pH stress. CONCLUSIONS: Sixty VcARF genes were identified and characterized, and their transcript profiles were surveyed during fruit development and in response to pH stress. These findings will contribute to future research for eliciting the functional roles of VcARFs and regulatory mechanisms, especially fruit development and adaption to pH stress.

Celastrol Attenuates Angiotensin II-Induced Cardiac Remodeling by Targeting STAT3.

RATIONALE: Excessive Ang II (angiotensin II) levels lead to a profibrotic and hypertrophic milieu that produces deleterious remodeling and dysfunction in hypertension-associated heart failure. Agents that disrupt Ang II-induced cardiac dysfunction may have clinical utility in the treatment of hypertension-associated heart failure. OBJECTIVE: We have examined the potential effect of celastrol-a bioactive compound derived from the Celastraceae family-on Ang II-induced cardiac dysfunction. METHODS AND RESULTS: In rat primary cardiomyocytes and H9C2 (rat cardiomyocyte-like H9C2) cells, celastrol attenuates Ang II-induced cellular hypertrophy and fibrotic responses. Proteome microarrays, surface plasmon resonance, competitive binding assays, and molecular simulation were used to identify the molecular target of celastrol. Our data showed that celastrol directly binds to and inhibits STAT (signal transducer and activator of transcription)-3 phosphorylation and nuclear translocation. Functional tests demonstrated that the protection of celastrol is afforded through targeting STAT3. Overexpression of STAT3 dampens the effect of celastrol by partially rescuing STAT3 activity. Finally, we investigated the in vivo effect of celastrol treatment in mice challenged with Ang II and in the transverse aortic constriction model. We show that celastrol administration protected heart function in Ang II-challenged and transverse aortic constriction-challenged mice by inhibiting cardiac fibrosis and hypertrophy. CONCLUSIONS: Our studies show that celastrol inhibits Ang II-induced cardiac dysfunction by inhibiting STAT3 activity.

Podophyllotoxin-combined 5-aminolevulinic acid photodynamic therapy significantly promotes HR-HPV-infected cell death.

BACKGROUND: Human papillomavirus (HPV) infection and related diseases are difficult clinical challenges. The efficacy of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) in treating condyloma acuminata is remarkable, with high virus clearance and low recurrence rates. Podophyllotoxin (POD) is the first-line drug with a significant therapeutic effect on condyloma acuminata. However, no studies have determined whether POD-combined ALA-PDT improves high-risk (HR)-HPV-infected cell killing. We aimed to investigate whether POD-combined ALA-PDT could promote HPV-infected cell death more effectively than the single treatment and explore the underlying mechanism. METHODS: In HeLa and SiHa cells, flow cytometry, EdU assay and LDH release test were used to detect apoptosis, cell proliferation change and necrosis, respectively. To investigate whether the combined therapy might activate apoptosis and induce endoplasmic reticulum (ER) stress, flow cytometry was used to determine intracellular levels of ROS and calcium, and Western blotting was used to determine the expression of related proteins. Mitochondrial membrane depolarization was detected by JC-1 assay. Immunofluorescence staining and Western blotting were used to detect the activation of autophagy. RESULTS: Podophyllotoxin -combined ALA-PDT inhibited the proliferation and promoted apoptosis and necrosis more effectively than the single treatment at the same intensity and concentration. The activation of the caspase-dependent apoptosis pathway, ER stress and autophagy was more substantial in POD-combined ALA-PDT than with single treatments. CONCLUSION: Podophyllotoxin -combined ALA-PDT effectively promoted cell death through several pathways in HeLa and SiHa cells. This combination might be a promising therapeutic strategy for the HR-HPV infection.

Is transcranial direct current stimulation, alone or in combination with antidepressant medications or psychotherapies, effective in treating major depressive disorder? A systematic review and meta-analysis.

BACKGROUND: Transcranial direct current stimulation (tDCS) has shown mixed results for depression treatment. The efficacies of tDCS combination therapies have not been investigated deliberately. This review aims to evaluate the clinical efficacy of tDCS as a monotherapy and in combination with medication, psychotherapy, and ECT for treating adult patients with major depressive disorder (MDD) and identified the factors influencing treatment outcome measures (i.e. depression score, dropout, response, and remission rates). METHODS: The systematic review was performed in PubMed/Medline, EMBASE, PsycINFO, Web of Sciences, and OpenGrey. Two authors performed independent literature screening and data extraction. The primary outcomes were the standardized mean difference (SMD) for continuous depression scores after treatment and odds ratio (OR) dropout rate; secondary outcomes included ORs for response and remission rates. Random effects models with 95% confidence intervals were employed in all outcomes. The overall effect of tDCS was investigated by meta-analysis. Sources of heterogeneity were explored via subgroup analyses, meta-regression, sensitivity analyses, and assessment of publication bias. RESULTS: Twelve randomised, sham-controlled trials (active group: N = 251, sham group: N = 204) were included. Overall, the integrated depression score of the active group after treatment was significantly lower than that of the sham group (g = - 0.442, p = 0.017), and further analysis showed that only tDCS + medication achieved a significant lower score (g = - 0.855, p < 0.001). Moreover, this combination achieved a significantly higher response rate than sham intervention (OR = 2.7, p = 0.006), while the response rate remained unchanged for the other three therapies. Dropout and remission rates were similar in the active and sham groups for each therapy and also for the overall intervention. The meta-regression results showed that current intensity is the only predictor for the response rate. None of publication bias was identified. CONCLUSION: The effect size of tDCS treatment was obviously larger in depression score compared with sham stimulation. The tDCS combined selective serotonin re-uptake inhibitors is the optimized therapy that is effective on depression score and response rate. tDCS monotherapy and combined psychotherapy have no significant effects. The most important parameter for optimization in future trials is treatment strategy.

Sorbitol Modulates Resistance to Alternaria alternata by Regulating the Expression of an NLR Resistance Gene in Apple.

In plant-microbe interactions, plant sugars produced by photosynthesis are not only a carbon source for pathogens, but may also act as signals that modulate plant defense responses. Here, we report that decreasing sorbitol synthesis in apple (Malus domestica) leaves by antisense suppression of ALDOSE-6-PHOSPHATE REDUCTASE (A6PR) leads to downregulation of 56 NUCLEOTIDE BINDING/LEUCINE-RICH REPEAT (NLR) genes and converts the phenotypic response to Alternaria alternata from resistant to susceptible. We identified a resistance protein encoded by the apple MdNLR16 gene and a small protein encoded by the fungal HRIP1 gene that interact in both a yeast two-hybrid assay and a bimolecular fluorescence complementation assay. Deletion of HRIP1 in A. alternata enables gain of virulence on the wild-type control plant. Overexpression of MdNLR16 in two antisense A6PR lines increases resistance, whereas RNAi suppression of MdNLR16 in the wild-type control decreases resistance against A. alternata MdWRKY79 transcriptionally regulates MdNLR16 by binding to the promoter of MdNLR16 in response to sorbitol, and exogenous sorbitol feeding partially restores resistance of the antisense A6PR lines to A. alternata These findings indicate that sorbitol modulates resistance to A. alternata via the MdNLR16 protein that interacts with the fungal effector in a classic gene-for-gene manner in apple.

ACCV: automatic classification algorithm of cataract video based on deep learning.

PURPOSE: A real-time automatic cataract-grading algorithm based on cataract video is proposed. MATERIALS AND METHODS: In this retrospective study, we set the video of the eye lens section as the research target. A method is proposed to use YOLOv3 to assist in positioning, to automatically identify the position of the lens and classify the cataract after color space conversion. The data set is a cataract video file of 38 people's 76 eyes collected by a slit lamp. Data were collected using five random manner, the method aims to reduce the influence on the collection algorithm accuracy. The video length is within 10 s, and the classified picture data are extracted from the video file. A total of 1520 images are extracted from the image data set, and the data set is divided into training set, validation set and test set according to the ratio of 7:2:1. RESULTS: We verified it on the 76-segment clinical data test set and achieved the accuracy of 0.9400, with the AUC of 0.9880, and the F1 of 0.9388. In addition, because of the color space recognition method, the detection per frame can be completed within 29 microseconds and thus the detection efficiency has been improved significantly. CONCLUSION: With the efficiency and effectiveness of this algorithm, the lens scan video is used as the research object, which improves the accuracy of the screening. It is closer to the actual cataract diagnosis and treatment process, and can effectively improve the cataract inspection ability of non-ophthalmologists. For cataract screening in poor areas, the accessibility of ophthalmology medical care is also increased.

Social support status and associated factors among people living with HIV/AIDS in Kunming city, China.

BACKGROUND: People living with HIV/AIDS not only require effective treatment for the alleviation of physical discomfort but also require social support to help them address difficulties in life and relieve their psychological anxiety and uneasiness. The social support network is of tremendous importance in helping people living with HIV/AIDS maintain good physical and mental health. This study aims to analyse the social support status among people living with HIV/AIDS in Kunming and explore associated factors. METHOD: The Social Support Rating Scale (SSRS) was used, and a questionnaire survey was conducted using convenience sampling to select people living with HIV/AIDS from 14 counties of Kunming. It collected information on general demographic information and social support status. Univariate and multivariate linear regression models were used to explore the associated factors. RESULTS: A total of 990 valid questionnaires were completed. Data from all participants were analysed. Univariate analysis suggested that the factors associated with social support may include marital status, monthly income, and antiretroviral therapy. On the other hand, factors including monthly income and antiretroviral therapy accounted for the social support total score in the multivariate analysis. CONCLUSION: Social support among people living with HIV/AIDS in Kunming was generally low. This study identified a number of factors associated with social support among people living with HIV/AIDS. Based on our findings, appropriate interventions should be introduced to provide social support for those living with HIV/AIDS.

Separation of Spin and Charge Transport in Pristine π-Conjugated Polymers.

We have experimentally tested whether spin-transport and charge-transport in pristine π-conjugated polymer films at room temperature occur via the same electronic processes. We have obtained the spin diffusion coefficient of several π-conjugated polymer films from the spin diffusion length measured by the technique of inverse spin Hall effect and the spin relaxation time measured by pulsed electrically detected magnetic resonance spectroscopy. The charge diffusion coefficient was obtained from the time-of-flight mobility measurements on the same films. We found that the spin diffusion coefficient is larger than the charge diffusion coefficient by about 1-2 orders of magnitude and conclude that spin and charge transports in disordered polymer films occur through different electronic processes.

Characterization of the metabolites of TUG-891 in rat, dog, and human hepatocytes using ultra-high-performance liquid chromatography tandem mass spectrometry and nuclear magnetic resonance spectroscopy.

RATIONALE: TUG-891 is a potent and selective agonist of the long chain free fatty acid receptor 4. However, its metabolic profiles have not been revealed. The aim of this study was to investigate the in vitro metabolism of TUG-891 in hepatocytes. METHODS: TUG-891 at a concentration of 20 µM was incubated with rat, dog, and human hepatocytes at 37°C for 120 min. The samples were analyzed using ultra-high-performance liquid chromatography combined with electrospray ionization tandem mass spectrometry. The structures of the metabolites were proposed according to their MS/MS product ions. Furthermore, M4 and M5 were biosynthesized using human liver microsomes, and their structures were characterized using 13 C-NMR spectroscopy. RESULTS: Under the current conditions, eight metabolites were detected and structurally identified using high-resolution LC/MS and MS/MS spectra. The metabolites M4 and M5 were unambiguously confirmed to be TUG-891 alcohol and TUG-891 acid, respectively, using 13 C-NMR spectroscopy. Our results revealed that hydroxylation of methyl group at C-21 position to form TUG-891 alcohol (M5) followed by oxidation to yield TUG-891 aldehyde (M7) and carboxylic acid (M4) were the major metabolism processes. Phase II metabolism processes included glucuronidation and sulphation. CONCLUSIONS: Hydroxylation at the C-21 position was the primary metabolic site of TUG-891. This study provided an overview of the metabolic profiles of TUG-891 in hepatocytes.

Characterization of the metabolites of gigantol in rat, dog, monkey, and human hepatocytes using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry.

RATIONALE: Gigantol (3',4-dihydroxy-3,5'-dimethoxybibenzyl) is a bibenzyl compound isolated from Dendrobii Caulis that has been widely used as a medicinal herb in China. To fully understand the mechanism of action of gigantol, it is necessary to determine its metabolic profile. METHODS: Gigantol at a concentration of 20 µM was incubated with hepatocytes (rat, dog, monkey, and human) at 37°C. After 120 min incubation, the samples were analyzed using liquid chromatography coupled with electrospray ionization tandem mass spectrometry. The structures of the metabolites were characterized by their molecular masses, product ions, and retention times. RESULTS: A total of 17 metabolites were detected and structurally identified. The metabolism involved the following pathways: (a) oxidation to form quinone-methide species and subsequently conjugation with glutathione (GSH); (b) demethylation to form demethylated gigantol, which was further conjugated with GSH; (c) hydroxylation to yield hydroxyl-gigantol followed by glucuronidation or GSH conjugation; and (d) glucuronidation to form glucuronide conjugates. Glucuronidation was the primary metabolic pathway in all tested species. CONCLUSIONS: Hydroxylation, demethylation, glucuronidation, and GSH conjugation were the major metabolic pathways of gigantol. This study provides new information on the metabolic profiles of gigantol and helps us understand the disposition of the compound.

Thalidomide as a potential adjuvant treatment for paraneoplastic pemphigus: A single-center experience.

Paraneoplastic pemphigus (PNP) is a rare autoimmune bullous disease associated with an underlying malignancy. The survival rate at 5 years is reported to be as low as 38%. Thalidomide is a medication with strong anti-inflammatory, immunomodulatory, antiangiogenic, and sedative properties. Recently, the successful application of thalidomide in several dermatological and hematological disorders inspired us to investigate its potential as an adjuvant treatment for PNP. Here, we report our experience of trial thalidomide therapy in 14 PNP patients. After treatment of their associated tumors, the patients were administered thalidomide (75-100 mg/d) combined with or without low- to mid-dose oral prednisone. Twelve patients completed the therapy. Seven patients (58%) achieved complete remission with no relapse, including two patients who received thalidomide monotherapy. Five patients (42%) died within 1 to 3 months. The 1-year and 2-year survival rates in our case series were 58% and 55%, respectively. The regimen was well tolerated. Although the treatment experience presented has a limited sample size and no control, our results imply that thalidomide may be an effective, safe, and economical treatment option for PNP patients. Further research is needed to better understand the mechanisms of action of thalidomide in PNP.

A Multi-Sensor Wearable System for the Quantitative Assessment of Parkinson's Disease.

The quantitative characterization of movement disorders and their related neurophysiological signals is important for the management of Parkinson's disease (PD). The aim of this study is to develop a novel wearable system enabling the simultaneous measurement of both motion and other neurophysiological signals in PD patients. We designed a wearable system that consists of five motion sensors and three electrophysiology sensors to measure the motion signals of the body, electroencephalogram, electrocardiogram, and electromyography, respectively. The data captured by the sensors are transferred wirelessly in real time, and the outcomes are analyzed and uploaded to the cloud-based server automatically. We completed pilot studies to (1) test its validity by comparing outcomes to the commercialized systems, and (2) evaluate the deep brain stimulation (DBS) treatment effects in seven PD patients. Our results showed: (1) the motion and neurophysiological signals measured by this wearable system were strongly correlated with those measured by the commercialized systems (r > 0.94, p < 0.001); and (2) by completing the clinical supination and pronation frequency test, the frequency of motion as measured by this system increased when DBS was turned on. The results demonstrated that this multi-sensor wearable system can be utilized to quantitatively characterize and monitor motion and neurophysiological PD.

A multi-faceted, location-specific assessment of land degradation threats to peri-urban agriculture at a traditional grain base in northeastern China.

Urbanization-induced cultivated land degradation can hamper the ability of peri-urban agriculture (PUA) to deliver clean food and agroecosystem services. Detailed geo-information about which cultivated lands are being influenced by urbanization will be important to designing future measures for the conservation of PUA. This information will be especially relevant for traditional grain bases because PUA is often underappreciated in these regions. For this reason, we performed a multi-faceted and location-specific assessment, including soil pollution, soil fertility, basic tillage conditions and land fragmentation, of cultivated land in a rural-urban transition zone outside of a city in northeast China. We also illustrated the combined risks in different urbanized environments via GIS-based two-step spatial clustering. The results indicated that, in general, cultivated lands were more polluted and fragmented, as well as less fertile and tillable, the closer they were to the urban area. Most of the affected cultivated lands were located within 8 km of the urban periphery. Furthermore, certain urban environments exposed the surrounding cultivated lands to specific degradation in relation to different combined risks. PUA in long-standing industrial areas mainly faced risks of polluted agricultural production, underutilization and impaired landscape ecological security (LES), whereas cultivated lands close to a recently developed residential area were characterized by risks of supplying service disruption, unsustainable agricultural production, underutilization and impaired LES. The present study highlighted that PUA associated with traditional grain bases must be preserved to enhance urban sustainability and resilience, and suggests that measures which can adapt to multi-faceted local degradation issues will be the most effective protection for peri-urban areas. Furthermore, the results also suggest that multi-functional and profitable agriculture will contribute to breaking the vicious circle of land degradation in peri-urban cultivated areas of traditional grain bases.

A novel MyD88 inhibitor LM9 prevents atherosclerosis by regulating inflammatory responses and oxidative stress in macrophages.

Development of atherosclerosis involves chronic and sustained inflammation and oxidative stress. Recent studies have linked atherosclerosis to the innate immune system. Genetic deficiency in myeloid differentiation primary-response protein 88 (MyD88) protects against the development and progression of atherosclerosis. However, it is unknown if pharmacological inhibition of MyD88 is able to be a therapeutic strategy for this disease. In this study, we evaluated the effect of a newly synthesized small-molecule inhibitor of MyD88, LM9, in an ApoE-/- mouse model of atherosclerosis. Our results showed that the major source of MyD88 in atherosclerotic lesions is infiltrated macrophage. Treatment of HFD-fed ApoE-/- mice with LM9 significantly attenuated the pathogenesis of atherosclerosis, accompanied with reduced vascular inflammatory responses and oxidative stress. These effects were achieved without changes to serum lipid levels. We further showed that LM9 inhibited oxidized-lipoprotein induced foam cell formation through suppression of MyD88 and inflammatory pathway in macrophages. Additionally, either LM9 treatment or MyD88 knockdown prevented ox-LDL-induced oxidative stress in macrophages. This study highlights the translational role of MyD88 as a therapeutic target and identifies the MyD88 inhibitor LM9 as a new candidate for the treatment of atherosclerosis.

Analysis of factors associated with dropping-out from HIV antiretroviral therapy in Kunming City, China.

BACKGROUND: The implementation of national antiretroviral therapy (ART) and expanded ART policies results in that more and more HIV-infected patients receive ART in Kunming, Yunnan province, China. At the same time, however, the number of patients, who drop-out from ART, are also increasing. In this study, we explored the factors that may account for drop-out. METHODS: Four hundred and thirty-nine HIV-infected patients, who received or used to receive ART, were recruited in this study. Their age is among 18 and 75. All patients were divided into two group: ART group (187 patients) and drop-out group (252 patients). Appropriate bio-statistics analysis, including univariate analysis and Multivariate analysis, were used to identify factors associated with drop-out. RESULTS: Data from all patients were analyzed. Univariate analysis suggested that the factors associated with drop-out may include age, residential area, educational level, occupation, monthly income, the access to minimum living allowance, HIV transmission route, and living status. On the other hand, factors including area, monthly income, the access to minimum living allowance, and referral methods of follow-up institutions account for drop-out in multivariate analysis. CONCLUSIONS: This study identified a number of factors associated with drop out from ART. Based on our findings,appropriate interventions should be introduced decrease drop-out.

Acoustic differences between healthy and depressed people: a cross-situation study.

BACKGROUND: Abnormalities in vocal expression during a depressed episode have frequently been reported in people with depression, but less is known about if these abnormalities only exist in special situations. In addition, the impacts of irrelevant demographic variables on voice were uncontrolled in previous studies. Therefore, this study compares the vocal differences between depressed and healthy people under various situations with irrelevant variables being regarded as covariates. METHODS: To examine whether the vocal abnormalities in people with depression only exist in special situations, this study compared the vocal differences between healthy people and patients with unipolar depression in 12 situations (speech scenarios). Positive, negative and neutral voice expressions between depressed and healthy people were compared in four tasks. Multiple analysis of covariance (MANCOVA) was used for evaluating the main effects of variable group (depressed vs. healthy) on acoustic features. The significances of acoustic features were evaluated by both statistical significance and magnitude of effect size. RESULTS: The results of multivariate analysis of covariance showed that significant differences between the two groups were observed in all 12 speech scenarios. Although significant acoustic features were not the same in different scenarios, we found that three acoustic features (loudness, MFCC5 and MFCC7) were consistently different between people with and without depression with large effect magnitude. CONCLUSIONS: Vocal differences between depressed and healthy people exist in 12 scenarios. Acoustic features including loudness, MFCC5 and MFCC7 have potentials to be indicators for identifying depression via voice analysis. These findings support that depressed people's voices include both situation-specific and cross-situational patterns of acoustic features.