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1.
Front Endocrinol (Lausanne) ; 12: 622647, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841327

RESUMO

Proinsulin is an abundant protein that is selectively expressed by pancreatic beta cells and has been a focus for development of antigen-specific immunotherapies for type 1 diabetes (T1D). In this study, we sought to comprehensively evaluate reactivity to preproinsulin by CD4 T cells originally isolated from pancreatic islets of organ donors having T1D. We analyzed 187 T cell receptor (TCR) clonotypes expressed by CD4 T cells obtained from six T1D donors and determined their response to 99 truncated preproinsulin peptide pools, in the presence of autologous B cells. We identified 14 TCR clonotypes from four out of the six donors that responded to preproinsulin peptides. Epitopes were found across all of proinsulin (insulin B-chain, C-peptide, and A-chain) including four hot spot regions containing peptides commonly targeted by TCR clonotypes derived from multiple T1D donors. Of importance, these hot spots overlap with peptide regions to which CD4 T cell responses have previously been detected in the peripheral blood of T1D patients. The 14 TCR clonotypes recognized proinsulin peptides presented by various HLA class II molecules, but there was a trend for dominant restriction with HLA-DQ, especially T1D risk alleles DQ8, DQ2, and DQ8-trans. The characteristics of the tri-molecular complex including proinsulin peptide, HLA-DQ molecule, and TCR derived from CD4 T cells in islets, provides an essential basis for developing antigen-specific biomarkers as well as immunotherapies.

2.
BMC Psychiatry ; 21(1): 184, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33827505

RESUMO

BACKGROUND: Tourette syndrome (TS) is a neurodevelopmental disorder defined by the continual presence of primary motor and vocal tics. Grey matter abnormalities have been identified in numerous studies of TS, but conflicting results have been reported. This study was an unbiased statistical meta-analysis of published neuroimaging studies of TS structures. METHODS: A voxel quantitative meta-analysis technique called activation likelihood estimation (ALE) was used. The meta-analysis included six neuroimaging studies involving 247 TS patients and 236 healthy controls. A statistical threshold of p < 0.05 was established based on the false discovery rate and a cluster extent threshold of 50 voxels. RESULTS: We found that grey matter volumes were significantly increased in the bilateral thalamus, right hypothalamus, right precentral gyrus, left postcentral gyrus, left inferior parietal lobule, right lentiform nucleus, and left insula of TS patients compared to those of healthy controls. In contrast, grey matter volumes were significantly decreased in the bilateral postcentral gyrus, bilateral anterior cingulate, bilateral insula, left posterior cingulate and left postcentral gyrus of TS patients compared to those of healthy controls. CONCLUSIONS: Our present meta-analysis primarily revealed significant increases in grey matter volumes in the thalamus and lentiform nucleus, and decreased grey matter volumes in the anterior cingulate gyrus, of TS patients compared to those in healthy controls. Most of these identified regions are associated with cortico-striato-thalamo-cortical circuits. Further studies with larger sample sizes are needed to confirm these changes in grey matter volumes in TS patients.


Assuntos
Substância Cinzenta , Síndrome de Tourette , Encéfalo , Substância Cinzenta/diagnóstico por imagem , Giro do Cíngulo , Humanos , Funções Verossimilhança , Imagem por Ressonância Magnética , Neuroimagem , Síndrome de Tourette/diagnóstico por imagem
3.
Endocr Connect ; 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33909592

RESUMO

OBJECTIVE: The most common coexisting organ-specific autoimmune disease in patients with type 1 diabetes mellitus (T1DM) is autoimmune thyroid disease (AITD). However, there have been little clinical reports based on large population about the prevalence of zinc transporter 8 autoantibody (ZnT8A) and other islet autoantibodies in AITD patients. We aimed to explore the presence of islet autoantibodies, ZnT8A, glutamic acid decarboxylase autoantibodies (GADA) and insulinoma-associated antigen 2 autoantibodies (IA-2A) compared with thyroid autoantibodies, thyroid peroxidase autoantibodies (TPOAb) and thyroglobulin autoantibodies (TGAb) and thyrotropin receptor autoantibodies (TRAb) in patients with Graves' disease (GD), Hashimoto's thyroiditis (HT) and T1DM patients with AITD. METHODS: Totally, 389 patients with GD, 334 patients with HT, 108 T1DM patients with AITD and 115 healthy controls (HC) were recruited in the study. Islet autoantibodies (ZnT8A, GADA and IA-2A) were detected by radioligand binding assay. Thyroid autoantibodies, TPOAb and TGAb were detected by chemiluminescence assay, and TRAb was detected by radioimmunoassay. RESULTS: The prevalence of ZnT8A, GADA and IA-2A was higher in GD and HT patients than that of HC (ZnT8A: GD 8.48%, HT 10.8% vs HC 1.74%; GADA: GD 7.46%, HT 7.74% vs HC 0.870%; IA-2A: GD 4.88%, HT 3.59% vs HC 0%; All P<0.05); but lower than that of T1DM subjects with AITD (ZnT8A: 42.6%; IA-2A: 44.4%; GADA: 74.1%; all P<0.0001). CONCLUSIONS: An increased prevalence of ZnT8A as well as GADA and IA-2A was found in both GD and HT patients, indicating that there is a potential link between thyroid autoimmunity and islet autoimmunity.

4.
Elife ; 102021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33913809

RESUMO

Working memory (WM), the ability to actively hold information in memory over a delay period of seconds, is a fundamental constituent of cognition. Delay-period activity in sensory cortices has been observed in WM tasks, but whether and when the activity plays a functional role for memory maintenance remains unclear. Here we investigated the causal role of auditory cortex (AC) for memory maintenance in mice performing an auditory WM task. Electrophysiological recordings revealed that AC neurons were active not only during the presentation of the auditory stimulus but also early in the delay period. Furthermore, optogenetic suppression of neural activity in AC during the stimulus epoch and early delay period impaired WM performance, whereas suppression later in the delay period did not. Thus, AC is essential for information encoding and maintenance in auditory WM task, especially during the early delay period.

5.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33669030

RESUMO

Potato tuber dormancy is critical for the post-harvest quality. Snakin/Gibberellic Acid Stimulated in Arabidopsis (GASA) family genes are involved in the plants' defense against pathogens and in growth and development, but the effect of Snakin-2 (SN2) on tuber dormancy and sprouting is largely unknown. In this study, a transgenic approach was applied to manipulate the expression level of SN2 in tubers, and it demonstrated that StSN2 significantly controlled tuber sprouting, and silencing StSN2 resulted in a release of dormancy and overexpressing tubers showed a longer dormant period than that of the control. Further analyses revealed that the decrease expression level accelerated skin cracking and water loss. Metabolite analyses revealed that StSN2 significantly down-regulated the accumulation of lignin precursors in the periderm, and the change of lignin content was documented, a finding which was consistent with the precursors' level. Subsequently, proteomics found that cinnamyl alcohol dehydrogenase (CAD), caffeic acid O-methyltransferase (COMT) and peroxidase (Prx), the key proteins for lignin synthesis, were significantly up-regulated in silencing lines, and gene expression and enzyme activity analyses also supported this effect. Interestingly, we found that StSN2 physically interacts with three peroxidases catalyzing the oxidation and polymerization of lignin. In addition, SN2 altered the hydrogen peroxide (H2O2) content and the activities of superoxide dismutase (SOD) and catalase (CAT). These results suggest that StSN2 negatively regulates lignin biosynthesis and H2O2 accumulation, and ultimately inhibits the sprouting of potato tubers.


Assuntos
Cisteína/metabolismo , Peróxido de Hidrogênio/metabolismo , Lignina/biossíntese , Proteínas de Plantas/metabolismo , Tubérculos/metabolismo , Solanum tuberosum/metabolismo , Oxirredutases do Álcool/metabolismo , Catalase/metabolismo , Regulação da Expressão Gênica de Plantas/genética , Inativação Gênica , Lignina/metabolismo , Peroxidase/metabolismo , Dormência de Plantas/genética , Proteínas de Plantas/genética , Caules de Planta/citologia , Caules de Planta/genética , Caules de Planta/metabolismo , Tubérculos/genética , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Ligação Proteica , Proteína O-Metiltransferase/metabolismo , Proteômica , Plântula/citologia , Plântula/genética , Plântula/metabolismo , Solanum tuberosum/enzimologia , Solanum tuberosum/genética , Superóxido Dismutase-1/metabolismo
6.
Pharmacol Res Perspect ; 9(1): e00701, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33547885

RESUMO

Previous work by ourselves and others showed that mitoquinone (mitoQ) reduced oxidative damage and prevented hepatic fat accumulation in mice made obese with high-fat (HF) feeding. Here we extended these studies to examine the effect of mitoQ on parameters affecting liver function in rats treated with HF to induce obesity and in rats treated with HF plus streptozotocin (STZ) to model a severe form of type 2 diabetes. In prior reported work, we found that mitoQ significantly improved glycemia based on glucose tolerance data in HF rats but not in the diabetic rats. Here we found only non-significant reductions in insulin and glucose measured in the fed state at sacrifice in the HF mice treated with mitoQ. Metabolomic data showed that mitoQ altered several hepatic metabolic pathways in HF-fed obese rats toward those observed in control normal chow-fed non-obese rats. However, mitoQ had little effect on pathways observed in the diabetic rats, wherein diabetes itself induced marked pathway aberrations. MitoQ did not alter respiration or membrane potential in isolated liver mitochondria. MitoQ reduced liver fat and liver hydroperoxide levels but did not improve liver function as marked by circulating levels of aspartate and alanine aminotransferase (ALT). In summary, our results for HF-fed rats are consistent with past findings in HF-fed mice indicating decreased liver lipid hydroperoxides (LPO) and improved glycemia. However, in contrast to the HF obese mice, mitoQ did not improve glycemia or reset perturbed metabolic pathways in the diabetic rats.

7.
Proc Natl Acad Sci U S A ; 118(6)2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33542101

RESUMO

T-cell responses to posttranslationally modified self-antigens are associated with many autoimmune disorders. In type 1 diabetes, hybrid insulin peptides (HIPs) are implicated in the T-cell-mediated destruction of insulin-producing ß-cells within pancreatic islets. The natural history of the disease is such that it allows for the study of T-cell reactivity prior to the onset of clinical symptoms. We hypothesized that CD4 T-cell responses to posttranslationally modified islet peptides precedes diabetes onset. In a cohort of genetically at-risk individuals, we measured longitudinal T-cell responses to native insulin and hybrid insulin peptides. Both proinflammatory (interferon-γ) and antiinflammatory (interluekin-10) cytokine responses to HIPs were more robust than those to native peptides, and the ratio of such responses oscillated between pro- and antiinflammatory over time. However, individuals who developed islet autoantibodies or progressed to clinical type 1 diabetes had predominantly inflammatory T-cell responses to HIPs. Additionally, several HIP T-cell responses correlated to worsening measurements of blood glucose, highlighting the relevance of T-cell responses to posttranslationally modified peptides prior to autoimmune disease development.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33544017

RESUMO

Objective: As diabetes is a risk factor for severe symptoms, hospitalization, and death with COVID-19 disease, we aimed to assess the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in children and adults with and without type 1 diabetes in Colorado during 2020. Research Design and Methods: We developed a highly sensitive and specific test for antibodies against SARS-CoV-2 and measured the antibodies in children and adults with new-onset (n = 129) and established type 1 diabetes (n = 94) seen for routine diabetes care at our center between January and October 2020. The antibodies were also measured in 562 children and 102 adults from the general population of Colorado. Results: The prevalence of SARS-CoV-2 antibodies in persons with new-onset type 1 diabetes (0.8%; 95% confidence interval 0.1%-4.2%) or those with established disease (4.3%; 1.7%-10.4%) did not differ from that in the general population children (2.8%; 1.8%-4.6%) or adults (3.9%; 1.5%-9.7%). In a subset of individuals with positive antibodies (n = 31), antibodies remained positive for up to 9 months, although the levels decreased starting 3 months after the infection (P = 0.007). Conclusions: From January to October 2020, the prevalence of SARS-CoV-2 antibodies were not different in children and adults with and without type 1 diabetes in Colorado. We found no evidence for increased prevalence of COVID-19 infections among youth with newly diagnosed type 1 diabetes. (COMIRB Protocol 20-1007).

9.
Mol Brain ; 14(1): 13, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33446258

RESUMO

Cross-modal interaction (CMI) could significantly influence the perceptional or decision-making process in many circumstances. However, it remains poorly understood what integrative strategies are employed by the brain to deal with different task contexts. To explore it, we examined neural activities of the medial prefrontal cortex (mPFC) of rats performing cue-guided two-alternative forced-choice tasks. In a task requiring rats to discriminate stimuli based on auditory cue, the simultaneous presentation of an uninformative visual cue substantially strengthened mPFC neurons' capability of auditory discrimination mainly through enhancing the response to the preferred cue. Doing this also increased the number of neurons revealing a cue preference. If the task was changed slightly and a visual cue, like the auditory, denoted a specific behavioral direction, mPFC neurons frequently showed a different CMI pattern with an effect of cross-modal enhancement best evoked in information-congruent multisensory trials. In a choice free task, however, the majority of neurons failed to show a cross-modal enhancement effect and cue preference. These results indicate that CMI at the neuronal level is context-dependent in a way that differs from what has been shown in previous studies.

10.
J Child Adolesc Psychopharmacol ; 31(2): 95-101, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33395547

RESUMO

Objective: The outcome of pediatric obsessive-compulsive disorder (OCD) is still unclear. In the present study, long-term rates and predictors of remission were used to identify potential factors influencing the outcome of pediatric OCD. Methods: Using meta-analysis techniques, we calculated the pooled rate of remission and performed subgroup analyses to identify potential heterogeneities, and the meta-regression analysis was used as a predictor. Results: A total of 18 studies including 1389 participants were identified, and the follow-up periods ranged from 1 to 16 years. The pooled remission rate of pediatric OCD was 62% (95% confidence interval: 52-72). Shorter duration of OCD at baseline (R2 = 78.04%, p < 0.0001) predicted higher rates of remission. Conclusions: The outcome of pediatric OCD seems to be better than the past. Shorter duration of illness appears to be related to a better outcome. Early detection of pediatric OCD and early intervention play an important role in good prognosis. In the future, studies based on multicenter, longer follow-up studies with larger samples were needed to confirm these issues for the outcome of pediatric OCD.

11.
Int Clin Psychopharmacol ; 36(3): 109-116, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33492013

RESUMO

Children and adolescents with ASD also have co-occurrence of attention deficit hyperactivity disorder (ADHD) symptoms. ADHD symptoms, especially hyperactivity, greatly increased the severity of autism symptoms. This study concentrated on two widely-used medications: the second generation of antipsychotics (SGAs) and ADHD medication, aiming to conduct a meta-analysis about their effect on hyperactivity, so it would offer some evidence for clinical medication choice. The Medline, Embase, Cochrane Central Register of Controlled Trials and China National Knowledge Infrastructure databases were searched from inception to July 2019 for studies exploring the use of SGAs and ADHD medications in autistic children and adolescents. Double-blind, randomized controlled trials that reported hyperactivity as an outcome were included in the study. A total of thirteen trials with 712 participants were included in our meta-analysis. For SGAs, the standardized mean difference (SMD) of hyperactivity subscale in Aberrant behavior checklist scale or conners rating scales was 0.59, 95% confidence interval (CI): 0.23-0.96, I2 = 74%, Q = 15.34, P < 0.01. For ADHD medications, SMD was -0.66, with 95% CI: -0.99 to 0.33, I2 = 53%, Q = 15.02, P = 0.04. As for adverse events, in the SGAs group, somnolence had the largest effect size, risk ratio = 5.62, 95% CI: 3.20- 9.87 (I2 = 0%, Q = 2.45, P = 0.65). In ADHD group, the side effect of decreased appetite showed the largest effect size (risk ratio = 2.63, 95% CI = 0.99-7.01, I2 = 65.7%, Q = 11.66, P = 0.02). Both ADHD medications and SGAs were effective in dealing with hyperactivity in children and adolescents with autism but were shown to increase the risk of decreased appetite, somnolence, headache and nausea or vomiting. The clinical use of these medications should carefully weigh the benefits and risks.

12.
Chembiochem ; 22(9): 1609-1620, 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33480159

RESUMO

Regulator of G protein signaling (RGS) proteins have attracted attention as a result of their primary role in directing the specificity as well as the temporal and spatial aspects of G protein-coupled receptor signaling. In addition, alterations in RGS protein expression have been observed in a number of disease states, including certain cancers. In this area, RGS17 is of particular interest. It has been demonstrated that, while RGS17 is expressed primarily in the central nervous system, it has been found to be inappropriately expressed in lung, prostate, breast, cervical, and hepatocellular carcinomas. Overexpression of RGS17 leads to dysfunction in inhibitory G protein signaling and an overproduction of the intracellular second messenger cAMP, which in turn alters the transcription patterns of proteins known to promote various cancer types. Suppressing RGS17 expression with RNA interference (RNAi) has been found to decrease tumorigenesis and sufficiently prevents cancer cell migration, leading to the hypothesis that pharmacological blocking of RGS17 function could be useful in anticancer therapies. We have identified small-molecule fragments capable of binding the RGS homology (RH) domain of RGS17 by using a nuclear magnetic resonance fragment-based screening approach. By chemical shift mapping of the two-dimensional 15 N,1 H heteronuclear single quantum coherence (HSQC) spectra of the backbone-assigned 15 N-labeled RGS17-RH, we determined the fragment binding sites to be distant from the Gα interface. Thus, our study identifies a putative fragment binding site on RGS17 that was previously unknown.

13.
Diabetes Res Clin Pract ; 171: 108624, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33338552

RESUMO

AIMS: To estimate incidence of type 1 diabetes (T1D) and to develop a T1D prediction model among young adults. METHODS: Adults 20-45 years newly-diagnosed with diabetes in 2017 were identified within Kaiser Permanente's healthcare systems in California and invited for diabetes autoantibody (DAA) testing. Multiple imputation was conducted to assign missing DAA status. The primary outcome for incidence rates (IR) and the prediction model was T1D defined by ≥1 positive DAA. RESULTS: Among 2,347,989 persons at risk, 7862 developed diabetes, 2063 had DAA measured, and 166 (8.0%) had ≥1 positive DAA. T1D IR (95% CI) per 100,000 person-years was 15.2 (10.2-20.1) for ages 20-29 and 38.2 (28.6-47.8) for ages 30-44 years. The age-standardized IRs were 32.5 (22.2-42.8) for men and 27.2 (21.0-34.5) for women. The age/sex-standardized IRs were 30.1 (23.5-36.8) overall; 41.4 (25.3-57.5) for Hispanics, 37.0 (11.6-62.4) for Blacks, 21.4 (14.3-28.6) for non-Hispanic Whites, and 19.4 (8.5-30.2) for Asians. Predictors of T1D among cases included female sex, younger age, lower BMI, insulin use and having T1D based on diagnostic codes. CONCLUSIONS: T1D may account for up to 8% of incident diabetes cases among young adults. Follow-up is needed to establish the clinical course of patients with one DAA at diagnosis.


Assuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Adulto , Diabetes Mellitus Tipo 1/tratamento farmacológico , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Compr Psychiatry ; 104: 152217, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33217635

RESUMO

BACKGROUND: The COVID-19 pandemic is putting healthcare workers across the world in an unprecedented situation. The purpose of this study was to evaluate the levels of depression, anxiety, and stress among Hubei pediatric nurses during the COVID-19 pandemic and to analyze the potential factors associated with them. MATERIALS AND METHODS: A self-designed online questionnaire survey, which consisted of the demographic and selected features, the occupational protection knowledge, attitudes, and practices of COVID-19, and the Chinese version of Depression, Anxiety, and Stress Scale, were used to assess the levels of depression, anxiety, and stress among Hubei pediatric nurses during COVID-19 pandemic. The logistic regression analyses were performed to analyze the potential factors associated with depression, anxiety, and stress. RESULTS: A total of 617 pediatric nurses were included in the survey. A considerable proportion of pediatric nurses reported symptoms of depression (95 [15.4%]), anxiety (201 [32.6%]), and stress (111 [18.0%]). Results of multivariable logistic regression analyses indicated that the good occupational protection practices (for depression: OR = 0.455, 95%CI: 0.281 to 0.739; for anxiety: OR = 0.597, 95%CI: 0.419 to 0.851; for stress: OR = 0.269, 95%CI: 0.166 to 0.438) and the personal protective equipment (PPE) meeting work requirements (for depression: OR = 0.438, 95%CI: 0.246 to 0.778; for anxiety: OR = 0.581, 95%CI: 0.352 to 0.959; for stress: OR = 0.504, 95%CI: 0.283 to 0.898) were independent protective factors against depression, anxiety, and stress, respectively. Yet, working in an isolation ward or fever clinic was an independent risk factor associated with depression, anxiety, and stress, respectively (for depression: OR = 1.809, 95%CI: 1.103 to 2.966; for anxiety: OR = 1.864, 95%CI: 1.221 to 2.846; for stress: OR = 2.974, 95%CI: 1.866 to 4.741). Having suspected or confirmed COVID-19 patients in the departments (OR = 1.554, 95%CI: 1.053 to 2.294) and coming in contact with the patient's bodily fluids or blood (OR = 1.469, 95%CI: 1.031 to 2.095) were independent risk factors for anxiety, while >3 times of training for COVID-19 related information was an independent protective factor for depression (OR = 0.592, 95%CI: 0.360 to 0.974). Moreover, >10 years of working was an independent risk factor for stress (OR = 1.678, 95%CI: 1.075 to 2.618). CONCLUSION: During the COVID-19 outbreak, a considerable proportion of Hubei pediatric nurses had psychological problems. The pediatric nurses endorsing the higher number of risk factors should be given special attention and necessary psychological intervention. Improving the levels of PPE so as to meet the work requirements and intensifying occupational protection practices might help safeguard pediatric nurses from depression, anxiety, and stress.

15.
Immune Netw ; 20(5): e41, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33163249

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is a positive-sense single-stranded RNA (+ssRNA) that causes coronavirus disease 2019 (COVID-19). The viral genome encodes twelve genes for viral replication and infection. The third open reading frame is the spike (S) gene that encodes for the spike glycoprotein interacting with specific cell surface receptor - angiotensin converting enzyme 2 (ACE2) - on the host cell membrane. Most recent studies identified a single point mutation in S gene. A single point mutation in S gene leading to an amino acid substitution at codon 614 from an aspartic acid 614 into glycine (D614G) resulted in greater infectivity compared to the wild type SARS-CoV2. We were interested in investigating the mutation region of S gene of SARS-CoV2 from Korean COVID-19 patients. New mutation sites were found in the critical receptor binding domain (RBD) of S gene, which is adjacent to the aforementioned D614G mutation residue. This specific sequence data demonstrated the active progression of SARS-CoV2 by mutations in the RBD of S gene. The sequence information of new mutations is critical to the development of recombinant SARS-CoV2 spike antigens, which may be required to improve and advance the strategy against a wide range of possible SARS-CoV2 mutations.

16.
MAbs ; 12(1): 1836714, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33151102

RESUMO

Activation of T cells specific for insulin B chain amino acids 9 to 23 (B:9-23) is essential for the initiation of type 1 diabetes (T1D) in non-obese diabetic mice. We previously reported that peptide/MHC complexes containing optimized B:9-23 mimotopes can activate most insulin-reactive pathogenic T cells. A monoclonal antibody (mAb287) targeting these complexes prevented disease in 30-50% of treated animals (compared to 10% of animals given an isotype control). The incomplete protection is likely due to the relatively low affinity of the antibody for its ligand and limited specificity. Here, we report an enhanced reagent, mAb757, with improved specificity, affinity, and efficacy in modulating T1D. Importantly, mAb757 bound with nanomolar affinity to agonists of both "type A" and "type B" cells and suppressed "type B" cells more efficiently than mAb287. When given weekly starting at 4 weeks of age, mAb757 protected ~70% of treated mice from developing T1D for at least 35 weeks, while mAb287 only delayed disease in 25% of animals under the same conditions. Consistent with its higher affinity, mAb757 was also able to stain antigen-presenting cells loaded with B:9-23 mimotopes in vivo. We conclude that monoclonal antibodies that can block the presentation of pathogenic T cell receptor epitopes are viable candidates for antigen-specific immunotherapy for T1D.

17.
Food Funct ; 11(10): 8560-8572, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33021306

RESUMO

Immune system dysfunction may contribute to the pathogenesis of hypertension in spontaneously hypertensive rats (SHR). We examined the effects of the anthocyanin, cyanidin 3-O-glucoside (C3G), and the diuretic, hydrochlorothiazide (HCT), on T-cell function in SHR. Five-week-old male SHR and Wistar-Kyoto (WKY) rats received water (n = 8/SHR; n = 8/WKY), 10 mg kg-1 day-1 C3G (n = 8/SHR; n = 8/WKY), 10 mg kg-1 day-1 HCT (n = 8/SHR; n = 8/WKY), or 10 mg kg-1 day-1 C3G + 10 mg kg-1 day-1 HCT (n = 8/SHR; n = 8/WKY) by oral gavage for 15 weeks. Spleens were used to assess T-cell phenotypes via flow cytometry and concanavalin A stimulated ex vivo cytokine production (IL-2, IL-10, TNFα, IFNγ) using a cytometric bead array. SHR had lower proportions of helper T-cells (Th) that were T-regulatory, CD62Llo, CD62L- and CD25+ compared to WKY. C3G treated SHR had higher proportions of Th that were CD62Llo and CD62L-, while HCT treated rats had higher CD62Lhi and CD62Llo and lower CD62L- compared to SHR control. The proportion of T-regulatory and Th that were CD25+ were not affected by treatment in SHR. Stimulated splenocytes from SHR produced lower concentrations of cytokines compared to WKY. C3G treated SHR produced higher while HCT treated SHR produced lower TNFα and IFNγ concentrations compared to controls. Our findings suggest that C3G has positive effects, whereas HCT further suppresses T-cell function in SHR.

18.
Expert Rev Neurother ; 20(11): 1197-1205, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32954857

RESUMO

OBJECTIVES: Nearly half of the patients with Tourette Syndrome (TS) present with comorbid Obsessive-Compulsive Symptoms (OCS) and premonitory urges (PUs). However, inconsistent results have been found in the correlation between PUs and OCS in patients with TS. METHODS: A meta-analysis was applied to identify the severity of OCS and its correlation with PUs in TS patients. Subgroup and meta-regression analyses were used to identify potential heterogeneity. RESULTS: A total of 13 studies, including 576 patients, were enrolled in this study. The pooled correlation coefficient (r) was 0.29 (95% confidence interval: 0.18, 0.38) and heterogeneity (I2) of pooled r was 40% based on a fixed-effect model. The mean level of OCS based on the assessment of Children's Yale-Brown Obsessive-Compulsive Symptom Scale/Yale-Brown Obsessive-Compulsive Symptom Scale was 14.99 (95% CI: 11.41, 18.57) by a random effect model. Results of meta-regression analysis demonstrated that the severity of tic symptoms based on the assessment of the Yale Global Tic Severity Scale was the predictor of severity of OCS (p = 0.018). CONCLUSION: There was a mild positive correlation between the PUs and OCS in patients with TS. The severity of OCS in TS patients was mild to moderate and positively predicted by the severity of tic symptoms.

19.
Elife ; 92020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32975514

RESUMO

Matriglycan [-GlcA-ß1,3-Xyl-α1,3-]n serves as a scaffold in many tissues for extracellular matrix proteins containing laminin-G domains including laminin, agrin, and perlecan. Like-acetyl-glucosaminyltransferase 1 (LARGE1) synthesizes and extends matriglycan on α-dystroglycan (α-DG) during skeletal muscle differentiation and regeneration; however, the mechanisms which regulate matriglycan elongation are unknown. Here, we show that Protein O-Mannose Kinase (POMK), which phosphorylates mannose of core M3 (GalNAc-ß1,3-GlcNAc-ß1,4-Man) preceding matriglycan synthesis, is required for LARGE1-mediated generation of full-length matriglycan on α-DG (~150 kDa). In the absence of Pomk gene expression in mouse skeletal muscle, LARGE1 synthesizes a very short matriglycan resulting in a ~ 90 kDa α-DG which binds laminin but cannot prevent eccentric contraction-induced force loss or muscle pathology. Solution NMR spectroscopy studies demonstrate that LARGE1 directly interacts with core M3 and binds preferentially to the phosphorylated form. Collectively, our study demonstrates that phosphorylation of core M3 by POMK enables LARGE1 to elongate matriglycan on α-DG, thereby preventing muscular dystrophy.

20.
BMC Cardiovasc Disord ; 20(1): 414, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917144

RESUMO

BACKGROUND: Electrocardiogram (ECG) is widely used to screen cardiac diseases. To date, no large population study has provided estimates of the prevalences of ECG findings in China. We aim to investigate the prevalences and associated factors of ECG abnormalities in a general population of Chinese adults. METHODS: ECG data were obtained from 34,965 participants in the 2007-2008 China National Diabetes and Metabolic Disorders Study. ECG abnormalities were classified according to the Minnesota coding (MC) criteria. Prevalences of variant ECG abnormalities were calculated. The associations between ECG abnormalities and gender, age and other risk factors for cardiovascular diseases (CVD) were analyzed by multivariate logistic regression test. RESULTS: The prevalences of major arrhythmias were 1.70, 2.37 and 1.04% in the whole population, men and women, respectively. Atrial fibrillation/flutter was found in 0.35% of men and 0.20% of women. ST depression and T abnormalities accounted for 10.96, 7.54 and 14.32% in the whole population, men and women, respectively. Independent of gender and other CVD risk factors, older age significantly increased the odds of having atrial fibrillation/flutter, complete left bundle branch block, complete right bundle branch block, sinus tachycardia, atrial/junctional/ventricular premature beats, ST depression and T abnormalities, tall R wave left, left/right atrial hypertrophy, left axis deviation and low voltage. Hypertension, overweight, obesity and hypercholesterolemia all independently increased the odds of having ST depression and T abnormalities. History of cardiovascular/cerebrovascular diseases was positively associated with major arrhythmias, ST depression and T abnormalities and tall R wave left. CONCLUSIONS: This study provides estimates of the prevalences of ECG findings in a large population of Chinese adults. Gender, age, CVD risk factors and history of cardiovascular/cerebrovascular diseases were significantly associated with ECG abnormalities.

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