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1.
Nat Commun ; 13(1): 2647, 2022 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-35551181

RESUMO

The brain is organized into networks at multiple resolutions, or scales, yet studies of functional network development typically focus on a single scale. Here, we derive personalized functional networks across 29 scales in a large sample of youths (n = 693, ages 8-23 years) to identify multi-scale patterns of network re-organization related to neurocognitive development. We found that developmental shifts in inter-network coupling reflect and strengthen a functional hierarchy of cortical organization. Furthermore, we observed that scale-dependent effects were present in lower-order, unimodal networks, but not higher-order, transmodal networks. Finally, we found that network maturation had clear behavioral relevance: the development of coupling in unimodal and transmodal networks are dissociably related to the emergence of executive function. These results suggest that the development of functional brain networks align with and refine a hierarchy linked to cognition.

2.
Zhongguo Zhong Yao Za Zhi ; 47(7): 1754-1764, 2022 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-35534246

RESUMO

Astragali Radix, a medicinal herb for invigorating Qi, has anti-aging, anti-tumor, immunoregulatory, blood sugar-and lipid-lowering, anti-fibrosis, anti-radiation and other pharmacological effects. This article reviewed the studies about the chemical components and pharmacological effects of Astragali Radix. According to the theory of quality markers(Q-markers) of Chinese medicinal materials, we predicted the Q-markers of Astragali Radix from traditional efficacy, chemical component validity, measurability, plant phylogeny, and pharmacokinetis. The results showed that total polysaccharides, flavonoids(e.g., calycosin-7-O-ß-D-glucoside, formononetin, calycosin, quercetin, and ononin), and saponins(e.g., astragalosides Ⅱ, Ⅲ, and Ⅳ) can be taken as the main Q-markers. This review lays a foundation for regulating the quality research and standard establishment of Astragali Radix, and benefits the control and quality supervision of the production process of Astragali Radix and its related products.


Assuntos
Astrágalo (Planta) , Medicamentos de Ervas Chinesas , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/farmacologia , Flavonoides , Raízes de Plantas
3.
J Biochem Mol Toxicol ; : e23044, 2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35499365

RESUMO

Inhibition of histone deacetylase (HDAC) may be a useful approach in the treatment of disorders characterized by cognitive dysfunction. Dexmedetomidine (DEX), an α2-adrenoceptor (α2-AR) agonist, has demonstrated neuroprotective effects. Here, we attempted to investigate the protective effects of DEX on postoperative cognitive dysfunction (POCD) involving HDAC2. Male C57BL/6 mice were selected to develop a POCD model, where HDAC2, HIF-1α, and PFKFB3 expression was quantified. DEX was administered before POCD modeling. Then the cognitive function of POCD mice was evaluated with the open field and Y-maze tests. Meanwhile, lipopolysaccharide (LPS) was employed to induce BV-2 microglial cells to simulate the inflammatory response. The contents of TNF-α, IL-6, and IL-10 were measured by enzyme-linked immunosorbent assay (ELISA) in mouse serum and BV-2 cell supernatant. Abundant expression of HDAC2, HIF-1α, and PFKFB3 was confirmed in POCD mice (p < 0.05). Cognitive dysfunction in POCD mice could be alleviated following pharmacological inhibition of HDAC2 by FK228 (p < 0.05). Mechanistically, HDAC2 upregulated HIF-1α and PFKFB3 and promoted the secretion of inflammatory factors in LPS-exposed BV-2 cells (p < 0.05). DEX attenuated neuroinflammation and the resulting cognitive dysfunction by decreasing HDAC2 expression and HIF-1α-dependent PFKFB3 upregulation in POCD mice (p < 0.05). In conclusion, DEX-regulated HDAC2 may play an inhibitory role in mice with POCD through regulation of the HIF-1α/PFKFB3 axis.

4.
IEEE Trans Cybern ; PP2022 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-35544505

RESUMO

Consensus reaching process (CRP) is a key topic in the area of group decision making (GDM). When the consensus level is not high enough, it becomes necessary to adjust the original opinions of decision makers (DMs). To offer the adjustment reference for DMs, we build the programming models to determine the minimum modification to be carried out from the individual and global perspectives. Meanwhile, all DMs are divided into two subgroups: DMs with acceptable and unacceptable consensus levels. If some DMs with unacceptable consensus level do not accept the relevant modifications, the Nash bargaining game-based programming model is built for the fairness and efficiency of modifications. When some DMs refuse to make any modifications or tend to modify the opinions in their way, with respect to different group consensus situations, we make the minimum hybrid penalty mechanism by the Nash bargaining game-based programming models. For each case, we determine the corresponding optimal modification mechanism in view of the fixed individual total modification and the maximum consensus level. Furthermore, we study the arrangements of weights of DMs according to their cardinal and ordinal consensus contributions. Based on these results, we present a new algorithm and illustrate its application by a numerical example. Moreover, we carry out the sensitivity and comparison analysis. We summarize the conclusions and future research directions in the end. The main originality of the new method includes: the fairness and efficiency of modifications, and the determination of the hybrid penalty mechanism.

5.
Hum Reprod ; 2022 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-35551387

RESUMO

STUDY QUESTION: Are there new genetic factors responsible for male infertility with normal sperm quantity and morphology? SUMMARY ANSWER: We identified the bi-allelic variants in KCNU1 and confirmed it a novel pathogenetic gene for male infertility mainly due to impaired sperm acrosome reactions (ARs). WHAT IS KNOWN ALREADY: Until now, the underlying genetic determinants for male affected individuals exhibiting normal sperm quantity and morphology have been largely unknown. Potassium/calcium-activated channel subfamily U member 1 (KCNU1) is a sperm-specific potassium channel. The Kcnu1 null mutation in male mice causes infertility due to the impaired progressive motility and AR. STUDY DESIGN, SIZE, DURATION: We recruited a cohort of 126 male infertility individuals with typical asthenospermia or fertilization failure and focused on two infertile males from two consanguineous families from 2015 to 2020; whole-exome sequencing and homozygosity mapping were performed. We identified a homozygous missense variant (c.2144A>G, p.His715Arg) and a homozygous donor splice-site variant (c.1295 + 3A>C, p.Val405Glyfs*8) in KCNU1. Then, we generated a knock-in (KI) mouse model in September 2020 and have now carried out functional studies and possible treatment strategies. PARTICIPANTS/MATERIALS, SETTING, METHODS: The affected individuals with infertility were recruited from the Shanghai Ninth Hospital affiliated to Shanghai Jiao Tong University. Genomic DNA from the affected individual was extracted from peripheral blood. Whole-exome sequencing, homozygosity mapping and in silico analyses were used to screen and identify KCNU1 variants, and the variants were confirmed by Sanger sequencing. We used C57BL/6N mouse to construct KI mouse model to mimic the reproductive phenotype in vivo. We performed functional experiments by western blotting, AR assay and immunofluorescent Staining. Finally, we performed IVF and ICSI to explore the treatment strategies. MAIN RESULTS AND THE ROLE OF CHANCE: We identified a homozygous missense variant (c.2144A>G, p.His715Arg) and a homozygous donor splice-site variant (c.1295 + 3A>C, p.Val405Glyfs*8) in KCNU1 in two infertile males. We demonstrated that the splice-site variant affected normal alternative splicing of KCNU1, thus leading to the loss of function of KCNU1. Meanwhile, the missense pathogenic variant reduced the KCNU1 protein levels in sperm of both the affected individual and the KI mouse model, resulting in impaired ARs and male infertility. Intracytoplasmic sperm injection was able to rescue the deficiencies. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The exact molecular mechanism of KCNU1 and pathways need to be further explore in the future. WIDER IMPLICATIONS OF THE FINDINGS: This is the first report that establishes a causal relationship between KCNU1 deficiency and male infertility, confirming the critical role of KCNU1 in human reproduction. Our findings expand our knowledge of the genes that play critical roles in the human sperm AR and provide a new genetic marker for infertility. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the SHIPM-pi fund no. JY201801 from the Shanghai Institute of Precision Medicine, Ninth People's Hospital Shanghai Jiao Tong University School of Medicine, the National Natural Science Foundation of China (81725006, 81771649, 81822019, 81771581, 81971450, 81971382, 82001538 and 82071642). The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

6.
Artigo em Inglês | MEDLINE | ID: mdl-35463062

RESUMO

Remyelination is a refractory feature of demyelinating diseases such as multiple sclerosis (MS). Studies have shown that promoting oligodendrocyte precursor cell (OPC) differentiation, which cannot be achieved by currently available therapeutic agents, is the key to enhancing remyelination. Bu Shen Yi Sui capsule (BSYSC) is a traditional Chinese herbal medicine over many years of clinical practice. We have found that BSYSC can effectively treat MS. In this study, the effects of BSYSC in promoting OPCs differentiation and remyelination were assessed using an experimental autoimmune encephalomyelitis (EAE) model in vivo and cultured OPCs in vitro. The results showed that BSYSC reduced clinical function scores and increased neuroprotection. The expression of platelet-derived growth factor receptor α (PDGFR-α) was decreased and the level of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) was increased in the brains and spinal cords of mice as well as in OPCs after treatment with BSYSC. We further found that BSYSC elevated the expression of miR-219 or miR-338 in the serum exosomes of mice with EAE, thereby suppressing the expression of Sox6, Lingo1, and Hes5, which negatively regulate OPCs differentiation. Therefore, serum exosomes of BSYSC-treated mice (exos-BSYSC) were extracted and administered to OPCs in which miR-219 or miR-338 expression was knocked down by adenovirus, and the results showed that Sox6, Lingo1, and Hes5 expression was downregulated, MBP expression was upregulated, OPCs differentiation was increased, and the ability of OPCs to wrap around neuronal axons was improved. In conclusion, BSYSC may exert clinically relevant effects by regulating microRNA (miR) levels in exosomes and thus promoting the differentiation and maturation of OPCs.

7.
Neuroimage ; 256: 119198, 2022 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-35421567

RESUMO

Community detection on graphs constructed from functional magnetic resonance imaging (fMRI) data has led to important insights into brain functional organization. Large studies of brain community structure often include images acquired on multiple scanners across different studies. Differences in scanner can introduce variability into the downstream results, and these differences are often referred to as scanner effects. Such effects have been previously shown to significantly impact common network metrics. In this study, we identify scanner effects in data-driven community detection results and related network metrics. We assess a commonly employed harmonization method and propose new methodology for harmonizing functional connectivity that leverage existing knowledge about network structure as well as patterns of covariance in the data. Finally, we demonstrate that our new methods reduce scanner effects in community structure and network metrics. Our results highlight scanner effects in studies of brain functional organization and provide additional tools to address these unwanted effects. These findings and methods can be incorporated into future functional connectivity studies, potentially preventing spurious findings and improving reliability of results.

8.
Am J Psychiatry ; : appiajp21070686, 2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35410495

RESUMO

OBJECTIVE: The prevalence and significance of schizophrenia-related phenotypes at the population level is debated in the literature. Here, the authors assessed whether two recently reported neuroanatomical signatures of schizophrenia-signature 1, with widespread reduction of gray matter volume, and signature 2, with increased striatal volume-could be replicated in an independent schizophrenia sample, and investigated whether expression of these signatures can be detected at the population level and how they relate to cognition, psychosis spectrum symptoms, and schizophrenia genetic risk. METHODS: This cross-sectional study used an independent schizophrenia-control sample (N=347; ages 16-57 years) for replication of imaging signatures, and then examined two independent population-level data sets: typically developing youths and youths with psychosis spectrum symptoms in the Philadelphia Neurodevelopmental Cohort (N=359; ages 16-23 years) and adults in the UK Biobank study (N=836; ages 44-50 years). The authors quantified signature expression using support-vector machine learning and compared cognition, psychopathology, and polygenic risk between signatures. RESULTS: Two neuroanatomical signatures of schizophrenia were replicated. Signature 1 but not signature 2 was significantly more common in youths with psychosis spectrum symptoms than in typically developing youths, whereas signature 2 frequency was similar in the two groups. In both youths and adults, signature 1 was associated with worse cognitive performance than signature 2. Compared with adults with neither signature, adults expressing signature 1 had elevated schizophrenia polygenic risk scores, but this was not seen for signature 2. CONCLUSIONS: The authors successfully replicated two neuroanatomical signatures of schizophrenia and describe their prevalence in population-based samples of youths and adults. They further demonstrated distinct relationships of these signatures with psychosis symptoms, cognition, and genetic risk, potentially reflecting underlying neurobiological vulnerability.

9.
ACS Appl Mater Interfaces ; 14(15): 17995-18003, 2022 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-35389609

RESUMO

Microstructured surfaces with stimuli-responsive performances have aroused great attention in recent years, but it still remains a significant challenge to endow surfaces with precisely controlled morphological changes in microstructures, so as to get the precise control of regional properties (e.g., friction, adhesion). Herein, a kind of carbonyl iron particle-doped shape memory polyurethane micropillar with precisely controllable morphological changes is realized, upon remote near-infrared light (NIR) irradiation. Owing to the reversible transition of micropillars between bent and upright states, the micro-structured surface exhibits precisely controllable low-to-high friction transitions, together with the changes of friction coefficient ranging from ∼0.8 to ∼1.2. Hence, the changes of the surface friction even within an extremely small area can be precisely targeted, under local NIR laser irradiation. Moreover, the water droplet adhesion force of the surface can be reversibly switched between ∼160 and ∼760 µN, demonstrating the application potential in precisely controllable wettability. These features indicate that the smart stimuli-responsive micropillar arrays would be amenable to a variety of applications that require remote, selective, and on-demand responses, such as a refreshable Braille display system, micro-particle motion control, lab-on-a-chip, and microfluidics.

10.
JAMA Psychiatry ; 79(5): 464-474, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35262657

RESUMO

Importance: Late-life depression (LLD) is characterized by considerable heterogeneity in clinical manifestation. Unraveling such heterogeneity might aid in elucidating etiological mechanisms and support precision and individualized medicine. Objective: To cross-sectionally and longitudinally delineate disease-related heterogeneity in LLD associated with neuroanatomy, cognitive functioning, clinical symptoms, and genetic profiles. Design, Setting, and Participants: The Imaging-Based Coordinate System for Aging and Neurodegenerative Diseases (iSTAGING) study is an international multicenter consortium investigating brain aging in pooled and harmonized data from 13 studies with more than 35 000 participants, including a subset of individuals with major depressive disorder. Multimodal data from a multicenter sample (N = 996), including neuroimaging, neurocognitive assessments, and genetics, were analyzed in this study. A semisupervised clustering method (heterogeneity through discriminative analysis) was applied to regional gray matter (GM) brain volumes to derive dimensional representations. Data were collected from July 2017 to July 2020 and analyzed from July 2020 to December 2021. Main Outcomes and Measures: Two dimensions were identified to delineate LLD-associated heterogeneity in voxelwise GM maps, white matter (WM) fractional anisotropy, neurocognitive functioning, clinical phenotype, and genetics. Results: A total of 501 participants with LLD (mean [SD] age, 67.39 [5.56] years; 332 women) and 495 healthy control individuals (mean [SD] age, 66.53 [5.16] years; 333 women) were included. Patients in dimension 1 demonstrated relatively preserved brain anatomy without WM disruptions relative to healthy control individuals. In contrast, patients in dimension 2 showed widespread brain atrophy and WM integrity disruptions, along with cognitive impairment and higher depression severity. Moreover, 1 de novo independent genetic variant (rs13120336; chromosome: 4, 186387714; minor allele, G) was significantly associated with dimension 1 (odds ratio, 2.35; SE, 0.15; P = 3.14 ×108) but not with dimension 2. The 2 dimensions demonstrated significant single-nucleotide variant-based heritability of 18% to 27% within the general population (N = 12 518 in UK Biobank). In a subset of individuals having longitudinal measurements, those in dimension 2 experienced a more rapid longitudinal change in GM and brain age (Cohen f2 = 0.03; P = .02) and were more likely to progress to Alzheimer disease (Cohen f2 = 0.03; P = .03) compared with those in dimension 1 (N = 1431 participants and 7224 scans from the Alzheimer's Disease Neuroimaging Initiative [ADNI], Baltimore Longitudinal Study of Aging [BLSA], and Biomarkers for Older Controls at Risk for Dementia [BIOCARD] data sets). Conclusions and Relevance: This study characterized heterogeneity in LLD into 2 dimensions with distinct neuroanatomical, cognitive, clinical, and genetic profiles. This dimensional approach provides a potential mechanism for investigating the heterogeneity of LLD and the relevance of the latent dimensions to possible disease mechanisms, clinical outcomes, and responses to interventions.


Assuntos
Doença de Alzheimer , Transtorno Depressivo Maior , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Encéfalo/diagnóstico por imagem , Cognição , Depressão , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/genética , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética/métodos , Masculino , Neuroimagem
11.
Lupus Sci Med ; 9(1)2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35241499

RESUMO

OBJECTIVE: To investigate the frequency and determinants of flare in Chinese patients with lupus, focusing on the effect of glucocorticoid (GC) tapering on flare in patients who achieved low disease activity or remission. METHODS: We collected baseline and follow-up data from all consecutive patients in a prospective lupus cohort between January 2017 and December 2020. We defined low disease activity using the lupus low disease activity status (LLDAS), applied the DORIS (Definitions of Remission in SLE) for remission criteria and then assessed flare using the SELENA-SLEDAI Flare Index. RESULTS: Among a total of 185 patients enrolled, 139 exhibited low disease activity or remission with a median follow-up of 29.8 (21.2-35.2) months. The flare rates after achievement of LLDAS, clinical remission and complete remission on treatment were 0.23, 0.12 and 0.1 per patient-year, respectively. In contrast, the flare rate of patients who never achieved remission or LLDAS was 0.49 per patient-year. In patients with LLDAS or remission achievement, multivariate Cox regression analysis showed that lower C3 level at the time of first achieving LLDAS or clinical remission was an independent predictive factor for subsequent flares. Kaplan-Meier curves showed a significantly lower flare-free survival during the subsequent follow-up in patients with GC withdrawal compared with those maintained on a low dose of prednisone (≤7.5 mg/day) (HR=6.94, 95% CI 1.86 to 25.86, p=0.004). However, no significant differences in flare were observed in patients maintained on different low doses of prednisone (>5 mg/day and ≤7.5 mg/day vs >2.5 mg/day and ≤5 mg/day vs >0 mg/day and ≤2.5 mg/day) (p=0.200). CONCLUSIONS: Target achievement significantly lowered the rate of subsequent flare, from the perspective of both stricter targets and longer period in targets. C3 level was a strong predictor of flare in patients who have achieved treatment targets. Although GC tapering to minimal doses was feasible, its withdrawal may accelerate the risk of recurrence.


Assuntos
Lúpus Eritematoso Sistêmico , Estudos de Coortes , Glucocorticoides/uso terapêutico , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Prednisona/uso terapêutico , Estudos Prospectivos , Índice de Gravidade de Doença
12.
Int J Biol Sci ; 18(4): 1569-1579, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35280690

RESUMO

Imbalance of Aß and tau protein production and clearance are the key factors among many causes of Alzheimer's disease that leading to neurons degeneration and cognitive disorders. As a novel approach, glymphatic system quickly clear metabolic waste (especially Aß and tau) from cerebral environment, and dysfunction of glymphatic system may relate to occurrence of Alzheimer's disease. Microinfarct is a common histopathologic situation occurring in aging brain and leads to dramatic increase the generation of metabolic by-product after neuronal injury, hindering the operation of glymphatic system and suppress cerebral spinal fluid (CSF) and cerebral interstitial fluid (interstitial fluid, ISF) exchange. Microinfarcts destruct the integrity of microvascular and microstructural tissue, result in Aß deposition and tau phosphorylation that form neurofibrillary tangles and associated with the cause of Alzheimer's disease. Currently, it has been found that glymphatic system is involved in the pathological process of Alzheimer's disease. Improving the function of glymphatic system after cerebral microinfarcts could be developed as a new approach for Alzheimer's disease prevention and treatment. In this review, we will provide in-depth discussion on functional changes of glymphatic system after cerebral microinfarcts, further reveal pathogenesis of Alzheimer's disease and provide a potentially more effective method for treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer , Sistema Glinfático , Doenças Neurodegenerativas , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Sistema Glinfático/metabolismo , Sistema Glinfático/patologia , Humanos , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo
13.
Rheumatol Ther ; 2022 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-35347662

RESUMO

INTRODUCTION: Treat-to-target (T2T) strategy has been the core of rheumatoid arthritis (RA) management for over a decade, although it implementation has varied distinctly in real practices. We report here our investigation of the differences in disease activity and target achievement of two patient cohorts with different T2T implementations. METHODS: Data of the CENTRA (Collaboratively intENsive Treat-to-target in RA) and TARRA (Treat-to-TARget in RA) cohorts were used. The CENTRA cohort is a RA cohort prospectively followed up by a fixed team with tight control, while the TARRA is a longitudinal observational cohort followed up by a rheumatologist with casual control. Patients from the two cohorts were matched 1:3 by propensity score matching. The primary outcome was the Simplified Disease Activity Index (SDAI) at the 1-year follow-up. RESULTS: Included in this analysis were 102 patients from the CENTRA cohort and 271 patients from the TARRA cohort. Both groups were comparable in terms of age, gender, disease course, and seropositivity. At the end of the 1-year follow-up, the SDAI of patients in the CENTRA cohort was significantly lower than that of patients in the TARRA cohort (2.1 vs. 3.4; p < 0.001). A similar result was obtained based on the generalized estimating equation (GEE) model (p = 0.009). In addition, more patients in the CENTRA cohort achieved SDAI-defined remission compared to the TARRA cohort [72 (70.6%) vs. 134 (49.4%); p < 0.001]. CONCLUSION: Patients with RA may benefit more from a tight control T2T strategy with closer follow-up and appropriate education compared with those with a casual T2T strategy.

14.
Exp Ther Med ; 23(4): 248, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35261620

RESUMO

Melatonin is a hormone produced by the pineal gland. Given its capabilities of neuroprotection and low neurotoxicity, melatonin could be a therapeutic strategy for traumatic brain injury (TBI). The present study was conducted to determine the neuroprotective effects of melatonin on TBI-induced anxiety and the possible molecular mechanism. Rats were randomly divided into seven groups. The rodent model of TBI was established using the weight-drop method. Melatonin was administered by intraperitoneal injection at a dose of 10 mg/kg after TBI. H89 (0.02 mg/kg), a special protein kinase A (PKA) inhibitor, or dibutyryl-cyclic adenosine monophosphate (cAMP; 0.1 mg/kg), an activator of PKA, were administered by stereotactic injection of the brain to evaluate the roles of PKA and cAMP-response element-binding protein (CREB) in melatonin-related mood regulation, respectively. At 30 days post-TBI, the changes in anxiety-like behaviors in rats were measured using the open field and elevated plus maze tests. At 24 h post-TBI, the number of activated astrocytes and neuronal apoptosis were evaluated using immunofluorescence assay. The expression levels of inflammatory cytokines (TNF-α and IL-6) in the amygdala were measured using an enzyme-linked immunosorbent assay. The expression levels of PKA, phosphorylated (p)-PKA, CREB, p-CREB, NF-κB and p-NF-κB in the amygdala were detected using western blotting. It was revealed that melatonin partially reversed TBI-induced anxiety-like behavior in rats, and decreased the number of activated astrocytes and neuronal apoptosis in the amygdala induced by TBI. H89 partially blocked the neuroprotective effects of melatonin; while dibutyryl-cAMP not only reduced the H89-induced emotional disturbance but also enhanced the protective effects of melatonin against TBI. Overall, melatonin can alleviate TBI-induced anxiety-like behaviors in rats. Moreover, the underlying mechanism may be associated with the activation of the PKA/CREB signaling pathway.

15.
J Orthop Surg Res ; 17(1): 129, 2022 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-35241120

RESUMO

OBJECTIVE: Inconsistent findings existed on the correlation of collagen type V α1 (COL5A1) gene polymorphisms and musculoskeletal soft tissue injuries (MSTIs). The purpose of this study was to collect and combine the current evidences by a meta-analysis approach. METHODS: Six online databases were searched up to August, 2021. The methodological quality of each individual study was evaluated based upon Newcastle-Ottawa Scale (NOS). The strength of the effect size was presented by odds ratio (OR) with 95% confidence interval (95%CI) in five genetic models. The data were analyzed using Review Manager 5.3. RESULTS: Twenty-one studies were eligible to this meta-analysis. The study quality was deemed fair to excellent according to NOS. In the overall analyses, the merged data suggested that rs12722, rs71746744, and rs3196378 polymorphisms were correlated to an increased susceptibility to MSTIs. But the association was not established in rs13946 or rs11103544 polymorphism. For rs12722 polymorphism, stratified analyses by injury type and ethnicity identified the association mainly existed in ligament injury and among Caucasian population. For rs13946 polymorphism, subgroup analysis suggested the association existed in tendon and ligament injuries. CONCLUSION: This study supports that rs12722 is associated with an elevated susceptibility to ligament injury, especially in the Caucasian population. Rs13946 polymorphism appears to increase the risk to tendon and ligament injuries. Rs71746744 and rs3196378 polymorphisms have a tendency to confer an elevated risk to MSTIs. However, no relevance is found between rs11103544 polymorphism and MSTIs.


Assuntos
Colágeno Tipo V/genética , Sistema Musculoesquelético , Polimorfismo de Nucleotídeo Único/genética , Lesões dos Tecidos Moles/genética , Predisposição Genética para Doença/genética , Humanos , Estudos Observacionais como Assunto
16.
Artigo em Inglês | MEDLINE | ID: mdl-35232347

RESUMO

AIM: This study aimed at a comprehensive analysis of Ribosomal Protein S6 Kinase A4 (RPS6KA4) and seeked the prognostic value for hepatocellular carcinoma (HCC). BACKGROUND: Liver cancer is a common type of tumor worldwide, and HCC accounts for about 75 to 85% of all primary liver cancer cases. The Ribosomal S6 protein kinases (RSK) family plays an important regulatory role in cell growth, movement, survival, and proliferation. METHODS: We collected the expression and clinicopathological features of RPS6KA4 in The Cancer Genome Atlas (TCGA) cohort and evaluated the prognostic value of RPS6KA4 in HCC. Gene Ontology (GO)/ Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) were performed to determine the enrichment pathways of RPS6KA4. Correlation between RPS6KA4 expression and immune infiltration was analyzed. Protein-protein interaction (PPI) network analysis was performed to screen hub genes. RESULTS: RPS6KA4 overexpression is statistically significant in HCC relative to normal tissues (P < 0.001). Increased expression of RPS6KA4 is associated with higher T stage (p=0.021), pathological stage (p=0.006), α-fetoprotein (AFP) value (p=0.026), and vascular invasion (p=0.023) of HCC. Overexpression of RPS6KA4 predicted worse overall survival (OS, P=0.002), disease-specific survival (DSS, P=0.012), and progress free interval (PFI, P=0.031) for HCC. Univariate/multivariate Cox regression analysis confirmed that RPS6KA4 was an independent risk factor for HCC (P=0.002 in univariate analysis; P=0.014 in multivariate analysis). GO/KEGG analysis and GSEA analysis suggest that RPS6KA4 plays a precancer role in HCC through epigenetics, cell adhesion, tumor-driven GTPase pathways, infection-related carcinogenesis and adaptive immunity. Immune infiltration analysis confirmed the strongly negative relationship between RPS6KA4 and B cells, CD4+ T cells, macrophages, neutrophil, as well as dendritic cells. Protein-protein interactions (PPI) analysis and hub gene identification revealed the cancer-promoting effects of RPS6KA4 related to RSKs, AP-2, clathrin, and MAPK/ ERK pathways. CONCLUSION: RPS6KA4 is a potentially valuable molecule for understanding HCC tumorigenesis. Increased RPS6KA4 might be a promising prognostic factor for low HCC survival.

18.
Cell Death Discov ; 8(1): 117, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35292660

RESUMO

The efficacy of immune checkpoint blockade (ICB) therapy depends on sufficient infiltration and activation of primed tumor-specific cytotoxic T lymphocytes (CTLs) in the tumor microenvironment. However, many tumor types, including osteosarcoma, mainly display immune-desert or immune-excluded phenotypes, which are characterized by a lack of tumor-infiltrating lymphocytes and a poor response to ICB monotherapy. Thus, novel therapeutic strategies are urgently needed to surmount these obstacles. In this study, we found that the expression of the c-Myc oncogene is negatively correlated with the T cell infiltration rate in osteosarcoma. Pharmacological inhibition of c-Myc with JQ-1 significantly reduced tumor burden and improved overall survival in an immunocompetent syngeneic murine model of osteosarcoma (K7M2). A mechanistic study revealed that JQ-1 administration dramatically reprogrammed the tumor immune microenvironment (TIME) within K7M2 tumors. On the one hand, JQ-1 can promote T cell trafficking into tumors by increasing the expression and secretion of T cell-recruiting chemokines. On the other hand, JQ-1 is capable of facilitating crosstalk between antigen-presenting dendritic cells and T cells through the CD40/CD40L costimulatory pathway, leading to activation of tumor-specific CTLs. Combined treatment with anti-PD-1 antibody and JQ-1 resulted in more pronounced tumor regression than either monotherapy, showing an obvious synergistic effect. These findings uncover for the first time that c-Myc inhibition can promote T cell infiltration and activation in osteosarcoma in multiple ways, delivering a one-two punch for modulating TIME. The present work also provides the basis for establishing c-Myc inhibitor and ICB coadministration as a novel therapeutic regimen for patients with osteosarcoma.

19.
Nat Plants ; 8(2): 125-135, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35102275

RESUMO

The rapid Cretaceous diversification of flowering plants remains Darwin's 'abominable mystery' despite numerous fossil flowers discovered in recent years. Wildfires were frequent in the Cretaceous and many such early flower fossils are represented by charcoalified fragments, lacking complete delicate structures and surface textures, making their similarity to living forms difficult to discern. Furthermore, scarcity of information about the ecology of early angiosperms makes it difficult to test hypotheses about the drivers of their diversification, including the role of fire in shaping flowering plant evolution. We report the discovery of two exquisitely preserved fossil flower species, one identical to the inflorescences of the extant crown-eudicot genus Phylica and the other recovered as a sister group to Phylica, both preserved as inclusions together with burned plant remains in Cretaceous amber from northern Myanmar (~99 million years ago). These specialized flower species, named Phylica piloburmensis sp. nov. and Eophylica priscastellata gen. et sp. nov., exhibit traits identical to those of modern taxa in fire-prone ecosystems such as the fynbos of South Africa, and provide evidence of fire adaptation in angiosperms.


Assuntos
Âmbar , Rhamnaceae , Ecossistema , Fósseis , Mianmar
20.
Nat Med ; 28(2): 303-314, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35177860

RESUMO

Previous microbiome and metabolome analyses exploring non-communicable diseases have paid scant attention to major confounders of study outcomes, such as common, pre-morbid and co-morbid conditions, or polypharmacy. Here, in the context of ischemic heart disease (IHD), we used a study design that recapitulates disease initiation, escalation and response to treatment over time, mirroring a longitudinal study that would otherwise be difficult to perform given the protracted nature of IHD pathogenesis. We recruited 1,241 middle-aged Europeans, including healthy individuals, individuals with dysmetabolic morbidities (obesity and type 2 diabetes) but lacking overt IHD diagnosis and individuals with IHD at three distinct clinical stages-acute coronary syndrome, chronic IHD and IHD with heart failure-and characterized their phenome, gut metagenome and serum and urine metabolome. We found that about 75% of microbiome and metabolome features that distinguish individuals with IHD from healthy individuals after adjustment for effects of medication and lifestyle are present in individuals exhibiting dysmetabolism, suggesting that major alterations of the gut microbiome and metabolome might begin long before clinical onset of IHD. We further categorized microbiome and metabolome signatures related to prodromal dysmetabolism, specific to IHD in general or to each of its three subtypes or related to escalation or de-escalation of IHD. Discriminant analysis based on specific IHD microbiome and metabolome features could better differentiate individuals with IHD from healthy individuals or metabolically matched individuals as compared to the conventional risk markers, pointing to a pathophysiological relevance of these features.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Microbiota , Humanos , Estudos Longitudinais , Metaboloma , Pessoa de Meia-Idade
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