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1.
J Exp Clin Cancer Res ; 42(1): 5, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36600258

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is a multifactor-driven malignant tumor with rapid progression, which causes the difficulty to substantially improve the prognosis of HCC. Limited understanding of the mechanisms in HCC impedes the development of efficacious therapies. Despite Krüpple-Like factors (KLFs) were reported to be participated in HCC pathogenesis, the function of KLF14 in HCC remains largely unexplored. METHODS: We generated KLF14 overexpressed and silenced liver cancer cells, and nude mouse xenograft models for the in vitro and in vivo study. Luciferase reporter assay, ChIP-qPCR, Co-IP, immunofluorescence were performed for mechanism research. The expression of KLF14 in HCC samples was analyzed by quantitative RT-PCR, Western blotting, and immunohistochemistry (IHC) analysis. RESULTS: KLF14 was significantly downregulated in human HCC tissues, which was highly correlated with poor prognosis. Inhibition of KLF14 promoted liver cancer cells proliferation and overexpression of KLF14 suppressed cells growth. KLF14 exerts its anti-tumor function by inhibiting Iron-responsive element-binding protein 2 (IRP2), which then causes transferrin receptor-1(TfR1) downregulation and ferritin upregulation on the basis of IRP-IREs system. This then leading to cellular iron deficiency and HCC cells growth suppression in vitro and in vivo. Interestingly, KLF14 suppressed the transcription of IRP2 via recruiting SIRT1 to reduce the histone acetylation of the IRP2 promoter, resulting in iron depletion and cell growth suppression. More important, we found fluphenazine is an activator of KLF14, inhibiting HCC cells growth through inducing iron deficiency. CONCLUSION: KLF14 acts as a tumor suppressor which inhibits the proliferation of HCC cells by modulating cellular iron metabolism via the repression of IRP2. We identified Fluphenazine, as an activator of KLF14, could be a potential compound for HCC therapy. Our findings therefore provide an innovative insight into the pathogenesis of HCC and a promising therapeutic target.


Assuntos
Carcinoma Hepatocelular , Proteína 2 Reguladora do Ferro , Ferro , Fatores de Transcrição Kruppel-Like , Animais , Humanos , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Flufenazina , Regulação Neoplásica da Expressão Gênica , Homeostase , Ferro/metabolismo , Proteína 2 Reguladora do Ferro/genética , Proteína 2 Reguladora do Ferro/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo
2.
Neurol Sci ; 2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36701017

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a debilitating and highly heritable neurodegenerative disease. Early-onset AD (EOAD) was defined as AD occurring before age 65. Although it has a high genetic risk, EOAD due to PSEN2 variation is very rare. ABCA7 is an important risk gene for AD. Previously reported cases mainly carried variations in a single pathogenic or risk gene. METHODS AND RESULTS: In this study, we report a 35-year-old female carrying variants in both the PSEN2 gene (c.640G > T p.V214L) and ABCA7 gene (c.2848G > A p.V950M). Four previously reported cases carried PSEN2 V214L, and no reported cases carried ABCA7 V950M. She had a history of migraine, patent foramen ovale, spontaneous subarachnoid hemorrhage without aneurysm, and multiple cerebral microhemorrhages. Her MMSE score was 24/30, and her MoCA score was 22/30. The concentration of Aß42 and the ratio of Aß42 to Aß40 in cerebral spinal fluid were obviously decreased. Published variants of PSEN2 and ABCA7 in PubMed were reviewed, and the patients' characteristics were summarized and compared to provide information for the clinical diagnosis of AD. CONCLUSIONS: It is necessary to conduct genetic screening in cases with atypical manifestations.

3.
BMC Cancer ; 23(1): 18, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36604642

RESUMO

BACKGROUND: SET domain containing 6 (SETD6) has been shown to be upregulated in multiple human cancers and can promote malignant cell survival. However, expression and function of SETD6 in lung adenocarcinoma (LUAD) remains unaddressed. This study aimed to demonstrate the expression pattern, biological roles and potential mechanisms by which SETD6 dysregulation is associated with LUAD. METHODS: The expression level of SETD6 was evaluated in LUAD clinical specimens and its correlation with clinical parameters were analyzed. In vitro, gain-of-function and loss-of-function experiments were performed to evaluate the effects of SETD6 on cell proliferation, apoptosis, migration, and colony formation of LUAD cell line A549. Western-blot was performed to investigate the involvement of nuclear factor-κB (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways as downstream signaling of SETD6 in LUAD cells. RESULTS: Compared with non-tumorous tissues, SETD6 was overexpressed in tumor tissues, and its overexpression significantly correlates with higher rates of regional lymph node metastasis and poor prognosis in patients with LUAD. In A549 cell line, SETD6 overexpression could promote cell proliferation, migration, colony formation and inhibit cell apoptosis, whereas SETD6 knockdown caused the opposite effects. Furthermore, we demonstrated that the mechanisms underlying the effect of SETD6 on LUAD biological behaviors may be through its interaction with NF-κB and Nrf2 signaling pathways. CONCLUSIONS: SETD6, which is highly expressed in LUAD tumor tissues, plays an important role in promoting the malignant behaviors of LUAD via likely the NF-κB and Nrf2 signaling pathways.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Linhagem Celular Tumoral , Adenocarcinoma de Pulmão/patologia , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genética , Proteínas Metiltransferases/genética
4.
Theor Appl Genet ; 136(1): 1-11, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36656369

RESUMO

KEY MESSAGE: A major QTL (qS7.1) for salinity damage score and Na+ exclusion was identified on chromosome 7H from a barley population derived from a cross between a cultivated variety and a wild accession. qS7.1 was fine-mapped to a 2.46 Mb physical interval and HvNCX encoding a sodium/calcium exchanger is most likely the candidate gene. Soil salinity is one of the major abiotic stresses affecting crop yield. Developing salinity-tolerant varieties is critical for minimizing economic penalties caused by salinity and providing solutions for global food security. Many genes/QTL for salt tolerance have been reported in barley, but only a few of them have been cloned. In this study, a total of 163 doubled haploid lines from a cross between a cultivated barley variety Franklin and a wild barley accession TAM407227 were used to map QTL for salinity tolerance. Four significant QTL were identified for salinity damage scores. One (qS2.1) was located on 2H, determining 7.5% of the phenotypic variation. Two (qS5.1 and qS5.2) were located on 5H, determining 5.3-11.7% of the phenotypic variation. The most significant QTL was found on 7H, explaining 27.8% of the phenotypic variation. Two QTL for Na+ content in leaves under salinity stress were detected on chromosomes 1H (qNa1.1) and 7H(qNa7.1). qS7.1 was fine-mapped to a 2.46 Mb physical interval using F4 recombinant inbred lines. This region contains 23 high-confidence genes, with HvNCX which encodes a sodium/calcium exchanger being most likely the candidate gene. HvNCX was highly induced by salinity stress and showed a greater expression level in the sensitive parent. Multiple nucleotide substitutions and deletions/insertions in the promoter sequence of HvNCX were found between the two parents. cDNA sequencing of the HvNCX revealed that the difference between the two parents is conferred by a single Ala77/Pro77 amino acid substitution, which is located on the transmembrane domain. These findings open new prospects for improving salinity tolerance in barley by targeting a previously unexplored trait.


Assuntos
Hordeum , Locos de Características Quantitativas , Tolerância ao Sal/genética , Hordeum/genética , Cálcio/metabolismo , Sódio/metabolismo , Salinidade
5.
J Clin Invest ; 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36626230

RESUMO

SIPRα on macrophages binds with CD47 to resist pro-engulfment signals, but how the downstream signal of SIPRα controls tumor-infiltrating macrophages (TIMs) is still poorly clarified. Here we reported that the CD47/SIRPα axis requires the deneddylation of tyrosine phosphatase SHP2. Mechanistically, SHP2 is constitutively neddylated on K358 and K364 sites, thus its auto-inhibited conformation is maintained. In response to CD47-liganded SIRPα, SHP2 is deneddylated by SENP8, which leads to the dephosphorylation of relevant substrates at the phagocytic cup and subsequent inhibition of macrophage phagocytosis. Furthermore, neddylation inactivated myeloid-SHP2 and greatly boosted the efficacy of colorectal cancer (CRC) immunotherapy. Importantly, we observed that the supplementation with SHP2 allosteric inhibitors sensitized the immune treatment-resistant CRC to immunotherapy. Our results emphasized that the CRC subtype which is unresponsive to immunotherapy relies on SIRPαhiSHP2hiNEDD8lo TIMs, and highlighted the need to further combine the strategy of SHP2 targeting in colorectal cancer therapy.

6.
Appetite ; 182: 106448, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36608768

RESUMO

Food addiction is associated with both physical and mental health conditions, such as obesity and depression, and is considered a public health problem. Based on life history (LH) theory, this study aimed to test the association between unpredictable childhood environment and food addiction in adulthood and to examine LH strategies and attitudes toward self as psychological mediators of this association. A random sample of 1010 adults, aged from 18 to 88 years (44.8% male; Mage = 38.52, SDage = 14.53), voluntarily participated in an anonymous telephone survey conducted in Macao, China. The results of a path analysis showed the significant and positive direct effect of childhood unpredictability on food addiction and its negative association with slow LH strategy, which in turn was negatively correlated with food addiction. In addition, slow LH strategy and self-judgment, rather than self-kindness, acted as serial mediators in the association between childhood unpredictability and food addiction. These findings support the applicability of LH theory to understanding food addiction, as well as pointing to the potential risk effect of self-judgment for food addiction in adulthood. Self-judgment reduction may be a potential supplementary approach for future food addiction intervention.


Assuntos
Dependência de Alimentos , Traços de História de Vida , Adulto , Humanos , Masculino , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Dependência de Alimentos/psicologia , Obesidade , Atitude , China
7.
Emerg Microbes Infect ; 12(1): 2165969, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36628606

RESUMO

Previous studies have shown that the increased prevalent ST764 clone in China, Japan, and other Asian areas. However, the knowledge of the genetic features and virulence characteristics of methicillin-resistant Staphylococcus aureus (MRSA) ST764 in China is still limited. In this study, we identified 52 ST764-SCCmec type II isolates collected from five cities in China between 2014 and 2021. Whole genome sequencing showed that the most common staphylococcal protein A (spa) types of ST764 in China were t002 (55.78%) and t1084 (40.38%). Virulence assays showed that ST764-t1084 isolates had high haemolytic activity and α-toxin levels. Of the critical regulatory factors affecting α-toxin production, only the SaeRS was highly expressed in ST764-t1084 isolates. Mouse abscess model indicated that the virulence of ST764-t1084 isolates was comparable to that of S. aureus USA300-LAC famous for its hypervirulence. Interestingly, ST764-t002 isolates exhibited stronger biofilm formation and cell adhesion capacities than ST764-t1084 isolates. This seems to explain why ST764-t002 subclone has become more prevalent in China in recent years. Phylogenetic analysis suggested that all ST764 isolates from China in Clade III were closely related to KUN1163 (an isolate from Japan). Notably, genomic analysis revealed that the 52 ST764 isolates did not carry arginine catabolic mobile element (ACME), which differed from ST764 isolates in Japan. Additionally, most ST764 isolates (69.23%) harboured an obvious deletion of approximately 5 kb in the SCCmec II cassette region compared to KUN1163. Our findings shed light on the potential global transmission and genotypic as well as phenotypic characteristics of ST764 lineage.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Animais , Camundongos , Staphylococcus aureus Resistente à Meticilina/genética , Antibacterianos , Filogenia , Infecções Estafilocócicas/epidemiologia , Staphylococcus aureus , Virulência , Genótipo , Fatores de Virulência/genética
8.
J Biomol Struct Dyn ; : 1-13, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36655391

RESUMO

CDC25B belongs to the CDC25 family, and it plays an important part in regulating the activity of CDK/CyclinA. Studies have shown that CDC25B is closely related to cancer development. When CYS473 on CDC25B is mutated into ASP, the affinity between CDC25B and CDK2/CyclinA weakens, and their dissociation speed is greatly improved. However, the mechanism by which the CDC25BC473D mutant weakens its binding to CDK2/CyclinA is unclear. In order to study the effect of CDC25BC473D mutants on CDK2/CyclinA substrates, we constructed and verified the rationality of the CDC25BWT:CDK2/CyclinA system and CDC25BC473D:CDK2/CyclinA system and conducted molecular dynamics (MD) simulation analysis. In the post-analysis, the fluctuations of residues ARG488-SER499, LYS541-TRP550 on CDC25B and residues ASP206-ASP210 on CDK2 were massive in the mutant CDC25BC473D:CDK2/CyclinA system. And the interactions between residue ARG492 and residue GLU208, residue ARG544 and residue GLU42, residue ARG544 and TRP550 were weakened in the mutant CDC25BC473D:CDK2/CyclinA system. The results showed that when CYS473 on CDC25B was mutated into ASP473, the mutant CDC25BC473D:CDK2/CyclinA system was less stable than the wild-type CDC25BWT:CDK2/CyclinA system. Finally, active site CYS473 of CDC25B was speculated to be the key residue, which had great effects on the binding between CDC25BCYS473 and CDK2 in the CDC25BC473D:CDK2/CyclinA system. Consequently, overall analyses appeared in this study ultimately provided a useful understanding of the weak interactions between CDC25BCYS473D and CDK2/CyclinA.Communicated by Ramaswamy H. Sarma.

9.
Artigo em Inglês | MEDLINE | ID: mdl-36650038

RESUMO

BACKGROUND: The pathogenic missense mutations of the gelsolin (GSN) gene lead to familial amyloidosis of the Finnish type (FAF); however, our previous study identified GSN frameshift mutations existed in patients with Alzheimer's disease (AD). The GSN genotype-phenotype heterogeneity and the role of GSN frameshift mutations in patients with AD are unclear. METHOD: In total, 1192 patients with AD and 1403 controls were screened through whole genome sequencing, and 884 patients with AD were enrolled for validation. Effects of GSN mutations were evaluated in vitro. GSN, Aß42, Aß40 and Aß42/40 were detected in both plasma and cerebrospinal fluid (CSF). RESULTS: Six patients with AD with GSN P3fs and K346fs mutations (0.50%, 6/1192) were identified, who were diagnosed with AD but not FAF. In addition, 13 patients with AD with GSN frameshift mutations were found in the validation cohort (1.47%, 13/884). Further in vitro experiments showed that both K346fs and P3fs mutations led to the GSN loss of function in inhibiting Aß-induced toxicity. Moreover, a higher level of plasma (p=0.001) and CSF (p=0.005) GSN was observed in AD cases than controls, and a positive correlation was found between the CSF GSN and CSF Aß42 (r=0.289, p=0.009). Besides, the GSN level was initially increasing and then decreasing with the disease course and cognitive decline. CONCLUSIONS: GSN frameshift mutations may be associated with AD. An increase in plasma GSN is probably a compensatory reaction in AD, which is a potential biomarker for early AD.

10.
Cereb Cortex ; 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36627244

RESUMO

Duchenne muscular dystrophy (DMD) is frequently associated with mild cognitive deficits. However, the underlying disrupted brain connectome and the neural basis remain unclear. In our current study, 38 first-episode, treatment-naive patients with DMD and 22 matched healthy controls (HC) were enrolled and received resting-sate functional magnetic resonance imaging scans. Voxel-based degree centrality (DC), seed-based functional connectivity (FC), and clinical correlation were performed. Relative to HC, DMD patients had lower height, full Intellectual Quotients (IQ), and IQ-verbal comprehension. Significant increment of DC of DMD patients were found in the left dorsolateral prefrontal cortex (DLPFC.L) and right dorsomedial prefrontal cortex (DMPFC.R), while decreased DC were found in right cerebellum posterior lobe (CPL.R), right precentral/postcentral gyrus (Pre/Postcentral G.R). DMD patients had stronger FC in CPL.R-bilateral lingual gyrus, Pre/Postcentral G.R-Insular, and DMPFC.R-Precuneus.R, had attenuated FC in DLPFC.L-Insular. These abnormally functional couplings were closely associated with the extent of cognitive impairment, suggested an over-activation of default mode network and executive control network, and a suppression of primary sensorimotor cortex and cerebellum-visual circuit. The findings collectively suggest the distributed brain connectome disturbances maybe a neuroimaging biomarker in DMD patients with mild cognitive impairment.

11.
J Biol Chem ; : 102911, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36642187

RESUMO

The attachment of a sugar to a hydrophobic lipid carrier is the first step in the biosynthesis of many glycoconjugates. In the halophilic archaeon Haloarcula hispanica, HAH_1206, renamed AepG, is a predicted glycosyltransferase belonging to the CAZy Group 2 family that shares a conserved amino acid sequence with dolichol phosphate mannose synthases. In this study, the function of AepG was investigated by genetic and biochemical approaches. We found that aepG deletion led to the disappearance of dolichol phosphate-glucuronic acid. Our biochemical assays revealed that recombinant cellulose-binding domain-tagged AepG could catalyze the formation of dolichol phosphate-glucuronic acid in time- and dose-dependent manners. Based on in vivo and in vitro analyses, AepG was confirmed to be a dolichol phosphate glucuronosyltransferase involved in the synthesis of the acidic exopolysaccharide (EPS) produced by Har. hispanica. Furthermore, lack of aepG resulted in hindered growth and cell aggregation in high salt medium, indicating that AepG is vital for the adaptation of Har. hispanica to a high salt environment. In conclusion, AepG is the first dolichol phosphate glucuronosyltransferase identified in any of the three domains of life, and, moreover, offers a starting point for further investigation into the diverse pathways used for extracellular polysaccharide biosynthesis in archaea.

12.
Nanomicro Lett ; 15(1): 35, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36629933

RESUMO

We conceptualize bioresource upgrade for sustainable energy, environment, and biomedicine with a focus on circular economy, sustainability, and carbon neutrality using high availability and low utilization biomass (HALUB). We acme energy-efficient technologies for sustainable energy and material recovery and applications. The technologies of thermochemical conversion (TC), biochemical conversion (BC), electrochemical conversion (EC), and photochemical conversion (PTC) are summarized for HALUB. Microalgal biomass could contribute to a biofuel HHV of 35.72 MJ Kg-1 and total benefit of 749 $/ton biomass via TC. Specific surface area of biochar reached 3000 m2 g-1 via pyrolytic carbonization of waste bean dregs. Lignocellulosic biomass can be effectively converted into bio-stimulants and biofertilizers via BC with a high conversion efficiency of more than 90%. Besides, lignocellulosic biomass can contribute to a current density of 672 mA m-2 via EC. Bioresource can be 100% selectively synthesized via electrocatalysis through EC and PTC. Machine learning, techno-economic analysis, and life cycle analysis are essential to various upgrading approaches of HALUB. Sustainable biomaterials, sustainable living materials and technologies for biomedical and multifunctional applications like nano-catalysis, microfluidic and micro/nanomotors beyond are also highlighted. New techniques and systems for the complete conversion and utilization of HALUB for new energy and materials are further discussed.

13.
Bioact Mater ; 24: 322-330, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36632507

RESUMO

Photodynamic Therapy (PDT) holds a great promise for cancer patients, however, due to the hypoxic characteristics of most solid tumors and the limited penetration depth of light in tissues, the extensive clinical application of PDT is limited. Herein, we report microwave induced copper-cysteamine (Cu-Cy) nanoparticles-based PDT as a promising cancer treatment to overcome cancer resistance in combination with ferroptosis. The treatment efficiency of Cu-Cy-mediated microwave dynamic therapy (MWDT) tested on HCT15 colorectal cancer (CRC) cells via cell titer-blue cell viability assay and live/dead assay reveal that Cu-Cy upon MW irradiation can effectively destroy HCT15 CRC cells with average IC-50 values of 20 µg/mL. The cytotoxicity of Cu-Cy to tumor cells after MW stimulation can be alleviated by ferroptosis inhibitor. Furthermore, Cu-Cy mediated MWDT could deplete glutathione peroxide 4 (GPX4) and enhance lipid peroxides (LPO) and malondialdehyde (MDA). Our findings demonstrate that MW-activated Cu-Cy killed CRC cells by inducing ferroptosis. The superior in vivo antitumor efficacy of the Cu-Cy was corroborated by a HCT15 tumor-bearing mice model. Immunohistochemical experiments showed that the GPX4 expression level in Cu-Cy + MW group was significantly lower than that in other groups. Overall, these findings demonstrate that Cu-Cy nanoparticles have a safe and promising clinical application prospect in MWDT for deep-seated tumors and effectively inhibit tumor cell proliferation by inducing ferroptosis, which provides a potential solution for cancer resistance.

14.
JAMA Netw Open ; 6(1): e2249930, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36607636

RESUMO

Importance: A higher percentage of non-Hispanic Black (hereinafter, Black) adults vs non-Hispanic White (hereinafter, White) adults with hypertension have uncontrolled blood pressure (BP) contributing to racial and ethnic disparities in cardiovascular disease. In 2010, Kaiser Permanente Southern California began implementing quality improvement (QI) strategies aimed at reducing this disparity. Objective: To examine the change in BP control between Black and White patients before and after the implementation of a QI program. Design, Setting, and Participants: A QI quasi-experimental, difference-in-difference analysis was conducted of Kaiser Permanente Southern California patients 18 years or older included in the population care management hypertension registry. The study was conducted from December 31, 2008, to December 31, 2019. Data analysis was performed from November 20, 2020, to November 7, 2022. Interventions: Quality improvement program implementation began in 2010. Main Outcomes and Measures: Blood pressure control (systolic BP <140 mm Hg and diastolic BP <90 mm Hg) was assessed using the last outpatient BP measurement in each calendar year. Changes in BP control between Black and White patients from before (2008-2009) to after (2016-2019) implementation of the QI program were examined using a difference-in-difference analysis. Blood pressure control disparities from 2008 through 2019 by age, sex, race and ethnicity, and factors associated with BP control were examined. Results: The number of patients with hypertension increased from 624 094 in 2008 (mean [SD] age, 61.8 [13.5] years; 330 551 [53.0%] female patients; 89 407 [14.3%] Black and 284 116 [45.5%] White patients) to 855 257 in 2019 (mean [SD] age, 64.5 [13.6] years; 444 422 [52.0%] female patients; 107 054 [12.5%] Black and 331 932 [38.8%] White patients). Blood pressure control increased an absolute 4.6% (95% CI, 4.3%-4.8%) among Black patients and 2.1% (95% CI, 2.0%-2.2%) among White patients from before to after the QI program implementation (difference-in-difference: 2.5%; 95% CI, 2.2%-2.8%). The largest reduction in BP control disparity between Black and White female patients was for those aged 50 to 64 years (difference-in-difference: 3.8%; 95% CI, 3.2%-4.4%) and for those aged 18 to 49 years between Black and White male patients (difference-in-difference: 4.2%; 95% CI, 3.0%-5.5%). The proportion of BP control among Black male patients aged 18 to 49 years was the lowest throughout 2008-2019 compared with male and female patients in other age and racial and ethnic groups. In 2019, uncontrolled BP was more common among Black vs White patients (prevalence ratio: 1.13; 95% CI, 1.12-1.14). Conclusions and Relevance: This QI program noted that disparities in BP control between Black and White patients were decreased but not eliminated following implementation of QI strategies aimed at reducing disparities in BP control. These findings suggest that more focused interventions may be needed to increase BP control among Black individuals.


Assuntos
Prestação Integrada de Cuidados de Saúde , Hipertensão , Adulto , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Pressão Sanguínea , Melhoria de Qualidade , Hipertensão/epidemiologia
15.
Anal Chem ; 95(2): 994-1001, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36601781

RESUMO

The dissociation of the walking strand from the track gives rise to decreased efficiency and long reaction time of DNA walkers. In this work, we constructed a DNA walker combining the introduction of a wedge segment with a bimetallic metal-organic framework (MOF) electrocatalyst to solve this problem. The target methylated DNA acted as a single-legged walker, and the immobilization probe assembled on the track contained a wedge segment that was complementary to the target methylated DNA persistently, inhibiting its dissociation from the track. The fuel strand modified with a bimetallic MOF would drive the target strand to conduct branch migration and move processively along the track. The stepwise movement of the target strand resulted in the loading of numerous bimetallic MOF catalysts to reduce H2O2 at the electrode interface, thereby a significantly increased current response would be obtained for the detection of methylated DNA. This DNA walker achieved a detection limit of 200 aM within 20 min and effectively distinguished DNA with different methylation statuses, which would pave a way for rapid and sensitive monitoring of DNA methylation.


Assuntos
Técnicas Biossensoriais , Estruturas Metalorgânicas , Metilação de DNA , Peróxido de Hidrogênio , Técnicas Biossensoriais/métodos , Limite de Detecção , DNA
16.
Am J Prev Med ; 64(2): 167-174, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36653099

RESUMO

INTRODUCTION: The Centers for Disease Control and Prevention Guideline for Prescribing Opioids for Chronic Pain released in 2016 had led to decreases in opioid prescribing. This study sought to examine chronic and sustained high-dose prescription opioid use in an integrated health system. METHODS: A serial cross-sectional study was conducted in 2021 to estimate the annual age-adjusted prevalence and incidence of chronic and high-dose opioid use among demographically diverse noncancer adults in an integrated health system in Southern California during 2013-2020. Interrupted time-series analysis with segmented regression was conducted to estimate changes in the trends in annual rates before (2013-2015) and after (2017-2020) the 2016 guideline, treating 2016 as a wash-out period. RESULTS: Prevalence and incidence of chronic use and sustained high-dose use had started to decrease after a health system intervention program before the 2016 Centers for Disease Control and Prevention guideline release and continued to decline after the guideline. Among those with sustained high-dose use, there was a substantial decrease in persons with an average daily dosage ≥90 morphine milligram equivalent and concurrent benzodiazepine use. An accelerated decrease in prevalent chronic use after the guideline was observed (slope change: -11.1 [95% CI= -20.3, -1.9] users/10,000 person-years, p=0.03). The incidence of chronic use and sustained high-dose use continued to decrease after the guideline release but at a slower pace. CONCLUSIONS: Implementing evidence-based prescribing guidelines was associated with a decrease in chronic and sustained high-dose prescription opioid use.


Assuntos
Dor Crônica , Prestação Integrada de Cuidados de Saúde , Transtornos Relacionados ao Uso de Opioides , Adulto , Humanos , Analgésicos Opioides/uso terapêutico , Estudos Transversais , Padrões de Prática Médica , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Dor Crônica/tratamento farmacológico , Prescrições de Medicamentos
17.
Gene ; 856: 147110, 2023 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-36543308

RESUMO

Optimizing prognostic stratification of patients with cytogenetic normal acute myeloid leukemia (CN-AML), a highly heterogeneous subgroup in AML, appears to be important to improve its treatment and clinical outcome. Here, we report a potential role of ELL, a gene associated with leukemogenesis in AML, in prognostic stratification of CN-AML patients. By analyzing public available databases, we found that ELL was highly expressed in AML patients compared with healthy donors. Kaplan-Meier analysis revealed that ELL expression markedly correlated with short overall survival (OS) of CN-AML patients. In COX multivariable regression analysis, higher ELL expression was an independent prognostic factor for OS in CN-AML. Knockdown of ELL by shRNAs sensitized KG-1α cells to anti-leukemic agents such as idarubicin (IDA) and chidamide (CS055), supporting its role in therapeutic response and outcome in AML. To understand its function in CN-AML, we further analyzed the ELL-driving gene signature. ELL-related genes were particularly enriched in cell adhesion molecules, cell differentiation, pathways in cancer, sequence-specific DNA binding, and extracellular matrix (ECM)-receptor interaction. Analysis of the PPI network identified 25 hub genes, including the stem cell gene BMP4. While BMP4 expression was significantly associated with ELL in CN-AML, knockdown of ELL markedly down-regulated BMP4 expression, suggesting that ELL might function via regulating BMP4 in AML. Together, these observations suggest a novel mechanism underlying pro-leukemogenic role of ELL via BMP4 up-regulation in AML and its potential value to serve as a predictive biomarker for therapeutic response and outcome of CN-AML patients.

18.
J Nat Prod ; 86(1): 119-130, 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36579935

RESUMO

Nine new sesquiterpenes, hyperhubeins A-I (1-9), and 14 known analogues (10-23) were isolated from the aerial portions of Hypericum hubeiense. Their structures and absolute configurations were determined unambiguously via spectroscopic analysis, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Compounds 1-3 possess an unprecedented sesquiterpene carbon skeleton. Further, a plausible biosynthetic pathway from farnesyl diphosphate (FPP) is proposed. The isolated phytochemicals were evaluated for neuroprotective and anti-neuroinflammatory properties in vitro. Compounds 1, 2, 5-8, 14, and 21 displayed notable neuroprotective activity against hydrogen peroxide (H2O2)-induced lesions in PC-12 cells at 10 µM. Additionally, compounds 1, 2, 12, and 13 exhibited inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) production in BV-2 microglial cells, with their IC50 values ranging from 4.92 to 6.81 µM. Possible interactions between these bioactive compounds and inducible nitric oxide synthase (iNOS) were predicted via molecular docking. Moreover, Western blotting indicated that compound 12 exerted anti-neuroinflammatory activity by suppressing LPS-stimulated expression of toll-like receptor-4 (TLR-4) and inhibiting consequent activation of nuclear factor-kappa-B (NF-κB) signaling.

19.
Neuroscience ; 510: 72-81, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36572173

RESUMO

Social anxiety is characterized by an intense fear of evaluation from others and/or withdrawal from social situations. Extreme social anxiety can lead to social anxiety disorder. There remains an urgent need to investigate the neural substrates of subclinical social anxiety for early diagnosis and intervention to reduce the risk to develop social anxiety disorder. Twenty-nine young adults were recruited (10 males/19 females; mean age (SD) = 20.34 (2.29)). Trait-like social anxiety was assessed by Liebowitz Social Anxiety Scale. Functional magnetic resonance imaging was used with an emotional face-matching paradigm to probe brain activation in response to emotional stimuli including angry, fearful, and happy faces, with shape-matching as a control condition. Behavioral results showed positive correlations between Liebowitz Social Anxiety Scale scores and the reaction time in both angry and fearful conditions. The activation of superficial amygdala and the deactivation of basal forebrain in response to angry condition showed positive correlations with the level of social anxiety. In addition, the resting-state functional connectivity between these two regions was negatively correlated with the level of social anxiety. These results may help to understand the individual difference and corresponding neural underpinnings of social anxiety in the subclinical population, and might provide some insight to develop strategies for early diagnosis and interventions of social anxiety to reduce the risk of deterioration from subclinical to clinical level of social anxiety.

20.
ACS Appl Mater Interfaces ; 15(1): 963-972, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36537553

RESUMO

The ε-LiVOPO4 cathode for Li-ion batteries has attracted wide attention with its multivalent electronic states and improved discharge capacity of over 300 mAh/g. Oxygen loss stands as a potential cause for structural degradations of the ε-LiVOPO4 cathode and its derivatives but has been barely studied. Through in situ environmental transmission electron microscopy, we probe lattice oxygen loss and the associated structural degradations by spatially and temporally resolving the atomic-scale structural dynamics and phase transformation pathways in ε-LiVOPO4. We demonstrate that the mild oxygen loss at 400 °C induces a topotactic phase transformation of ε-LiVOPO4 → α-Li3V2(PO4)3 in the particle surface via a nucleation and growth mechanism, leading to the formation of a core-shell configuration. The phase transformation can be reversed by switching to an oxidizing environment, in which the α-Li3V2(PO4)3 is reoxidized to ε-LiVOPO4. By contrast, oxygen loss at higher temperatures of 500 and 600 °C results in a high concentration of oxygen vacancies that subsequently induces irreversible structural damages including lattice amorphization and formation of nanocavities. This work illustrates the fundamental mechanisms governing the structural failure of oxide cathodes and underlines possible strategies to overcome such issues by exploiting environmental constraints.

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