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Neurons receive input from the outside world or from other neurons through neuronal receptive endings (NREs). Glia envelop NREs to create specialized microenvironments; however, glial functions at these sites are poorly understood. Here, we report a molecular mechanism by which glia control NRE shape and associated animal behavior. The C. elegans AMsh glial cell ensheathes the NREs of 12 neurons, including the thermosensory neuron AFD. KCC-3, a K/Cl transporter, localizes specifically to a glial microdomain surrounding AFD receptive ending microvilli, where it regulates K(+) and Cl(-) levels. We find that Cl(-) ions function as direct inhibitors of an NRE-localized receptor-guanylyl-cyclase, GCY-8, which synthesizes cyclic guanosine monophosphate (cGMP). High cGMP mediates the effects of glial KCC-3 on AFD shape by antagonizing the actin regulator WSP-1/NWASP. Components of this pathway are broadly expressed throughout the nervous system, suggesting that ionic regulation of the NRE microenvironment may be a conserved mechanism by which glia control neuron shape and function.
Assuntos
Caenorhabditis elegans/metabolismo , Neuroglia/metabolismo , Células Receptoras Sensoriais/metabolismo , Simportadores/metabolismo , Animais , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/metabolismo , GMP Cíclico/metabolismo , Guanilato Ciclase/química , Guanilato Ciclase/metabolismo , Potássio/metabolismo , Domínios Proteicos , Simportadores/química , Simportadores/genética , Sensação Térmica , Cotransportadores de K e Cl-RESUMO
Cardiac disease remains the leading cause of morbidity and mortality worldwide. The ß1-adrenergic receptor (ß1-AR) is a major regulator of cardiac functions and is downregulated in the majority of heart failure cases. A key physiological process is the activation of heterotrimeric G-protein Gs by ß1-ARs, leading to increased heart rate and contractility. Here, we use cryo-electron microscopy and functional studies to investigate the molecular mechanism by which ß1-AR activates Gs. We find that the tilting of α5-helix breaks a hydrogen bond between the sidechain of His373 in the C-terminal α5-helix and the backbone carbonyl of Arg38 in the N-terminal αN-helix of Gαs. Together with the disruption of another interacting network involving Gln59 in the α1-helix, Ala352 in the ß6-α5 loop, and Thr355 in the α5-helix, these conformational changes might lead to the deformation of the GDP-binding pocket. Our data provide molecular insights into the activation of G-proteins by G-protein-coupled receptors.
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Subunidades alfa Gs de Proteínas de Ligação ao GTP/química , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Isoproterenol/metabolismo , Receptores Adrenérgicos beta 1/química , Receptores Adrenérgicos beta 1/metabolismo , Animais , Sítios de Ligação , Bovinos , Linhagem Celular , Guanosina Difosfato/metabolismo , Guanosina Trifosfato/metabolismo , Modelos Moleculares , Ligação Proteica , Domínios Proteicos , Estrutura Secundária de ProteínaRESUMO
Aging is a major risk factor for multiple chronic disorders in the elderly population, including Alzheimer's disease (AD) and Osteoporosis. AD is a progressive neurodegenerative disease characterized by memory loss. In addition to dementia, several studies have shown that AD patients experience an increased rate of musculoskeletal co-morbidities, such as osteoporosis. Since tissue-specific macrophages contribute to both diseases, this study analyzed the microglia transcriptome of AD mice to determine a common gene signature involved in osteoclast biology. After comparing differentially regulated genes from GEO data sets (GSE93824 and GSE212277), there were 35 common upregulated genes and 89 common downregulated genes. Of these common genes, seven genes are known to play an important role in bone homeostasis. CSF1, SPP1, FAM20C, and Cst7 were upregulated and are associated with osteoclastogenesis and inflammation. Among the downregulated genes, LILRA6, MMP9, and COL18A1 are involved in bone formation and osteoclast regulation. We further validated some of these genes (CSF1, Cst7, and SPP1) in the cortex and the bone of AD mice models. The dysregulation of these microglial genes in AD might provide insights into the co-occurrence of AD and osteoporosis and offer potential therapeutic targets to combat disease progression.
Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Osteoporose , Idoso , Humanos , Camundongos , Animais , Doença de Alzheimer/genética , Transcriptoma , Microglia , Osteoporose/genética , Proteínas de Ligação ao Cálcio/genética , Proteínas da Matriz ExtracelularRESUMO
Chronic stress exposure induces maladaptive behavioral responses and increases susceptibility to neuropsychiatric conditions. However, specific neuronal populations and circuits that are highly sensitive to stress and trigger maladaptive behavioral responses remain to be identified. Here we investigate the patterns of spontaneous activity of proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) of the hypothalamus following exposure to chronic unpredictable stress (CUS) for 10 days, a stress paradigm used to induce behavioral deficits such as anhedonia and behavioral despair [1, 2]. CUS exposure increased spontaneous firing of POMC neurons in both male and female mice, attributable to reduced GABA-mediated synaptic inhibition and increased intrinsic neuronal excitability. While acute activation of POMC neurons failed to induce behavioral changes in non-stressed mice of both sexes, subacute (3 days) and chronic (10 days) repeated activation of POMC neurons was sufficient to induce anhedonia and behavioral despair in males but not females under non-stress conditions. Acute activation of POMC neurons promoted susceptibility to subthreshold unpredictable stress in both male and female mice. Conversely, acute inhibition of POMC neurons was sufficient to reverse CUS-induced anhedonia and behavioral despair in both sexes. Collectively, these results indicate that chronic stress induces both synaptic and intrinsic plasticity of POMC neurons, leading to neuronal hyperactivity. Our findings suggest that POMC neuron dysfunction drives chronic stress-related behavioral deficits.
Assuntos
Anedonia , Núcleo Arqueado do Hipotálamo , Depressão , Neurônios , Pró-Opiomelanocortina , Estresse Psicológico , Animais , Feminino , Masculino , Camundongos , Doença Aguda , Anedonia/fisiologia , Núcleo Arqueado do Hipotálamo/metabolismo , Núcleo Arqueado do Hipotálamo/fisiopatologia , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Doença Crônica , Excitabilidade Cortical/fisiologia , Depressão/metabolismo , Depressão/fisiopatologia , Modelos Animais de Doenças , Transtornos Mentais/metabolismo , Transtornos Mentais/fisiopatologia , Camundongos Endogâmicos C57BL , Fenômenos Fisiológicos do Sistema Nervoso , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Pró-Opiomelanocortina/biossíntese , Pró-Opiomelanocortina/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Sinapses/metabolismo , Sinapses/fisiologiaRESUMO
Posttraumatic stress disorder (PTSD) after the pandemic has emerged as a major neuropsychiatric component of post-acute COVID-19 syndrome, yet the current pharmacotherapy for PTSD is limited. The use of adrenergic drugs to treat PTSD has been suggested; however, it is hindered by conflicting clinical results and a lack of mechanistic understanding of drug actions. Our studies, using both genetically modified mice and human induced pluripotent stem cell-derived neurons, reveal a novel α2A adrenergic receptor (α2AAR)-spinophilin-cofilin axis in the hippocampus that is critical for regulation of contextual fear memory reconsolidation. In addition, we have found that two α2 ligands, clonidine and guanfacine, exhibit differential abilities in activating this signaling axis to disrupt fear memory reconsolidation. Stimulation of α2AAR with clonidine, but not guanfacine, promotes the interaction of the actin binding protein cofilin with the receptor and with the dendritic spine scaffolding protein spinophilin to induce cofilin activation at the synapse. Spinophilin-dependent regulation of cofilin is required for clonidine-induced disruption of contextual fear memory reconsolidation. Our results inform the interpretation of differential clinical observations of these two drugs on PTSD and suggest that clonidine could provide immediate treatment for PTSD symptoms related to the current pandemic. Furthermore, our study indicates that modulation of dendritic spine morphology may represent an effective strategy for the development of new pharmacotherapies for PTSD.
Assuntos
COVID-19 , Células-Tronco Pluripotentes Induzidas , Animais , Humanos , Camundongos , Fatores de Despolimerização de Actina/farmacologia , Adrenérgicos/farmacologia , Clonidina/farmacologia , Medo/fisiologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Proteínas dos Microfilamentos/metabolismo , Receptores Adrenérgicos alfa 2/metabolismoRESUMO
[This corrects the article DOI: 10.1371/journal.pbio.3000901.].
RESUMO
Antibody-drug conjugates (ADCs) represent a crucial component of targeted therapies in gastric cancer, potentially altering traditional treatment paradigms. Many ADCs have entered rigorous clinical trials based on biological theories and preclinical experiments. Modality trials have also been conducted in combination with monoclonal antibody therapies, chemotherapies, immunotherapies, and other treatments to enhance the efficacy of drug coordination effects. However, ADCs exhibit limitations in treating gastric cancer, including resistance triggered by their structure or other factors. Ongoing intensive researches and preclinical experiments are yielding improvements, while enhancements in drug development processes and concomitant diagnostics during the therapeutic period actively boost ADC efficacy. The optimal treatment strategy for gastric cancer patients is continually evolving. This review summarizes the clinical progress of ADCs in treating gastric cancer, analyzes the mechanisms of ADC combination therapies, discusses resistance patterns, and offers a promising outlook for future applications in ADC drug development and companion diagnostics.
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Imunoconjugados , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Imunoconjugados/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Terapia de Alvo Molecular/métodos , Antineoplásicos Imunológicos/uso terapêuticoRESUMO
Acute kidney injury (AKI) is a common disease, but lacking effective drug treatments. Chromodomain Y-like (CDYL) is a kind of chromodomain protein that has been implicated in transcription regulation of autosomal dominant polycystic kidney disease. Benzo[d]oxazol-2(3H)-one derivative (compound D03) is the first potent and selective small-molecule inhibitor of CDYL (KD = 0.5 µM). In this study, we investigated the expression of CDYL in three different models of cisplatin (Cis)-, lipopolysaccharide (LPS)- and ischemia/reperfusion injury (IRI)-induced AKI mice. By conducting RNA sequencing and difference analysis of kidney samples, we found that tubular CDYL was abnormally and highly expressed in injured kidneys of AKI patients and mice. Overexpression of CDYL in cisplatin-induced AKI mice aggravated tubular injury and pyroptosis via regulating fatty acid binding protein 4 (FABP4)-mediated reactive oxygen species production. Treatment of cisplatin-induced AKI mice with compound D03 (2.5 mg·kg-1·d-1, i.p.) effectively attenuated the kidney dysfunction, pathological damages and tubular pyroptosis without side effects on liver or kidney function and other tissue injuries. Collectively, this study has, for the first time, explored a novel aspect of CDYL for tubular epithelial cell pyroptosis in kidney injury, and confirmed that inhibition of CDYL might be a promising therapeutic strategy against AKI.
RESUMO
The etiology of Alzheimer's dementia has been hypothesized in terms of basal forebrain cholinergic decline, and in terms of reflecting beta-amyloid neuropathology. To study these different biological elements, we activated the basal forebrain in 5xFAD Alzheimer's model mice and littermates. Mice received 5 months of 1 h per day intermittent stimulation of the basal forebrain, which includes cholinergic projections to the cortical mantle. Then, mice were behaviorally tested followed by tissue analysis. The 5xFAD mice performed worse in water-maze testing than littermates. Stimulated groups learned the water maze better than unstimulated groups. Stimulated groups had 2-3-fold increases in frontal cortex immunoblot measures of the neurotrophin receptors for nerve growth factor and brain-derived neurotrophic factor, and a more than 50% decrease in the expression of amyloid cleavage enzyme BACE1. Stimulation also led to lower Aß42 in 5xFAD mice. These data support a causal relationship between basal forebrain activation and both neurotrophin activation and reduced Aß42 generation and accumulation. The observation that basal forebrain activation suppresses Aß42 accumulation, combined with the known high-affinity antagonism of nicotinic receptors by Aß42, documents bidirectional antagonism between acetylcholine and Aß42.
Assuntos
Doença de Alzheimer , Prosencéfalo Basal , Camundongos , Animais , Doença de Alzheimer/patologia , Receptores de Fator de Crescimento Neural , Camundongos Transgênicos , Memória Espacial , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Peptídeos beta-Amiloides/metabolismo , ColinérgicosRESUMO
CONTEXT: Pyrus calleryana Decne (Rosaceae), renowned for its therapeutic properties, is known to moisturize the lungs (removing dryness; relieving cough), clear heat (acting as an antipyretic; febrifuge) and aid in detoxification (relieving pyogenic inflammation; eliminating toxins). However, scientific evidence supporting its efficacy in wound healing is lacking. OBJECTIVE: This study investigated P. calleryana samples collected over a year to explore metabolite variations and their impact on skin wound-healing activities. MATERIALS AND METHODS: P. calleryana (PC) twigs and leaves were collected from the Matsu Islands, Taiwan, spanning 2018-2020. Extracts were prepared using 95% ethanol or water, and we assessed the chemical composition, total phenolic/triterpenoid contents and antioxidant properties. Metabolites were analysed via LC-MS/MS and molecular networking. Wound healing potential was evaluated on WS-1 cells through MTT and migration assays, and gene expression analyses, with tests including control (DMSO), compounds 1 (3'-hydroxylbenzyl-4-hydroxybenzoate-4'-O-ß-glucopyranoside) and 2 (vanilloylcalleryanin) (100 µM), and a positive control (ascorbic acid, 100 µM) for 24 h. RESULTS: Significant variations in extract compositions were observed based on the solvent used, with distinct metabolomic profiles in extracts collected during different months. Notably, compounds 1 and 2 showed no cytotoxic effects on human dermal fibroblast cells and significantly accelerated wound closure at 100 µM. A gene expression analysis indicated upregulation of wound healing-associated genes, including MMP-1 (matrix metalloproteinase-1) and COL1A1 (collagen, type 1, alpha 1). CONCLUSIONS: This study reports the first evidence of PC compounds aiding wound healing. Utilizing Global Natural Products Social Molecular Networking (GNPS) and principal component analysis (PCA) approaches, we unveiled metabolomic profiles, suggesting the potential to expedite wound-healing.
Assuntos
Extratos Vegetais , Pyrus , Cicatrização , Cicatrização/efeitos dos fármacos , Humanos , Extratos Vegetais/farmacologia , Pyrus/química , Estações do Ano , Taiwan , Antioxidantes/farmacologia , Folhas de Planta , Espectrometria de Massas em Tandem , Linhagem Celular , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Movimento Celular/efeitos dos fármacos , Pele/metabolismo , Pele/efeitos dos fármacosRESUMO
Based on the systematic deconstruction of multi-dimensional and multi-target biological networks, modular pharmacology explains the complex mechanism of diseases and the interactions of multi-target drugs. It has made progress in the fields of pathogenesis of disease, biological basis of disease and traditional Chinese medicine(TCM) syndrome, pharmacological mechanism of multi-target herbs, compatibility of formulas, and discovery of new drug of TCM compound. However, the complexity of multi-omics data and biological networks brings challenges to the modular deconstruction and analysis of the drug networks. Here, we constructed the "Computing Platform for Modular Pharmacology" online analysis system, which can implement the function of network construction, module identification, module discriminant analysis, hub-module analysis, intra-module and inter-module relationship analysis, and topological visualization of network based on quantitative expression profiles and protein-protein interaction(PPI) data. This tool provides a powerful tool for the research on complex diseases and multi-target drug mechanisms by means of modular pharmacology. The platform may have broad range of application in disease modular identification and correlation mechanism, interpretation of scientific principles of TCM, analysis of complex mechanisms of TCM and formulas, and discovery of multi-target drugs.
Assuntos
Medicamentos de Ervas Chinesas , Medicina Tradicional Chinesa , Humanos , Biologia Computacional/métodos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Farmacologia/métodos , Mapas de Interação de Proteínas/efeitos dos fármacosRESUMO
C-reactive protein (CRP) is a major acute phase protein and inflammatory marker, the expression of which is largely liver specific and highly inducible. Enhancers are regulatory elements critical for the precise activation of gene expression, yet the contributions of enhancers to the expression pattern of CRP have not been well defined. Here, we identify a constitutively active enhancer (E1) located 37.7 kb upstream of the promoter of human CRP in hepatocytes. By using chromatin immunoprecipitation, luciferase reporter assay, in situ genetic manipulation, CRISPRi, and CRISPRa, we show that E1 is enriched in binding sites for transcription factors STAT3 and C/EBP-ß and is essential for the full induction of human CRP during the acute phase. Moreover, we demonstrate that E1 orchestrates with the promoter of CRP to determine its varied expression across tissues and species through surveying activities of E1-promoter hybrids and the associated epigenetic modifications. These results thus suggest an intriguing mode of molecular evolution wherein expression-changing mutations in distal regulatory elements initiate subsequent functional selection involving coupling among distal/proximal regulatory mutations and activity-changing coding mutations.
Assuntos
Proteína C-Reativa , Elementos Facilitadores Genéticos , Sítios de Ligação , Proteína C-Reativa/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Regulação da Expressão Gênica , Hepatócitos , Humanos , Regiões Promotoras Genéticas , Fator de Transcrição STAT3/metabolismo , Transcrição GênicaRESUMO
Pustular psoriasis (PP) is an uncommon subtype of psoriasis with distinct genetic features and clinical phenotypes. Patients with PP tend to experience frequent flares and significant morbidity. This study aims to determine the clinical characteristics, co-morbidities and treatment of PP patients in Malaysia. This was a cross-sectional study of patients with PP notified to the Malaysian Psoriasis Registry (MPR) between January 2007 and December 2018. Of 21 735 psoriasis patients, 148 (0.7%) had pustular psoriasis. Of these, 93 (62.8%) were diagnosed with generalized pustular psoriasis (GPP) and 55 (37.2%) with localized PP (LPP). The mean age for pustular psoriasis onset was 31.71 ± 18.33 years with a male to female ratio of 1:2.1. Patients with PP were more likely to have dyslipidaemia (23.6% vs. 16.5%, p = 0.022), severe disease (Body surface area >10 and/or Dermatology Life Quality Index [DLQI] >10) (64.8% vs. 50%, p = 0.003) and require systemic therapy (51.4% vs. 13.9%, p < 0.001) compared to non-PP patients. Patients with PP also suffered greater impairment to their quality of life (DLQI >10, 48.9% vs. 40.3%, p = 0.046), had more days off school/work (2.06 ± 6.09 vs. 0.5 ± 4.91, p = 0.004) and a higher mean number of hospitalizations (0.31 ± 0.95 vs. 0.05 ± 1.22, p = 0.001) in 6 months compared to non-PP patients. Overall, 0.7% of psoriasis patients in the MPR had pustular psoriasis. Patients with PP had a higher rate of dyslipidaemia, severe disease, greater impairment of quality of life and systemic therapy usage compared to other psoriasis subtypes.
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Psoríase , Qualidade de Vida , Feminino , Humanos , Masculino , Estudos Transversais , Malásia/epidemiologia , Psoríase/tratamento farmacológico , Índice de Gravidade de Doença , Adulto , Pessoa de Meia-IdadeRESUMO
While chronic stress increases hyperpolarization-activated current (Ih) in dorsal hippocampal CA1 neurons, the underlying molecular mechanisms are entirely unknown. Following chronic social defeat stress (CSDS), susceptible mice displayed social avoidance and impaired spatial working memory, which were linked to decreased neuronal excitability, increased perisomatic hyperpolarization-activated cyclic nucleotide-gated (HCN) 1 protein expression, and elevated Ih in dorsal but not ventral CA1 neurons. In control mice, bath application of corticosterone reduced neuronal excitability, increased tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) and HCN1 protein expression, and elevated Ih in dorsal but not ventral CA1 region/neurons. Corticosterone-induced upregulation of functional Ih was mediated by the glucocorticoid receptor (GR), HCN channels, and the protein kinase A (PKA) but not the calcium/calmodulin-dependent protein kinase II (CaMKII) pathway. Three months after the end of CSDS, susceptible mice displayed persistent social avoidance when exposed to a novel aggressor. The sustained behavioral deficit was associated with lower neuronal excitability and higher functional Ih in dorsal CA1 neurons, both of which were unaffected by corticosterone treatment. Our findings show that corticosterone treatment mimics the pathophysiological effects of dorsal CA1 neurons/region found in susceptible mice. The aberrant expression of HCN1 protein along the somatodendritic axis of the dorsal hippocampal CA1 region might be the molecular mechanism driving susceptibility to social avoidance.
Assuntos
Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização , Receptores de Glucocorticoides , Camundongos , Animais , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Receptores de Glucocorticoides/metabolismo , Glucocorticoides/metabolismo , Corticosterona/farmacologia , Corticosterona/metabolismo , Neurônios/metabolismo , Região CA1 Hipocampal/metabolismo , Hipocampo/metabolismo , Transtornos da Memória/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Canais de Cátion Regulados por Nucleotídeos Cíclicos/metabolismo , Canais de Potássio/metabolismoRESUMO
Social anhedonia, a loss of interest and pleasure in social interactions, is a common symptom of major depression as well as other psychiatric disorders. Depression can occur at any age, but typically emerges in adolescence or early adulthood, which represents a sensitive period for social interaction that is vulnerable to stress. In this study, we evaluated social interaction reward using a conditioned place preference (CPP) paradigm in adolescent male and female mice. Adolescent mice of both sexes exhibited a preference for the social interaction-associated context. Chronic unpredictable stress (CUS) impaired the development of CPP for social interaction, mimicking social anhedonia in depressed adolescents. Conversely, administration of leptin, an adipocyte-derived hormone, enhanced social interaction-induced CPP in non-stressed control mice and reversed social anhedonia in CUS mice. By dissecting the motivational processes of social CPP into social approach and isolation avoidance components, we demonstrated that leptin treatment increased isolation aversion without overt social reward effect. Further mechanistic exploration revealed that leptin stimulated oxytocin gene transcription in the paraventricular nucleus of the hypothalamus, while oxytocin receptor blockade abolished the leptin-induced enhancement of socially-induced CPP. These results establish that chronic unpredictable stress can be used to study social anhedonia in adolescent mice and provide evidence that leptin modulates social motivation possibly via increasing oxytocin synthesis and oxytocin receptor activation.
Assuntos
Anedonia , Leptina , Motivação , Animais , Feminino , Masculino , Camundongos , Anedonia/efeitos dos fármacos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/metabolismo , Leptina/farmacologia , Leptina/uso terapêutico , Motivação/efeitos dos fármacos , Ocitocina , Receptores de Ocitocina , Recompensa , Estresse Psicológico/complicaçõesRESUMO
The steroid hormone progesterone (P4) mediates many physiological processes through either nuclear receptors that modulate gene expression or membrane P4 receptors (mPRs) that mediate nongenomic signaling. mPR signaling remains poorly understood. Here we show that the topology of mPRß is similar to adiponectin receptors and opposite to that of G-protein-coupled receptors (GPCRs). Using Xenopus oocyte meiosis as a well-established physiological readout of nongenomic P4 signaling, we demonstrate that mPRß signaling requires the adaptor protein APPL1 and the kinase Akt2. We further show that P4 induces clathrin-dependent endocytosis of mPRß into signaling endosome, where mPR interacts transiently with APPL1 and Akt2 to induce meiosis. Our findings outline the early steps involved in mPR signaling and expand the spectrum of mPR signaling through the multitude of pathways involving APPL1.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Progesterona/metabolismo , Proteínas de Xenopus/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Animais , Endocitose , Endossomos/metabolismo , Feminino , Meiose/fisiologia , Oócitos/metabolismo , Progesterona/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Proteínas de Xenopus/fisiologia , Xenopus laevisRESUMO
BACKGROUND: Genome-wide association studies (GWAS) are an effective way to explore genotype-phenotype associations in humans, animals, and plants. Various GWAS methods have been developed based on different genetic or statistical assumptions. However, no single method is optimal for all traits and, for many traits, the putative single nucleotide polymorphisms (SNPs) that are detected by the different methods do not entirely overlap due to the diversity of the genetic architecture of complex traits. Therefore, multi-tool-based GWAS strategies that combine different methods have been increasingly employed. To take this one step further, we propose an ensemble-like GWAS strategy (E-GWAS) that statistically integrates GWAS results from different single GWAS methods. RESULTS: E-GWAS was compared with various single GWAS methods using simulated phenotype traits with different genetic architectures. E-GWAS performed stably across traits with different genetic architectures and effectively controlled the number of false positive genetic variants detected without decreasing the number of true positive variants. In addition, its performance could be further improved by using a bin-merged strategy and the addition of more distinct single GWAS methods. Our results show that the numbers of true and false positive SNPs detected by the E-GWAS strategy slightly increased and decreased, respectively, with increasing bin size and when the number and the diversity of individual GWAS methods that were integrated in E-GWAS increased, the latter being more effective than the bin-merged strategy. The E-GWAS strategy was also applied to a real dataset to study backfat thickness in a pig population, and 10 candidate genes related to this trait and expressed in adipose-associated tissues were identified. CONCLUSIONS: Using both simulated and real datasets, we show that E-GWAS is a reliable and robust strategy that effectively integrates the GWAS results of different methods and reduces the number of false positive SNPs without decreasing that of true positive SNPs.
Assuntos
Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Humanos , Animais , Suínos , Estudo de Associação Genômica Ampla/métodos , Estudos de Associação Genética , FenótipoRESUMO
This randomized phase II trial (NCT05978193) combines low-dose radiotherapy (LDRT) and conventionally fractionated radiotherapy (CFRT) with immunochemotherapy for metastatic esophageal squamous cell carcinoma, aiming to assess the potential enhanced effect of radiotherapy on immunotherapy. Patients are administered a PD-1 inhibitor along with paclitaxel and platinum-based chemotherapy (arm B), or combined with LDRT and CFRT (arm A). Immunotherapy is given every 3 weeks with chemotherapy for 4 cycles, followed by immunotherapy maintenance therapy for up to 24 months. In arm A, LDRT (2 Gy, 2 fractions; delivered to the primary and all metastatic tumors) precedes each immunochemotherapy cycle for 4 cycles, followed by CFRT (40-50 Gy, 20-25 fractions; delivered to the primary tumor) starting from the fifth immunotherapy cycle. The primary end point is median progression-free survival. Clinical Trial Registration: NCT05978193 (clinicaltrials.gov).
Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Paclitaxel/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Imunoterapia/efeitos adversos , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como AssuntoRESUMO
An obligately anaerobic, Gram-positive, rod-shaped bacterium (1.8-5.5 µm long, 0.6-0.9 µm wide), designated ZC22-4T, was isolated from a pickle-processing wastewater treatment plant in Zhejiang province, P.R. China. Strain ZC22-4T grows optimally at 37-40 °C and pH 7.0 in the presence of 1% (w/v) NaCl or 2.0% (w/v) sea salts. It contained C16:0 (25.9%), C14:0 (13.6%), and C16:1 cis 9 (10.6%) as the dominant cellular fatty acid (> 10%). Polar lipids include phosphatidylglycerol (PG), diphosphatidylglycerol (DPG), phosphatidylethanolamine (PE), one unidentified phospholipid (PL), two unidentified glycolipids (GL), three unidentified amino phosphoglycolipids (APGL1-3), one unidentified aminoglycolipid (AGL), and one unidentified lipid (L). The genomic DNA G + C content of ZC22-4T was 28.7%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain ZC22-4T belonged to the genus Clostridium and formed a clade with the most closely related Clostridium aestuarii HY-45-18T (96.3%), Clostridium ganghwense HY-42-06T (95.9%). The average nucleotide identity and DNA-DNA hybridization values among the genomes of strain ZC22-4T and C. aestuarii HY-45-18T and C. ganghwense HY-42-06T were 75.7% and 77.3%, 21.7% and 23.0%, respectively. Based on the phenotypic, phylogenetic, and genetic data, strain ZC22-4T represents a novel species in the Clostridium cluster I, for which the name Clostridium brassicae sp. nov. is proposed. The type strain is ZC22-4T (= MCCC 1K07510T = JCM 35370T).
Assuntos
Cloreto de Sódio , Águas Residuárias , Filogenia , Anaerobiose , RNA Ribossômico 16S/genética , Composição de Bases , Análise de Sequência de DNA , Clostridium , Ácidos Graxos/química , Fosfolipídeos/química , Bactérias Anaeróbias/genética , DNA , DNA Bacteriano/genética , Técnicas de Tipagem BacterianaRESUMO
BACKGROUND: Global warming and increasing extreme weather have become a severe problem in recent years, posing a significant threat to human health worldwide. Research exploring the link between injury as one of the leading causes of death globally and ambient temperature was lacking. Based on the hourly injury emergency ambulance dispatch (IEAD) records from 2019-2021 in the main urban area of Chongqing, this study explored the role of temperature extremes on the pathogenesis of injury by different mechanisms and identified sensitive populations for different mechanisms of injury. METHODS: In this study, we collected hourly injury emergency ambulance dispatch (IEAD) records from Chongqing Emergency Dispatch Center in the main urban area of Chongqing from 2019 to 2021, and used a distributed lagged nonlinear model (DLNM) with quasi-Poisson distribution to evaluate the association between ambient temperature and IEADs. And the stratified analysis was performed by gender, age and different injury mechanisms to identify susceptible groups. Finally, the attributable burden of ambient extreme temperatures was also investigated. RESULTS: The risk for total IEADs increased significantly at high temperature (32 °C) compared with optimal temperature (9 °C) (CRR: 1.210; 95%CI[1.127,1.300]). The risks of traffic accident injury (CRR: 1.346; 95%CI[1.167,1.552]), beating injury (CRR: 1.508; 95%CI[1.165,1.952]), fall-height injury (CRR: 1.871; 95%CI[1.196-2.926]) and injury of sharp penetration (CRR: 2.112; 95%CI[1.388-3.213]) were significantly increased. At low temperature (7 °C), the risk of fall injury (CRR: 1.220; 95% CI [1.063,1.400]) increased significantly. Lag for 24 hours at extreme low temperature (5 °C), the risk of 18-45 years (RR: 1.016; 95%CI[1.009,1.024]) and over 60 years of age (RR: 1.019; 95%CI[1.011,1.025]) increased significantly. The effect of 0 h delay in extreme high temperature (36 °C) on males aged 18-45 years (RR: 1.115; 95%CI[1.071,1.162]) and 46-59 years (RR: 1.069; 95%CI[1.023,1.115]) had significant impact on injury risk. CONCLUSIONS: This study showed that ambient temperature was significantly related to the risk of injury, and different mechanisms of injury were affected differently by extreme temperature. The increasing risk of traffic accident injury, beating injury, fall-height injury and sharp penetrating injury was associated with extreme heat, while fall injury was associated with extreme cold. The risk of injury in high temperature environment was mainly concentrated in males and young adults. The results of this study can help to identify the sensitive population with different injury mechanisms in extreme temperature environment, and provide reference for public health emergency departments to respond to relevant strategies in extreme temperature environment to minimize the potential risk to the public.