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We report genome-wide ancient DNA from 49 individuals forming four parallel time transects in Belize, Brazil, the Central Andes, and the Southern Cone, each dating to at least â¼9,000 years ago. The common ancestral population radiated rapidly from just one of the two early branches that contributed to Native Americans today. We document two previously unappreciated streams of gene flow between North and South America. One affected the Central Andes by â¼4,200 years ago, while the other explains an affinity between the oldest North American genome associated with the Clovis culture and the oldest Central and South Americans from Chile, Brazil, and Belize. However, this was not the primary source for later South Americans, as the other ancient individuals derive from lineages without specific affinity to the Clovis-associated genome, suggesting a population replacement that began at least 9,000 years ago and was followed by substantial population continuity in multiple regions.
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Genética Populacional/história , Genoma Humano , América Central , DNA Antigo/análise , DNA Mitocondrial/genética , Fluxo Gênico , História Antiga , Humanos , Modelos Teóricos , América do SulRESUMO
The deep population history of East Asia remains poorly understood owing to a lack of ancient DNA data and sparse sampling of present-day people1,2. Here we report genome-wide data from 166 East Asian individuals dating to between 6000 BC and AD 1000 and 46 present-day groups. Hunter-gatherers from Japan, the Amur River Basin, and people of Neolithic and Iron Age Taiwan and the Tibetan Plateau are linked by a deeply splitting lineage that probably reflects a coastal migration during the Late Pleistocene epoch. We also follow expansions during the subsequent Holocene epoch from four regions. First, hunter-gatherers from Mongolia and the Amur River Basin have ancestry shared by individuals who speak Mongolic and Tungusic languages, but do not carry ancestry characteristic of farmers from the West Liao River region (around 3000 BC), which contradicts theories that the expansion of these farmers spread the Mongolic and Tungusic proto-languages. Second, farmers from the Yellow River Basin (around 3000 BC) probably spread Sino-Tibetan languages, as their ancestry dispersed both to Tibet-where it forms approximately 84% of the gene pool in some groups-and to the Central Plain, where it has contributed around 59-84% to modern Han Chinese groups. Third, people from Taiwan from around 1300 BC to AD 800 derived approximately 75% of their ancestry from a lineage that is widespread in modern individuals who speak Austronesian, Tai-Kadai and Austroasiatic languages, and that we hypothesize derives from farmers of the Yangtze River Valley. Ancient people from Taiwan also derived about 25% of their ancestry from a northern lineage that is related to, but different from, farmers of the Yellow River Basin, which suggests an additional north-to-south expansion. Fourth, ancestry from Yamnaya Steppe pastoralists arrived in western Mongolia after around 3000 BC but was displaced by previously established lineages even while it persisted in western China, as would be expected if this ancestry was associated with the spread of proto-Tocharian Indo-European languages. Two later gene flows affected western Mongolia: migrants after around 2000 BC with Yamnaya and European farmer ancestry, and episodic influences of later groups with ancestry from Turan.
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Genoma Humano/genética , Genômica , Migração Humana/história , China , Produção Agrícola/história , Feminino , Haplótipos/genética , História Antiga , Humanos , Japão , Idioma/história , Masculino , Mongólia , Nepal , Oryza , Polimorfismo de Nucleotídeo Único/genética , Sibéria , TaiwanRESUMO
During 2010 to 2020, Northeast Pacific (NEP) sea surface temperature (SST) experienced the warmest decade ever recorded, manifested in several extreme marine heatwaves, referred to as "warm blob" events, which severely affect marine ecosystems and extreme weather along the west coast of North America. While year-to-year internal climate variability has been suggested as a cause of individual events, the causes of the continuous dramatic NEP SST warming remain elusive. Here, we show that other than the greenhouse gas (GHG) forcing, rapid aerosol abatement in China over the period likely plays an important role. Anomalous tropospheric warming induced by declining aerosols in China generated atmospheric teleconnections from East Asia to the NEP, featuring an intensified and southward-shifted Aleutian Low. The associated atmospheric circulation anomaly weakens the climatological westerlies in the NEP and warms the SST there by suppressing the evaporative cooling. The aerosol-induced mean warming of the NEP SST, along with internal climate variability and the GHG-induced warming, made the warm blob events more frequent and intense during 2010 to 2020. As anthropogenic aerosol emissions continue to decrease, there is likely to be an increase in NEP warm blob events, disproportionately large beyond the direct radiative effects.
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Spinal muscular atrophy (SMA), which results from the deletion or/and mutation in the SMN1 gene, is an autosomal recessive neuromuscular disorder that leads to weakness and muscle atrophy. SMN2 is a paralogous gene of SMN1. SMN2 copy number affects the severity of SMA, but its role in patients treated with disease modifying therapies is unclear. The most appropriate individualized treatment for SMA has not yet been determined. Here, we reported a case of SMA type I with normal breathing and swallowing function. We genetically confirmed that this patient had a compound heterozygous variant: one deleted SMN1 allele and a novel splice mutation c.628-3T>G in the retained allele, with one SMN2 copy. Patient-derived sequencing of 4 SMN1 cDNA clones showed that this intronic single transversion mutation results in an alternative exon (e)5 3' splice site, which leads to an additional 2 nucleotides (AG) at the 5' end of e5, thereby explaining why the patient with only one copy of SMN2 had a mild clinical phenotype. Additionally, a minigene assay of wild type and mutant SMN1 in HEK293T cells also demonstrated that this transversion mutation induced e5 skipping. Considering treatment cost and goals of avoiding pain caused by injections and starting treatment as early as possible, risdiplam was prescribed for this patient. However, the patient showed remarkable clinical improvements after treatment with risdiplam for 7 months despite carrying only one copy of SMN2. This study is the first report on the treatment of risdiplam in a patient with one SMN2 copy in a real-world setting. These findings expand the mutation spectrum of SMA and provide accurate genetic counseling information, as well as clarify the molecular mechanism of careful genotype-phenotype correlation of the patient.
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Mutação , Splicing de RNA , Atrofias Musculares Espinais da Infância , Proteína 2 de Sobrevivência do Neurônio Motor , Feminino , Humanos , Alelos , Compostos Azo , Éxons/genética , Células HEK293 , Pirimidinas/uso terapêutico , Splicing de RNA/genética , Atrofias Musculares Espinais da Infância/genética , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Recém-Nascido , LactenteRESUMO
Causal discovery is a powerful tool to disclose underlying structures by analyzing purely observational data. Genetic variants can provide useful complementary information for structure learning. Recently, Mendelian randomization (MR) studies have provided abundant marginal causal relationships of traits. Here, we propose a causal network pruning algorithm MRSL (MR-based structure learning algorithm) based on these marginal causal relationships. MRSL combines the graph theory with multivariable MR to learn the conditional causal structure using only genome-wide association analyses (GWAS) summary statistics. Specifically, MRSL utilizes topological sorting to improve the precision of structure learning. It proposes MR-separation instead of d-separation and three candidates of sufficient separating set for MR-separation. The results of simulations revealed that MRSL had up to 2-fold higher F1 score and 100 times faster computing time than other eight competitive methods. Furthermore, we applied MRSL to 26 biomarkers and 44 International Classification of Diseases 10 (ICD10)-defined diseases using GWAS summary data from UK Biobank. The results cover most of the expected causal links that have biological interpretations and several new links supported by clinical case reports or previous observational literatures.
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Algoritmos , Estudo de Associação Genômica Ampla , Causalidade , Fenótipo , Transporte Proteico , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Itching is an aversive somatosensation that triggers the desire to scratch. Transient receptor potential (TRP) channel proteins are key players in acute and chronic itch. However, whether the modulatory effect of fibroblast growth factor 13 (FGF13) on acute and chronic itch is associated with TRP channel proteins is unclear. Here, we demonstrated that conditional knockout of Fgf13 in dorsal root ganglion neurons induced significant impairment in scratching behaviors in response to acute histamine-dependent and chronic dry skin itch models. Furthermore, FGF13 selectively regulated the function of the TRPV1, but not the TRPA1 channel on Ca2+ imaging and electrophysiological recordings, as demonstrated by a significant reduction in neuronal excitability and current density induced by TRPV1 channel activation, whereas TRPA1 channel activation had no effect. Changes in channel currents were also verified in HEK cell lines. Subsequently, we observed that selective modulation of TRPV1 by FGF13 required its microtubule-stabilizing effect. Furthermore, in FGF13 knockout mice, only the overexpression of FGF13 with a tubulin-binding domain could rescue TRP channel function and the impaired itch behavior. Our findings reveal a novel mechanism by which FGF13 is involved in TRPV1-dependent itch transduction and provide valuable clues for alleviating pathological itch syndrome.
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Fatores de Crescimento de Fibroblastos , Camundongos Knockout , Microtúbulos , Prurido , Canais de Cátion TRPV , Animais , Humanos , Masculino , Camundongos , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Gânglios Espinais/metabolismo , Células HEK293 , Camundongos Endogâmicos C57BL , Microtúbulos/metabolismo , Prurido/metabolismo , Prurido/genética , Canal de Cátion TRPA1/metabolismo , Canal de Cátion TRPA1/genética , Canais de Cátion TRPV/metabolismo , Canais de Cátion TRPV/genéticaRESUMO
Iodine-induced cleavage at phosphorothioate DNA (PT-DNA) is characterized by extremely high sensitivity (â¼1 phosphorothioate link per 106 nucleotides), which has been used for detecting and sequencing PT-DNA in bacteria. Despite its foreseeable potential for wide applications, the cleavage mechanism at the PT-modified site has not been well established, and it remains unknown as to whether or not cleavage of the bridging P-O occurs at every PT-modified site. In this work, we conducted accurate ωB97X-D calculations and high-performance liquid chromatography-mass spectrometry to investigate the process of PT-DNA cleavage at the atomic and molecular levels. We have found that iodine chemoselectively binds to the sulfur atom of the phosphorothioate link via a strong halogen-chalcogen interaction (a type of halogen bond, with binding affinity as high as 14.9 kcal/mol) and thus triggers P-O bond cleavage via phosphotriester-like hydrolysis. Additionally, aside from cleavage of the bridging P-O bond, the downstream hydrolyses lead to unwanted P-S/P-O conversions and a loss of the phosphorothioate handle. The mechanism we outline helps to explain specific selectivity at the PT-modified site but also predicts the dynamic stoichiometry of P-S and P-O bond breaking. For instance, Tris is involved in the cascade derivation of S-iodo-phosphorothioate to S-amino-phosphorothioate, suppressing the S-iodo-phosphorothioate hydrolysis to a phosphate diester. However, hydrolysis of one-third of the Tris-O-grafting phosphotriester results in unwanted P-S/P-O conversions. Our study suggests that bacterial DNA phosphorothioation may more frequently occur than previous bioinformatic estimations have predicted from iodine-induced deep sequencing data.
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Iodo , Clivagem do DNA , DNA Bacteriano/genética , Iodetos , Fosfatos/química , EnxofreRESUMO
BACKGROUND: Immunosuppressive status is prevalent in cancer patients and increases the complexity of tumor immunotherapy. It has been found that Listeria-vectored tumor vaccines had the potential ability of two-side regulatory effect on the immune response during immunotherapy. RESULTS: The results show that the combined immunotherapy with the LM∆E6E7 and LI∆E6E7, the two cervical cancer vaccine candidate strains constructed by our lab, improves the antitumor immune response and inhibits the suppressive immune response in tumor-bearing mice in vivo, confirming the two-sided regulatory ability of the immune response caused by Listeria-vectored tumor vaccines. The immunotherapy reduces the expression level of myeloid-derived suppressor cells (MDSCs)-inducing factors and then inhibits the phosphorylation level of STAT3 protein, the regulatory factor of MDSCs differentiation, to reduce the MDSCs formation ability. Moreover, vaccines reduce the expression of functional molecules associated with MDSCs may by inhibiting the phosphorylation level of the JAK1-STAT1 and JAK2-STAT3 pathways in tumor tissues to attenuate the immunosuppressive function of MDSCs. CONCLUSIONS: Immunotherapy with Listeria-vectored cervical cancer vaccines significantly reduces the level and function of MDSCs in vivo, which is the key point to the destruction of immunosuppression. The study for the first to elucidate the mechanism of breaking the immunosuppression.
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Vacinas Anticâncer , Células Supressoras Mieloides , Neoplasias do Colo do Útero , Feminino , Humanos , Camundongos , Animais , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/patologia , Vacinas Anticâncer/metabolismo , Neoplasias do Colo do Útero/prevenção & controle , Neoplasias do Colo do Útero/metabolismo , Fosforilação , Transdução de SinaisRESUMO
BACKGROUND: The underrepresentation of human genomic resources from Southern Chinese populations limited their health equality in the precision medicine era and complete understanding of their genetic formation, admixture, and adaptive features. Besides, linguistical and genetic evidence supported the controversial hypothesis of their origin processes. One hotspot case was from the Chinese Guangxi Pinghua Han people (GPH), whose language was significantly similar to Southern Chinese dialects but whose uniparental gene pool was phylogenetically associated with the indigenous Tai-Kadai (TK) people. Here, we analyzed genome-wide SNP data in 619 people from four language families and 56 geographically different populations, in which 261 people from 21 geographically distinct populations were first reported here. RESULTS: We identified significant population stratification among ethnolinguistically diverse Guangxi populations, suggesting their differentiated genetic origin and admixture processes. GPH shared more alleles related to Zhuang than Southern Han Chinese but received more northern ancestry relative to Zhuang. Admixture models and estimates of genetic distances showed that GPH had a close genetic relationship with geographically close TK compared to Northern Han Chinese, supporting their admixture origin hypothesis. Further admixture time and demographic history reconstruction supported GPH was formed via admixture between Northern Han Chinese and Southern TK people. We identified robust signatures associated with lipid metabolisms, such as fatty acid desaturases (FADS) and medically relevant loci associated with Mendelian disorder (GJB2) and complex diseases. We also explored the shared and unique selection signatures of ethnically different but linguistically related Guangxi lineages and found some shared signals related to immune and malaria resistance. CONCLUSIONS: Our genetic analysis illuminated the language-related fine-scale genetic structure and provided robust genetic evidence to support the admixture hypothesis that can explain the pattern of observed genetic diversity and formation of GPH. This work presented one comprehensive analysis focused on the population history and demographical adaptative process, which provided genetic evidence for personal health management and disease risk prediction models from Guangxi people. Further large-scale whole-genome sequencing projects would provide the entire landscape of southern Chinese genomic diversity and their contributions to human health and disease traits.
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Aclimatação , Genômica , Humanos , China , Alelos , IdiomaRESUMO
Kidney stone, one of the oldest known diseases, has plagued humans for centuries, consistently imposing a heavy burden on patients and healthcare systems worldwide due to their high incidence and recurrence rates. Advancements in endoscopy, imaging, genetics, molecular biology and bioinformatics have led to a deeper and more comprehensive understanding of the mechanism behind nephrolithiasis. Kidney stone formation is a complex, multi-step and long-term process involving the transformation of stone-forming salts from free ions into asymptomatic or symptomatic stones influenced by physical, chemical and biological factors. Among the various types of kidney stones observed in clinical practice, calcareous nephrolithiasis is currently the most common and exhibits the most intricate formation mechanism. Extensive research suggests that calcareous nephrolithiasis primarily originates from interstitial subepithelial calcified plaques and/or calcified blockages in the openings of collecting ducts. These calcified plaques and blockages eventually come into contact with urine in the renal pelvis, serving as a nidus for crystal formation and subsequent stone growth. Both pathways of stone formation share similar mechanisms, such as the drive of abnormal urine composition, involvement of oxidative stress and inflammation, and an imbalance of stone inhibitors and promoters. However, they also possess unique characteristics. Hence, this review aims to provide detailed description and present recent discoveries regarding the formation processes of calcareous nephrolithiasis from two distinct birthplaces: renal interstitium and tubule lumen.
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Calcinose , Cálculos Renais , Humanos , Medula Renal/metabolismo , Cálculos Renais/complicações , Cálculos Renais/metabolismo , Calcinose/metabolismo , Endoscopia , Inflamação/metabolismoRESUMO
Exploring high-sloping-capacity carbons is of great significance in the development of high-power lithium-ion batteries/capacitors (LIBs/LICs). Herein, an ion-catalyzed self-template method is utilized to synthesize the hydrogen-rich carbon nanoribbon (HCNR), achieving high specific and rate capacity (1144.2/471.8 mAh g-1 at 0.1/2.5 A g-1). The Li+ storage mechanism of the HCNR is elucidated by in situ spectroscopic techniques. Intriguingly, the protonated aromatic sp2-hybridized carbon (C(sp2)-H) can provide additional active sites for Li+ uptake via reversible rehybridization to sp3-C, which is the origin of the high sloping capacity. The presence of this sloping feature suggests a highly capacitance-dominated storage process, characterized by rapid kinetics that facilitates superior rate performance. For practical usage, the HCNR-based LIC device can deliver high energy/power densities of 198.3 Wh kg-1/17.9 kW kg-1. This work offers mechanistic insights on the crucial role of aromatic C(sp2)-H in boosting Li+ storage and opens up new avenues to develop such sloping-type carbons for high-performance rechargeable batteries/capacitors.
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Recombinant human granulocyte colony-stimulating factor (G-CSF) administration in patients with cancer and coronavirus disease (COVID-19) remains controversial. Concerns exist that it may worsen COVID-19 outcomes by triggering an inflammatory cytokine storm, despite its common use for managing chemotherapy-induced neutropenia (CIN) or febrile neutropenia post-chemotherapy. Here, we determined whether prophylactic or therapeutic G-CSF administration following chemotherapy exacerbates COVID-19 progression to severe/critical conditions in breast cancer patients with COVID-19. Between December 2022 and February 2023, all 503 enrolled breast cancer patients had concurrent COVID-19 and received G-CSF post-chemotherapy, with most being vaccinated pre-chemotherapy. We prospectively observed COVID-19-related adverse outcomes, conducted association analyses, and subsequently performed Mendelian randomization (MR) analyses to validate the causal effect of genetically predicted G-CSF or its associated granulocyte traits on COVID-19 adverse outcomes. Only 0.99% (5/503) of breast cancer patients experienced COVID-19-related hospitalization following prophylactic or therapeutic G-CSF administration after chemotherapy. No mortality or progression to severe/critical COVID-19 occurred after G-CSF administration. Notably, no significant associations were observed between the application, dosage, or response to G-CSF and COVID-19-related hospitalization (all p >.05). Similarly, the MR analyses showed no evidence of causality of genetically predicted G-CSF or related granulocyte traits on COVID-19-related hospitalization or COVID-19 severity (all p >.05). There is insufficient evidence to substantiate the notion that the prophylactic or therapeutic administration of G-CSF after chemotherapy for managing CIN in patients with breast cancer and COVID-19 would worsen COVID-19 outcomes, leading to severe or critical conditions, or even death, especially considering the context of COVID-19 vaccination.
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Neoplasias da Mama , COVID-19 , Fator Estimulador de Colônias de Granulócitos , Análise da Randomização Mendeliana , SARS-CoV-2 , Humanos , COVID-19/virologia , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Pessoa de Meia-Idade , SARS-CoV-2/genética , Idoso , Adulto , Estudos Prospectivos , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , Estudos de CoortesRESUMO
Linear IgA bullous dermatosis (LABD) and dermatitis herpetiformis (DH) represent the major subtypes of IgA mediated autoimmune bullous disorders. We sought to understand the disease etiology by using serum proteomics. We assessed 92 organ damage biomarkers in LABD, DH, and healthy controls using the Olink high-throughput proteomics. The positive proteomic serum biomarkers were used to correlate with clinical features and HLA type. Targeted proteomic analysis of IgA deposition bullous disorders vs. controls showed elevated biomarkers. Further clustering and enrichment analyses identified distinct clusters between LABD and DH, highlighting the involvement of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Comparative analysis revealed biomarkers with distinction between LABD and DH and validated in the skin lesion. Finally, qualitative correlation analysis with DEPs suggested six biomarkers (NBN, NCF2, CAPG, FES, BID, and PXN) have better prognosis in DH patients. These findings provide potential biomarkers to differentiate the disease subtype of IgA deposition bullous disease.
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Biomarcadores , Dermatite Herpetiforme , Dermatose Linear Bolhosa por IgA , Proteoma , Humanos , Dermatite Herpetiforme/sangue , Dermatite Herpetiforme/diagnóstico , Dermatite Herpetiforme/imunologia , Biomarcadores/sangue , Feminino , Masculino , Adulto , Dermatose Linear Bolhosa por IgA/sangue , Dermatose Linear Bolhosa por IgA/diagnóstico , Pessoa de Meia-Idade , Diagnóstico Diferencial , Proteômica/métodos , Imunoglobulina A/sangue , Adolescente , Adulto Jovem , Idoso , CriançaRESUMO
The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia-telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion. We further demonstrate that CHK2-mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2-/- mice display aggravated infarct phenotypes and reduced Beclin 1 p-Ser90/Ser93 in a cerebral stroke model, suggesting an in vivo role of CHK2-induced autophagy in cell survival. Taken together, these results indicate that the ROS-ATM-CHK2-Beclin 1-autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress-induced tissue damage.
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Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteína Beclina-1/metabolismo , Quinase do Ponto de Checagem 2/metabolismo , AVC Isquêmico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Autofagia , Linhagem Celular , Modelos Animais de Doenças , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Camundongos , Estresse Oxidativo , FosforilaçãoRESUMO
Diabetes is linked to male infertility, but the mechanisms and therapeutic options remain unclear. This study investigates the effects of semaglutide on testicular function in a diabetes mouse model. Clinical data shows that diabetes affects blood glucose, lipid levels, and sperm quality. Single-cell and transcriptome analyses reveal changes in testicular tissue cell proportions and activation of ferroptosis pathways in diabetic patients/rats. In the diabetes mouse model, sperm quality decreases significantly. Treatment with semaglutide (Sem) and the ferroptosis inhibitor ferrostatin-1 (Fer-1) alleviates testicular damage, as evidenced by improved lipid peroxidation and ferroptosis markers. Moreover, the diabetes-induced decrease in the TM-3 cell line's vitality, increased lipid peroxidation, ROS, ferrous ions, and mitochondrial membrane potential damage are all improved by semaglutide and ferrostatin-1 intervention. Overall, these findings highlight semaglutide's potential as a therapeutic approach for mitigating diabetes-induced testicular damage through modulation of the ferroptosis pathway.
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Ferroptose , Peptídeos Semelhantes ao Glucagon , Testículo , Masculino , Ferroptose/efeitos dos fármacos , Animais , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Peptídeos Semelhantes ao Glucagon/farmacologia , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Camundongos , Humanos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/complicações , Linhagem Celular , Camundongos Endogâmicos C57BL , Peroxidação de Lipídeos/efeitos dos fármacos , RatosRESUMO
BACKGROUND: Plant height (PH) is an important agronomic trait influenced by a complex genetic network. However, the genetic basis for the variation in PH in Medicago sativa remains largely unknown. In this study, a comprehensive genome-wide association analysis was performed to identify genomic regions associated with PH using a diverse panel of 220 accessions of M. sativa worldwide. RESULTS: Our study identified eight novel single nucleotide polymorphisms (SNPs) significantly associated with PH evaluated in five environments, explaining 8.59-12.27% of the phenotypic variance. Among these SNPs, the favorable genotype of chr6__31716285 had a low frequency of 16.4%. Msa0882400, located proximal to this SNP, was annotated as phosphate transporter 3;1, and its role in regulating alfalfa PH was supported by transcriptome and candidate gene association analysis. In addition, 21 candidate genes were annotated within the associated regions that are involved in various biological processes related to plant growth and development. CONCLUSIONS: Our findings provide new molecular markers for marker-assisted selection in M. sativa breeding programs. Furthermore, this study enhances our understanding of the underlying genetic and molecular mechanisms governing PH variations in M. sativa.
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Estudo de Associação Genômica Ampla , Medicago sativa , Polimorfismo de Nucleotídeo Único , Medicago sativa/genética , Fenótipo , Genes de Plantas , Locos de Características Quantitativas/genética , GenótipoRESUMO
PURPOSE: Optimal extended adjuvant endocrine therapy (ET) duration and strategy for hormone receptor-positive (HR +) early breast cancer remain unclear. In this network meta-analysis (NMA), the efficacy and safety of all available extended adjuvant ETs were compared and ranked. METHODS: PubMed, Embase, and Cochrane Library and abstracts presented at ASCO, SABCS, and ESMO were searched on March 5, 2022. Fourteen randomized controlled trials (RCTs) comprising eight extended adjuvant ETs for HR + breast cancer and 38,070 patients were analyzed. Main outcomes were disease-free survival (DFS), overall survival (OS), grade ≥ 3 adverse events (AEs), and contralateral breast cancer (CBC). Direct and indirect comparisons were integrated via Bayesian NMA. Hierarchical cluster analysis was performed to jointly rank efficacy and safety outcomes. RESULTS: Compared with that of 5 year ET, extended 10 year aromatase inhibitor (AI) treatment provided the greatest DFS benefit (HR = 0.45, 95%CrI 0.23-0.83), whereas no strategy differed significantly in terms of the other main outcomes. Extended 10 year AI treatment was the preferred strategy for DFS improvement and CBC prevention (surface under the cumulative ranking curve: 93.51% and 91.29% probability, respectively). All strategies had comparable safeties (grade ≥ 3 AEs). Compared with that of 5 year ET, 10 year extended AI significantly increased arthralgia (OR = 1.65, 95%CrI 1.02-2.93) and osteoporosis (OR = 3.33, 95%CrI 1.19-9.68). CONCLUSION: Extended 10 year AI therapy may be optimal for HR + early breast cancer given its relatively high efficacy and safety.
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Neoplasias da Mama , Humanos , Feminino , Metanálise em Rede , Quimioterapia Adjuvante , Inibidores da Aromatase/efeitos adversos , Intervalo Livre de Doença , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Lithium-oxygen (Li-O2) battery with large theoretical energy density (≈3500 Wh kg-1) is one of the most promising energy storage and conversion systems. However, the slow kinetics of oxygen electrode reactions inhibit the practical application of Li-O2 battery. Thus, designing efficient electrocatalysts is crucial to improve battery performance. Here, Ti3C2 MXene/Mo4/3B2-x MBene superlattice is fabricated its electrocatalytic activity toward oxygen redox reactions in Li-O2 battery is studied. It is found that the built-in electric field formed by a large work function difference between Ti3C2 and Mo4/3B2-x will power the charge transfer at the interface from titanium (Ti) site in Ti3C2 to molybdenum (Mo) site in Mo4/3B2-x. This charge transfer increases the electron density in 4d orbital of Mo site and decreases the d-band center of Mo site, thus optimizing the adsorption of intermediate product LiO2 at Mo site and accelerating the kinetics of oxygen electrode reactions. Meanwhile, the formed film-like discharge products (Li2O2) improve the contact with electrode and facilitate the decomposition of Li2O2. Based on the above advantages, the Ti3C2 MXene/Mo4/3B2-x MBene superlattice-based Li-O2 battery exhibits large discharge specific capacity (17 167 mAh g-1), low overpotential (1.16 V), and superior cycling performance (475 cycles).
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Garnet-type solid-state electrolytes attract abundant attentions due to the broad electrochemical window and remarkable thermal stability while their poor ionic conductivity obstructs their widespread application in all-solid-state batteries. Herein, the enhanced ionic conductivity of garnet-type solid electrolytes is achieved by partially substituting O2- sites with Cl- anions, which effectively reduce Li+ migration barriers while preserving the highly conductive cubic phase of garnet-type solid-state electrolytes. This substitution not only weakens the anchoring effect of anions on Li+ to widen the size of Li+ diffusion channel but also optimizes the occupancy of Li+ at different sites, resulting in a substantial reduction of the Li+ migration barrier and a notable improvement in ionic conductivity. Leveraging these advantageous properties, the developed Li6.35La3Zr1.4Ta0.6O11.85-Cl0.15 (LLZTO-0.15Cl) electrolyte demonstrates high Li+ conductivity of 4.21×10-6 S cm-1. When integrated with LiFePO4 (LFP) cathode and metallic lithium anode, the LLZTO-0.15Cl electrolyte enables the solid-state battery to operate for more than 100 cycles with a high capacity retention of 76.61% and superior Coulombic efficiency of 99.48%. This work shows a new strategy for modulating anionic framework to enhance the conductivity of garnet-type solid-state electrolytes.
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Practical applications of lithium metal batteries are limited by unstable solid electrolyte interphase (SEI) and uncontrollable dendrite Li deposition. Regulating the solvation structure of Li+ via modifying electrolyte components enables optimizing the structure of the SEI and realizing dendrite-free Li deposition. In this work, it is found that the ionic-dipole interactions between the electron-deficient B atoms in lithium oxalyldifluoro borate (LiDFOB) and the O atoms in the DME solvent molecule can weaken the interaction between the DME molecule and Li+, accelerating the desolvation of Li+. On this basis, the ionic-dipole interactions facilitate the entry of abundant anions into the inner solvation sheath of Li+, which promotes the formation of inorganic-rich SEI. In addition, the interaction between DFOB- and DME molecules reduces the highest occupied molecular orbital energy level of DME molecules in electrolytes, which improves the oxidative stability of the electrolytes system. As a result, the Li||Li cells in LiDFOB-containing electrolytes exhibit an excellent cyclability of over 1800 h with a low overpotential of 18.2 mV, and the Li||LiFePO4 full cells display a high-capacity retention of 93.4% after 100 cycles with a high Coulombic efficiency of 99.3%.