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The large-scale open access whole-exome sequencing (WES) data of the UK Biobank ~200,000 participants is accelerating a new wave of genetic association studies aiming to identify rare and functional loss-of-function (LoF) variants associated with complex traits and diseases. We proposed to merge the WES genotypes and the genome-wide genotyping (GWAS) genotypes of 167,000 UKB homogeneous European participants into a combined reference panel, and then to impute 241,911 UKB homogeneous European participants who had the GWAS genotypes only. We then used the imputed data to replicate association identified in the discovery WES sample. The average imputation accuracy measure r2 is modest to high for LoF variants at all minor allele frequency intervals: 0.942 at MAF interval (0.01, 0.5), 0.807 at (1.0 × 10-3 , 0.01), 0.805 at (1.0 × 10-4 , 1.0 × 10-3 ), 0.664 at (1.0 × 10-5 , 1.0 × 10-4 ) and 0.410 at (0, 1.0 × 10-5 ). As applications, we studied associations of LoF variants with estimated heel BMD and four lipid traits. In addition to replicating dozens of previously reported genes, we also identified three novel associations, two genes PLIN1 and ANGPTL3 for high-density-lipoprotein cholesterol and one gene PDE3B for triglycerides. Our results highlighted the strength of WES based genotype imputation as well as provided useful imputed data within the UKB cohort.
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Bancos de Espécimes Biológicos , Exoma , Humanos , Sequenciamento do Exoma , Genótipo , Frequência do Gene , Reino Unido , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Proteína 3 Semelhante a AngiopoietinaRESUMO
Age at menarche (AAM) is a sign of puberty of females. It is a heritable trait associated with various adult diseases. However, the genetic mechanism that determines AAM and links it to disease risk is poorly understood. Aiming to uncover the genetic basis for AAM, we conducted a joint association study in up to 438,089 women from 3 genome-wide association studies of European and East Asian ancestries. A series of bioinformatical analyses and causal inference were then followed to explore in-depth annotations at the associated loci and infer the causal relationship between AAM and other complex traits/diseases. This largest meta-analysis identified a total of 21 novel AAM associated loci at the genome wide significance level (P < 5.0 × 10-8), 4 of which were European ancestry-specific loci. Functional annotations prioritized 33 candidate genes at newly identified loci. Significant genetic correlations were observed between AAM and 67 complex traits. Further causal inference demonstrated the effects of AAM on 13 traits, including forced vital capacity (FVC), high blood pressure, age at first live birth, etc, indicating that earlier AAM causes lower FVC, worse lung function, hypertension and earlier age at first (last) live birth. Enrichment analysis identified 5 enriched tissues, including the hypothalamus middle, hypothalamo hypophyseal system, neurosecretory systems, hypothalamus and retina. Our findings may provide useful insights that elucidate the mechanisms determining AAM and the genetic interplay between AAM and some traits of women.
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The present study aims to assess the risk factors for foot ulcers in patients undergoing dialysis for end-stage renal disease (ESRD) and to provide evidence-based guidance for prevention and treatment. A systematic search was conducted on PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, Chinese Biomedical Literature Database and Wanfang Data from the database inception until May 2023 to identify relevant studies investigating the risk factors for foot ulcers in dialysis patients with ESRD. Two independent researchers conducted the literature screening and data extraction. The meta-analysis was performed using STATA 17.0 software. Ultimately, six articles comprising 1620 patients were included for analysis. The meta-analysis revealed that male (OR, 1.464; 95% CI: 1.082-1.980, p = 0.013), hypertension (OR, 1.781; 95% CI: 1.293-2.4550, p < 0.001), peripheral artery disease (PAD) (OR, 5.014; 95% CI: 2.514-9.998, p < 0.001), type 1 diabetes mellitus (T1DM) (OR, 2.993; 95% CI: 1.477-6.065, p = 0.002) and type 2 diabetes mellitus (T2DM) (OR, 2.498; 95% CI:1.466-4.256, p = 0.001) were risk factors for foot ulcers in dialysis patients with ESRD. Conversely, the female sex (OR, 0.683; 95% CI: 0.505-0.924, p = 0.013) was a protective factor against foot ulcers. Our analysis revealed that male sex, hypertension, PAD, T1DM and T2DM were risk factors for foot ulcers in patients undergoing dialysis for ESRD. Conversely, the female sex was a protective factor against foot ulcers. Therefore, it is crucial to strengthen health education that targets patients with these risk factors and regularly screen high-risk individuals. Early detection and treatment can help delay disease progression.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Pé Diabético , Úlcera do Pé , Hipertensão , Falência Renal Crônica , Doença Arterial Periférica , Humanos , Masculino , Feminino , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 1/complicações , Pé Diabético/terapia , Pé Diabético/etiologia , Diálise Renal/efeitos adversos , Fatores de Risco , Úlcera do Pé/etiologia , Úlcera do Pé/terapia , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Doença Arterial Periférica/complicações , Hipertensão/epidemiologiaRESUMO
Hypoxic-ischemic encephalopathy (HIE) is a leading cause of long-term neurological disability in neonates and adults. Despite emerging advances in supportive care, like the most effective approach, hypothermia, poor prognosis has still been present in current clinical treatment for HIE. Stem cell therapy has been adopted for treating cerebral ischemia in preclinical and clinical trials, displaying its promising therapeutic value. At present, reported treatments for stroke employed stem cells to replace the lost neurons and integrate them into the existing host circuitry, promoting the release of growth factors to support and stimulate endogenous repair processes and so on. In this review, a meaningful overview to numerous studies published up to now was presented by introducing the preclinical and clinical research status of stem cell therapy for cerebral ischemia and hypoxia, discussing potential therapeutic mechanisms of stem cell transplantation for curing HI-induced brain injury, summarizing a series of approaches for marking transplanted cells and existing imaging systems for stem cell labelling and in vivo tracking and expounding the endogenous regeneration capability of stem cells in the newborn brain when subjected to an HI insult. Additionally, it is promising to combine stem therapy with neuromodulation through specific regulation of neural circuits. The crucial neural circuits across different brain areas related to functional recovery are of great significance for the application of neuromodulation strategies after the occurrence of neonatal hypoxic-ischemic encephalopathy (NHIE).
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Hipotermia Induzida , Hipóxia-Isquemia Encefálica , Recém-Nascido , Humanos , Hipóxia-Isquemia Encefálica/terapia , Transplante de Células-Tronco , Hipóxia , Neurônios , Hipotermia Induzida/métodosRESUMO
The two-sample Mendelian randomization (MR) study revealed a causal association of plasma proteins with osteoporosis (OP) and osteoarthritis (OA). Bone mineral density (BMD) is the gold standard for the clinical assessment of OP. Recent studies have shown that plasma proteins play an essential role in the regulation of bone development. However, the causal association of plasma proteins with BMD and OA remains unclear. We estimated the effects of 2889 plasma proteins on 2 BMD phenotypes and 6 OA phenotypes using two-sample MR analysis based on the genome-wide association study summary statistics. Then, we performed sensitivity analysis and reverse-direction MR analysis to evaluate the robustness of the MR analysis results, followed by gene ontology (GO) enrichment analysis and KEGG pathway analysis to explore the functional relevance of the identified plasma proteins. Overall, we observed a total of 257 protein-estimated heel BMD associations, 17 protein-total-body BMD associations, 2 protein-all-OA associations, and 2 protein-knee-OA associations at PFDR < 0.05. Reverse-direction MR analysis demonstrated that there was little evidence of the causal association of BMD and OA with plasma proteins. GO enrichment analysis and KEGG pathway analysis identified multiple pathways, which may be involved in the development of OP and OA. Our findings recognized plasma proteins that could be used to regulate changes in OP and OA, thus, providing new insights into protein-mediated mechanisms of bone development.
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Osteoartrite do Joelho , Osteoporose , Humanos , Proteoma/genética , Estudo de Associação Genômica Ampla , Osteoporose/metabolismo , Densidade Óssea/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Carpal tunnel syndrome (CTS) is one of the most common work-related musculoskeletal disorders. The present study sought to identify putative causal proteins for CTS. We conducted a two-sample Mendelian randomization (MR) analysis to evaluate the causal association between 2859 plasma proteins (N = 35,559) and CTS (N = 1,239,680) based on the published GWAS summary statistics. Then we replicated the significant associations using an independent plasma proteome GWAS (N = 10,708). Sensitivity analyses were conducted to validate the robustness of MR results. Multivariate MR and mediation analyses were conducted to evaluate the mediation effects of body mass index (BMI), type 2 diabetes (T2D), and arm tissue composition on the association between putative causal proteins and CTS. Colocalization analysis was used to examine whether the identified proteins and CTS shared causal variant(s). Finally, we evaluated druggability of the identified proteins. Ten plasma proteins were identified as putative causal markers for CTS, including sCD14, PVR, LTOR3, CTSS, SIGIRR, IFNL3, ASPN, TM11D, ASIP, and ITIH1. Sensitivity analyses and reverse MR analysis validated the robustness of their causal effects. Arm tissue composition, BMI, and T2D may play a fully/partial mediating role in the causal relationships of ASIP, TM11D, IFNL3, PVR, and LTOR3 with CTS. The association of ASPN and sCD14 with CTS were supported by colocalization analysis. Druggability assessment demonstrated that sCD14, CTSS, TM11D, and IFNL3 were potential drug therapeutic targets. The present study identified several potential plasma proteins that were causally associated with CTS risk, providing new insights into the pathogenesis of protein-mediated CTS and offering potential targets for new therapies.
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Síndrome do Túnel Carpal , Diabetes Mellitus Tipo 2 , Humanos , Proteínas Sanguíneas/genética , Síndrome do Túnel Carpal/tratamento farmacológico , Síndrome do Túnel Carpal/genética , Síndrome do Túnel Carpal/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicações , Receptores de Lipopolissacarídeos , Análise da Randomização MendelianaRESUMO
A fluorescence quenching enhanced immunoassay has been developed to achieve ultrasensitive recognition of human epididymal 4 (HE4) modifying the fluorescence quencher. The carboxymethyl cellulose sodium-functionalized Nb2C MXene nanocomposite (CMC@MXene) was firstly introduced to quench the fluorescence signal of the luminophore Tb-Norfloxacin coordination polymer nanoparticles (Tb-NFX CPNPs). The Nb2C MXene nanocomposite as fluorescent nanoquencher inhibits the electron transfer between Tb and NFX to quench the fluorescent signal by coordinating the strongly electronegative carboxyl group on CMC with Tb (III) of Tb-NFX complex. Simultaneously, due to the superior photothermal conversion capability of CMC@MXene, the fluorescence signal has been further weakened by the photothermal effect driven non-radiative decay of the excited state under near-infrared laser irradiation. The constructed fluorescent biosensor based on CMC@MXene probe finally realized the enhanced fluorescence quenching effect, and achieved ultra-high sensitivity and selective detection of HE4, exhibiting a wide linear relationship with HE4 concentration on the logarithmic axis in the range of 10-5 to 10 ng/mL and a low detection limit of 3.3 fg/mL (S/N = 3). This work not only provides an enhanced fluorescent signal quenching method for the detection of HE4, but also provides novel insights for the design of fluorescent sensor toward different biomolecules.
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Carboximetilcelulose Sódica , Norfloxacino , Humanos , Fluorescência , Corantes , Raios InfravermelhosRESUMO
Colloidal all-inorganic perovskites nanocrystals (NCs) have emerged as a promising material for display and lighting due to their excellent optical properties. However, blue emissive NCs usually suffer from low photoluminescence quantum yields (PLQYs) and poor stability, rendering them the bottleneck for full-color all-perovskite optoelectronic applications. Herein, a facile approach is reported to enhance the emission efficiency and stability of blue emissive perovskite nano-structures via surface passivation with potassium bromide. By adding potassium oleate and excess PbBr2 to the perovskite precursor solutions, potassium bromide-passivated (KBr-passivated) blue-emitting (≈450 nm) CsPbBr3 nanoplatelets (NPLs) is successfully synthesized with a respectably high PLQY of 87%. In sharp contrast to most reported perovskite NPLs, no shifting in emission wavelength is observed in these passivated NPLs even after prolonged exposures to intense irradiations and elevated temperature, clearly revealing their excellent photo- and thermal-stabilities. The enhancements are attributed to the formation of K-Br bonding on the surface which suppresses ion migration and formation of Br-vacancies, thus improving both the PL emission and stability of CsPbBr3 NPLs. Furthermore, all-perovskite white light-emitting diodes (WLEDs) are successfully constructed, suggesting that the proposed KBr-passivated strategy can promote the development of the perovskite family for a wider range of optoelectronic applications.
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The nucleic acids of Mycobacterium tuberculosis can be detected by intracellular DNA sensors, such as cyclic GMP-AMP synthase and absent in melanoma 2 (AIM2), which results in the release of type I IFN and the proinflammatory cytokine IL-1ß. However, whether cross-talk occurs between AIM2-IL-1ß and cyclic GMP-AMP synthase-type I IFN signaling upon M. tuberculosis infection in vivo is unclear. In this article, we demonstrate that mycobacterial infection of AIM2-/- mice reciprocally induces overreactive IFN-ß and depressive IFN-γ responses, leading to higher infection burdens and more severe pathology. We also describe the underlying mechanism whereby activated apoptosis-associated speck-like protein interacts with a key adaptor, known as stimulator of IFN genes (STING), and inhibits the interaction between STING and downstream TANK-binding kinase 1 in bone marrow-derived macrophages and bone marrow-derived dendritic cells, consequently reducing the induction of type I IFN. Of note, apoptosis-associated speck-like protein expression is inversely correlated with IFN-ß levels in PBMCs from tuberculosis patients. These data demonstrate that the AIM2-IL-1ß signaling pathway negatively regulates the STING-type I IFN signaling pathway by impeding the association between STING and TANK-binding kinase 1, which protects the host from M. tuberculosis infection. This finding has potential clinical significance.
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Proteínas de Ligação a DNA/imunologia , Interferon beta/metabolismo , Interferon gama/imunologia , Interleucina-1beta/imunologia , Proteínas de Membrana/metabolismo , Mycobacterium bovis/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Tuberculose/patologia , Animais , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Linhagem Celular , Proteínas de Ligação a DNA/genética , Células HEK293 , Humanos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Serina-Treonina Quinases/imunologia , Células RAW 264.7 , Transdução de Sinais/imunologia , Tuberculose/microbiologiaRESUMO
Infectious diseases are major threats to human health and lead to a serious public health burden. The emergence of new pathogens and the mutation of known pathogens challenge our ability to diagnose and control infectious diseases. Nanopore sequencing technology exhibited versatile applications in pathogenic microorganism detection due to its flexible data throughput. This review article introduced the applications of nanopore sequencing in clinical microbiology and infectious diseases management, including the monitoring of emerging infectious diseases outbreak, identification of pathogen drug resistance, and disease-related microbial communities characterization.
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BACKGROUND: MiRNAs (microRNA) are 18-24 nt endogenous noncoding RNAs that regulate gene expression at the post-transcriptional level, including tissue-specific, developmental timing and evolutionary conservation gene expression. RESULTS: This study used high-throughput sequencing technology for the first time in Larix olgensis, predicted 78 miRNAs, including 12,229,003 reads sRNA, screened differentially expressed miRNAs. Predicting target genes was helpful for understanding the miRNA regulation function and obtained 333 corresponding target genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional annotation were analysed, mostly including nucleic acid binding, plant hormone signal transduction, pantothenate and CoA biosynthesis, and cellulose synthase. This study will lay the foundation for clarifying the complex miRNA-mediated regulatory network for growth and development. In view of this, spatio-temporal expression of miR396, miR950, miR164, miR166 and miR160 were analysed in Larix olgensis during the growth stages of not lignified, beginning of lignification, and completely lignified in different tissues (root, stem, and leaf) by quantitative real-time PCR (qRT-PCR). There were differences in the expression of miRNAs in roots, stems and leaves in the same growth period. At 60 days, miR160, miR166 and miR396-2 exhibited the highest expression in leaves. At 120 days, most miRNAs in roots and stems decreased significantly. At 180 days, miRNAs were abundantly expressed in roots and stems. Meanwhile, analysis of the expression of miRNAs in leaves revealed that miR396-2 was reduced as time went on, whereas other miRNAs increased initially and then decreased. On the other hand, in the stems, miR166-1 was increase, whereas other miRNAs, especially miR160, miR164, miR396 and miR950-1, first decreased and then increased. Similarly, in the roots, miR950-2 first decreased and then increased, whereas other miRNAs exhibited a trend of continuous increase. CONCLUSIONS: The present investigation included rapid isolation and identification of miRNAs in Larix olgensis through construction of a sRNA library using Solexa and predicted 78 novel miRNAs, which showed differential expression levels in different tissues and stages. These results provided a theoretical basis for further revealing the genetic regulation mechanism of miRNA in the growth and development of conifers and the verification of function in target genes.
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Regulação da Expressão Gênica de Plantas , Larix/genética , MicroRNAs/genética , RNA de Plantas/genética , Perfilação da Expressão Gênica , Biblioteca Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Larix/metabolismo , MicroRNAs/metabolismo , RNA de Plantas/metabolismoRESUMO
OBJECTIVE: To determine expression levels of glial fibrillary acidic protein in patients of sepsis-associated encephalopathy (SAE) and its clinical significance.â© Methods: Patients, admitted to intensive care units and diagnosed as sepsis, were recruited to our study from October 2016 to August 2018 in the Third Xiangya Hospital, Central South University. SAE is defined as a brain dysfunction secondary to sepsis and without evidence of a primary central nervous system infection or encephalopathy due to other reasons. The SAE group and non-SAE group were classed by Confusion Assessment Method for the ICU (CAM-ICU) score. We measured the levels of serum GFAP, S100ß and neuron-specific enolase (NSE) within 24 hours after diagnosis of sepsis, and compared the patients' general clinical data, ICU stay time, 28-day and 180-day mortality.â© Results: Among 152 enrolled patients, 58 and 94 were assigned to the SAE group and the non-SAE group, respectively. There were a significantly higher Sequential Organ Failure Assessment (SOFA) scores, 28-day mortality rate, as well as 180-day mortality rate in the SAE group (all P<0.001). The levels of GFAP, NSE and S100ß in the SAE group were significantly higher than those in the non-SAE group (all P<0.001). The diagnostic values of GFAP was 0.67 µg/L, with sensitivity at 75.9% and specificity at 77.7%. Area under the receiver operating characteristic curve (AUROC) of GFAP, NSE and S100ß were 0.803, 0.795 and 0.750, respectively. Pearson analysis showed that serum GFAP level was positively correlated with Acute Physiology and Chronic Health Evaluation II (APACHE II) score, but it was negatively correlated with Glasgow Coma Scale (GCS) score, 28-day survival rate and 180-day survival rate.â© Conclusion: The level of serum GFAP is significantly increased in SAE, which shows certain correlation with incidence, severity and prognosis of the disease.
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Proteína Glial Fibrilar Ácida/sangue , Encefalopatia Associada a Sepse , Sepse , APACHE , Humanos , Unidades de Terapia Intensiva , Escores de Disfunção Orgânica , Prognóstico , Curva ROC , Encefalopatia Associada a Sepse/diagnósticoRESUMO
Femtosecond laser ionization time-of-flight mass spectrometry (fs-LI-TOFMS) is introduced for the three-dimensional elemental analysis of a Nantan meteorite. Spatially resolved multielemental imaging of major and minor compositions in a meteorite are presented with a lateral resolution of 50 µm and a depth resolution of 7 µm. Distinct 3D distributions of siderophile, lithophile, and chalcophile elements are revealed. Co and Ni are highly siderophile (Iron-loving), mainly enriched in the metal phase. Cr, Cu, V, and Mn are enriched in the sulfide for their chalcophile (S-loving) tendency. S, P, and C aggregate together in the analytical volume. Silicate inclusion, containing lithophile elements of Al, Ca, Mg, K, and so on, is embedded within the metal phase for the immiscibility between silicate inclusion and the melted metal phase. These 3D distributions of elements aid the exploration of the formation and evolution of the meteorite. They also reveal the feasibility of fs-LI-TOFMS as a versatile tool for 3D imaging.
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Uncontrolled immune responses to intracellular DNA have been shown to induce autoimmune diseases. Homeostasis regulation of immune responses to cytosolic DNA is critical for limiting the risk of autoimmunity and survival of the host. Here, we report that the E3 ubiquitin ligase tripartite motif protein 30α (TRIM30α) was induced by herpes simplex virus type 1 (HSV-1) infection in dendritic cells (DCs). Knockdown or genetic ablation of TRIM30α augmented the type I IFNs and interleukin-6 response to intracellular DNA and DNA viruses. Trim30α-deficient mice were more resistant to infection by DNA viruses. Biochemical analyses showed that TRIM30α interacted with the stimulator of interferon genes (STING), which is a critical regulator of the DNA-sensing response. Overexpression of TRIM30α promoted the degradation of STING via K48-linked ubiquitination at Lys275 through a proteasome-dependent pathway. These findings indicate that E3 ligase TRIM30α is an important negative-feedback regulator of innate immune responses to DNA viruses by targeting STING.
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Vírus de DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , DNA/metabolismo , Proteínas de Membrana/metabolismo , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular , Vírus de DNA/genética , Imunidade Inata , Camundongos Endogâmicos C57BL , Transdução de Sinais/imunologia , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
Objective:To investigate the changes of nasal ventilation before and after septoplasty by using NOSE scoring scale and nasal function examination, and to explore the correlation between subjective nasal obstruction and nasal function examination and its clinical application value. Methods:A total of 129 cases of nasal septum deviation from December 2021 to April 2023 in our hospital were selected for study. All patients underwent septoplasty. Nasal obstruction symptom evaluationï¼NOSEï¼ was performed in all patients before surgery and 3 months after surgery. nasal minimal cross-sectional areaï¼MCAï¼ and nasal cavity volumeï¼NCVï¼ were recorded by nasal acoustic reflex, nasal resistance meter and nasal respiration apparatus, nasal resistanceï¼NRï¼, distance between the nostril to minimum cross-sectional area,ï¼the distance between the nostril to minimum cross-sectional area, MDï¼, nasal inspiratory volumeï¼IVï¼, nasal expiratory volumeï¼EVï¼, the nasal partitioning ratio, NPR includes objective indicators such as inspiratory volume difference ratioï¼NPRiï¼ and expiratory volume difference ratioï¼NPReï¼. Paired test was used to compare and analyze the changes of various indicators before and after surgery, and the differenceï¼P<0.05ï¼ was statistically significant, and Pearson correlation linear analysis was used to analyze the correlation between subjective and objective indicators. Results:There were statistically significant differences in NOSE score, NCV, NR, MD, EV, IV, NPRe and NPRi of 129 patients before and after surgeryï¼P<0.05ï¼, while there was no statistically significant difference between MCA before and after surgeryï¼P>0.05ï¼. Preoperative NOSE score was correlated with NR, NCV, EV, IV, NPRe and NPRiï¼P<0.05ï¼, but not with MD and MCAï¼P>0.05ï¼. There was correlation between NOSE score and NR, MCA, NCV, EV, IV, NPRe and NPRiï¼P<0.05ï¼, but no correlation between nose score and MDï¼P>0.05ï¼. Conclusion:The subjective NOSE scale combined with nasal function test has certain clinical reference value in evaluating the surgical effect of patients with deviated nasal septum.
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Obstrução Nasal , Rinoplastia , Humanos , Obstrução Nasal/cirurgia , Nariz , Respiração , ExpiraçãoRESUMO
Breast cancer is the most common diagnosed cancer, the HER2-positive subtype account for 15% of all breast cancer. HER2-targeted therapy is the mainstay treatment for HER2-positive breast cancer. Cuproptosis is a novel form of programmed cell death, and is caused by mitochondrial lipoylation and destabilization of iron-sulfur proteins triggered by copper, which was considered as a key player in various biological processes. However, the roles of cuproptosis-related genes in HER2-positive breast cancer remain largely unknown. In the present study, we constructed a prognostic prediction model of HER2-positive breast cancer patients using TCGA database. Dysregulated genes for cells resistant to HER2-targeted therapy were analyzed in the GEO dataset. KEGG pathway, GO enrichment and GSEA was performed respectively. The immune landscape of DLAT was analyzed by CIBERSORT algorithm and TIDE algorithm. HER2-positive breast cancer patients with high CRGs risk score showed shorter OS. DLAT was downregulated and correlated with better survival of HER2-positive breast cancer patients (HR = 3.30, p = 0.022). High expressed DLAT was associated with resistant to HER2-targeted therapy. Knocking down DLAT with siRNA increased sensitivity of breast cancer to trastuzumab. KEGG pathway and GO enrichment of DEGs indicated that DLAT participates in various pathways correlated with organelle fission, chromosome segregation, nuclear division, hormone-mediated signaling pathway, regulation of intracellular estrogen receptor signaling pathway, condensed chromosome and PPAR signaling pathway. There was a negative correlation between TIDE and DLAT expression (r = - 0.292, p < 0.001), which means high DLAT expression is an indicator of sensitivity to immunotherapy. In conclusion, our study constructed a four CRGs signature prognostic prediction model and identified DLAT as an independent prognostic factor and associated with resistant to HER2-targeted therapy for HER2-positive breast cancer patients.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Prognóstico , Algoritmos , Apoptose , CobreRESUMO
The magnetic skyrmions exhibit intriguing topological behaviors, holding promise for future applications in the realm of spintronic devices. Despite recent advancements, achieving spontaneous magnetic skyrmions and topological transitions in magnets featuring uniaxial magnetic anisotropy, particularly at elevated temperatures (>100 K), remains a challenging endeavor. Here, single-crystal Fe5Si3 nanorods with the central symmetry and uniaxial magnetic anisotropy were successfully synthesized on a mica substrate through chemical vapor deposition, which exhibit a high Curie temperature (TC) of about 372 K. The real-time observation, facilitated by Lorentz transmission electron microscopy, revealed the spontaneous formation of magnetic skyrmions and evolution of domains in focused ion beam-prepared Fe5Si3 thin foils. Moreover, Fe5Si3 device transport measurements expose notable magnetoresistance (MR) effects, enabling the interchange between positive and negative MR across specific temperature settings. These results offer various potential avenues for exploring diverse topological spin textures and their formation mechanisms, indicating inventive applications for iron-silicon alloy in the realm of spintronics.
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Sarcopenic obesity (SO) is an age-related disease characterized by the coexistence of excessive adiposity and low muscle mass or function. Although obesity and sarcopenia are heritable conditions, the genetic determinants of SO have not been fully understood. We conducted a large-scale exome-wide association analysis of SO in a sequenced sample of 2 887 cases and 113 284 controls and an imputed sample of 4 003 cases and 161 990 controls in the UK Biobank cohort. Single-variant association analysis identified one locus 1q41 (lead SNP rs1417066, LYPLAL1-AS1, odds ratio [OR]â =â 1.15, 95% confidence interval [CI]â =â [1.11-1.19], pâ =â 1.75â ×â 10-14) that was significantly associated with SO at the exome-wide significance level (pâ <â 1â ×â 10-8). Colocalization analysis in the Genotype-Tissue Expression expression quantitative trait locus database showed that LYPLAL1-AS1 was colocalized with SO in multiple musculoskeletal-related tissues. Gene-based burden test of rare loss-of-function variants identified 5 genes at the gene-wise significance level (pâ <â 4.3â ×â 10-6): PDE3B (ORâ =â 2.48, pâ =â 1.10â ×â 10-6), MYOZ3 (ORâ =â 25.49, pâ =â 1.41â ×â 10-7), SLC15A3 (ORâ =â 4.75, pâ =â 6.82â ×â 10-7), RNF130 (ORâ =â 25.83, pâ =â 4.07â ×â 10-6), and TNK2 (ORâ =â 4.25, pâ =â 8.75â ×â 10-8). Overall, our study uncovered the genetic effects of both common and rare variants on SO susceptibility, expanded existing knowledge of the genetic architecture of SO, and improved understanding of the genetic mechanisms underlying SO.
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Sarcopenia , Humanos , Sarcopenia/genética , Predisposição Genética para Doença , Exoma/genética , Estudo de Associação Genômica Ampla , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Proteínas Tirosina Quinases/genéticaRESUMO
The rapid evolution of the Internet of Things has engendered increased requirements for low-cost, self-powered UV photodetectors. Herein, high-performance self-driven UV photodetectors are fabricated by designing asymmetric metal-semiconductor-metal structures on the high-quality large-area CsCu2I3 microwire arrays. The asymmetrical depletion region doubles the photocurrent and response speed compared to the symmetric structure device, leading to a high responsivity of 233 mA/W to 355 nm radiation. Notably, at 0 V bias, the asymmetric device produces an open-circuit voltage of 356 mV and drives to a short-circuit current of 372 pA; meanwhile, the switch ratio (Iph/Idark) reaches up to 103, indicating its excellent potential for detecting weak light. Furthermore, the device maintains stable responses throughout 10000 UV-light switch cycles, with negligible degradation even after 90-day storage in air. Our work establishes that CsCu2I3 is a good candidate for self-powered UV detection and thoroughly demonstrates its potential as a passive device.