A shock flash breaking out of a dusty red supergiant.

Shock-breakout emission is light that arises when a shockwave, generated by the core-collapse explosion of a massive star, passes through its outer envelope. Hitherto, the earliest detection of such a signal was at several hours after the explosion1, although a few others had been reported2-7. The temporal evolution of early light curves should provide insights into the shock propagation, including explosion asymmetry and environment in the vicinity, but this has been hampered by the lack of multiwavelength observations. Here we report the instant multiband observations of a type II supernova (SN 2023ixf) in the galaxy M101 (at a distance of 6.85 ± 0.15 Mpc; ref. 8), beginning at about 1.4 h after the explosion. The exploding star was a red supergiant with a radius of about 440 solar radii. The light curves evolved rapidly, on timescales of 1-2 h, and appeared unusually fainter and redder than predicted by the models9-11 within the first few hours, which we attribute to an optically thick dust shell before it was disrupted by the shockwave. We infer that the breakout and perhaps the distribution of the surrounding dust were not spherically symmetric.

Pollution sources and risk assessment of potentially toxic elements in soils of multiple land use types in the arid zone of Northwest China based on Monte Carlo simulation.

The concentration of potentially toxic elements (PTEs) in soils of different land-use types varies depending on climatic conditions and human. Topsoil samples were collected in Northwest China to investigate PTE pollution and risk in different land uses, and thereby estimate the risk of various pollution sources. The results showed that human activity had an impact on PTE concentrations in the study area across all land use types, with farmland, grassland, woodland, and the gobi at moderate pollution levels and the desert at light pollution levels. Different PTE sources pose different risks depending on the land-use type. Apart from deserts, children are exposed to carcinogenic risk from a variety of sources. A mixed natural and agricultural source was the main source of public health risk in the study area, contributing 38.7% and 39.0% of the non-carcinogenic and 40.7% and 35.5% of the carcinogenic risks, respectively. Monte Carlo simulations showed children were at a higher health risk from PTEs than adult s under all land uses, which ranked in severity as farmland > woodland > grassland > gobi > desert. As and Ni has a higher probability of posing both a non-carcinogenic and a carcinogenic risk to children. Sensitivity analysis showed that the contribution of parameters to the assessment model of PTEs exhibited the following contribution pattern: concentration > average body weight > ingestion rate > other parameters. The PTEs affecting the risk assessment model were not common among different land use types, where the importance distribution pattern of each parameter was basically the same in woodland, grassland, and farmland, and Ni contributed the most to carcinogenic risk. However, Cr contributed the most to the carcinogenic risk in the desert and gobi.

Identification of a novel nonsense mutation in SH2D1A in a patient with X-linked lymphoproliferative syndrome type 1: a case report.

BACKGROUND: X-linked lymphoproliferative syndrome type 1 (XLP1) is an X-linked recessive genetic disorder with a strong resemblance to hemophagocytic lymphohistiocytosis (HLH). Causative mutations for XLP1 have been identified in SH2D1A, located on chromosome Xq25. CASE PRESENTATION: We report a case of an 18-month-old male with a novel nonsense mutation in SH2D1A. The patient presented the typical phenotype of HLH, including splenomegaly and hemophagocytosis in the bone marrow. Thus, he was initially diagnosed with HLH based on HLH-2004 guidelines. High-throughput amplicon sequencing was performed to detect mutations in the most commonly reported causative genes of HLH, i.e., PRF1, UNC13D, STX11, STXBP2, SH2D1A, and XIAP. A likely pathogenic nonsense mutation was detected in SH2D1A (NM_002351.4:c.300T>A). The mutation was inherited from the patient's mother, and an X-linked recessive mode of inheritance was confirmed by a two-generation pedigree analysis based on Sanger sequencing results. CONCLUSIONS: The nonsense mutation in SH2D1A (NM_002351.4:c.300T>A) was reported for the first time in a case of XLP1 and was considered to be likely pathogenic based on the truncation of the mRNA sequence. This finding expands the spectrum of known XLP-related mutations in Chinese patients and indicates the utility of amplicon sequencing for XLP and HLH diagnosis.

C1qTNF-related protein 1 improve insulin resistance by reducing phosphorylation of serine 1101 in insulin receptor substrate 1.

C1qTNF-related protein 1 (CTRP1) is independently associated with type 2 diabetes. However, the relationship between CTRP1 and insulin resistance is still not established. This study aimed to explore the role of CTRP1 under the situation of insulin resistance in adipose tissue. Plasma CTRP1 level was investigated in type 2 diabetic subjects (n = 35) and non-diabetic subjects (n = 35). The relationship between CTRP1 and phosphorylation of multi insulin receptor substrate 1 (IRS-1) serine (Ser) sites was further explored. Our data showed that Plasma CTRP1 was higher and negative correlation with insulin resistance in diabetic subjects (r = -0.283, p = 0.018). Glucose utilisation test revealed that the glucose utilisation rate of mature adipocytes was improved by CTRP1 in the presence of insulin. CTRP1 was not only related to IRS-1 protein, but also negatively correlated with IRS-1 Ser1101 phosphorylation (r = -0.398, p = 0.031). Furthermore, Phosphorylation levels of IRS-1 Ser1101 were significantly lower after incubation with 40 ng/mL CTRP1 in mature adipocytes than those with no intervention (p < 0.05). There was no significant correlation between CTRP1 and other IRS-1 serine sites (Ser302, Ser307, Ser612, Ser636/639, and Ser789). Collectively, our results suggested that CTRP1 might improve insulin resistance by reducing the phosphorylation of IRS-1 Ser1101, induced in the situation of insulin resistance as a feedback adipokine.

Non-small cell lung cancer with EML4-ALK translocation in Chinese male never-smokers is characterized with early-onset.

BACKGROUND: The translocations of the anaplastic lymphoma kinase (ALK) gene with the echinoderm microtubule-associated protein-like 4 (EML4) gene on chromosome 2p have been identified in non-small-cell lung cancers (NSCLCs) as oncogenic driver mutations. It has been suggested that EML4-ALK fusion is associated with the resistance in NSCLCs to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), such as gefitinib and erlotinib. In contrast, ALK tyrosine kinase inhibitor (ALK TKI) crizotinib has shown superior effects in combating NSCLCs with EML4-ALK. Thus, characterization of EML4-ALK fusion genes and clinical features of resulting carcinomas would be a great benefit to disease diagnosis and designing customized treatment plans. Studies have suggested that EML4-ALK translocation occurs more frequently in never-smokers with NSCLC, especially in female patients. However, it is not clear whether this is the case in male patients, too. In this study, we have determined the frequency of EML4-ALK translocation in male never-smokers with NSCLC in a cohort of Chinese patients. The clinical features associated with EML4-ALK translocation were also investigated. METHODS: A cohort of 95 Chinese male never-smokers with NSCLC was enrolled in this study. EML4-ALK fusion genes were detected using one-step real time RT-PCR and DNA sequencing. We further determined the expression levels of ALK mRNA by RT-PCR and ALK protein by immunohistochemistry in these specimens. The clinical features of EML4-ALK-positive carcinomas were also determined. RESULTS: We have identified EML4-ALK fusion genes in 8 out of 95 carcinoma cases, accounting for 8.42% in Chinese male never-smokers with NSCLC. It is significantly higher than that in all Chinese male patients (3.44%) regardless smoking habit. It is also significantly higher than that in all Chinese smokers (8/356 or 2.25%) or in smokers worldwide (2.9%) by comparing to published data. Interestingly, EML4-ALK fusion genes are more frequently found in younger patients and associated with less-differentiated carcinomas. CONCLUSIONS: The frequency of EML4-ALK translocation is strongly associated with smoking habits in Chinese male patients with higher frequency in male never-smokers. EML4-ALK translocation is associated with early-onset and less-differentiated carcinomas.

Elevated circulating levels of CTRP1, a novel adipokine, in diabetic patients.

Complement C1q tumor necrosis factor-related protein 1 (CTRP1), an adipose tissue-derived adipokine has been shown to decrease blood glucose levels and to improve metabolism of glucose in mice. In addition, CTRP1 has exhibited significant association with BMI, adiponectin and TNF-α in diabetic animal models. However, there are no published studies addressing CTRP1 levels in type 2 diabetic patients. Therefore, it was of interest to evaluate plasma CTRP1 levels and associated clinical parameters and biomarkers in patients with type 2 diabetes. 135 subjects were recruited to this study, including 62 type 2 diabetic patients (DM group) and 73 healthy subjects (control group). We measured biochemical parameters, CTRP1, TNF-α and adiponectin using enzyme-linked immunosorbent assay (ELISA). Plasma CTRP1 levels showed a significant difference between the DM group and the control group (646.3 ± 154.4 ng/mL vs. 442.6 ± 165.4 ng/mL, p < 0.01). In addition, CTRP1 was strongly positively associated with BMI, glucose levels, HbA1c, HOMA-IR and TNF-α in diabetic patients. CTRP1 showed negative correlation with adiponectin. In Multivariate regression analysis, CTRP1 was strongly independently associated with diabetes when CTRP1 levels were analyzed by both as a continuous variable and quartile (OR: 1.009, 95% CI: 1.004-1.015, p < 0.05; OR: 2.443, 95% CI: 1.379-4.182, p < 0.01, respectively). Increased plasma CTRP1 was independently associated with type 2 diabetes. Profiling of plasma adipokines such as CTRP1 is particularly important to obtain a greater understanding of their contribution to the type 2 diabetic state.

[Clinical Value of Detecting ABL Kinase Domain Mutations in Patients with Chronic Myeloid Leukemia Based on High-Throughput Sequencing Technology].

OBJECTIVE: To compare the efficacy and clinical value of high-throughput sequencing (HTS) and Sanger sequencing in detecting ABL kinase domain mutations in patients with chronic myeloid leukemia (CML). METHODS: A total of 198 samples of 147 CML patients from July 2017 to March 2021 in Henan Cancer Hospital were collected and underwent high-throughput sequencing and Sanger sequencing to detect the mutations in ABL kinase domain, and the relevant clinical data were collected for comparative analysis. RESULTS: The proportion of total mutations and ≥2 mutations detected by high-throughput sequencing were significantly higher than those detected by Sanger sequencing (P =0.01; P =0.046). ≥2 mutations were detected in 22 cases, of which 5 cases (22.7%) had compound mutations. High-throughput sequencing can detect low level mutations that cannot be detected by Sanger sequencing. In 198 samples, 25 (12.6%) were low level mutations, 33 (16.7%) were high level mutations and 10 (5.1%) were mixed high and low level mutations. In the analysis of related clinical factors, the total mutation rate and the low level mutation rate in the optimal period, failure period and warning period were gradually increased (total mutation rate, P =0.016; low level mutation rate, P =0.005). The mutation rate of the samples with additional chromosomal abnormalities was also significantly increased (P =0.009). The mutation rate of patients who received first- and second-line treatment was significantly lower than that of patients who received third- or higher-line treatment (P =0.006). Analysis based on variant allele frequency (VAF) of the mutation site was helpful to visually evaluate the clonal evolution status of TKI-resistance CML cells. CONCLUSION: High-throughput sequencing is more sensitive and accurate than Sanger sequencing in mutation detection, which is helpful to accurately and visually evaluate TKI treatment response and optimize treatment strategy for CML.

Discovery of CZL-046 with an (S)-3-Fluoropyrrolidin-2-one Scaffold as a p300 Bromodomain Inhibitor for the Treatment of Multiple Myeloma.

E1A binding protein (p300) is a promising therapeutic target for the treatment of cancer. Herein, we report the discovery of a series of novel inhibitors with an (S)-3-fluoropyrrolidin-2-one scaffold targeting p300 bromodomain. The best compound 29 (CZL-046) shows potent inhibitory activity of p300 bromodomain (IC50 = 3.3 nM) and antiproliferative activity in the multiple myeloma (MM) cell line (OPM-2 IC50 = 51.5 nM). 29 suppressed the mRNA levels of c-Myc and IRF4 and downregulated the expression of c-Myc and H3K27Ac. Compared to the lead compound 5, 29 exhibits significantly improved in vitro and in vivo metabolic properties. Oral administration of 29 with 30 mg/kg achieved a TGI value of 44% in the OPM-2 xenograft model, accompanied by good tolerability. The cocrystal structure of CREB binding protein bromodomain with 29 provides an insight into the precise binding mode. The results demonstrate that 29 is a promising p300 bromodomain inhibitor for the treatment of MM.

[The role of group 3 innate lymphoid cells(ILC3) in the evolution of the immune system: An update].

Group 3 innate lymphoid cells (ILC3) are an ILC subset that is characterized by the expression of retinoic acid-related orphan nuclear receptor γt (RORγt) and interleukin 22 (IL-22). This review summarizes the role of ILC3 in coordinating innate immunity and adaptive immunity based on current research and elaborate the significance of ILC3 from the perspective of immune system evolution. In addition, based on immune-related functions, we propose a possible time when ILC3 appears in the evolution of the immune system. And then, the research limitations and prospects are discussed.

Genetic mutation signature for relapse prediction in normal karyotype acute myeloid leukemia.

Risk stratification for normal karyotype acute myeloid leukemia (NK-AML) remains unsatisfactory, which is reflected by the high incidence of leukemia relapse. This study aimed to evaluate the role of gene mutations and clinical characterization in predicting the relapse of patients with NK-AML. A prognostic system for NK-AML was constructed. A panel of gene mutations was explored using next-generation sequencing. A nomogram algorithm was used to build a genomic mutation signature (GMS) nomogram (GMSN) model that combines GMS, measurable residual disease, and clinical factors to predict relapse in 347 patients with NK-AML from four centers. Patients in the GMS-high group had a higher 5-year incidence of relapse than those in the GMS-low group (p < 0.001). The 5-year incidence of relapse was also higher in patients in the GMSN-high group than in those in the GMSN-intermediate and -low groups (p < 0.001). The 5-year disease-free survival and overall survival rates were lower in patients in the GMSN-high group than in those in the GMSN-intermediate and -low groups (p < 0.001) as confirmed by training and validation cohorts. This study illustrates the potential of GMSN as a predictor of NK-AML relapse.