A combination of resistance genes confers high and durable resistance against stripe rust in wheat cultivar Lantian 26.

Lantian 26, a leading elite winter wheat cultivar in Gansu Province since its release in 2010, exhibits high resistance or immunization to stripe rust in adult-plant stage under a high disease pressure in Longnan (southeastern Gansu). Identifying the resistance genes in Lantian 26 could provide a basis for enhanced durability and high levels of resistance in wheat cultivars. Here, a segregating population was developed from a cross between a highly susceptible wheat cv. Mingxian 169 and the highly stripe rust-resistant cv. Lantian 26. The F2 and F2:3 progenies of the cross were inoculated with multiple prevalent virulent races of stripe rust for adult plant-stage resistance evaluation in two different environments. Exon sequence alignment analysis revealed that a stripe rust resistance gene on the 718.4-721.2 Mb region of chromosome 7BL, tentatively named as YrLT26, and a co-segregation STS marker GY17 was developed and validated using the F2:3 population and 103 wheat cultivars. The other two resistance genes, Yr9 and Yr30, were also identified in Lantian 26 using molecular markers. Therefore, the key to high and durable resistance to stripe rust at adult stage is the combination of Yr9, Yr30 and YrLT26 genes in Lantian 26. This could be a considerable strategy for improving the wheat cultivars with effective and durable resistance in the high-pressure region for stripe rust.

Analysis and Monitoring of Indoor Radon Concentrations of 37 Kindergartens - Beijing Municipality, China, 2023.

Introduction: Radon (222Rn or 222radon) is a radioactive gas emitted from building materials, foundations, and soil. Children are especially susceptible to radon exposure, underscoring the need to assess indoor radon levels in kindergartens. This study monitored radon concentrations in 37 Beijing kindergartens from June to October 2023. Methods: A random sample of 37 kindergartens was selected from 18 administrative districts in Beijing. The indoor radon concentration was measured using the solid track accumulation method, with radon detectors continuously monitored over a 3-month period. Results: The mean indoor radon level in 37 kindergartens, observed at 252 monitoring points, was 84.3 Bq/m3, with values varying from 12.9 to 263.5 Bq/m3. About 20.2% of points showed radon levels between 100.0 and 200.0 Bq/m3, while 2.4% exceeded 200.0 Bq/m3. Notably, radon levels were significantly elevated on the ground floor compared to the upper floors. Conclusion: Indoor radon levels in 37 kindergartens remained below the national standard limit of 300.0 Bq/m3 for buildings (GB/T 16146-2015). Nonetheless, 18.9% of the kindergartens exceeded the 100.0 Bq/m3 limit set for new constructions. It is advised to improve radon monitoring in kindergartens and consider developing a national standard for maximum permissible radon levels in such facilities.

Contributing factors related to abnormal uterine bleeding in perimenopausal women: a case-control study.

Abnormal uterine bleeding (AUB) during the menopausal transition results in reproductive endocrine disorders and both physiological and pathological changes, substantially impacting women's health. This study aimed to investigate the factors influencing AUB in perimenopausal women. Between April 2021 and June 2022, 120 perimenopausal women with AUB in the menopausal transition, diagnosed and treated at the Gynaecology Department of Kunming Tongren Hospital, were included in the case group. Concurrently, women undergoing routine health examinations at the same hospital were randomly selected as the control group. Univariate and multivariate logistic regression analyses identified factors related to AUB. The univariate analysis revealed significant associations (P < 0.05) between AUB and several factors, including age, body mass index (BMI), age at menarche, gravidity, and intrauterine device (IUD) placement in perimenopausal women. The multivariate regression analysis indicated that the independent risk factors for AUB include benign endometrial lesions (odds ratio [OR] 5.243, 95% confidence interval [CI] 3.082-9.458, P < 0.001), endometrial thickness ≥ 10 mm (OR 1.573, 95% CI 0.984-3.287, P < 0.001), age ≥ 50 years (OR 2.045, 95% CI 1.035-4.762, P = 0.001), BMI ≥ 25 kg/m2 (OR 2.436, 95% CI 1.43-4.86, P = 0.002), and IUD placement (OR 2.458, 95% CI 1.253-4.406, P < 0.001). Abnormal uterine bleeding during the menopausal transition is associated with several factors, including age, BMI, and IUD placement, highlighting the importance of early screening for these risk factors in the diagnosis and treatment of AUB.

OsKASI-2 is required for the regulation of unsaturation levels of membrane lipids and chilling tolerance in rice.

Chilling stress has seriously limited the global production and geographical distribution of rice. However, the molecular mechanisms associated with plant responses to chilling stress are less known. In this study, we revealed a member of ß-ketoacyl-ACP synthase I family (KASI), OsKASI-2 which confers chilling tolerance in rice. OsKASI-2 encodes a chloroplast-localized KASI enzyme mainly expressed in the leaves and anthers of rice and strongly induced by chilling stress. Disruption of OsKASI-2 led to decreased KAS enzymatic activity and the levels of unsaturated fatty acids, which impairs degree of unsaturation of membrane lipids, thus increased sensitivity to chilling stress in rice. However, the overexpression of OsKASI-2 significantly improved the chilling tolerance ability in rice. In addition, OsKASI-2 may regulate ROS metabolism in response to chilling stress. Natural variation of OsKASI-2 might result in difference in chilling tolerance between indica and japonica accessions, and Hap1 of OsKASI-2 confers chilling tolerance in rice. Taken together, we suggest OsKASI-2 is critical for regulating degree of unsaturation of membrane lipids and ROS accumulation for maintenance of membrane structural homeostasis under chilling stress, and provide a potential target gene for improving chilling tolerance of rice.

Structural basis and analysis of hamster ACE2 binding to different SARS-CoV-2 spike RBDs.

Pet golden hamsters were first identified being infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) delta variant of concern (VOC) and transmitted the virus back to humans in Hong Kong in January 2022. Here, we studied the binding of two hamster (golden hamster and Chinese hamster) angiotensin-converting enzyme 2 (ACE2) proteins to the spike protein receptor-binding domains (RBDs) of SARS-CoV-2 prototype and eight variants, including alpha, beta, gamma, delta, and four omicron sub-variants (BA.1, BA.2, BA.3, and BA.4/BA.5). We found that the two hamster ACE2s present slightly lower affinity for the RBDs of all nine SARS-CoV-2 viruses tested than human ACE2 (hACE2). Furthermore, the similar infectivity to host cells expressing hamster ACE2s and hACE2 was confirmed with the nine pseudotyped SARS-CoV-2 viruses. Additionally, we determined two cryo-electron microscopy (EM) complex structures of golden hamster ACE2 (ghACE2)/delta RBD and ghACE2/omicron BA.3 RBD. The residues Q34 and N82, which exist in many rodent ACE2s, are responsible for the lower binding affinity of ghACE2 compared to hACE2. These findings suggest that all SARS-CoV-2 VOCs may infect hamsters, highlighting the necessity of further surveillance of SARS-CoV-2 in these animals.IMPORTANCESARS-CoV-2 can infect many domestic animals, including hamsters. There is an urgent need to understand the binding mechanism of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants to hamster receptors. Herein, we showed that two hamster angiotensin-converting enzyme 2s (ACE2s) (golden hamster ACE2 and Chinese hamster ACE2) can bind to the spike protein receptor-binding domains (RBDs) of SARS-CoV-2 prototype and eight variants and that pseudotyped SARS-CoV-2 viruses can infect hamster ACE2-expressing cells. The binding pattern of golden hamster ACE2 to SARS-CoV-2 RBDs is similar to that of Chinese hamster ACE2. The two hamster ACE2s present slightly lower affinity for the RBDs of all nine SARS-CoV-2 viruses tested than human ACE2. We solved the cryo-electron microscopy (EM) structures of golden hamster ACE2 in complex with delta RBD and omicron BA.3 RBD and found that residues Q34 and N82 are responsible for the lower binding affinity of ghACE2 compared to hACE2. Our work provides valuable information for understanding the cross-species transmission mechanism of SARS-CoV-2.

WAY-262611 ameliorates the inflammatory bowel disease by activating Wnt/ß-catenin pathway.

Inflammatory bowel disease (IBD) is a non-specific and relapsing intestinal inflammation. The injury and repair of intestinal epithelial together determine the occurrence and development of IBD. Wnt/ß-catenin pathway is considered as the key role in the proliferation and differentiation of intestinal stem cells which is negative regulated by Dickkiop (DKKs). WAY-262611 is a novel inhibitor of DKK-1, and has demonstrated therapeutic effect on some disease including osteoporosis. Thus, we investigated the effect of WAY-262611 on IBD. Firstly, a mice model of IBD was established by DSS induction, by which the expression of Wnt3a and DKK-1 were detected by immumohistochemical staining to display their correlation. Next, using WAY-262611 the ameliorative effect on IBD was validated by histopathological staining. Using Mode-k cells the experiments in vitro were also conducted, in which the viability and apoptosis were determined. By detecting expression of Wnt3a and DKK-1 and observing nuclear translocation of ß-catenin, the activation of Wnt/ß-catenin pathway was validated. Finally, the incidence of the orthotopic colorectal cancer was calculated under continuous administration by DSS. Results demonstrated that the expression of Wnt3a is negative correlated with DKK-1. WAY-262611 ameliorated the IBD and reduced apoptosis of Mode-k cells induced by DSS. The protective effect of WAY-262611 on Mode-k cells is mediated by Wnt/ß-catenin pathway activation. In addition, WAY-262611 lowered the incidence rate of orthotopic colorectal cancer. All these results concluded that WAY-262611 could mitigate the IBD by activating Wnt/ß-catenin pathway in mice.

Physical and psychological correlates of somatic symptom in patients with functional constipation: a cross-sectional study.

BACKGROUND: The symptoms of functional constipation (FC) were obviously affected by mental symptoms, which was consistent with somatic symptoms. However, the characteristics of FC patients with somatic symptom remains unexplored. METHODS: Clinical characteristics including somatic symptom (SOM, PHQ-15), depression (PHQ-9), anxiety (GAD-7), quality of life (PAC-QOL), constipation (KESS), demographic variables, anatomical abnormalities and symptoms were investigated. Subsequent analyses encompassed the comparison of clinical parameters between patients with SOM + group (PHQ-15 ≥ 10) and SOM- group (PHQ-15 < 10), subgroup analysis, correlation analysis, and logistic regression. Lastly, we evaluated the somatic symptom severity (SSS) among FC patients subjected to various stressors. RESULTS: Notable disparities were observed between SOM + and SOM- groups in variety of physiological and psychological variables, including gender, stressful events, sleep disorders, reduced interest, GAD-7, PHQ-15, PHQ-9, PAC-QOL, anterior rectocele, KESS, and internal anal sphincter achalasia (IASA) (P < 0.05). Subgroup analysis affirmed consistent findings across mental symptoms. Correlation analyses revealed significant associations between SSS and KESS, anterior rectocele, GAD-7, PHQ-9, and PAC-QOL (P < 0.05). Logistic regression identified PHQ-9 (OR = 7.02, CI: 2.06-27.7, P = 0.003), GAD-7 (OR = 7.18, CI: 2.00-30.7, P = 0.004), and KESS (OR = 16.8, CI: 3.09-113, P = 0.002) as independent predictors of SSS. Elevated SSS scores were significantly associated with couple, parental, and work-related stressors (P < 0.05). CONCLUSION: A marked heterogeneity was observed between SOM + and SOM- patients of FC, with SOM + accompanied by more severe constipation, anxiety and depression symptoms. This finding underscores the importance of considering somatic symptoms in diagnosis and treatment of FC.

Costunolide attenuates LPS-induced inflammation and lung injury through inhibiting IKK/NF-κB signaling.

Inflammation is an important pathological process of many acute and chronic diseases, such as sepsis, arthritis, and cancer. Many factors can lead to an inflammatory state of the body, among which bacterial infection plays an important role. Bacterial infection often leads to sepsis, acute lung injury (ALI), or its more serious form of acute respiratory distress syndrome, which are the main fatal diseases in intensive care units. Costunolide has been reported to possess excellent anti-inflammatory activity; however, whether it can affect inflammation induced by gram-negative bacterial is still unclear. Lipopolysaccharide (LPS) stimulated mouse peritoneal macrophages (MPMs) to release proinflammatory cytokines was used as the cell model. The mouse model of sepsis and ALI was built through injecting intravenously and intratracheally of LPS. In the present study, costunolide inhibited LPS-induced inflammatory response through IKK/NF-κB signaling pathway in macrophages. In vivo, costunolide attenuated LPS-induced septic death in mice. Meanwhile, costunolide treatment alleviated LPS-induced lung injury and inflammation via inhibiting the infiltration of inflammatory cells and the expression of inflammatory cytokines. Taken together, these results demonstrated that costunolide could attenuate gram-negative bacterial induced inflammation and diseases and might be a potential candidate for the treatment of inflammatory diseases.

Comprehensive Analysis of Alternative Polyadenylation Events Associated with the Tumor Immune Microenvironment in Colon Adenocarcinoma.

Objective: Colon adenocarcinoma (COAD) is one of the leading causes of cancer death worldwide. Alternative polyadenylation (APA) is relevant to the variability of the 3'-UTR of mRNA. However, the posttranscriptional dysregulation of APA in COAD is poorly understood. Methods: We collected APA data from The Cancer Genome Atlas (TCGA) COAD (n =7692). APA events were evaluated using PDUI values, and the prognostically significant APA events were screened by LASSO Cox regression to construct a prognostic model. Then, prognostic model functions and possible regulatory genes of characteristic APA events were analyzed. Finally, the immune regulatory network based on APA regulatory genes was analyzed and established. Results: A total of 95 APA events were found to influence the COAD outcomes. Among them, 39 genes were screened as characteristic prognostic APA events by LASSO Cox regression to construct a COAD prognostic signature. The analysis results suggested that a high signature score was associated with poor prognosis and was significantly correlated with a variety of immune cells, including NK and Th1, 2 and 17 cells. Further analysis showed that APA regulators mainly served roles in the prognosis of COAD. Based on the above results, we constructed an immunoregulatory network for APA regulatory genes-APA genes-immune cells. Conclusion: Our study revealed that APA events in COAD may regulate tumor progression by influencing immune cells, which provides a new direction for exploring the influencing mechanism of the tumor immune microenvironment and is expected to provide a potential new target for COAD immunotherapy.

The Tyrosine Phosphatase Activity of PTPN22 Is Involved in T Cell Development via the Regulation of TCR Expression.

The protein tyrosine phosphatase PTPN22 inhibits T cell activation by dephosphorylating some essential proteins in the T cell receptor (TCR)-mediated signaling pathway, such as the lymphocyte-specific protein tyrosine kinase (Lck), Src family tyrosine kinases Fyn, and the phosphorylation levels of Zeta-chain-associated protein kinase-70 (ZAP70). For the first time, we have successfully produced PTPN22 CS transgenic mice in which the tyrosine phosphatase activity of PTPN22 is suppressed. Notably, the number of thymocytes in the PTPN22 CS mice was significantly reduced, and the expression of cytokines in the spleen and lymph nodes was changed significantly. Furthermore, PTPN22 CS facilitated the positive and negative selection of developing thymocytes, increased the expression of the TCRαß-CD3 complex on the thymus cell surface, and regulated their internalization and recycling. ZAP70, Lck, Phospholipase C gamma1(PLCγ1), and other proteins were observed to be reduced in PTPN22 CS mouse thymocytes. In summary, PTPN22 regulates TCR internalization and recycling via the modulation of the TCR signaling pathway and affects TCR expression on the T cell surface to regulate negative and positive selection. PTPN22 affected the development of the thymus, spleen, lymph nodes, and other peripheral immune organs in mice. Our study demonstrated that PTPN22 plays a crucial role in T cell development and provides a theoretical basis for immune system construction.

Exergy destruction analysis of a power generation system utilizing the cold energy of LNG.

The purpose of this research is in-depth understanding of the internal causes of exergy destruction in various parts of the system and to identify potential improvements for the components. The focus is on a combined cycle power generation system that utilizes the organic Rankine cycle (ORC) and direct expansion cycle (DEC). To investigate the primary sources of exergy destruction in each component, advanced exergy analysis (AEA) is utilized. The result demonstrates that the net out power of the proposed system can reach 106.64 kW with energy efficiency of 11.22%, and exergy efficiency of 21.40%. The heat exchanger is identified as the primary contributor to exergy destruction, constituting 81.70% of the total ratio. Specifically, the condenser exhibits the highest exergy destruction ratio at 59.82%, indicating a need for prioritized optimization efforts. The findings of AEA reveal that the primary source of component irreversibility stems from the endogenous part. This shows that, while most exergy destruction is unavoidable, there remains room for system improvement. Regarding the turbine, its exergy destruction is primarily attributed to inefficiencies, leading to irreversibility. Nevertheless, there is exergy destruction that may be avoidable and can be reduced by 25.93 kW, which is 2.5 times greater than that of the heat exchanger. This finding underscores the high potential for improvement in ORC and DEC turbines, making them a priority for optimization efforts.

Association of CDX2 and mucin expression with chemotherapeutic benefits in patients with stage II/III gastric cancer.

BACKGROUND: Better predictors of patients with stage II/III gastric cancer (GC) most likely to benefit from adjuvant chemotherapy are urgently needed. This study aimed to assess the ability of CDX2 and mucin markers to predict prognosis and fluorouracil-based adjuvant chemotherapy benefits. METHODS: CDX2 and mucin protein expressions were examined by immunohistochemistry and compared with survival and adjuvant chemotherapy benefits in a prospective evaluation cohort of 782 stage II/III GC patients. Then, the main findings were validated in an independent validation cohort (n = 386) and an external mRNA sequencing dataset (ACRG cohort, n = 193). RESULTS: In the evaluation cohort, CDX2, CD10, MUC2, MUC5AC, and MUC6 expressions were observed in 59.7%, 26.7%, 27.6%, 55.1%, and 57.7% of patients, respectively. However, only the expression of CDX2 was found to be associated with adjuvant chemotherapy benefits. Most importantly, CDX2-negative patients had a poorer prognosis when treated with surgery only, while the prognosis of CDX2-negative and CDX2-positive patients was similar when receiving postoperative adjuvant chemotherapy. Further analysis revealed that patients with CDX2 negative tumors benefited from chemotherapy (5-year overall survival rates: 60.0% with chemotherapy vs. 23.2% with surgery-only, p < 0.001), whereas patients with CDX2 positive tumors did not (pinteraction = 0.004). Consistent results were obtained in the validation and ACRG cohorts. CONCLUSIONS: Negative expression of CDX2 is an independent risk factor for survival in stage II/III GC, but subsequent adjuvant chemotherapy is able to compensate for this unfavorable effect. Therefore, active chemotherapy is more urgent for patients with negative CDX2 expression than for patients with positive CDX2 expression.

Climate Penalty on Air Pollution Abated by Anthropogenic Emission Reductions in the United States.

Climate change poses direct and indirect threats to public health, including exacerbating air pollution. However, how a warmer temperature deteriorates air quality, known as the "climate penalty" effect, remains highly uncertain in the United States, particularly under rapid reduction in anthropogenic emissions. Here we examined the sensitivity of surface-level fine particulate matter (PM2.5) and ozone (O3) to summer temperature anomalies in the contiguous US and their decadal changes using high-resolution datasets generated by machine learning models. Our findings demonstrate that, in the eastern US, efficient emission control strategies have significantly reduced the climate penalty effects on PM2.5 and O3, lowering the associated population exposure. In contrast, summer and annual PM2.5 in the western US became more sensitive to temperature, highlighting the urgent need for the management and mitigation of worsening wildfires. Our results have important implications for air quality management and risk assessments of future climate change.

Genetic analysis of stripe rust resistance in the common wheat line Kfa/2*Kachu under a Chinese rust environment.

KEY MESSAGE: We mapped a new race-specific seedling stripe rust resistance gene on wheat chromosome 5BL and a new APR locus QYr.hazu-2BS from CIMMYT wheat line Kfa/2*Kachu. Breeding resistant wheat (Triticum aestivum) varieties is the most economical and efficient way to manage wheat stripe rust, but requires the prior identification of new resistance genes and development of associated molecular markers for marker-assisted selection. To map stripe rust resistance loci in wheat, we used a recombinant inbred line population generated by crossing the stripe rust-resistant parent 'Kfa/2*Kachu' and the susceptible parent 'Apav#1'. We employed genotyping-by-sequencing and bulked segregant RNA sequencing to map a new race-specific seedling stripe rust resistance gene, which we designated YrK, to wheat chromosome arm 5BL. TraesCS5B02G330700 encodes a receptor-like kinase and is a high-confidence candidate gene for YrK based on virus-induced gene silencing results and the significant induction of its expression 24 h after inoculation with wheat stripe rust. To assist breeding, we developed functional molecular markers based on the polymorphic single nucleotide polymorphisms in the coding sequence region of YrK. We also mapped four adult plant resistance (APR) loci to wheat chromosome arms 1BL, 2AS, 2BS and 4AL. Among these APR loci, we determined that QYr.hazu-1BL and QYr.hazu-2AS are allelic to the known pleiotropic resistance gene Lr46/Yr29/Pm39 and the race-specific gene Yr17, respectively. However, QYr.hazu-2BS is likely a new APR locus, for which we converted closely linked SNP polymorphisms into breeder-friendly Kompetitive allele-specific PCR (KASP) markers. In the present study, we provided new stripe rust resistance locus/gene and molecular markers for wheat breeder to develop rust-resistant wheat variety.

Genetic dissection of grain morphology and yield components in a wheat line with defective grain filling.

KEY MESSAGE: We identified stable QTL for grain morphology and yield component traits in a wheat defective grain filling line and validated genetic effects in a panel of cultivars using breeding-relevant markers. Grain filling capacity is essential for grain yield and appearance quality in cereal crops. Identification of genetic loci for grain filling is important for wheat improvement. However, there are few genetic studies on grain filling in wheat. Here, a defective grain filling (DGF) line wdgf1 characterized by shrunken grains was identified in a population derived from multi-round crosses involving nine parents and a recombinant inbreed line (RIL) population was generated from the cross between wdgf1 and a sister line with normal grains. We constructed a genetic map of the RIL population using the wheat 15K single nucleotide polymorphism chip and detected 25 stable quantitative trait loci (QTL) for grain morphology and yield components, including three for DGF, eleven for grain size, six for thousand grain weight, three for grain number per spike and two for spike number per m2. Among them, QDGF.caas-7A is co-located with QTGW.caas-7A and can explain 39.4-64.6% of the phenotypic variances, indicating that this QTL is a major locus controlling DGF. Sequencing and linkage mapping showed that TaSus2-2B and Rht-B1 were candidate genes for QTGW.caas-2B and the QTL cluster (QTGW.caas-4B, QGNS.caas-4B, and QSN.caas-4B), respectively. We developed kompetitive allele-specific PCR markers tightly linked to the stable QTL without corresponding to known yield-related genes, and validated their genetic effects in a diverse panel of wheat cultivars. These findings not only lay a solid foundation for genetic dissection underlying grain filling and yield formation, but also provide useful tools for marker-assisted breeding.

A splicing mutation of the FLCN gene is associated with Birt-Hogg-Dubé syndrome characterized by familial and recurrent spontaneous pneumothorax: A case report.

RATIONALE: Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal recessive genetic disorder caused mainly by mutations in the tumor suppressor FLCN gene. Tumors caused by FLCN mutations are frequently benign and develop in skin, lungs, kidney, and other organs, leading to a variety of phenotypes that make early diagnoses of BHD challenging. PATIENT CONCERNS: A 51-year-old female was admitted to Shanghai Seventh People Hospital due to chest congestion and dyspnea that had persisted for 3 years and aggravated for 1 month. She had been diagnosed with pneumothorax prior to this submission, but the etiology was unknown. DIAGNOSES: Chest computed tomography (CT) revealed multiple pulmonary cysts and pneumothorax, and her family members shared similar manifestation. Whole-exome sequencing analysis indicated a heterozygous FLCN splicing mutation (c.1432 + 1G > A; rs755959303), which was a pathogenic variant indicated in ClinVar. Based on FLCN mutation and the family history of pulmonary cysts and pneumothorax, BHD syndrome was finally diagnosed, which had been delayed for 3 years since her first pneumothorax. INTERVENTIONS: Pulmonary bullectomy and pleurodesis were finally conducted due to the poor effects of thoracic close drainage. OUTCOMES: Her pneumothorax was resolved, and no recurrence was found in 2 years. LESSONS: Our study highlights the importance of genetic analysis in diagnosis and clinical management of BHD syndrome.

Structural basis for receptor binding and broader interspecies receptor recognition of currently circulating Omicron sub-variants.

Multiple SARS-CoV-2 Omicron sub-variants, such as BA.2, BA.2.12.1, BA.4, and BA.5, emerge one after another. BA.5 has become the dominant strain worldwide. Additionally, BA.2.75 is significantly increasing in some countries. Exploring their receptor binding and interspecies transmission risk is urgently needed. Herein, we examine the binding capacities of human and other 28 animal ACE2 orthologs covering nine orders towards S proteins of these sub-variants. The binding affinities between hACE2 and these sub-variants remain in the range as that of previous variants of concerns (VOCs) or interests (VOIs). Notably, R493Q reverse mutation enhances the bindings towards ACE2s from humans and many animals closely related to human life, suggesting an increased risk of cross-species transmission. Structures of S/hACE2 or RBD/hACE2 complexes for these sub-variants and BA.2 S binding to ACE2 of mouse, rat or golden hamster are determined to reveal the molecular basis for receptor binding and broader interspecies recognition.

PTPN22 activates the PI3K pathway via 14-3-3τ in T cells.

The protein tyrosine phosphatase PTPN22 inhibits T cell activation by dephosphorylating some essential proteins in the T cell receptor-mediated signalling pathway, and its negative regulatory function protects organisms from autoimmune disease. 14-3-3τ is an adaptor protein that regulates target protein function through its intracellular localization. In the present study, we determined that PTPN22 binds to 14-3-3τ via the PTPN22-Ser640 phosphorylation side. PTPN22 binding to 14-3-3τ resulted in 14-3-3τ-Tyr179 dephosphorylation, and reduced the association between 14-3-3τ and Shc, which competitively increased 14-3-3ζ binding to Shc and activated phosphoinositide 3-kinase (PI3K) by bringing it to the membrane. In addition, PTPN22 decreased the tyrosine phosphorylation of p110 to activate PI3K. These two pathways cooperatively affect PI3K activity and the expression of PI3K downstream proteins, such as phosphorylated Akt, mammalian target of rapamycin and forkhead box O1, which inhibited the expression of some proinflammatory factors such as interleukin-1ß, interleukin-2, interleukin-6, interferon-γ and tumour necrosis factor-α. Our research provides a preliminary theory for PTPN22 regulating T cell activation, development and immune response via the PI3K/Akt/mammalian target of rapamycin pathway and brings new information for clarifying the functions of PTPN22 in autoimmune diseases.

Temporal variations of 7Be and 210Pb activity concentrations in the atmospheric aerosols during 2018-2019 in Beijing, China and their correlations with meteorological parameters.

In order to establish a regional database on natural radioactivity, a series of measurements of 713 atmospheric aerosol samples collected on filters over a two-year period (2018-2019) in center of Beijing, northeastern China have been performed to analyze 7Be and 210Pb activity concentrations. The mean activity concentrations of 7Be and 210Pb were found to be 7.10 ± 2.44 mBq m-3 and 2.93 ± 1.52 mBq m-3, respectively. Both the radionuclides exhibited strong seasonal variations, with maximum concentration of 7Be occurring in the spring and that of 210Pb in the winter. The concentration of both the radionuclides was minimum in the rainy summer. Higher 7Be concentration in the spring was mainly caused by the stratosphere to troposphere exchange. Higher 210Pb concentration during winter was maybe attributed to the combustion processes in heating systems and the ingression of continental air masses resulted from winds originating from northwest. The dependence of the activity concentrations of 7Be and 210Pb with meteorological parameters such as rainfall, temperature, and humidity was studied through linear correlation analysis. Statistically significant negative correlations were observed between 7Be and 210Pb activity concentrations with rainfall, respectively, which suggested that the removal mechanisms of these two radionuclides were similar. Lead-210 showed statistically significant correlations with temperature, humidity and PM10. A comparison of the data obtained in the present study for Beijing with the northern hemisphere literature values of 7Be and 210Pb in the atmospheric aerosols showed that the values were smaller than the ones observed in the present study. Overall, the study provides an improved understanding of the temporal variability and correlation of 7Be and 210Pb concentrations in the atmosphere in center of Beijing, northeastern China.

Multilevel proteomic analyses reveal molecular diversity between diffuse-type and intestinal-type gastric cancer.

Diffuse-type gastric cancer (DGC) and intestinal-type gastric cancer (IGC) are the major histological types of gastric cancer (GC). The molecular mechanism underlying DGC and IGC differences are poorly understood. In this research, we carry out multilevel proteomic analyses, including proteome, phospho-proteome, and transcription factor (TF) activity profiles, of 196 cases covering DGC and IGC in Chinese patients. Integrative proteogenomic analysis reveals ARIDIA mutation associated with opposite prognostic effects between DGC and IGC, via diverse influences on their corresponding proteomes. Systematical comparison and consensus clustering analysis identify three subtypes of DGC and IGC, respectively, based on distinct patterns of the cell cycle, extracellular matrix organization, and immune response-related proteins expression. TF activity-based subtypes demonstrate that the disease progressions of DGC and IGC were regulated by SWI/SNF and NFKB complexes. Furthermore, inferred immune cell infiltration and immune clustering show Th1/Th2 ratio is an indicator for immunotherapeutic effectiveness, which is validated in an independent GC anti-PD1 therapeutic patient group. Our multilevel proteomic analyses enable a more comprehensive understanding of GC and can further advance the precision medicine.