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Histidine phosphorylation (pHis), occurring on the histidine of substrate proteins, is a hidden phosphoproteome that is poorly characterized in mammals. LHPP (phospholysine phosphohistidine inorganic pyrophosphate phosphatase) is one of the histidine phosphatases and its encoding gene was recently identified as a susceptibility gene for major depressive disorder (MDD). However, little is known about how LHPP or pHis contributes to depression. Here, by using integrative approaches of genetics, behavior and electrophysiology, we observed that LHPP in the medial prefrontal cortex (mPFC) was essential in preventing stress-induced depression-like behaviors. While genetic deletion of LHPP per se failed to affect the mice's depression-like behaviors, it markedly augmented the behaviors upon chronic social defeat stress (CSDS). This augmentation could be recapitulated by the local deletion of LHPP in mPFC. By contrast, overexpressing LHPP in mPFC increased the mice's resilience against CSDS, suggesting a critical role of mPFC LHPP in stress-induced depression. We further found that LHPP deficiency increased the levels of histidine kinases (NME1/2) and global pHis in the cortex, and decreased glutamatergic transmission in mPFC upon CSDS. NME1/2 served as substrates of LHPP, with the Aspartic acid 17 (D17), Threonine 54 (T54), or D214 residue within LHPP being critical for its phosphatase activity. Finally, reintroducing LHPP, but not LHPP phosphatase-dead mutants, into the mPFC of LHPP-deficient mice reversed their behavioral and synaptic deficits upon CSDS. Together, these results demonstrate a critical role of LHPP in regulating stress-related depression and provide novel insight into the pathogenesis of MDD.

People who inject drugs (PWIDs) are primarily the high-risk population for HCV infection. This study aims to determine the optimal cut-off values for predicting HCV infection status based on the Signal-to-Cutoff (S/CO) ratio. In this study, a total of 719 PWIDs' samples were collected, and performed for screening test by ELISA assay, and followed by RIBA assay and NAT assay to detect HCV antibody and HCV RNA levels, respectively. The findings revealed that the prevalence of HCV infection among PWIDs was 54.66% (393/719), and the false-positive rate of HCV antibody detection by ELISA assay among PWIDs was only 3.85% (16/416). In addition, when the optimal cut-off value for S/CO ratio was 2.0, the sensitivity and specificity of HCV antibody were 100.00% and 93.55%, respectively. And when the optimal cut-off value for S/CO ratio was 21.36, the sensitivity and specificity of HCV RNA positive were 89.90% and 72.73%, respectively. In conclusion, the status of HCV infection can be predicted based on the S/CO ratios of the ELISA assay, which can improve diagnosis and facilitate timely treatment to effectively prevent the spread of HCV infection.

Patients with severe psoriasis are prone to deterioration of renal function. Whether biologics with potent anti-inflammatory action can prevent deterioration of renal function in psoriatic patients was unclear.To investigate the effects of different biologics on renal function in patients with severe psoriasis.By using the Chang Gung Research Database in Taiwan during 2006-2018, we analyzed the changes in renal function of psoriatic patients from 2 years before biologic treatments to baseline (start of biologic treatment) to after 2 years' treatment with different classes of biologics (anti-TNF, anti-IL-12/23, and anti-IL-17 agents). The renal function was evaluated by estimated glomerular filtration rate (eGFR) and the staging of chronic kidney disease (CKD). We further analyzed the risk factors of progression on the staging of CKD during biologics treatment.We included 601 patients with severe psoriasis receiving continuous use of biologics for ≥ 2 years. We detected no significant differences between pre-biologic treatment with conventional systemic treatment and post-biologic treatment in the levels of eGFR and progression of CKD staging among psoriatic patients receiving different classes of biologics. Most patients (97.8%) remained at stable CKD stage, while progression of CKD stage over time occurred in 13 patients (2.2%), with seven treated with anti-TNF biologics and six treated with anti-IL-12/23 biologics. Of note, all 52 patients receiving anti-IL-17 biologics had stable CKD. Progression of CKD during biologics use was associated with lower baseline levels of eGFR, higher baseline CKD stage, older age, diabetes, and dyslipidemia. Further multiple logistic regression analysis showed diabetes as an independent factor for the deterioration of renal function during biologic treatment.Biologic treatments failed to improve but did not worsen renal function of psoriatic patients during a 2-year follow-up period. Diabetes is an important risk factor for the deterioration of renal function.

A novel rice resistance gene, Xo2, influencing pathogenesis of the bacterial leaf streak disease, has been identified, and candidate genes for Xo2 in the fine mapping region have been shown to be involved in bacterial leaf streak resistance. Rice (Oryza sativa) bacterial leaf streak, caused by Xanthomonas oryzae pv. oryzicola (Xoc), is one of the most serious rice bacterial diseases. The deployment of host resistance genes is an effective approach for controlling this disease. The cultivar BHADOIA 303 (X455) from Bangladesh is resistant to most of Chinese Xoc races. To identify and map the resistance gene(s) involved in Xoc resistance, we examined the association between phenotypic and genotypic variations in two F

Quantum conference key agreement is an important cryptographic primitive for future quantum network. Realizing this primitive requires high-brightness and robust multiphoton entanglement sources, which is challenging in experiment and unpractical in application because of limited transmission distance caused by channel loss. Here we report a measurement-device-independent quantum conference key agreement protocol with enhanced transmission efficiency over lossy channel. With spatial multiplexing nature and adaptive operation, our protocol can break key rate bounds on quantum communication over quantum network without quantum memory. Compared with previous work, our protocol shows superiority in key rate and transmission distance within the state-of-the-art technology. Furthermore, we analyse the security of our protocol in the composable framework and evaluate its performance in the finite-size regime to show practicality. Based on our results, we anticipate that our protocol will play an indispensable role in constructing multipartite quantum network., 9 pages, 4 figures, 1 table

Vascular smooth muscle cells (VSMCs) are involved in restenosis of bypass grafts and cause artery graft occlusion. This study aimed to explore the role of Slit2 in phenotypic switching of VSMCs and its effect on restenosis of vascular conduits. An animal model of vascular graft restenosis (VGR) was produced in SD rats and assessed by echocardiography. The expression of Slit2 and Hif-1α was measured in vivo and in vitro. After Slit2 overexpression, the migration and proliferation of VSMCs were detected in vitro, and the restenosis rates and phenotype of VSMCs were tested in vivo. The arteries of the VGR model presented significant stenosis, and Slit2 was decreased in VSMCs of the VGR model. In vitro, Slit2 overexpression inhibited the migration and proliferation of VSMCs, but Slit2 knockdown promoted migration and proliferation. Hypoxia induced Hif-1α but reduced Slit2, and Hif-1α negatively regulated Slit2 expression. Moreover, Slit2 overexpression weakened the rate of VGR and maintained the patency of artery bypass grafts, which suppressed the phenotypic switching of VSMCs. Slit2 inhibited the synthetic phenotype transformation to inhibit the migration and proliferation of VSMCs and delayed the VGR via Hif-1α.

Osteoporosis is characterized by decreased bone mass, microarchitectural deterioration, and increased bone fragility. High-fat diet (HFD)-induced obesity also results in bone loss, which is associated with an imbalanced gut microbiome. However, whether HFD-induced obesity or HFD itself promotes osteoclastogenesis and consequent bone loss remains unclear. In this study, we developed HFD-induced obesity (HIO) and non-obesity (NO) mouse models to evaluate the effect of HFD on bone loss. NO mice were defined as body weight within 5% of higher or lower than that of chow diet fed mice after 10 weeks HFD feeding. NO was protected from HIO-induced bone loss by the RANKL /OPG system, with associated increases in the tibia tenacity, cortical bone mean density, bone volume of cancellous bone, and trabecular number. This led to increased bone strength and improved bone microstructure via the microbiome-short-chain fatty acids (SCFAs) regulation. Additionally, endogenous gut-SCFAs produced by the NO mice activated free fatty acid receptor 2 and inhibited histone deacetylases, resulting in the promotion of Treg cell proliferation in the HFD-fed NO mice; thereby, inhibiting osteoclastogenesis, which can be transplanted by fecal microbiome. Furthermore, T cells from NO mice retain differentiation of osteoclast precursors of RAW 264.7 macrophages ex vivo. Our data reveal that HFD is not a deleterious diet; however, the induction of obesity serves as a key trigger of bone loss that can be blocked by a NO mouse-specific gut microbiome.

Anthropogenic heat release (AHR) is the release of heat generated by anthropogenic energy consumption. The global mean flux of AHR is 0.03 W m−2, while AHR is geographically concentrated and fundamentally correlates with economic activity; furthermore, AHR can reach a level sufficient for impacting regional even large-scale climate. In this study, the impacts of AHR on the summer European heatwaves (EHWs) are examined by using the Community Earth System Model version 1 (CESM1). The results show that in Europe, AHR increases the summer mean 2-m temperature by 0.26 °C and the surface minimum and maximum temperatures by 0.14 °C and 0.41 °C, respectively. AHR exacerbates the extreme high temperatures in the summer in Europe, increasing EHW days by 1–2 days in central and eastern Europe in the summer annually from 1992 to 2013. AHR strengthens the surface wind that flows from the ocean to the land in Europe by increasing the land surface temperatures. AHR decreases the lower-troposphere stability (LTS) and reduces the low-cloud amounts in Europe, which leads to more solar shortwave radiation reaching the surface. AHR affects water vapor and the surface energy balance in Europe, which impacts on European summer heatwaves further. AHR acts as a non-negligible factor for summer extreme high temperature in Europe and a potential factor impacting EHW days.

GDP-amylose transporter protein 1 (SLC35C1) plays an important role in many types of cancer. Therefore, it is clinically important to further investigate the expression profile of SLC35C1 in human tumors to provide new molecular clues for the pathogenesis of glioma. In this study, we performed a comprehensive pan-cancer analysis of SLC35C1 using a series of bioinformatics approaches and validated its differential tissue expression and biological function. The results showed that SLC35C1 was aberrantly expressed in different types of tumors and significantly correlated with overall survival (OS) and progression-free interval (PFI). More importantly, the expression level of SLC35C1 was closely correlated with Tumor Microenvironment (TME), immune infiltration and immune-related genes. In addition, we found that SLC35C1 expression was also closely related to Tumor Mutation Burden (TMB), Microsatellite Instability (MSI) and antitumor drug sensitivity in various cancer types. Functional bioinformatics analysis indicated that SLC35C1 may be involved in multiple signaling pathways and biological processes in glioma. Based on SLC35C1 expression, a risk factor model was found to predict OS of glioma. In addition, in vitro experiments showed that SLC35C1 knockdown significantly inhibited the proliferation, migration and invasive ability of glioma cells, while SLC35C1 overexpression promoted proliferation, migration, invasion and colony formation of glioma cells. Finally, quantitative real-time PCR confirmed that SLC35C1 was highly expressed in gliomas.

Background Malnutrition is a common complication after stroke and may worsen neurological outcomes for patients. There are still no uniform tools for screening nutritional status for the patients with stroke. We aimed to explore the relationship between the baseline geriatric nutritional risk index (GNRI) and neurological function at the convalescence stage for patients with stroke and assessed the predictive value of the GNRI for adverse neurological outcomes. Methods A total of 311 patients with stroke were enrolled retrospectively. Basic information and laboratory results on admission since onset of stroke were collected. The GNRI on admission was calculated and neurological outcomes evaluated by the Barthel index at 1 month after the onset of stroke. Statistical analyses, including correlation coefficient tests, multivariate regression analyses, and receiver operating characteristic (ROC) analyses, were applied in this study. Results Compared with the good outcome group, the poor outcome group showed a significantly lower GNRI on admission (P P P P P for trend P P Conclusions For patients with stroke, higher nutritional risk grades at baseline indicated worse neurological function at the convalescence stage. Compared with NIHSS, BMI, and Albumin, GNRI was a competitive indicator for the risk of poor neurological outcome. The predictive property of GNRI for adverse neurological outcomes might be more powerful when combined with NIHSS.

Genomic studies have demonstrated a high frequency of genetic alterations in components of the SWI/SNF complex including the core subunit SMARCA4. However, the mechanisms of tumorigenesis driven by SMARCA4 mutations, particularly in colorectal cancer (CRC), remain largely unknown. In this study, we identified a specific, hotspot mutation in SMARCA4 (c. 3721C>T) which results in a conversion from arginine to tryptophan at residue 1157 (R1157W) in human CRC tissues associated with higher-grade tumors and controls CRC progression. Mechanistically, we found that the SMARCA4R1157W mutation facilitated its recruitment to PRMT1-mediated H4R3me2a (asymmetric dimethylation of Arg 3 in histone H4) and enhanced the ATPase activity of SWI/SNF complex to remodel chromatin in CRC cells. We further showed that the SMARCA4R1157W mutant reinforced the transcriptional expression of EGFR and TNS4 to promote the proliferation of CRC cells and patient-derived tumor organoids. Importantly, we demonstrated that SMARCA4R1157W CRC cells and mutant cell-derived xenografts were more sensitive to the combined inhibition of PRMT1 and SMARCA4 which act synergistically to suppress cell proliferation. Together, our findings show that SMARCA4-R1157W is a critical activating mutation, which accelerates CRC progression through facilitating chromatin recruitment and remodeling. Our results suggest a potential precision therapeutic strategy for the treatment of CRC patients carrying the SMARCA4R1157W mutation.

Background The aim of this study was to investigate the prevalence and risk factors of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae related urinary tract infections (UTI) in adult cancer patients. Methods We conducted a retrospective study of three cancer hospitals centered on Cancer Hospital of Chinese Academy of Medical Sciences from 2015 to 2019. The clinical characters, risk factors and antimicrobial susceptibility of ESBL-producing Enterobacteriaceae UTI in adult cancer patients were described and analyzed. Results A total of 4967 specimens of UTI were evaluated, of which 909 were positive. After excluding multiple infection bacteria, non-conforming strains, inconsistent pathological information, no drug sensitivity test or medical records, 358 episodes remained. Among them, 160 episodes belonged to ESBL-producing Enterobacteriaceae, while 198 were classified into non-ESBL group. The prevalence of ESBL UTI circled around 39.73 to 53.03% for 5 years. Subgroup analysis by tumor type revealed that 62.5% of isolates from patients with urological tumors were ESBL positive. Multivariate analysis showed that tumor metastasis (OR 3.41, 95%CI 1.84–6.30), urological cancer (OR 2.96, 95%CI 1.34–6.53), indwelling catheter (OR 2.08, 95%CI 1.22–3.55) and surgery or invasive manipulation (OR 1.98, 95%CI 1.13–3.50) were the independent risk factors. According to antimicrobial sensitivity, meropenem, imipenem and piperacillin/tazobactam were the most commonly used antibiotics for ESBL-producing Enterobacteriaceae UTI. Conclusions In view of the high prevalence, clinicians should be alert to the occurrence of ESBL UTI, especially for patients with urological cancer or metastatic tumors. Regular replacement of urinary catheters, reduction of unnecessary invasive operations and selection of appropriate antibiotics are the necessary conditions to deal with the occurrence of ESBL UTI in adult cancer patients.

Current guidelines suggest antibiotics prophylaxis is not necessary for patients with orthopedic prosthetics undergoing gastrointestinal endoscopy. Clinical evidence to support this recommendation is lacking.To analyze the association between inpatient gastrointestinal endoscopy and prosthetic joint infection (PJI) in patients with a recent arthroplasty.We included patients admitted from July to October of each calendar year (index admissions) who had an arthroplasty in the same calendar year prior to the index admission. We followed the occurrence of PJI for 60 days after the index admission. Only admissions from July to October were chosen as index admissions, and the follow-up period was limited to 60 days because the database structure prohibits the analysis of events in different calendar years. We compared the rate of 60-day PJI between those who had gastrointestinal endoscopy on index admissions to those who had not. We excluded patients aged less than 18 years, who died on index admission, or had any infection in the same calendar year before or during the index admission.Of 1,831,218 patients with arthroplasty, 88,345 met the inclusion criteria, out of which 5,855 had gastrointestinal endoscopy. The rate of 60-day PJI in those who had endoscopy was 0.23%, and in those who had not was 0.52% (P 0.001). EGD without excision (adjusted odds ratio [95% confidence interval]: 0.20 [0.03-1.42], P = 0.107), EGD with excision (0.58 [0.21-1.60], P = 0.295), colonoscopy without excision (0.43 [0.11-1.72], P = 0.233), colonoscopy with excision (0.31 [0.04-2.21], P = 0.241), and PEG/PEJ (0.38 [0.05-2.71], P = 0.337) were not associated with risk of 60-day PJI. We found no PJI cases in patients underwent esophageal dilation, ERCP, and EUS with FNA.Gastrointestinal endoscopy in hospitalized patients with a recent previous arthroplasty is not associated with an increased risk of 60-day prosthetic joint infection.

To present the clinical characteristics and the misdiagnosis rate of acute coronary syndrome manifested primarily as throat discomfort, we conducted a multicentric and retrospective study in the cardiology and otorhinolaryngology departments. Records of patients with primary complaint of throat discomfort, absence of chest pain at onset, and an ultimate diagnosis of acute coronary syndrome, as well as patients with pharyngitis (as controls) were collected from May 2015 to April 2016. The patients' main manifestations were compared. Logistic regression results showed that chest tightness, dyspnea, perspiring, and exertional throat symptoms were significantly associated with acute coronary syndrome, with odds ratios of 8.3 (95% CI 2.2-31.5), 10.9 (95% CI 1.8-66.9), 25.4 (95% CI 3.6-179.9), and 81.2 (95% CI 13.0-506.7). A total of 25 (56.82%) out of 44 acute coronary syndrome patients, who were first admitted to the otorhinolaryngology department, were misdiagnosed, with a 12% (3/25) mortality rate. Throat discomfort can be the principal manifestation of acute coronary syndrome. Such patients exhibit high misdiagnosis and mortality rates. Exertional throat symptoms, chest tightness, perspiring, and dyspnea were important indicators of acute coronary syndrome in patients whose main complaint was throat discomfort. The awareness of this condition will result in prompt diagnosis and reduce morbidity and mortality.

Background Multiple myeloma (MM) is an incurable and relapse-prone disease with apparently prognostic heterogeneity. At present, the risk stratification of myeloma is still incomplete. Pyroptosis, a type of programmed cell death, has been shown to regulate tumor growth and may have potential prognostic value. However, the role of pyroptosis-related genes (PRGs) in MM remains undetermined. The aims of this study were to identify potential prognostic biomarkers and to construct a predictive model related to PRGs. Methods Sequencing and clinical data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Non-negative matrix factorization (NMF) was performed to identify molecular subtype screening. LASSO regression was used to screen for prognostic markers, and then a risk score model was constructed. The Maxstat package was utilized to calculate the optimal cutoff value, according to which patients were divided into a high-risk group and a low-risk group, and the survival curves were plotted using the Kaplan-Meier (K-M) method. Nomograms and calibration curves were established using the rms package. Results A total of 33 PRGs were extracted from the TCGA database underlying which 4 MM molecular subtypes were defined. Patients in cluster 1 had poorer survival than those in cluster 2 (p = 0.035). A total of 9 PRGs were screened out as prognostic markers, and the predictive ability of the 9-gene risk score for 3-year survival was best (AUC = 0.658). Patients in the high-risk group had worse survival than those in the low-risk group (p < 0.001), which was consistent with the results verified by the GSE2658 dataset. The nomogram constructed by gender, age, International Staging System (ISS) stage, and risk score had the best prognostic predictive performance with a c-index of 0.721. Conclusion Our model could enhance the predictive ability of ISS staging and give a reference for clinical decision-making. The new, prognostic, and pyroptosis-related markers screened out by us may facilitate the development of novel risk stratification for MM. Clinical trial registration Not applicable.

Background Triclosan [5-chloro-2-(2,4-dichlorophenoxy) phenol, TCS], a common antimicrobial additive in many personal care and health care products, is frequently detected in human blood and urine. Therefore, it has been considered an emerging and potentially toxic pollutant in recent years. Long-term exposure to TCS has been suggested to exert endocrine disruption effects, and promote liver fibrogenesis and tumorigenesis. This study was aimed at clarifying the underlying cellular and molecular mechanisms of hepatotoxicity effect of TCS at the initiation stage. Methods C57BL/6 mice were exposed to different dosages of TCS for 2 weeks and the organ toxicity was evaluated by various measurements including complete blood count, histological analysis and TCS quantification. Single cell RNA sequencing (scRNA-seq) was then carried out on TCS- or mock-treated mouse livers to delineate the TCS-induced hepatotoxicity. The acquired single-cell transcriptomic data were analyzed from different aspects including differential gene expression, transcription factor (TF) regulatory network, pseudotime trajectory, and cellular communication, to systematically dissect the molecular and cellular events after TCS exposure. To verify the TCS-induced liver fibrosis, the expression levels of key fibrogenic proteins were examined by Western blotting, immunofluorescence, Masson’s trichrome and Sirius red staining. In addition, normal hepatocyte cell MIHA and hepatic stellate cell LX-2 were used as in vitro cell models to experimentally validate the effects of TCS by immunological, proteomic and metabolomic technologies. Results We established a relatively short term TCS exposure murine model and found the TCS mainly accumulated in the liver. The scRNA-seq performed on the livers of the TCS-treated and control group profiled the gene expressions of > 76,000 cells belonging to 13 major cell types. Among these types, hepatocytes and hepatic stellate cells (HSCs) were significantly increased in TCS-treated group. We found that TCS promoted fibrosis-associated proliferation of hepatocytes, in which Gata2 and Mef2c are the key driving TFs. Our data also suggested that TCS induced the proliferation and activation of HSCs, which was experimentally verified in both liver tissue and cell model. In addition, other changes including the dysfunction and capillarization of endothelial cells, an increase of fibrotic characteristics in B plasma cells, and M2 phenotype-skewing of macrophage cells, were also deduced from the scRNA-seq analysis, and these changes are likely to contribute to the progression of liver fibrosis. Lastly, the key differential ligand-receptor pairs involved in cellular communications were identified and we confirmed the role of GAS6_AXL interaction-mediated cellular communication in promoting liver fibrosis. Conclusions TCS modulates the cellular activities and fates of several specific cell types (including hepatocytes, HSCs, endothelial cells, B cells, Kupffer cells and liver capsular macrophages) in the liver, and regulates the ligand-receptor interactions between these cells, thereby promoting the proliferation and activation of HSCs, leading to liver fibrosis. Overall, we provide the first comprehensive single-cell atlas of mouse livers in response to TCS and delineate the key cellular and molecular processes involved in TCS-induced hepatotoxicity and fibrosis.

This study analyses the influence of the Asian summer monsoon on volcanic aerosol transport. Realistic, altitude-resolved SO2 emissions of a middle-latitude volcanic eruption (Sarychev 2009) and a tropical volcanic eruption (Nabro 2011) were retrieved and used to initialize the simulations of the long-range transport and dispersion of the sulfate aerosol plumes. The barrier effect of the Asian summer monsoon anticyclone (ASMA) isolated the Sarychev eruption plume outside of the ASMA but constrained the Nabro eruption plume inside of the ASMA, which is most evident in the UTLS region between isotropic surfaces of 360–420 K. Meanwhile, the ASMA could transport a fraction of the plume outside of ASMA quasi-horizontally to the tropical tropopause layer along the southeastern periphery of the anticyclonic circulation, and lift the volcanic plume inside the ASMA anticyclonically across the tropopause with an ascent rate of approximately 0.8 K/day. By enhancing the meridional transport in the UTLS region and lifting volcanic aerosols across the tropopause, the ASMA significantly expanded the potential effects of volcanic eruptions.

Alterations in energy metabolism are associated with depression. However, the role of glycolysis in the pathogenesis of depression and the underlying molecular mechanisms remain unexplored. Through an unbiased proteomic screen coupled with biochemical verifications, we show that the levels of glycolysis and lactate dehydrogenase A (LDHA), a glycolytic enzyme that catalyzes L-lactate production, are reduced in the dorsomedial prefrontal cortex (dmPFC) of stress-susceptible mice in chronic social defeat stress (CSDS) model. Conditional knockout of LDHA from the brain promotes depressive-like behaviors in both male and female mice, accompanied with reduced L-lactate levels and decreased neuronal excitability in the dmPFC. Moreover, these phenotypes could be duplicated by knockdown of LDHA in the dmPFC or specifically in astrocytes. In contrast, overexpression of LDHA reverses these phenotypic changes in CSDS-susceptible mice. Mechanistic studies demonstrate that L-lactate promotes neuronal excitability through monocarboxylic acid transporter 2 (MCT2) and by inhibiting large-conductance Ca2+-activated potassium (BK) channel. Together, these results reveal a role of LDHA in maintaining neuronal excitability to prevent depressive-like behaviors.