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A novel goose astrovirus (GAstV) has broken out across China in recent years, causing widespread damage to the poultry industry. In goslings infected with GAstV, the leading cause of death is visceral gout. However, our understanding of the mechanism of gout formation in GAstV infection is largely inadequate. The aim of this study was to examine the pathogenicity of a GAstV strain and explore the molecular mechanisms of visceral gout caused by viral infection in goslings. The virulent GAstV strain HR2105/1 was effectively isolated from the visceral tissue of goslings in gout-affected areas. The whole genome of the HR2105/1 strain was sequenced and analyzed. Subsequently, we established a gosling gout models with experimental GAstV infection. Finally, we conducted a study on the mechanism of GAstV induced acute kidney injury. Phylogenetic analysis of the complete genome sequence showed that it was closely related to the strain circulating in China since 2016, and it was grouped within the GAstV-1 cluster. The clinical signs were reproduced by experimental infection of healthy goslings with the isolated strain and were found to be similar to those reported in clinical cases. Moreover, the virus exhibits strong renal tropism. Infection with the GAstV strain HR2105/1 was found to cause acute kidney injury, as evidenced by increased levels of uric acid and creatinine as well as severe pathological damage. Mechanistic experiments with Masson and Picrosirius Red staining revealed fibrosis in renal tissues after GAstV infection. Furthermore, TUNEL staining revealed that GAstV infection triggered renal cell apoptosis. Additionally, RT-qPCR revealed that GAstV infection caused an excessive inflammatory response by upregulating the expression of IL-1β, IL-6, IL-10, TGF-β, and iNOS in renal tissues. Overall, our findings demonstrate that GAstV infection causes renal damage by inducing renal cell apoptosis, fibrosis, and excessive inflammatory response, which subsequently leads to hyperuricemia and lethal visceral gout formation. This is the first systematic study on the etiology of lethal gout in goslings caused by GAstV infection, and we believe that the findings can guide vaccine development and therapeutic targets for GAstV-associated renal diseases.

Summary: Long-lived individuals have been extensively studied as a model to investigate the role of the gut microbiota in aging, but their gut fungi remain almost unexplored. Here, we recruited a community-dwelling cohort of 251 participants (24–108 years, including 47 centenarians) from Guangxi in China to characterize the gut mycobiome signatures. We found gut mycobiome markedly varied during aging and determined aging as a predominant factor driving these variations. For long-lived individuals, core taxa, including Penicillium and Aspergillus, were maintained and Candida enterotype was enriched when compared with old counterparts. Individuals with this enterotype were more likely to possess Bacteroides enterotype enriched in young and centenarians. Moreover, the drivers from Candida enterotype were positively linked with the bacteria components dominated in Bacteroides enterotype. We also identified potentially beneficial yeasts-enriched features to differentiate long-lived individuals from others. Our findings suggest that the gut mycobiome develops with aging, and long-lived individuals possess unique fungal signatures.

Background: We compared heart rate variability (HRV) indices between people living with HIV (PLWH) and HIV-negative individuals to ascertain the independent association between HIV infection and reduced HRV, and further investigated whether distinct clinical laboratory profiles exist between PLWH with and without reduced HRV. Methods: This cross-sectional analysis included 304 PLWH and 147 HIV-negative individuals with comparable age and sex. Thirty-two routine clinical laboratory indices (including hematology and biochemistry) closest to the survey were extracted from the Electronic Medical Record System. HRV indices were divided into two categories: low (lowest quartile, Q1) and moderate-to-high (combined, Q2‒Q4). Results: The time domain indices, ln(SDNN), ln(RMSSD), and ln(PNN50), as well as the frequency domain indices, ln(HF), ln(LF), and ln(VLF), were all significantly reduced in PLWH versus HIV-negative individuals (all p

Creating a cleaner, more sustainable, low-carbon energy system is the essential prerequisite for the coordinated governance of pollution reduction and carbon reduction (CGPRCR). This paper focuses on the impact of the pilot policy of the new energy demonstration city on CGPRCR. Based on the research purpose, this paper takes the Whole Process Governance Theory as the theoretical foundation, and employs panel data of 280 prefecture-level cities from 2011 to 2020. The transmission mechanism of new energy demonstration city policy aims at advancing CGPRCR is analyzed by using the DID model. The impact of city heterogeneity on policy effects is examined from the perspective of multidimensional heterogeneity. The findings indicate that: (1) The implementation of the new energy demonstration city policy can greatly contribute to the CGPRCR. This finding remains valid even after conducting a series of robustness tests, such as PSM-DID and placebo test; (2) The mechanism test demonstrates that the policy can optimize the industrial structure, encourage the development of green technologies, and strengthen environmental regulations, all of which can empower the entire governance process and indirectly support the CGPRCR; (3) The policy has a more noticeable impact on the CGPRCR in eastern cities, large cities, and cities with better innovation foundations.

Abstract Background The correlation between the preoperative splenic area measured on CT scans and the overall survival (OS) of early-stage non-small cell lung cancer (NSCLC) patients remains unclear. Methods A retrospective discovery cohort and validation cohort consisting of consecutive NSCLC patients who underwent resection and preoperative CT scans were created. The patients were divided into two groups based on the measurement of their preoperative splenic area: normal and abnormal. The Cox proportional hazard model was used to analyse the correlation between splenic area and OS. Results The discovery and validation cohorts included 2532 patients (1374 (54.27%) males; median (IQR) age 59 (52–66) years) and 608 patients (403 (66.28%) males; age 69 (62–76) years), respectively. Patients with a normal splenic area had a 6% higher 5-year OS (n = 727 (80%)) than patients with an abnormal splenic area (n = 1805 (74%)) (p = 0.007) in the discovery cohort. A similar result was obtained in the validation cohort. In the univariable analysis, the OS hazard ratios (HRs) for the patients with abnormal splenic areas were 1.32 (95% confidence interval (CI): 1.08, 1.61) in the discovery cohort and 1.59 (95% CI: 1.01, 2.50) in the validation cohort. Multivariable analysis demonstrated that abnormal splenic area was independent of shorter OS in the discovery (HR: 1.32, 95% CI: 1.08, 1.63) and validation cohorts (HR: 1.84, 95% CI: 1.12, 3.02). Conclusion Preoperative CT measurements of the splenic area serve as a prognostic indicator for early-stage NSCLC patients, offering a novel metric with potential implications for personalized therapeutic strategies in top-tier oncology research.

Abstract Full activation of the NLRP3 inflammasome needs two sequential signals: a priming signal, followed by a second, assembly signal. Several studies have shown that the two signals trigger post-translational modification (PTM) of NLRP3, affecting activity of the inflammasome, however, the PTMs induced by the second signal are less well characterized. Here, we show that the assembly signal involves acetylation of NLRP3 at lysine 24, which is important for the oligomerization and the actual assembly of NLRP3 without affecting its recruitment to dispersed trans-Golgi network (dTGN). Accordingly, NLRP3 inflammasome activation is impaired in NLRP3-K24R knock-in mice. We identify KAT5 as an acetyltransferase able to acetylate NLRP3. KAT5 deficiency in myeloid cells and pharmacological inhibition of KAT5 enzymatic activity reduce activation of the NLRP3 inflammasome, both in vitro and in vivo. Thus, our study reveals a key mechanism for the oligomerization and full activation of NLRP3 and lays down the proof of principle for therapeutic targeting of the KAT5-NLRP3 axis.

There is an urgent need for effective disease-modifying therapeutic interventions for Alzheimer’s disease (AD)—the most prevalent cause of dementia with a profound socioeconomic burden. Most clinical trials targeting the classical hallmarks of this disease—β-amyloid plaques and neurofibrillary tangles—failed, showed discrete clinical effects, or were accompanied by concerning side effects. There has been an ongoing search for novel therapeutic targets. Neuroinflammation, now widely recognized as a hallmark of all neurodegenerative diseases, has been proven to be a major contributor to AD pathology. Here, we summarize the role of neuroinflammation in the pathogenesis and progression of AD and discuss potential targets such as microglia, TREM2, the complement system, inflammasomes, and cytosolic DNA sensors. We also present an overview of ongoing studies targeting specific innate immune system components, highlighting the progress in this field of drug research while bringing attention to the delicate nature of innate immune modulations in AD.

Primary pontine hemorrhage (PPH) is a particularly grave form of hemorrhagic stroke, characterized by its significant mortality rate. stereotactic hematoma puncture and drainage is a procedure that has been shown to improve the prognosis of patients with PPH. However, there are currently no established criteria for selecting patients for this procedure. We contrasted the clinical outcomes of PPH patients treated with stereotactic hematoma puncture and drainage with those who received conservative treatment in this study. We conducted logistic regression analysis to identify the risk factors associated with postoperative mortality. A mortality risk nomogram was then constructed using these risk factors. A total of 127 conservatively treated patients and 96 patients who underwent stereotactic hematoma puncture and drainage were included in this study. In the surgical group, the 30-day mortality rate stood at 28.1%, significantly lower than the 43.3% observed in the control group (p = 0.02). Age, along with the Glasgow Coma Scale (GCS) score and hematoma size, were identified as independent risk factors associated with death within 30 days post-surgery. The mortality risk nomogram was well calibrated and discriminatory, with a c-index of 0.878 (95% CI 0.80–0.95) as validated by bootstrapping, and a c-index of 0.849. This study provides a predictive model for selecting patients who are most likely to benefit from stereotactic hematoma puncture and drainage. The results of this study could be helpful to neurosurgeons in their decision-making process. However, further external validation is necessary to confirm these findings.

Innovation is a necessary guarantee for sustainable development. Stepping into the digital age, digital transformation has triggered the innovation revolution. This paper takes 30 provinces in China from 2012 to 2022 as the research sample, we verify whether digital transformation has improved innovation performance. Based on the Solow growth model and agglomeration economics theory, we also explore the moderating role and threshold effect of agglomeration in productive service industry between digital transformation and innovation performance. To achieve this, we apply the methods of machine learning and text analysis to construct an evaluation index of regional digital transformation and measure it. The paper finds that China's digital transformation index is increasing, but there is a digital divide between regions. We also determine that digital transformation significantly and positively contributes to the level of innovation performance. Considering the threshold effect of agglomeration in productive service industry, the impact of digital transformation on innovation performance exhibits non-linear characteristics, As the level of agglomeration continues to exceed the threshold, the innovation-driven effect of digital transformation increases. The research results help clarify the relationship between digital transformation and innovation performance, and provide favorable policy directions for regional governments to identify digital divides and make reasonable industrial layouts. Thus, it can promote the construction of digital China and innovation power, injecting strong innovation force into the realization of SDGs.

Abstract Toxoplasma gondii is thought to infect all nucleated cells in warm-blooded animals, including poultry, mammals, and humans. However, it is unclear whether T. gondii can infect chicken erythrocytes due to the nucleated nature of these cells. Due to the special role of chicken erythrocytes in innate immunity, we investigated the cell‒cell interaction between T. gondii and erythrocytes to elucidate the role of chicken erythrocytes in T. gondii infection. Cellular apoptosis was analyzed by transwell assay and flow cytometry. An immunofluorescence method was used to examine the reorganization of vimentin during T. gondii infection in both Vero cells and chicken erythrocytes. The reorganization of actin was evaluated to further examine the invasion capacity of tachyzoites on chicken erythrocytes during infection. We discovered that T. gondii can adhere to but not invade chicken erythrocytes and eventually cause apoptosis in chicken erythrocytes. When tachyzoites were cocultured with chicken erythrocytes in vitro, the transcriptional levels of T. gondii MIC3, ROP16, and ROP18 were significantly decreased. In addition, the rearrangement of host cell vimentin, a type III cytoskeleton protein regulated by T. gondii infection, was not observed. Similarly, the parasite-induced ring-shaped actin structure was not formed in the host-parasite junction. T. gondii (RH strain) tachyzoites preferentially invaded Vero cells and replicated in chicken blood monocytes, but they were not found in chicken erythrocytes. These findings showed that although T. gondii could attach to the surface of chicken erythrocytes, but couldn’t invade successfully. Interestingly, we found that the T. gondii secretome, lysates, and intact tachyzoites could cause apoptosis of chicken erythrocytes, which suggested a complex mechanism involved in the apoptosis of chicken erythrocytes induced by T. gondii. This study elucidated that T. gondii could not infect nucleated chicken erythrocytes and enriched our understanding of the transmission mechanism of T. gondii among avian species.

The discipline of mine water prevention and control in China as a whole has undergone two major development processes: the initial development period in the 20th century and the growth and maturity period in the 21st century, with its basic structure and connotation already mature. According to the system theory, the generalized connotation of mine water has been expanded, the terminology and scientific scope of mine water prevention and control have been standardized, and a mine water system has been proposed, that is, a highly complex system involving a boundary from water supply to water inflow discharge and time-varying internal media structure. The water input and water inflow output are complete, and the system responds in a timely manner when mining disturbances are triggered; The basic framework of mine water prevention and control has been constructed, including two core systems: theoretical and technical systems and technical management systems; The theoretical and technical system covers theoretical basis, technical support, and engineering support, with disaster mechanism, condition evaluation, and prediction as the theoretical basis, condition exploration, prevention and treatment, and geological support as the technical support, and seven types of projects such as water exploration, waterproofing, water blocking, drainage, drainage, water interception, and water regime monitoring as the measure support; The technical management system includes advanced concepts, overall ideas, and working systems. Guided by the overall idea of “predicting and forecasting, exploring if there is any doubt, exploring before excavating, and treating before mining”, and guided by the advanced concept of combining prevention at the source, regional governance, engineering governance, and protection, the construction concept is advanced, the foundation is solid, exploration is clear, scientific and technological breakthroughs are tackled, and comprehensive governance is conducted, The “seven in one” water disaster prevention and control work system for effect evaluation and emergency rescue achieves the overall goal of reducing the impact of mine water, preventing water disaster accidents, and mitigating environmental impact. Looking forward to the future, the physical mechanism of flood disasters, the law of data driven disasters, or the integration of the two are key directions for fundamental theoretical breakthroughs, which will drive comprehensive breakthroughs in technology and engineering.

Abstract Background Due to individual differences and lack of objective biomarkers, only 30-40% patients with major depressive disorder (MDD) achieve remission after initial antidepressant medication (ADM). We aimed to employ radiomics analysis after ComBat harmonization to predict early improvement to ADM in adolescents with MDD by using brain multiscale structural MRI (sMRI) and identify the radiomics features with high prediction power for selection of selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). Methods 121 MDD patients were recruited for brain sMRI, including three-dimensional T1 weighted imaging (3D-T1WI)and diffusion tensor imaging (DTI). After receiving SSRIs or SNRIs for 2 weeks, the subjects were divided into ADM improvers (SSRIs improvers and SNRIs improvers) and non-improvers according to reduction rate of the Hamilton Depression Rating Scale, 17 item (HAM-D17) score. Then, sMRI data were preprocessed, and conventional imaging indicators and radiomics features of gray matter (GM) based on surface-based morphology (SBM) and voxel-based morphology (VBM) and diffusion properties of white matter (WM) were extracted and harmonized with ComBat harmonization. Two-level reduction strategy with analysis of variance (ANOVA) and recursive feature elimination (RFE) was utilized sequentially to decrease high-dimensional features. Support vector machine with radial basis function kernel (RBF-SVM) was used to integrate multiscale sMRI features to construct models for early improvement prediction. Area under the curve (AUC), accuracy, sensitivity, and specificity based on the leave-one-out cross-validation (LOO-CV) and receiver operating characteristic (ROC) curve analysis were calculated to evaluate the model performance. Permutation tests were used for assessing the generalization rate. Results After 2-week ADM, 121 patients were divided into 67 ADM improvers (31 SSRIs improvers and 36 SNRIs improvers) and 54 ADM non-improvers. After two-level dimensionality reduction, 8 conventional indicators (2 VBM-based features and 6 diffusion features) and 49 radiomics features (16 VBM-based features and 33 diffusion features) were selected. The overall accuracy of RBF-SVM models based on conventional indicators and radiomics features was 74.80% and 88.19%. The radiomics model achieved the AUC, sensitivity, specificity, and accuracy of 0.889, 91.2%, 80.1% and 85.1%, 0.954, 89.2%, 87.4% and 88.5%, 0.942, 91.9%, 82.5% and 86.8% for predicting ADM improvers, SSRIs improvers and SNRIs improvers, respectively. P value of permutation tests were less than 0.001. The radiomics features predicting ADM improver were mainly located in the hippocampus, medial orbitofrontal gyrus, anterior cingulate gyrus, cerebellum (lobule vii-b), body of corpus callosum, etc. The radiomics features predicting SSRIs improver were primarily distributed in hippocampus, amygdala, inferior temporal gyrus, thalamus, cerebellum (lobule vi), fornix, cerebellar peduncle, etc. The radiomics features predicting SNRIs improver were primarily located in the medial orbitofrontal cortex, anterior cingulate gyrus, ventral striatum, corpus callosum, etc. Conclusions These findings suggest the radiomics analysis based on brain multiscale sMRI after ComBat harmonization could effectively predict the early improvement of ADM in adolescent MDD patients with a high accuracy, which was superior to the model based on the conventional indicators. The radiomics features with high prediction power may help for the individual selection of SSRIs and SNRIs.

IntroductionThe host immune response determines the differential outcome of acute or chronic viral infections. The comprehensive comparison of lymphoid tissue immune cells at the single-cell level between acute and chronic viral infections is largely insufficient.MethodsTo explore the landscape of immune responses to acute and chronic viral infections, single-cell RNA sequencing(scRNA-seq), scTCR-seq and scBCR-seq were utilized to evaluate the longitudinal dynamics and heterogeneity of lymph node CD45+ immune cells in mouse models of acute (LCMV Armstrong) and chronic (LCMV clone 13) viral infections.ResultsIn contrast with acute viral infection, chronic viral infection distinctly induced more robust NK cells and plasma cells at the early stage (Day 4 post-infection) and acute stage (Day 8 post-infection), respectively. Moreover, chronic viral infection exerted decreased but aberrantly activated plasmacytoid dendritic cells (pDCs) at the acute phase. Simultaneously, there were significantly increased IgA+ plasma cells (MALT B cells) but differential usage of B-cell receptors in chronic infection. In terms of T-cell responses, Gzma-high effector-like CD8+ T cells were significantly induced at the early stage in chronic infection, which showed temporally reversed gene expression throughout viral infection and the differential usage of the most dominant TCR clonotype. Chronic infection also induced more robust CD4+ T cell responses, including follicular helper T cells (Tfh) and regulatory T cells (Treg). In addition, chronic infection compromised the TCR diversity in both CD8+ and CD4+ T cells.DiscussionIn conclusion, gene expression and TCR/BCR immune repertoire profiling at the single-cell level in this study provide new insights into the dynamic and differential immune responses to acute and chronic viral infections.

Without affecting the application effect of BIM (Building Information Modeling) model, appropriate simplification of the model is a key step to promote BIM technology in the construction of engineering informatization. Aiming at the problems of large amount of model data, weak universality of data format and low network transmission efficiency, a research method for lightweight visualization application of signal BIM models based on glTF format and WebGL technology is presented. Firstly, the geometric spatial information and semantic attribute information required by the models are extracted through the idea of digital - analog separation, so as to realize the lightweight of the internal data of the models. Secondly, the QEM (Quadric Error Metrics) algorithm is used to simplify the external geometric triangles of the models and the Draco algorithm is used to compress and reduce the model file. On this basis, the geometric information and attribute information of the models are stored separately in the glTF file and MySQL database. Finally, the lightweight processed files are connected to the developed Three.js rendering engine to realize the development of visualization application based on WebGL technology. The research shows that this method realizes the data format conversion of the signal BIM models, and can effectively reduce the data volume of the model at the same time. In addition, the lightweight display and attribute information query of the models on the web pages are realized. It is beneficial to improve the application value of the signal BIM models in the digital development of railway signals.

Abstract Background Genome-wide association studies (GWAS) have identified some variants associated with subclinical atherosclerosis (SCA) in general population but lacking sufficient validation. Besides traditional risk factors, whether and how would genetic variants associate with SCA among people with HIV (PWH) remains to be elucidated. Method A large original GWAS and gene-environment interaction analysis of SCA were conducted among Chinese PWH (n = 2850) and age/sex-matched HIV-negative controls (n = 5410). Subgroup analyses by age and functional annotations of variants were also performed. Results Different from HIV-negative counterparts, host genome had a greater impact on young PWH rather than the elders: one genome-wide significant variant (rs77741796, P = 2.20 × 10−9) and eight suggestively significant variants (P

Abstract Objective Whether preoperative serum carbohydrate antigen 19–9 (CA19-9) is an independent prognostic factor and there are interactions of serum CA19-9 with carcinoembryonic antigen (CEA) on the risk of recurrence in colorectal cancer (CRC) patients are still not clarified. Methods Consecutive patients with CRC who underwent curative resection for stage II-III colorectal adenocarcinoma at five hospitals were collected. Based on Cox models, associations of preoperative CA19-9 with recurrence-free survival (RFS) and overall survival (OS) were evaluated in patients with or without elevated CEA, and interactions between CEA and CA19-9 were also calculated. Restricted cubic spline (RCS) curves were used to evaluate the associations between preoperative CA19-9 and CRC outcomes on a continuous scale. Results A total of 5048 patients (3029 [60.0%] men; median [interquartile range, IQR] age, 61.0 [51.0, 68.0] years; median [IQR] follow-up duration 46.8 [36.5–62.4] months) were included. The risk of recurrence increased with the elevated level of preoperative CA19-9, with the slope steeper in patients with normal CEA than those with elevated CEA. Worse RFS was observed for elevated preoperative CA19-9 (> 37 U/mL) (n = 738) versus normal preoperative CA19-9 (≤ 37 U/mL) (n = 4310) (3-year RFS rate: 59.4% versus 78.0%; unadjusted hazard ratio [HR]: 2.02; 95% confidence interval [CI]:1.79 to 2.28), and significant interaction was found between CA19-9 and CEA (P for interaction = 0.001). Increased risk and interaction with CEA were also observed for OS. In the Cox multivariable analysis, elevated CA19-9 was associated with shorter RFS and OS regardless of preoperative CEA level, even after adjustment for other prognostic factors (HR: 2.08, 95% CI:1.75 to 2.47; HR: 2.25, 95% CI:1.80 to 2.81). Subgroup analyses and sensitivity analyses yielded largely similar results. These associations were maintained in patients with stage II disease (n = 2724). Conclusions Preoperative CA19-9 is an independent prognostic factor in CRC patients. Preoperative CA19-9 can be clinically used as a routine biomarker for CRC patients, especially with preoperative normal serum CEA.

【Objective】With the continuous development of the information age, science and technology has become the fundamental driving force for the development of rural industries. In order to further activate the vitality of rural development and promote the integration of three industries in rural areas, it has become a strong support for rural revitalization.【Method】Based on the vector auto regression (VAR) model and relevant data of science and technology and industry in China from 2011 to 2019, the study explores the relationship between the integration of three industries in rural areas and the input of scientific and technological innovation through nine secondary indicators under three first-level indicators corresponding to the output of science and technology, the input of science and technology, and the integration of three industries in rural areas.【Result】Empirical analysis results show that, there is still a lot of room for continuous improvement in the degree of integration of three industries in rural areas. There are dynamic interactions and high correlations among the input intensity of science and technology, the output level of science and technology and the integration of three industries in rural areas in the index systems; the input of science and technology innovation can promote the development of integration of three industries in rural areas, which will increase 0.767% when the output of science and technology is increased by 1% in the current period; the development of integration of three industries in rural areas will promote further investment in science and technology innovation. When the comprehensive score of integration of three industries in rural areas increases by 0.881%, the comprehensive score of science and technology output increases by 1%.【Conclusion】Based on the above conclusions, we should focus on promoting agricultural scientific and technological innovation to overcome technical barriers, support and encourage agricultural scientific research workers to develop products and technological innovation, build a platform for scientific and technological innovation alliances, increase investment in scientific and technological research and development, create an environment for scientific research and innovation, and accelerate the pace of agricultural technological innovation in our country to realize the deep integration between traditional agriculture and high-tech industries.

Abstract Background Disruption of the postsynaptic density protein-95 (PSD95)—neuronal nitric oxide synthase (nNOS) coupling is an effective way to treat ischemic stroke, however, it still faces some challenges, especially lack of satisfactory PSD95-nNOS uncouplers and the efficient high throughput screening model to discover them. Results Herein, the multifunctional metal–organic framework (MMOF) nanoparticles as a new screening system were innovatively fabricated via layer-by-layer self-assembly in which His-tagged nNOS was selectively immobilized on the surface of magnetic MOF, and then PSD95 with green fluorescent protein (GFP-PSD95) was specifically bound on it. It was found that MMOF nanoparticles not only exhibited the superior performances including the high loading efficiency, reusability, and anti-interference ability, but also possessed the good fluorescent sensitivity to detect the coupled GFP-PSD95. After MMOF nanoparticles interacted with the uncouplers, they would be rapidly separated from uncoupled GFP-PSD95 by magnet, and the fluorescent intensities could be determined to assay the uncoupling efficiency at high throughput level. Conclusions In conclusion, MMOF nanoparticles were successfully fabricated and applied to screen the natural actives as potential PSD95-nNOS uncouplers. Taken together, our newly developed method provided a new material as a platform for efficiently discovering PSD95-nNOS uncouplers for stoke treatment. Graphical Abstract

Abstract Epigenetic regulation of inflammatory macrophages governs inflammation initiation and resolution in the pathogenesis of rheumatoid arthritis (RA). Nevertheless, the mechanisms underlying macrophage‐mediated arthritis injuries remain largely obscure. Here, we found that increased expression of lysine acetyltransferase 2A (KAT2A) in synovial tissues was closely correlated with inflammatory joint immunopathology in both RA patients and experimental arthritis mice. Administration of MB‐3, the KAT2A‐specific chemical inhibitor, significantly ameliorated the synovitis and bone destruction in collagen‐induced arthritis model. Both pharmacological inhibition and siRNA silencing of KAT2A, not only suppressed innate stimuli‐triggered proinflammatory gene (such as Il1b and Nlrp3) transcription but also impaired NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in vivo and in vitro. Mechanistically, KAT2A facilitated macrophage glycolysis reprogramming through suppressing nuclear factor‐erythroid 2‐related factor 2 (NRF2) activity as well as downstream antioxidant molecules, which supported histone 3 lysine 9 acetylation (H3K9ac) and limited NRF2‐mediated transcriptional repression of proinflammatory genes. Our study proves that acetyltransferase KAT2A licenses metabolic and epigenetic reprogramming for NLRP3 inflammasome activation in inflammatory macrophages, thereby targeting KAT2A represents a potential therapeutic approach for patients suffering from RA and relevant inflammatory diseases.

Since 2010, the Tembusu virus (TMUV) has been highly prevalent in China, causing significant economic losses to the poultry industry. In 2022, a suspected outbreak of TMUV occurred at a goose farm located in Anhui Province. A strain of TMUV, TMUV HQ-22, was isolated from the infected geese. Phylogenetic analysis using the E gene of the HQ-22 strain demonstrated its affiliation with cluster 3, a less commonly reported cluster in comparison to the main circulating cluster, cluster 2. Through a comparison of the envelope (E) protein of HQ-22 with other typical TMUV strains, a mutation at the 157th amino acid position was identified, wherein valine (V) in cluster 3 changed to alanine (A), a characteristic that is unique to cluster 2. These findings highlight the diversity and complexity of the TMUV strains circulating in China. In our experimental analysis, an injection of TMUV HQ-22 into the muscles of 3-day-old goslings resulted in severe neurological symptoms and a mortality rate of 60%. Similarly, the intracranial or intranasal infection of 3-week-old ICR mice with TMUV HQ-22 led to severe neurological symptoms and respective mortality rates of 100% or 10%. In summary, our study isolated a TMUV strain, TMUV HQ-22, from geese that belongs to cluster 3 and exhibits significant pathogenicity in both goslings and ICR mice. These results emphasize the genetic diversity of the TMUV circulating in China and expand the host range beyond mosquitoes to include ducks, chickens, geese, and even mice. It is crucial to not underestimate the risk of TMUV infection in mammals, warranting our utmost attention.

Objective: Females are more vulnerable to renal impairment (RI) in people living with HIV (PLWH), but few studies have examined sex disparity in the association of HIV serostatus with RI. Methods: In total, 2,101 PLWH on antiretroviral treatment (ART) and 4,202 HIV-negative people were selected and frequency matched in 1:2 ratio by sex and age categories. RI was defined as estimated glomerular filtration rate (eGFR)

Abstract Background In the era of combination antiretroviral therapy (ART), the incidence, manifestations and severity of kidney diseases have dramatically changed in people living with HIV (PLWH). Little is known about the incidence of impaired kidney function (IKF) measured by serum creatine-based estimated glomerular filtration rate (eGFR) in PLWH. Methods In this systematic review and meta-analysis, we searched PubMed, Ovid, Medline, Embase and Web of Science for studies published before May 7th, 2021, with estimates of incidence of IKF among PLWH. We independently reviewed each study for quality by using the Newcastle-Ottawa scale. The incidence and 95% confidence intervals (CIs) were calculated using random-effects model. Results Sixty out of 3797 identifiable studies were eligible for the meta-analysis. A total of 19 definitions of IKF were described and categorized into three types: the threshold of eGFR, an absolute or percent decrease in eGFR, and certain eGFR threshold combined with decrement in eGFR. The eGFR 25% decrease in eGFR, followed by eGFR 25% decrease in eGFR, while the lowest was observed in those with eGFR

Abstract Objectives This study aims to investigate the association between CD4+ T cell count and combined antiretroviral therapy (cART) with the prevalence of anal human papillomavirus (HPV) infection among HIV-positive male cohort in China. Methods A survey was conducted in men from a HIV cohort in Taizhou, China between 2016 and 2019. A face-to-face questionnaire interview was administered, and an anal-canal swab was collected for HPV genotyping. Results A total of 766 HIV-positive men were recruited. The HPV prevalence was lower among those with increased CD4+ T cell count than those with decreased or unchanged (46.5 vs. 56.6%, p = 0.033) from baseline. In multivariable models, having the current CD4+ T cell count of 350–499 cells/µL (aOR 0.28, 95% CI 0.13–0.64), and of ≥ 500 cells/µL (aOR 0.26, 95% CI 0.11–0.60) were associated with lower prevalence of any type HPV infection compared with those with

Terahertz radiation can provide unprecedented vistas in physical studies such as transient matter state control and advanced free-electron manipulation. Here, we present one feasible path towards high-repetition-rate, intense THz sources by combining the wire-based THz source on a consecutively running, wire-conveying tape design. The proof-of-principle experimental results show an upper 30 mW average THz power output under 1 kHz laser excitation, which presents the first high-repetition-rate, and most importantly, portable and application in handy THz source that is generated by solid plasmas. The generated THz pulses are characterized with a 0.3 THz center frequency and ∼0.3 THz bandwidth. We believe this tabletop laser-driven high-repetition-rate THz source will open a new door for THz and related interdisciplinary sciences.

Spinocerebellar ataxia (SCA) is an autosomal dominant neurodegenerative disease (ND) with a high mortality rate. Symptomatic treatment is the only clinically adopted treatment. However, it has poor effect and serious complications. Traditional diagnostic methods [such as magnetic resonance imaging (MRI)] have drawbacks. Presently, the superiority of RNA interference (RNAi) and extracellular vesicles (EVs) in improving SCA has attracted extensive attention. Both can serve as the potential biomarkers for the diagnosing and monitoring disease progression. Herein, we analyzed the basis and prospect of therapies for SCA. Meanwhile, we elaborated the development and application of miRNAs, siRNAs, shRNAs, and EVs in the diagnosis and treatment of SCA. We propose the combination of RNAi and EVs to avoid the adverse factors of their respective treatment and maximize the benefits of treatment through the technology of EVs loaded with RNA. Obviously, the combinational therapy of RNAi and EVs may more accurately diagnose and cure SCA.

BackgroundThe identification of high-risk population patients is key to the personalized treatment options for the stage II colorectal cancers. The use of proteomics in the prognosis of patients with stage II colorectal cancer remains unclear.MethodsUsing quantitative proteomics, we analyzed proteins that are differentially expressed in the tumor and adjacent normal tissues of 11 paired colorectal cancer patients with and without recurrence selected by a nested case-control design. Of the 21 identified proteins, we selected one candidate protein. The association of the corresponding gene of the selected protein with overall survival (OS) and adjuvant chemotherapy was analyzed using two independent cohorts of patients with stages II colorectal cancer.ResultsSterile α motif and histidine-aspartate domain-containing protein 1 (SAMHD1) was selected as the candidate biomarker. A group of 124 patients (12.5%) were stratified into SAMHD1-high subgroup. The 5-year OS rate of SAMHD1-high patients was lower than that of SAMHD1-low patients with stage II colorectal cancer (discovery cohort: hazard ratio [HR] = 2.89, 95% confidence interval [CI], 1.17-7.18, P = 0.016; validation cohort: HR = 2.25, 95% CI, 1.17-4.34, P = 0.013). The Cox multivariate analysis yielded similar results. In a pooled database, the 5-year OS rate was significantly different between patients with and without adjuvant chemotherapy among stage II SAMHD1-low tumors than in patients with stage II SAMHD1-high tumors (88% vs. 77%, P = 0.032).ConclusionsSAMHD1-high expression could help in identifying patients with stage II colorectal cancer with poor prognosis and less benefit from adjuvant chemotherapy.

Enhancing industrial carbon productivity is the key to China's sustainable economic development. Along with the application and development of new-generation network information technologies such as big data, Internet of Things, cloud computing, etc., information communication technology (ICT) has become an essential means to improve national innovation, productivity and strengthen industrial competitiveness, and plays a crucial role in promoting industrial carbon productivity enhancement. Based on China's interprovincial panel data from 2009-2017, this study measured the ICT level through Projection Pursuit improved by an accelerated genetic algorithm and adopted a non-linear threshold regression model to investigate the non-linear impact and its Spatio-temporal heterogeneity of ICT on China's industrial carbon productivity improvement from the perspective of science and technology(S&T) human capital accumulation. The study shows that the overall level of ICT in China is high. There is a digital divide between regions; in general, ICT plays a positive role in enhancing industrial carbon productivity, but there are significant heterogeneous threshold characteristics of science and technology human capital accumulation accumulation. Once the accumulation of science and technology human resource accumulation breaks through the critical scale, the positive effect of ICT on industrial carbon productivity will gradually appear and show a strengthening trend. The temporal and spatial distribution of the threshold for accumulating science and technology human capital accumulation is different.

It has become an urgent issue for all countries to ease the sharp conflict between economic growth and ecological conservation. The fundamental way to achieve low-carbon economic growth is to make the energy consumption structure upgrade and develop towards a cleaner direction. Standing at the point of clean production, this study empirically analyses the nonlinear mechanism of the transformation of energy consumption structure on China's regional carbon productivity by using the threshold model based on the inter-provincial data from 2009 to 2017 (30 provinces in China). The research shows that there are significant differences in cleaner production levels in different parts of China. In contrast, the cleaner production capacity in most regions has been significantly improved during the sample period. It shows the energy consumption structure transformation has a remarkable double threshold effect on regional carbon productivity in China. While clean production keeps crossing the threshold value, the effect direction of energy consumption transformation on regional carbon productivity changes from negative to positive, with both the coefficient value and significance increasing. According to the research results, the paper focuses on adjusting energy resource consumption and improving the clean production level. Eventually, some policy inspirations are proposed for the lower emissions and sustainable process of the Chinese economy.

Summary: When a biased electric/light field is applied to centrosymmetric crystals like silicon, the broken symmetry creates even-order harmonics radiation which can reveal key insights into the material. Recently, the second harmonic has been generated by THz-induced symmetry breaking, but the observation of higher-order radiation remains largely unexplored. Here, we demonstrate picosecond-level ultrafast, nondestructive symmetry manipulation of silicon crystal by using a 500 kV/cm intense terahertz (THz) electric field. The THz-induced fourth harmonic of the infrared probe is also observed and characterized for the first time. In addition, we find that the even-order harmonics show no dependence on the THz field direction thus it allows for sub-cycle symmetry manipulations. Our study paves the way toward ultrafast all-optical crystal symmetry control in the future high-speed electronics and photonics.

Abstract To solve the problem that the overlapping parts of a retractable pier column are prone to damage, this paper proposed the reinforcing measure of setting a stiffener ring at the bottom of the steel pipe. To study how the stiffener-ring parameters influence the mechanical properties of the pier column, 12 scale model specimens (including nine specimens with stiffener-ring widths of 40, 50, and 60 mm and three unstiffened comparison specimens) were tested under axial compression. Based on the test results, the specimen load–displacement, load–deflection, and load–strain curves were analyzed, and a finite-element model of a pier column under axial compression was established to determine the optimal stiffener size. The results show that setting a stiffener ring enhances the cooperative working ability between the steel pipe and the internal filling material and restrains the lateral deformation of the pier column, thereby improving the ultimate bearing capacity and overall stability of the pier column. The ultimate bearing capacity of the pier column is related to the width and thickness of the stiffener ring. The optimal size of the stiffener ring of the model pier column is 70 mm in width and 4 mm in thickness. The present research results provide a reference for designing compressible pier columns and column stiffening in mines and have important practical significance.

Distant metastasis (DM) is the main cause of treatment failure in locally advanced rectal cancer. Here, the authors developed and validated a radiomic signature (RS) for prediction of DM within a multicenter dataset, and suggest that it may help with stratification of patients who might benefit from adjuvant chemotherapy for DM.

Objectives: To report the cost-effectiveness of Xpert in detecting Mycobacterium tuberculosis (MTB) through a comprehensive systematic review. Methods: Specialized bibliographic databases were searched. Study quality was evaluated by commonly-used industry standards. Due to heterogeneity, evidences were synthesized narratively. Results: Four studies from intermediate-to-low tuberculosis (TB)-burdern areas and 17 studies from high-TB-burden areas were included. Smear microscopy, clinical diagnosis and chest radiography were mostly used for comparison. Cost elements varied considerably depending on the perspectives. Cost-effectiveness and cost-utility analyses were used by seven and fourteen studies, respectively. All studies were of high quality (CHEERS score of 78.4 and QHES score of 86.9). Average cost per test was 29.8 US$ for Xpert compared with 3.83 US$ for smear microscopy. Cost-effectiveness analyses mostly supported application of Xpert into areas under varying TB burdens. Conclusions: Xpert seems cost-effective under respective willingness-to-pay thresholds in nations with differences in socioeconomy, HIV stress and geographical distribution. Nevertheless, policymakers will benefit from localized studies since regional economic/financial statuses and health-care system should also be considered apart from the reports of cost-effectiveness.

A near-infrared (NIR) supercontinuum and ultrashort pulses are generated via phase-mismatched cascaded frequency conversion in DSTMS (4-N, N-dimethylamino-4'-N'-methyl-stilbazolium 2, 4, 6-trimethylbenzenesulfonate) crystal. NIR pulses with a central wavelength of 1.5 μm and 63 fs pulse duration are incident into the crystal, and the spectrum is broadened to over 1200-2100 nm. Compensating the dispersion by fused silica, ultrashort NIR pulses with 16.6 fs pulse duration are obtained. Meanwhile, intense single-cycle terahertz pulses are generated via optical rectification in DSTMS crystal.

Green total factor productivity is not merely an inevitable choice to continuously increase the quality of China's economy, but also a booming demand to promote global development. With the fast development of the new generation information technology represented by world comprehensive web technology, Internet growth may well play a more crucial role in enhancing green total factor productivity in China. Based on 2009-2017 China's inter-provincial panel data, this article uses the threshold regression model and fixed-effect model to empirically investigate the influence intensity and internal mechanism of green total factor productivity in areas affected by the Internet development. We ultimately come to the following conclusions. First, there is a digital divide between the regions of China. Second, many factors such as Internet development, human capital, urbanization, energy efficiency, and external dependence all exert a positive influence on China's green total factor productivity. At the same time, government intervention is not conducive to green total factor productivity. Third, the influence of Internet growth on China's green total factor productivity is non-linear, based on the significant double threshold effect of human capital. As the level of human capital continues to exceed the threshold value, the effect of Internet expansion on the green total factor productivity of China has undergone a structural change. The result has changed from a weak negative influence to a positive one, and the significance is increasing. To advance the smart, green, and coordinated development among regions, it is necessary to bring “Internet +” into full play in promoting China's green total factor productivity, strengthen the deep integration of Internet development and industrial development, and improve the level of clean production utilizing network information.

Neurocognitive impairment (NCI) and gut microbiota dysbiosis are prevalent in patients with HIV infection. Docosahexanoic acid (DHA) supplementation may alleviate multiple neurocognitive diseases symptoms and plays important role in regulating gut microbiota. However, it is not known whether DHA algae oil supplements can alleviate neurocognitive impairment (NCI) and regulate gut microbiota and fecal metabolites. A randomized, double-blind, placebo-controlled trial was performed on 68 HIV-infected patients with NCI. Participants were randomized to receive a 3.15 g daily DHA algae oil supplement or placebo for 6 months. We collected blood and fecal samples from these patients before and after the trial. Mini mental state examination (MMSE) and neuropsychological tests (NP tests) were administered to assess the cognitive status of participants. The influence of DHA algae oil on the gut microbiota, fecal metabolomics, plasma proinflammatory, and oxidative stress factors was also investigated. There were no significant changes in NCI according to global diagnosis score (GDS) and MMSE score within the two groups, while patients receiving DHA had improvement in several blood lipids, pro-inflammatory and oxidative stress factors. The DHA supplement increased α-diversity indexes, increased abundances of Blautia, Bifidobacterium, Dorea, Lactobacillus, Faecalibacterium, Fusobacterium, and Agathobacter, and decreased abundances of Bacteroides and Prevotella_9. Furthermore, DHA supplement was correlated with improved fecal lipid metabolites as indicated by ceramides, bile acids, glycerophospholipids. In addition, the DHA supplement was associated with altered cholesterol metabolism and purine metabolism pathways. A daily supplement of DHA algae oil for 6 months has been shown to promote favorable transformations in gut microbiota, profiles of fecal metabolomic, and factors responsible for proinflammatory and oxidative stress, which might be beneficial for the prognosis of HIV-infected patients with NCI in the long-term.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT04242004, identifier: NCT04242004.

The spatial resolution of Chinese Gaofen-3 (GF-3) Synthetic Aperture Radar (SAR) image, a pixel size of 500 m at azimuth/flight direction for Global Observation (GLO) and 100 m for Wide ScanSAR (WSC) modes, is relatively coarse, and waves shorter than 100 m are undetectable. In this study, SAR images collected under typhoon conditions by the GF-3 mission are exploited for wave retrieval purposes. In detail, six imagery collected during 2017 and 2018 over the China Seas captured four typhoons. The GLO and WSC modes images are collocated with simulated wave fields using a numeric wave model, called WAVEWATCH-III (WW3) and are processed using a machine learning method to retrieve sea surface waves. In this work, the criterion for the training completion in the process of machine learning is set as 0.15 m of Root mean Square Error (RMSE) for the Significant Wave Height (SWH). Then, the retrieved SWH is compared with measurements collected by the Jason-2 altimeter, showing a 0.61 m RMSE. The proposed algorithm is shown to outperform empirical approaches developed to retrieve the SWH using GF-3 SAR imagery acquired in the GLO and WSC imaging modes.

BackgroundMitochondrial DNA (mtDNA) profiles and contributions of mtDNA variants to CD4+T-cell recovery in Euramerican people living with HIV (PLWH) may not be transferred to East-Asian PLWH, highlighting the need to consider more regional studies. We aimed to identify mtDNA characteristics and mutations that explain the variability of short-term CD4+T-cell recovery in East-Asian PLWH.MethodEight hundred fifty-six newly reported antiretroviral therapy (ART)-naïve Chinese PLWH from the Comparative HIV and Aging Research in Taizhou (CHART) cohort (Zhejiang Province, Eastern China) were enrolled. MtDNA was extracted from peripheral whole blood of those PLWH at HIV diagnosis, amplified, and sequenced using polymerase chain reaction and gene array. Characterization metrics such as mutational diversity and momentum were developed to delineate baseline mtDNA mutational patterns in ART-naïve PLWH. The associations between mtDNA genome-wide single nucleotide variants and CD4+T-cell recovery after short-term (within ~48 weeks) ART in 724 PLWH were examined using bootstrapping median regressions.ResultsOf 856 participants, 74.18% and 25.82% were male and female, respectively. The median age was 37 years; 94.51% were of the major Han ethnicity, and 69.04% and 28.62% were of the heterosexual and homosexual transmission, respectively. We identified 2,352 types of mtDNA mutations and mtDNA regions D-loop, ND5, CYB, or RNR1 with highest mutational diversity or volume. Female PLWH rather than male PLWH at the baseline showed remarkable age-related uptrends of momentum and mutational diversity as well as correlations between CD4+T C, m.1824T>C, m.3394T>C, m.4491G>A, m.7828A>G, m.9814T>C, m.10586G>A, m.12338T>C, m.13708G>A, and m.14308T>C (at the Bonferroni-corrected significance) were negatively associated with short-term CD4+T-cell recovery whereas m.93A>G, m.15218A>G, and m.16399A>G were positively associated with short-term CD4+T-cell recovery.ConclusionOur baseline mtDNA characterization stresses the attention to East-Asian female PLWH at risk of CD4+T-cell loss-related aging and noncommunicable chronic diseases. Furthermore, mtDNA variants identified in regression analyses account for heterogeneity in short-term CD4+T-cell recovery of East-Asian PLWH. These results may help individualize the East-Asian immune recovery strategies under complicated HIV management caused by CD4+T-cell loss.

ObjectivesTo evaluate the value of synthetic magnetic resonance imaging (syMRI), diffusion-weighted imaging (DWI), DCE-MRI, and clinical features in breast imaging–reporting and data system (BI-RADS) 4 lesions, and develop an efficient method to help patients avoid unnecessary biopsy.MethodsA total of 75 patients with breast diseases classified as BI-RADS 4 (45 with malignant lesions and 30 with benign lesions) were prospectively enrolled in this study. T1-weighted imaging (T1WI), T2WI, DWI, and syMRI were performed at 3.0 T. Relaxation time (T1 and T2), apparent diffusion coefficient (ADC), conventional MRI features, and clinical features were assessed. “T” represents the relaxation time value of the region of interest pre-contrast scanning, and “T+” represents the value post-contrast scanning. The rate of change in the T value between pre- and post-contrast scanning was represented by ΔT%.ResultsΔT1%, T2, ADC, age, body mass index (BMI), menopause, irregular margins, and heterogeneous internal enhancement pattern were significantly associated with a breast cancer diagnosis in the multivariable logistic regression analysis. Based on the above parameters, four models were established: model 1 (BI-RADS model, including all conventional MRI features recommended by BI-RADS lexicon), model 2 (relaxation time model, including ΔT1% and T2), model 3 [multi-parameter (mp)MRI model, including ΔT1%, T2, ADC, margin, and internal enhancement pattern], and model 4 (combined image and clinical model, including ΔT1%, T2, ADC, margin, internal enhancement pattern, age, BMI, and menopausal state). Among these, model 4 has the best diagnostic performance, followed by models 3, 2, and 1.ConclusionsThe mpMRI model with DCE-MRI, DWI, and syMRI is a robust tool for evaluating the malignancies in BI-RADS 4 lesions. The clinical features could further improve the diagnostic performance of the model.

Background: HIV infection and normal aging share immune and inflammatory changes that result in premature aging and non-communicable diseases (NCDs), but the exact pathophysiology is not yet uncovered. We identified the common metabolic pathways underlying various NCDs in treated HIV infection. Methods: We performed untargeted metabolomics including 87 HIV-negative (–) normal controls (NCs), 87 HIV-positive (+) NCs, and 148 HIV+ subjects with only one type of NCDs, namely, subclinical carotid atherosclerosis, neurocognitive impairment (NCI), liver fibrosis (LF) and renal impairment. All HIV+ subjects were virally suppressed. Results: HIV+ patients presented widespread alterations in cellular metabolism compared to HIV– NCs. Glycerophospholipid (GPL) metabolism was the only one disturbed pathway presented in comparisons including HIV– NCs across age groups, HIV+ NCs across age groups, HIV+ NCs vs HIV– NCs and each of HIV+ NCDs vs HIV+ NCs. D-glutamine and D-glutamate metabolism and alanine-aspartate-glutamate metabolism were presented in comparisons between HIV+ NCs vs HIV– NCs, HIV+ LF or HIV+ NCI vs HIV+ NCs. Consistently, subsequent analysis identified a metabolomic fingerprint specific for HIV+ NCDs, containing 42 metabolites whose relative abundance showed either an upward (mainly GPL-derived lipid mediators) or a downward trend (mainly plasmalogen phosphatidylcholines, plasmalogen phosphatidylethanolamines, and glutamine) from HIV– NCs to HIV+ NCs and then HIV+ NCDs, reflecting a trend of increased oxidative stress. Interpretation: GPL metabolism emerges as the common metabolic disturbance linking HIV to NCDs, followed by glutamine and glutamate metabolism. Together, our data point to the aforementioned metabolisms and related metabolites as potential key targets in studying pathophysiology of NCDs in HIV infection and developing therapeutic interventions. Funding: China National Science and Technology Major Projects on Infectious Diseases, National Natural Science Foundation of China, Yi-wu Institute of Fudan University, and Shanghai Municipal Health and Family Planning Commission.

Background: Accurate predictions of distant metastasis (DM) in locally advanced rectal cancer (LARC) patients receiving neoadjuvant chemoradiotherapy (nCRT) are helpful in developing appropriate treatment plans. This study aimed to perform DM prediction through deep learning radiomics. Methods: We retrospectively sampled 235 patients receiving nCRT with the minimum 36 months’ postoperative follow-up from three hospitals. Through transfer learning, a deep learning radiomic signature (DLRS) based on multiparametric magnetic resonance imaging (MRI) was constructed. A nomogram was established integrating deep MRI information and clinicopathologic factors for better prediction. Harrell's concordance index (C-index) and time-dependent receiver operating characteristic (ROC) were used as performance metrics. Furthermore, the risk of DM in patients with different response to nCRT was evaluated with the nomogram. Findings: DLRS performed well in DM prediction, with a C-index of 0·747 and an area under curve (AUC) at three years of 0·894 in the validation cohort. The performance of nomogram was better, with a C-index of 0·775. In addition, the nomogram could stratify patients with different responses to nCRT into high- and low-risk groups of DM (P < 0·05). Interpretation: MRI-based deep learning radiomics had potential in predicting the DM of LARC patients receiving nCRT and could help evaluate the risk of DM in patients who have different responses to nCRT. Funding: The funding bodies that contributed to this study are listed in the Acknowledgements section.

PurposeTo compare survival in different strategies, preoperative systemic treatment versus upfront surgery, in HER2-positive early breast cancer patients in the real world.MethodsAccording to the actual upfront treatment, eligible patients from 2012 to 2015 were classified as preoperative systemic treatment or upfront surgery group prospectively. The primary endpoint is disease-free survival; the second endpoint is overall survival. All the outcomes were examined in the propensity score matching model and inverse probability of treatment weighting model.ResultsIncluded in the analysis were 1,067 patients (215 in the preoperative systemic treatment group, 852 in the upfront surgery group). In the propensity score matching model (matching at 1:1 ratio), the disease-free survival of the preoperative systemic treatment group was significantly higher than that of the upfront surgery group (hazard ratio, 0.572, 95%CI, 0.371–0.881, P, 0.012). In the inverse probability of treatment weighting model, there was no significant difference in disease-free survival between the two groups (hazard ratio, 0.946, 95%CI, 0.763–1.172, P, 0.609). For overall survival, there was no significant difference between the two groups.ConclusionThe HER2-positive patients who accepted preoperative systemic treatment had better disease-free survival than those who underwent upfront surgery by real-world statistic methods.Clinical Trial RegistrationClinicaltrials.gov, identifier NCT04249440.

Abstract Background Relapse represents the leading cause of death in both child and adult patients with acute lymphoblastic leukemia (ALL). Development of chemo-resistance is ultimately responsible for treatment failure and relapse, therefore understanding the molecular basis underlying resistance is imperative for developing innovative treatment strategies. Glucocorticoids (GCs) such dexamethasone and prednisolone are the backbone of combination chemotherapy regimens for treating all lymphoid tumors. However, the biological mechanisms of primary GC resistance in ALL is not completely understood. We previously performed a longitudinal whole-exome sequencing analysis on diagnosis/relapse pairs from adult patients with ALL. Our data revealed that relapse-specific truncation mutations in the NR3C1 gene, encoding the GC receptor, are frequently detected. Methods In the current study, we used discovery-based strategies including RNA sequencing (RNA-seq) and CRISPR/Cas9, followed by confirmatory testing, in human ALL cell lines, bone marrow blast samples from ALL patients and xenograft models, to elucidate the mechanisms responsible for resistance. Results Our results revealed a positive correlation between endogenous expression of NR3C1 in ALL cells and sensitivity to GCs and clinical outcomes. We further confirmed that ectopic expression of NR3C1 in ALL cells could reverse GC resistance, while deletion of NR3C1 confers resistance to GCs in ALL cell lines and xenograft models. RNA-seq analysis revealed a remarkable abundance of gene signatures involved in pathways in cancer, DNA replication, mismatch repair, P53 signalling, cell cycle, and apoptosis regulated by NR3C1. Significantly increased expression of pro-apoptotic genes including BCL2L11/Bim, BMF, BAD, BAX and BOK, and decreased transcription of anti-apoptotic genes including BCL2, BCL2L1 and BAG2 were observed in GC-resistant ALL cells following ectopic expression of NR3C1. Finally, we explored that GC resistance in ALL cells with haploinsufficiency of NR3C1 can be treated with Bcl-2 blockage. Conclusions Our findings suggest that the status of NR3C1 gene mutations and basal expression levels of NR3C1 in ALL cells are associated with sensitivity to GCs and clinical treatment outcomes. Early intervention strategies by rational combination of Bcl-2 blockage may constitute a promising new treatment option to GC-resistant ALL and significantly improving the chances of treating poor prednisone responders.

Objectives The HIV epidemic is around 7%–20% among men who have sex with men (MSM) in Southwest China. The low HIV-testing rate highlights the need for tools to identify high-risk MSM in resource-limited regions. Our aim was, therefore, to evaluate the HIV RISK Assessment Tool for HIV prediction and to characterise the primary infection among MSM in Southwest China.Design A cross-sectional survey was conducted in Guizhou province between January and December 2018. Participants were recruited from gay communities, among whom the HIV RISK Assessment Tool was evaluated. Logistic regression was used to analyse items associated with HIV and the area under the curve (AUC) of the receiver operating curve was calculated to quantify discrimination performance.Participants 1330 MSM participants, of which 83 (6.2%) tested as HIV positive.Results A higher composite score of the tool (adjusted OR (aOR) 9.33, 95% CI 4.57 to 19.05) was independently associated with HIV infection. Items positively associated with HIV infection included having 2–5 same sex partners (aOR 2.43, 95% CI 1.28 to 4.64), always (aOR 5.93, 95% CI 1.59 to 22.13) or sometimes (aOR 4.25, 95% CI 2.09 to 8.64) having unprotected anal intercourse, taking both insertive and receptive sex roles (aOR 4.95, 95% CI 2.57 to 9.53) or only the receptive sex role (aOR 2.26, 95% CI 1.21 to 4.24). The tool showed an optimal discrimination ability (AUC=0.827), with a specificity of 0.747 and sensitivity of 0.785. Five MSM were identified with primary infection and had similar sexual risk behaviors as HIV-positive participants.Conclusions The HIV RISK Assessment Tool showed an overall good performance in predicting HIV risk among MSM in Guizhou province where the prevalence is still severe. This tool also demonstrated a potential to identify primary infection and is worth being promoted in resource-limited regions.

Host cell invasion by Toxoplasma gondii is crucial for the survival and proliferation of parasite. The process of T. gondii tachyzoite invasion requires interaction between parasite proteins and receptors on the surface of host cells. Sialic acid is one of the important receptors for host cell invasion by T. gondii. However, the parasite-derived proteins interacting with sialic acid have not been well characterized. In this study, a novel protein named putative TCP-1 chaperonin (TGME49_318410) in T. gondii (TgTCP-1) was targeted and characterized. TgTCP-1 protein colocalized with MIC3 protein, which could be secreted from T. gondii tachyzoites, and this protein showed a specific binding activity to sialic acid, and DC and Vero cells in vitro. The binding of TgTCP-1 protein to DC and Vero cells were inhibited by either pre-incubation with free sialic acid or neuraminidase treatment of the cells. Moreover, a significant reduction of T. gondii invasion in Vero cells was observed after pre-incubation of the cells with recombinant TgTCP-1 protein. These results illustrated that TgTCP-1 is an important molecule involved in sialic acid-dependent host cell invasion by T. gondii.

In this paper, the partial eigenvalue assignment problem of gyroscopic second-order systems with time delay is considered. We propose a multi-step method for solving this problem in which the undesired eigenvalues are moved to desired values and the remaining eigenvalues are required to remain unchanged. Using the matrix vectorization and Hadamard product, we transform this problem into a linear systems of lower order, and analysis the computational costs of our method. Numerical results exhibit the efficiency of our method.

Coxsackievirus A16 (CA16) is one of the major causative agents of hand, foot, and mouth disease worldwide. The non-neutralizing antibody response that targets CA16 VP1 remains poorly elucidated. In the present study, antibody responses against CA16 VP1 in Shanghai blood donors and Shanxi individuals were analyzed by ELISA and inhibitory ELISA using five CA16 VP1 antigens: VP11-297, VP141-297, VP11-60, VP145-58 and VP161-297. The correlation coefficients for most of the reactions against each of the five antigens and the inhibition of the anti-CA16 VP1 antibody response produced by the various antigens were higher in Shanghai blood donors compared to those in Shanxi individuals. VP11-297 and VP141-297 strongly inhibited the anti-CA16 VP1 response in serum samples from both populations, while VP145-58 and VP161-297 intermediately and weakly inhibited the anti-CA16 VP1 response, respectively, in only Shanghai group. A specific type of inhibition (anti-CA16 VP1 was completely inhibited by both VP11-60 and VP141-297) characterized by high neutralizing antibody titers was identified and accounted for 71.4% of the strongly reactive samples from the Shanghai group. These results indicate that the Shanghai blood donors exhibited a consistent and specific antibody response, while the Shanxi individuals showed an inconsistent and non-specific antibody response. These findings may improve the understanding of host humoral immunity against CA16 and help to identify an effective approach for seroepidemiological surveillance and specific diagnosis of CA16 infection based on normal and competitive ELISA.

To examine homosexual and heterosexual behaviors, behavioral networks and HIV infection among men who have sex with men (MSM) in Eastern China.A cross-sectional survey was conducted among MSM in 2013 in a rural prefecture of Zhejiang province. Participants were interviewed for their sexual behaviors and sexual networks and were tested for HIV infection.A total of 620 MSM from gay bath houses and bars participated in the survey. Of them, 58.2% aged 18 to 39 years and 49.5% were currently married with a female. The age of first homosexual contact was 26.7 years on average, ranging from 12 to 66 years. 91.0% had multiple male sex partners and 86.1% also had female sex partners in lifetime. 70 (11.3%) of the participants were tested HIV-positive. A total of 620 independent egocentric sexual networks involving 620 study participants and 1,971 reported sexual partners in the past 12 months were constructed, including 70 networks for the 70 HIV-positive participants with their 221 sexual partners and 550 networks for the 550 HIV-negative participants with their 1,750 sexual partners. The median network degree was 3 (IQR 2-4) overall and was not different between HIV-positive participants (Median: 3; IQR: 2-4) and HIV-negative participants (Median: 3; IQR: 2-4) (Mann-Whitney test, Z=-0.015, P=0.998). The proportion of networks with a multiple male sexual partnership was 63.7% overall, 62.8% for HIV-positive participants and 63.8% for HIV-negative participants (χ2=0.025, P=0.875). The proportion of networks with both male and female sexual partners was 44.8% overall, 47.1% for HIV-positive participants and 44.5% for HIV-negative participants (χ2=0.169, P=0.681). Consistent condom use and knowledge of HIV infection status were rare within the network partners.The currently high HIV prevalence and complicated bisexual networks among MSM in the study area provides enhanced evidence for developing tailored prevention strategies for HIV transmission among and beyond the MSM population.

Methadone maintenance treatment (MMT) was introduced to China in 2004 to reduce the harm of injecting drug users (IDUs). However, little is known about continued drug use, especially methamphetamine (MAMP), among MMT patients.A survey was conducted among patients attending five major MMT clinics in Dehong Prefecture in 2014 to investigate the heroin and MAMP use and their associated risk factors. Participants were administered with face-to-face interviews, and urine tests for morphine and MAMP.A total of 2,121 were eligible and participated in the study. Among them, 220 (10.4%) were only positive for morphine, 12.9% were only positive for MAMP, and 196 (9.2%) were positive for both morphine and MAMP. Compared with neither use of heroin nor MAMP during MMT, heroin use (not using MAMP) was associated with ethnicity, shorter duration of MMT, lower dose of methadone, and having had no more than two sex partners in the past year; MAMP use (not using heroin) was associated with ethnicity, longer duration of MMT, higher dose of methadone and being aged

ObjectiveTo describe changes in sexual behaviors among HIV-infected individuals after their HIV diagnosis.MethodsAll HIV-infected individuals diagnosed by the end of 2009 in Taizhou Prefecture were invited to participate in this 12-month prospective study. Assessments including the total number and types of sexual contacts, and condom use details for up to their most familiar eight sexual contacts were collected both at enrollment and 12-month follow-up.Results262 HIV-infected individuals were eligible for analysis. The total number of sexual contacts reported by participants was 4,017, 1,496 and 356 during the 12- month period prior to HIV diagnosis (T1), the 12-month period prior to the baseline survey (T2), and the 12-month follow-up period (T3), respectively. The difference in the number of sexual contacts between T2 and T1 was -5 in median (IQR -1, -14), and the difference between T3 and T2 was 0 in median (IQR: 0, -6). A larger proportion of spousal or long-term heterosexual contact was reported from T1(27.7%) to T2(42.5%) to T3(76.1%), whereas a smaller proportion of commercial heterosexual contacts was reported from T1 (48.6%) to T2 (33.2%) to T3 (7.0%) as well as a smaller proportion of non-commercial casual homosexual contacts was reported from T2 (8.4%) to T3 (3.8%).The proportion of consistent condom use increased significantly from T1 (9.3%) to T2 (35.3%) to T3 (91.5%).ConclusionSexual behaviors did not change in a uniform manner for the participants in our study. Sexual behaviors and sexual networks vis-à-vis HIV diagnosis and follow-up were associated with the participant's characteristics and HIV infection and treatment status. The overall lesson is that individuals who are unaware of their HIV infection are the main drivers of secondary transmission. Early identification of HIV infection and access to antiretroviral therapy (ART) are both key strategies to the control and prevention.