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Abstract Background Loss-of-function mutations of ZBTB24 cause immunodeficiency, centromeric instability, and facial anomalies syndrome 2 (ICF2). ICF2 is a rare autosomal recessive disorder with immunological defects in serum antibodies and circulating memory B cells, resulting in recurrent and sometimes fatal respiratory and gastrointestinal infections. The genotype–phenotype correlation in patients with ICF2 indicates an essential role of ZBTB24 in the terminal differentiation of B cells. Methods We used the clustered regularly interspaced short palindromic repeats (CRISPER)/Cas9 technology to generate B cell specific Zbtb24-deficient mice and verified the deletion specificity and efficiency by quantitative polymerase chain reaction (Q-PCR) and western blotting analyses in fluorescence-activated cell sorting (FACS)-sorted cells. The development, phenotype of B cells and in vivo responses to T cell dependent or independent antigens post immunization were analyzed by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Adoptive transfer experiment in combination with in vitro cultures of FACS-purified B cells and RNA-Seq analysis were utilized to specifically determine the impact of Zbtb24 on B cell biology as well as the underlying mechanisms. Results Zbtb24 is dispensable for B cell development and maintenance in naive mice. Surprisingly, B cell specific deletion of Zbtb24 does not evidently compromise germinal center reactions and the resulting primary and secondary antibody responses induced by T cell dependent antigens (TD-Ags), but significantly inhibits T cell independent antigen-elicited antibody productions in vivo. At the cellular level, Zbtb24-deficiency specifically impedes the plasma cell differentiation of B1 cells without impairing their survival, activation and proliferation in vitro. Mechanistically, Zbtb24-ablation attenuates heme biosynthesis partially through mTORC1 in B1 cells, and addition of exogenous hemin abrogates the differentiation defects of Zbtb24-null B1 cells. Conclusions Zbtb24 seems to regulate antibody responses against TD-Ags B cell extrinsically, but it specifically promotes the plasma cell differentiation of B1 cells via heme synthesis in mice. Our study also suggests that defected B1 functions contribute to recurrent infections in patients with ICF2.

Abstract The average five-year survival rate for esophageal cancer, a common malignant tumor of the digestive system, is barely 20%. The majority of esophageal squamous cell carcinoma (ESCC) patients had already progressed to a locally advanced or even advanced stage at initial diagnosis, making routine surgery ineffective. Chemotherapy and immunotherapy are important neoadjuvant treatments for ESCC, however, it remains unknown how treatment will affect the immunological microenvironment, especially at the spatial level. Here, we presented the TME characters of ESCC from the temporal and spatial dimensions using scRNA-seq and ST, investigated the changes of immune cell clusters in the TME under neoadjuvant chemotherapy and preoperative immunotherapy, and explored the potential mechanisms. It was found that compared with chemotherapy, immunotherapy combined with chemotherapy increased the level of T cell proliferation, partially restored the function of exhausted T cells, induced the expansion of specific exhausted CD8 T cells, increased the production of dendritic cells (DCs), and supported the immune hot microenvironment of the tumor. We also found that CD52 and ID3 have potential as biomarkers of ESCC. Particularly, CD52 may be served as a predictor of the efficacy to screen the advantaged population of different regimens. Through multiple pathways, CAF2 and CAF5’s antigen-presenting role affected the other fibroblast clusters, resulting in malignant transformation. We analyzed the immune microenvironment differences between the two regimens to provide a more thorough description of the ESCC microenvironment profile and serve as a foundation for customized neoadjuvant treatment of ESCC.

Abstract Arboviruses, transmitted by medical arthropods, pose a serious health threat worldwide. During viral infection, Post Translational Modifications (PTMs) are present on both host and viral proteins, regulating multiple processes of the viral lifecycle. In this study, a mammalian E3 ubiquitin ligase WWP2 (WW domain containing E3 ubiquitin ligase 2) is identified, which interacts with the NS1 protein of Zika virus (ZIKV) and mediates K63 and K48 ubiquitination of Lys 265 and Lys 284, respectively. WWP2‐mediated NS1 ubiquitination leads to NS1 degradation via the ubiquitin‐proteasome pathway, thereby inhibiting ZIKV infection in mammalian hosts. Simultaneously, it is found Su(dx), a protein highly homologous to host WWP2 in mosquitoes, is capable of ubiquitinating NS1 in mosquito cells. Unexpectedly, ubiquitination of NS1 in mosquitoes does not lead to NS1 degradation; instead, it promotes viral infection in mosquitoes. Correspondingly, the NS1 K265R mutant virus is less infectious to mosquitoes than the wild‐type (WT) virus. The above results suggest that the ubiquitination of the NS1 protein confers different adaptations of ZIKV to hosts and vectors, and more importantly, this explains why NS1 K265‐type strains have become predominantly endemic in nature. This study highlights the potential application in antiviral drug and vaccine development by targeting viral proteins' PTMs.

Background In addition to their established action of synthetic lethality in tumor cells, poly(ADP-ribose) polymerase inhibitors (PARPis) also orchestrate tumor immune microenvironment (TIME) that contributes to suppressing tumor growth. However, it remains not fully understood whether and how PARPis trigger tumor-targeting immune responses.Methods To decode the immune responses reshaped by PARPis, we conducted T-cell receptor (TCR) sequencing and immunohistochemical (IHC) analyses of paired clinical specimens before and after niraparib monotherapy obtained from a prospective study, as well as ID8 mouse ovarian tumors. To validate the induction of immunogenic cell death (ICD) by PARPis, we performed immunofluorescence/IHC staining with homologous recombination deficiency tumor cells and patient-derived xenograft tumor tissues, respectively. To substantiate that PARPis elicited tumor cell pyroptosis, we undertook comprehensive assessments of the cellular morphological features, cleavage of gasdermin (GSDM) proteins, and activation of TNF-caspase signaling pathways through genetic downregulation/depletion and selective inhibition. We also evaluated the critical role of pyroptosis in tumor suppression and immune activation following niraparib treatment using a syngeneic mouse model with implanting CRISPR/Cas9 edited Gsdme−/− ID8 tumor cells into C57BL/6 mice.Results Our findings revealed that PARPis augmented the proportion of neoantigen-recognized TCR clones and TCR clonal expansion, and induced an inflamed TIME characterized by increased infiltration of both innate and adaptive immune cells. This PARPis-strengthened immune response was associated with the induction of ICD, specifically identified as pyroptosis, which possessed distinctive morphological features and GSDMD/E cleavage. It was validated that the cleavage of GSDMD/E was due to elevated caspase 8 activity downstream of the TNFR1, rather than FAS and TRAIL-R. On PARP inhibition, the NF-κB signaling pathway was activated, leading to increased secretion of TNF-α and subsequent initiation of the TNFR1–caspase 8 cascade. Impeding pyroptosis through the depletion of Gsdme significantly compromised the tumor-suppressing effects of PARP inhibition and undermined the anti-immune response in the syngeneic ID8 mouse model.Conclusions PARPis induce a specific type of ICD called pyroptosis via TNF–caspase 8–GSDMD/E axis, resulting in an inflamed TIME and augmentation of tumor-targeting immune responses. These findings deepen our understanding of PARPis activities and point toward a promising avenue for synergizing PARPis with immunotherapeutic interventions.Trial registration number NCT04507841.

The Nanhua Basin of South China recorded complete Cryogenian stratigraphic sequence from the Sturtian Glaciation (~717–660 Ma) to the Marinoan Glaciation (~654–635 Ma). The interglacial Datangpo Fm in the Nanhua Basin is divided into two members, and the first member consists of the Mn-carbonate unit and the overlying black shale unit, containing a series of large and superlarge manganese deposits. The metallogenic process of manganese deposits is not clear, and the Mn-carbonates formed through the precursor of Mn-oxide/oxyhydroxide reduction or directly precipitated from an anoxic water column. Moreover, the redox conditions in the deep Nanhua Basin during the precipitation of manganese deposits are also controversial. In this study, the high-resolution nitrogen contents (TN), isotope compositions, carbon isotope compositions of organic and inorganic matter from the first member of the Datangpo Fm are analyzed. The δ15N values of the Mn-carbonate unit (+1.53‰ to +5.26‰, mean +3.36‰) are higher than those of the overlying black shale unit (−3.74‰ to +3.54‰, mean +0.89‰). The Mn contents show a negative relationship with TN but a positive relationship with δ15N in the Mn-carbonate unit, implying that the formation of Mn-carbonates is related to redox variations. The relatively higher δ15N values in the Mn-carbonate unit indicated oxic conditions, and NH4+can be released and partially oxidized during the mineralization of organic matter, resulting in the residual 15N-enriched NH4+ being transferred into clay minerals. Meanwhile, the lower δ15N values in the black shale unit indicated anoxic conditions, which recorded primary N isotope signals. The Mn-carbonate unit is characterized by negative δ13Ccarb values (−11.17‰ to −5.22‰, mean −8.30‰), which show a positive relationship with δ13Corg, but a negative relationship with Mn contents, implying that the negative δ13Ccarb excursions were related to the organic matter degradation during Mn-carbonate formation. The findings of this study indicated that the metallogenesis of manganese deposits in the Cryogenian Nanhua Basin was constrained mainly by the oxic interval in the deep basin. The nitrogen and carbon cycling process can provide new insights into geochemical cycling after the Sturtian Glaciation.

Mitochondrial dysfunction is a prominent hallmark of Alzheimer's disease (AD). The transcriptional coactivator PPARγ coactivator 1 (PGC-1a) has been identified as a key regulator of mitochondrial biogenesis and function. However, the precise structure/function relationship between PGC-1a and mitochondrial quality control remains incompletely understood. In this study, we investigated the impact of PGC-1a on AD pathology and its underlying mechanisms with a specific focus on mitochondrial axonal transport. Additionally, we generated two PGC-1α mutants by substituting leucine residues at positions 148 and 149 within the LKKLL motif or at positions 209 and 210 within the LLKYL motif with alanine. Subsequently, we examined the effects of these mutants on mutAPP-induced abnormalities in anterograde and retrograde axonal transport, disrupted mitochondrial distribution, and impaired mitophagy.Mutagenesis studies revealed that the LLKYL motif at amino acid position 209–210 within PGC-1α plays an essential role in its interaction with estrogen-related receptors (ERRα), which is necessary for restoring normal mitochondrial anterograde axonal transport, maintaining proper mitochondrial distribution, and ultimately preventing neuronal apoptosis. Furthermore, it was found that the Leu-rich motif at amino acids 209–210 within PGC-1α is crucial for rescuing mutAPP-induced impairment in mitophagy and loss of membrane potential by restoring normal mitochondrial retrograde axonal transport. Conversely, mutation of residues 148 and 149 in the LKKLL motif does not compromise the effectiveness of PGC-1α. These findings provide valuable insights into the molecular determinants governing specificity of action for PGC-1α involved in regulating mutAPP-induced deficits in mitochondrial axonal trafficking. Moreover, they suggest a potential therapeutic target for addressing Alzheimer's disease.

Abstract Background There is still limited research on the prognostic value of Presepsin as a biomarker for predicting the outcome of COVID-19 patients. Additionally, research on the combined predictive value of Presepsin with clinical scoring systems and inflammation markers for disease prognosis is lacking. Methods A total of 226 COVID-19 patients admitted to Beijing Youan Hospital’s emergency department from May to November 2022 were screened. Demographic information, laboratory measurements, and blood samples for Presepsin levels were collected upon admission. The predictive value of Presepsin, clinical scoring systems, and inflammation markers for 28-day mortality was analyzed. Results A total of 190 patients were analyzed, 83 (43.7%) were mild, 61 (32.1%) were moderate, and 46 (24.2%) were severe/critically ill. 23 (12.1%) patients died within 28 days. The Presepsin levels in severe/critical patients were significantly higher compared to moderate and mild patients (p

Abstract A higher incidence of chronic atrophic gastritis (CAG) is generally considered as a precancerous lesion in gastric cancer (GC). The aim of this study was to identify potential molecules involved in the pathogenesis of CAG in the Tibetan plateau, hoping to help the diagnosis and management of the disease. Atrophic and non-atrophic gastric mucosal tissue samples were collected from seven patients with chronic gastritis (CG). Differentially expressed lncRNAs, circRNAs, miRNAs, and mRNAs between CAG and chronic non-atrophic gastritis (CNAG) groups were identified based on DNBSEQ-G99 RNA sequencing. Subsequently, competitive endogenous RNA (ceRNA) regulatory networks (lncRNA/circRNA-miRNA-mRNA networks) were constructed. Two datasets (GSE153224 and GSE163416), involving data from non-Tibetan plateau areas, were used to further screen out Tibetan plateau key mRNAs, followed by the common genes of Tibetan plateau key and ferroptosis-related mRNAs were also identified. Functional enrichment analyses were performed to investigate the biological functions of Tibetan plateau mRNAs in the CAG. A total of seven lncRNA-miRNA-mRNA relationship pairs and 424 circRNA-miRNA-mRNA relationship pairs were identified in this study. The relationship pairs of hsa_circ_0082984-hsa-miR-204-5p-CACNG8, lncRNA DRAIC/has_circ_0008561-hsa-miR-34a-5p-AR/GXYLT2, lncRNA GAS1RR/RGMB-AS1/hsa_circ_0008561-hsa-miR-3614-5p-TMEM216/SUSD5, and LINC00941/hsa_circ_0082984-hsa-miR-873-3p-TMC5 can be involved in the pathogenesis of CAG. Additionally, eight common genes of Tibetan plateau key and ferroptosis-related differentially expressed mRNAs (DEmRNAs) (CBS, SLC2A4, STAT3, ALOX15B, ATF3, IDO1, NOX4, and SOCS1) were identified in CAG. The common genes of Tibetan plateau key and ferroptosis-related DEmRNAs can play a role in the JAK-STAT signaling pathway. This study identified important molecular biomarkers that may be involved in regulating the pathological mechanisms of CAG in the Tibetan plateau, which provides potential research directions for future research.

Abstract Epithelial barrier dysfunction and crypt destruction are hallmarks of inflammatory bowel disease (IBD). Intestinal stem cells (ISCs) residing in the crypts play a crucial role in the continuous self-renewal and rapid recovery of intestinal epithelial cells (IECs). However, how ISCs are dysregulated in IBD remains poorly understood. Here, we observe reduced DHX9 protein levels in IBD patients, and mice with conditional DHX9 depletion in the intestinal epithelium (Dhx9 ΔIEC) exhibit an increased susceptibility to experimental colitis. Notably, Dhx9 ΔIEC mice display a significant reduction in the numbers of ISCs and Paneth cells. Further investigation using ISC-specific or Paneth cell-specific Dhx9-deficient mice demonstrates the involvement of ISC-expressed DHX9 in maintaining epithelial homeostasis. Mechanistically, DHX9 deficiency leads to abnormal R-loop accumulation, resulting in genomic instability and the cGAS-STING-mediated inflammatory response, which together impair ISC function and contribute to the pathogenesis of IBD. Collectively, our findings highlight R-loop-mediated genomic instability in ISCs as a risk factor in IBD.

Background Since the outbreak of coronavirus disease 2019 (COVID-19), studies have found correlations between blood cell count-derived inflammatory markers (BCDIMs) and disease severity and prognosis in COVID-19 patients. However, there is currently a lack of systematic comparisons between procalcitonin (PCT), C-reactive protein (CRP), C-reactive protein-to-albumin ratio (CAR) and BCDIMs for assessing the severity and prognosis of COVID-19 patients.Methods A total of 1040 COVID-19 patients were included in the study. Demographics, comorbidities and laboratory results were analysed. BCDIMs refer to the following ratios: neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-C-reactive protein ratio (LCR), systemic inflammation response index (SIRI) and systemic inflammation index (SII). Disease severity and 28-day mortality are clinical outcomes of this study. Area under the curve (AUC) of receiver operating characteristic (ROC) curve was calculated for these markers, and DeLong’s test compared their statistical differences. Cox regression analysis assessed their predictive value for the 28-day mortality rate.Results Among the 1040 patients, 35.3% were severe/critical, 49.6% were moderate and 15.1% were mild cases. Within 28 days, 15.1% died. The NLR had the highest predictive value for disease severity (AUC: 0.790, 95% CI: 0.762–0.818). NLR differed significantly from other markers, except LCR. LCR best predicted 28-day mortality (AUC: 0.798, 95% CI: 0.766–0.829). Some markers showed significant differences in AUC with LCR. Multivariable Cox regression identified BCDIMs, PCT, CRP and CAR as significant risk factors for 28-day mortality.Conclusions PCT, CRP, CAR and BCDIMs, easily obtained in clinical settings, are valuable predictors of disease severity and the 28-day mortality in COVID-19 patients. The NLR is particularly effective for disease severity, while the LCR is highly predictive of 28-day mortality. These markers provide guidance for stratified management of COVID-19 patients.

BackgroundRecently, the multisociety Delphi consensus renamed non-alcoholic fatty liver disease (NAFLD) terminology [previously renamed metabolic-associated fatty liver disease (MAFLD)] as metabolic dysfunction-associated steatotic liver disease (MASLD). The aim of this study was to compare the similarities and differences between NAFLD, MAFLD, and MASLD and to clarify the impact of this new name change.MethodsA cross-sectional study of 3,035 general subjects with valid vibration-controlled transient elastography data was conducted based on data from the National Health and Nutrition Examination Survey (NHANES) 2017–2020. NAFLD, MAFLD, and MASLD were defined according to the corresponding consensus criteria.ResultsUsing controlled attenuation parameter (CAP) ≥274 dB/m and liver stiffness measurements (LSM) ≥9.7 kPa as the cutoff values for the presence of hepatic steatosis and advanced liver fibrosis (ALF), the prevalence of NAFLD, MAFLD, and MASLD were 38.01% (95% CI 35.78–40.29%), 41.09% (39.09–43.12%), and 37.9% (35.70–40.14%), respectively, and the corresponding prevalence of ALF was 10.21% (7.09–14.48%), 10.13% (7.06-14.35%), and 10.24% (7.11–14.53%), respectively. The kappa values for the three definitions were above 0.9. The prevalence and severity of the three definitions remained similar when the sensitivity analyses were performed using different CAP thresholds. The prevalence of NAFLD, MAFLD, MASLD, and ALF increased as the number of cardiometabolic risk factors (CMRF) increased.ConclusionsOur findings highlight the consistency among the three definitions, especially between NAFLD and MASLD, so that the new consensus will not disturb the original NAFLD-related findings. Additionally, more attention should be paid to patients with a high number of CMRFs.

With the development of energy storage technology, the new energy storage materials are more diverse. The sodium metal has the advantages of high energy density, rich resource reserves, and low costs for raw materials, becoming promising advanced energy storage materials for application. However, the low tensile strength of sodium metal makes it difficult to process deformation while its severe viscosity and low melting point affect the subsequent manufactory and application of batteries. These characteristics hinder the processing and preparation of thin‐sodium metal. The designs of composite‐supporting structure, alloying, and the interface strengthening for sodium metal can effectively overcome the difficulties in preparation of the thin sodium. In this review, the design principles of thin sodium in terms of processing and preparation, according to the physical and chemical properties of sodium metal, are discussed. Meanwhile, the key challenges and new development opportunities are addressed for the processing and preparation of the thin‐sodium metal, which is beneficial for deeply understanding the reliable fabrication and realizing the practical application of thin‐sodium metals.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease that causes obstructed airflow from the lungs. DNA methylation can regulate gene expression. Understanding the potential molecular mechanism of COPD is of great importance. The aim of this study was to find differentially methylated/expressed genes in COPD. DNA methylation and gene expression profiles in COPD were downloaded from the dataset, followed by functional analysis of differentially-methylated/expressed genes. The potential diagnostic value of these differentially-methylated/expressed genes was determined by receiver operating characteristic (ROC) analysis. Expression validation of differentially-methylated/expressed genes was performed by in vitro experiment and extra online datasets. Totally, 81 hypermethylated-low expression genes and 121 hypomethylated-high expression genes were found in COPD. Among which, 9 core hypermethylated-low expression genes (CD247, CCR7, CD5, IKZF1, SLAMF1, IL2RB, CD3E, CD7 and IL7R) and 8 core hypomethylated-high expression genes (TREM1, AQP9, CD300LF, CLEC12A, NOD2, IRAK3, NLRP3 and LYZ) were identified in the protein-protein interaction (PPI) network. Moreover, these genes had a potential diagnostic utility for COPD. Some signaling pathways were identified in COPD, including T cell receptor signaling pathway, cytokine-cytokine receptor interaction, hematopoietic cell lineage, HTLV-I infection, endocytosis and Jak-STAT signaling pathway. In conclusion, differentially-methylated/expressed genes and involved signaling pathways are likely to be associated with the process of COPD.

BackgroundChildren with autoimmune hepatitis (AIH) often present with symptoms similar to those of other liver diseases. This study consists of a comparison between the clinical and histological characteristics of AIH and those of other four AIH-like liver diseases [i.e., drug-induced liver injury (DILI), gene deficiency, infectious liver disease and other etiology of liver disease], as well as an evaluation of the AIH scoring system's diagnostic performance.MethodsAll children with AIH-like liver disease at our center from January 2013 to December 2022 were included. The clinical and histological characteristics of the AIH group were retrospectively analyzed and compared with those of the other four groups.ResultsA total of 208 children were included and divided into AIH group (18 patients), DILI group (38 patients), gene deficiency group (44 patients), infectious liver disease group (74 patients), and other etiology group (34 patients). The antinuclear antibodies (ANA) ≥ 1:320 rate was significantly higher in the AIH compared to the other four groups after multiple testing correction (p 0.73) and the revised systems (AUC > 0.93) for AIH have good diagnostic performance, with the latter being superior (p

Abstract Gastric cancer (GC) is among the most lethal human malignancies, yet it remains hampered by challenges in fronter of molecular‐guided targeted therapy to direct clinical treatment strategies. The protein tyrosine phosphatase Src homology 2 domain‐containing phosphatase 2 (SHP2) is involved in the malignant progression of GC. However, the detailed mechanisms of the posttranslational modifications of SHP2 remain poorly understood. Herein, we demonstrated that an allosteric SHP2 inhibitor, SHP099, was able to block tumor proliferation and migration of GC by dephosphorylating the pyruvate kinase M2 type (PKM2) protein. Mechanistically, we found that PKM2 is a bona fide target of SHP2. The dephosphorylation and activation of PKM2 by SHP2 are necessary to exacerbate tumor progression and GC glycolysis. Moreover, we demonstrated a strong correlation between the phosphorylation level of PKM2 and adenosine 5‘‐monophosphate (AMP)‐activated protein kinase (AMPK) in GC cells. Notably, the low phosphorylation expression of AMPK was negatively correlated with activated SHP2. Besides, we proved that cisplatin could activate SHP2 and SHP099 increased sensitivity to cisplatin in GC. Taken together, our results provide evidence that the SHP2/PKM2/AMPK axis exerts a key role in GC progression and glycolysis and could be a viable therapeutic approach for the therapy of GC.

Abstract Lymph node metastasis (LNM) is the prominent route of gastric cancer dissemination, and usually leads to tumor progression and a dismal prognosis of gastric cancer. Although exosomal lncRNAs have been reported to be involved in tumor development, whether secreted lncRNAs can encode peptides in recipient cells remains unknown. Here, we identified an exosomal lncRNA (lncAKR1C2) that was clinically correlated with lymph node metastasis in gastric cancer in a VEGFC-independent manner. Exo-lncAKR1C2 secreted from gastric cancer cells was demonstrated to enhance tube formation and migration of lymphatic endothelial cells, and facilitate lymphangiogenesis and lymphatic metastasis in vivo. By comparing the metabolic characteristics of LN metastases and primary focuses, we found that LN metastases of gastric cancer displayed higher lipid metabolic activity. Moreover, exo-lncAKR1C2 encodes a microprotein (pep-AKR1C2) in lymphatic endothelial cells and promotes CPT1A expression by regulating YAP phosphorylation, leading to enhanced fatty acid oxidation (FAO) and ATP production. These findings highlight a novel mechanism of LNM and suggest that the microprotein encoded by exosomal lncAKR1C2 serves as a therapeutic target for advanced gastric cancer.

Currently, the energy dissipation efficiency of intermediate column dampers is extremely low, and traditional lever amplification damping systems occupy a large space in buildings. Aiming at solving these problems, this paper puts forward a new intermediate column–lever negative stiffness viscous damper (CLNVD), which has the characteristics of small impact on building space and significant amplification of the damper displacement. The CLNVD consists of the following four parts: the viscous damper, the negative stiffness device, the lever, and the intermediate column. This paper introduces the displacement amplification coefficient (fd) to assess the CLNVD’s displacement amplification effect and introduces the energy dissipation coefficient (fE) to assess the CLNVD’s energy dissipation effect. The expressions for fd and fE are derived according to the geometric magnification coefficient and effective displacement factor. Moreover, the impacts of multiple factors including the CLNVD’s position, the lever’s amplification coefficient, the bending line stiffness of beam, the negative stiffness, the damping coefficient, the damping index, and the inter-story displacement on the CLNVD’s fd and fE are elaborated. The analysis results reveal the following: when the CLNVD is located in the middle of the span, the fd and fE of the CLNVD will be maximized, and fE will increase first and then decrease as the beam’s bending line stiffness increases. Meanwhile, the amplification capability of the CLNVD increases as the lever’s amplification coefficient χ rises. When the negative stiffness does not exist, there exists an optimum lever’s amplification coefficient χ that maximizes fE. When the combination of damping coefficient c and index α satisfies a specific relationship, fE of the CLNVD reaches its largest value. When the negative stiffness and the loss stiffness of VD are within the region proposed in this paper, the CLNVD will achieve a higher fd and avoid providing significant negative stiffness. Subsequently, this paper proposes an optimization design method of the CLNVD. Finally, the amplification effect of CLNVD as well as the effectiveness of its optimization design method are verified through examples. In the case study, the CLNVD offers a larger damping ratio under the circumstance of fortification earthquakes. Under fortification and rare earthquakes, the inter-story displacement of Scheme 1 has been decreased by half roughly. According to the above-mentioned results, the CLNVD provides a brand-new approach for designers in the seismic design of buildings. Furthermore, this paper will provide beneficial reference for the damping design of other amplification devices equipped with negative stiffness dampers.

With the installation of rubber isolation bearings in the upper and lower ground layers, an isolated step-terrace structure was created. Considering the ultimate bearing capacity of the rubber bearing under tension as the critical condition, a comprehensive framework was established to evaluate the overturning failure mechanisms present in isolated step-terrace structures. The bound of nominal aspect ratio was identified as the principal control index within this framework, which incorporates critical parameters such as height ratio (α), width ratio (β), vertical tensile stiffness to compressive stiffness ratio (γ), seismic coefficient (k), and nominal vertical compressive stress (σ0) to provide a thorough analysis of the structural responses and potential failure scenarios. In order to further investigate this matter, a scaled model of an isolated step-terrace concrete frame structure featuring two dropped layers and a single span within an 8° seismic fortification zone was meticulously crafted at a 1:10 similarity ratio. Subsequently, a series of shaking table tests were conducted to analyze the structural response under seismic excitation. The findings indicate that: utilizing the bound of nominal aspect ratio as a metric to gauge the anti-overturning capacity of isolated step-terrace structures is a justified approach. In instances where the height ratio remains constant, the bound of nominal aspect ratio for both positive and negative overturning trended upward with an increase in the width ratio. Notably, the bound of nominal aspect ratio for positive overturning consistently registered lower values compared to that of the negative overturning, underscoring the heightened susceptibility of step-terrace structures to positive overturning. Moreover, in scenarios characterized by higher height and width ratios, the structural integrity remained unscathed by any overturning effects arising from insufficient tensile strength in rubber bearings. Furthermore, the bound of nominal aspect ratio exhibited an ascending trend as the seismic coefficient, nominal vertical compressive stress, and vertical tensile stiffness to compressive stiffness ratio decreased. The outcomes derived from the shaking table test not only confirm the impressive seismic performance of the structure, but also, by closely examining the instantaneous stress variations within the upper and lower isolation layers of the model, substantiate the existence of a positive overturning hazard in scenarios marked by higher seismic coefficients (k). This observation aligns seamlessly with the theoretical projections, thereby substantiating the efficacy of the structural overturning failure theory through direct empirical verification.

This paper proposes a new toggle-style negative stiffness viscous damper (TNVD), and evaluates the performance of the TNVD with the displacement amplification factor (fd) and the energy dissipation factor (fE). Firstly, the composition and characteristics of the TNVD are introduced. Subsequently, the displacement amplification factor is introduced to evaluate the displacement amplification ability of the TNVD, and it is decomposed into a geometric amplification factor and an effective displacement coefficient. Then, based on the geometric amplification factor and effective displacement coefficient, the correlation between the TNVD’s displacement amplification ability and inter-story deformation is studied, and an improved TNVD is proposed. By the comparison of the finite element calculation results, it is found that the improved TNVD can utilize the assumption of small structural deformation. After that, the impacts of plentiful aspects, such as the length of the lower connecting rod, the horizontal inclination angle of the lower connecting rod, the inter-story deformation limit, the cross-sectional area of the connecting rod, the damping coefficient, and the negative stiffness on the fd and fE of the improved TNVD, are expounded. The research results show that when the length of the TNVD’s lower connecting rod remains unchanged, the fd and fE present a trend of increasing first and then decreasing with the increase in the horizontal inclination angle of the lower connecting rod. When the inter-story deformation is fixed, there exists an optimal lower connecting rod’s length that satisfies a specific relationship to achieve the optimal geometric amplification factor of the TNVD. By adjusting the damping parameters of the TNVD, we can obtain a better effective displacement coefficient greater than 0.95 in the proposed target region. Meanwhile, the fd and fE increase with the decrease in the negative stiffness. An optimization strategy for the improved TNVD has been proposed to ensure that the TNVD has the characteristics of operational safety, ideal displacement amplification capability, and energy dissipation capability. Furthermore, a multi-objective control design method with an additional improved TNVD structure is proposed. The vibration reduction effect of the structure with the improved TNVD and the effectiveness of the optimization strategy are verified through examples.

Generally speaking, the traditional lever amplification damping system is installed between adjacent columns in a building, which occupies a significant amount of space in the building. In contrast to amplification devices in different forms, the damper displacement of the intermediate column damper system is smaller, and the vibration reduction efficiency is lower. In light of these drawbacks, this study proposes a new amplification device for energy dissipation and vibration reduction, which is based on an intermediate column–lever mechanism with a viscous damper (CLVD). Initially, a specific simplified mechanical model of CLVD is derived. Subsequently, an equivalent Kelvin mechanical model of CLVD is derived to intuitively reflect CLVD’s damping and stiffness effect. The damping ratio added by CLVDs to the structure is calculated according to that model; the additional damping ratio and additional stiffness are utilized to calculate the displacement ratio Rd and shear force ratio Rv of the structure with CLVDs to the structure without CLVDs. Rd and Rv are introduced to evaluate the vibration reduction effect of the structure with CLVDs, and the effects of various parameters (such as intermediate column position, beam’s bending line stiffness, lever amplification factor, damping coefficient, and earthquake intensity) on Rd and Rv are analyzed. The results indicate that when the ratio of the distance from the intermediate column to the edge column to the span of the beam is 0.5, CLVD owns the optimal vibration reduction effect. Increasing the beam’s bending line stiffness is beneficial for CLVD to control structural displacement and shear force; when the leverage amplification factor is too large, the CLVD provides the structure with stiffness as the main factor, followed by damping. Additionally, when the ratio of the displacement amplification factor to the geometric amplification factor satisfies fd/γ = 1/21−0.5α, the CLVD has the optimal displacement control effect on the structure. After that, measures are provided to optimize the CLVD in different situations in order to effectively control the inter-story displacement and the story shear force of the structure. Consequently, a nine-story frame is taken as an example to elaborate the application of CLVDs in the design for energy dissipation and vibration reduction. The results reveal that the CLVD scheme adopting the proposed optimization method can effectively enhance the displacement amplification ability of CLVDs, resulting in an additional damping ratio of up to 12%. At the same time, the inter-story displacement was reduced by almost 40% under fortification earthquakes. Through the research in this study, designers can obtain a new choice in structural vibration reduction design.

【Objective】Barthea barthei (Hance ex Benth.) Krass. is a unique shrub of the genus Barthea in Melastomataceae in China, which has important ornamental value. However, it is mainly distributed in the wild, and its artificial cultivation technology system has not been fully established, which greatly limits its application potential as a landscape plant. In this study, by comparing the effects of different types in nutrients and different application concentrations on the growth and root indexes of the seedlings, the main nutrient dosage affecting the growth of the seedlings was determined, providing a scientific basis for the cultivation of the seedlings.【Method】The tissue culture seedlings of B. barthei were used as materials, and they were transplanted into the seedling cups with yellow soil as the cultivation substrate. After 3 months' culture, 6 kinds of N nutrients (Glutamic acid, Alanine, Aspartic acid, Compound fertilizer, Urea, Controlled-released fertilizer) and 3 kinds of application amount (0.7, 1.4 and 2.8 mg/plant) were applied respectively. The seedling height and chlorophyll content of B. barthei were measured monthly, and the root indexes of B. barthei was measured after the experiment.【Result】Nutrient type and application amount had significant effects on the early growth and development of B. barthei seedlings. The highest increment of seedling height was 5.18±0.13 cm after 1 month of treatment with T9 (Aspartic acid, 2.8 mg/plant). The increment became smaller after 4~5 months. The seedling height increment of seedlings treated with T5 (Alanine, 1.4 mg/plant) was not significantly different from that of the control in the first 2 months, but it was much higher than that of the control after the 4th and 5th months. The increment of seedling height of T18 (Controlled-released fertilizer, 2.8 mg/plant) was the largest after 4 and 5 months. The root biomass of T14 (Urea, 1.4 mg/plant), T9 (Aspartic acid, 2.8 mg/plant) and T15 (Urea, 2.8 mg/plant) were the largest, which were 0.71 (±0.40) g, 0.65 (±0.21) g and 0.64 (±0.24) g, respectively. The root surface area with diameter less than or equal to 2 mm under T9 treatment was 273.63 cm2, which was significantly higher than that under other treatments.【Conclusion】Considering the seedling height and root index of root surface area with diameter ≤ 2 mm, the best nutrient for the early stage of B. barthei growth was Aspartic acid with the amount of 2.8 mg/plant.

A solvent–non-solvent approach was used to create a CL-20-based aluminum-containing explosive with a composite structure. The SEM results demonstrate that the aluminum powder is equally embedded on the surface of the CL-20 crystal in the CL-20/Al explosive with a composite structure but the aluminum powder in the mechanically mixed CL-20/Al explosive is agglomerated and spread unevenly. The maximum expansion velocity of the composite structure CL-20/Al explosive was 17.74% higher than that of the mechanically mixed explosive in the cylinder test, and the acceleration ability of the CL-20/Al explosive with a composite structure to the cylinder wall is superior to that of the mechanically mixed explosive. In the air explosion test, the shock wave overpressure and impulse of the CL-20/Al explosive with a composite structure are superior to those of the mechanically mixed explosive, but as the distance increases, the gap between the two explosives gradually narrows until it is flat. The results of interfacial particle velocity show that the length of the reaction zone and duration of CL-20/Al explosives with composite structures are longer than those of mechanically mixed structures, and the interfacial particle velocity of CL-20/Al explosives with composite structures is higher than that of mechanically mixed structures.

This study specifically focuses on the damping efficiency of a damped structure with additional viscous dampers. A two-layer steel frame structure with eight sets of viscous dampers is used to conduct a series of seismic simulation shaking table tests, including a non-damped structure without dampers and two damped structures with dampers placed at 1/2 and 1/6 of the beam span, respectively. By conducting these tests, the energy dissipation, force, and displacement of the damper, as well as the parameters of the structure such as floor displacement and acceleration, are obtained. The main damping efficiency indicators of the damped structure are calculated, including the additional damping ratio, inter-story displacement utilization rate, as well as the reduction rate of the vertex displacement and the base shear relative to the non-damped structure. The study shows that the viscous dampers exhibit full hysteresis loops and a strong energy dissipation capacity in the structure. The seismic response of the vertex displacement and base shear in the damped structure is significantly smaller than that in the non-damped structure. Under different seismic levels, including frequent earthquakes, occasional earthquakes, and rare earthquakes, the damping effect of the dampers placed at 1/2 of the beam span is significantly better than that placed at 1/6 of the beam span. For example, the additional damping ratio for the X-direction artificial wave REN is 19% and 11%, 20% and 13%, and 13% and 11%, respectively. The patterns for inter-story displacement utilization ratio, reduction rate of the vertex displacement, and reduction rate of the base shear are similar. The research findings strongly indicate that the damped structure with additional viscous dampers exhibits excellent damping efficiency. In future damping design, designers need to fully consider the placement of viscous dampers within the beam span.

A commingled production scheme, where wells are simultaneously completed in multiple reservoir units, offers a cost-effective alternative worldwide. However, their behavior can be more complex than single-unit wells in sequential production. Limited completion studies exist for the unique Paleogene Gulf of Mexico fields. To aid decision-making, we conducted a numerical study using geological and reservoir models of Lower and Upper Wilcox units, based on publicly available data. Results show that commingled production maximizes per-well oil production compared to sequential schemes. Over 30 years, it provides 61% more oil recovery, and over 50 years, it yields 21% more. One-factor-at-a-time design of experiments sensitivity analysis identifies that key reservoir properties influencing oil recovery in both schemes are upper and lower unit thicknesses, facies proportion of the upper unit. Additionally, average permeability of the lower unit plays a significant role in sequential production schemes.

Abstract Background Karst vegetation is of great significance for ecological restoration in karst areas. Vegetation Indices (VIs) are mainly related to plant yield which is helpful to understand the status of ecological restoration in karst areas. Recently, karst vegetation surveys have gradually shifted from field surveys to remote sensing-based methods. Coupled with the machine learning methods, the Unmanned Aerial Vehicle (UAV) multispectral remote sensing data can effectively improve the detection accuracy of vegetation and extract the important spectrum features. Results In this study, UAV multispectral image data at flight altitudes of 100 m, 200 m, and 400 m were collected to be applied for vegetation detection in a karst area. The resulting ground resolutions of the 100 m, 200 m, and 400 m data are 5.29, 10.58, and 21.16 cm/pixel, respectively. Four machine learning models, including Random Forest (RF), Support Vector Machine (SVM), Gradient Boosting Machine (GBM), and Deep Learning (DL), were compared to test the performance of vegetation coverage detection. 5 spectral values (Red, Green, Blue, NIR, Red edge) and 16 VIs were selected to perform variable importance analysis on the best detection models. The results show that the best model for each flight altitude has the highest accuracy in detecting its training data (over 90%), and the GBM model constructed based on all data at all flight altitudes yields the best detection performance covering all data, with an overall accuracy of 95.66%. The variables that were significantly correlated and not correlated with the best model were the Modified Soil Adjusted Vegetation Index (MSAVI) and the Modified Anthocyanin Content Index (MACI), respectively. Finally, the best model was used to invert the complete UAV images at different flight altitudes. Conclusions In general, the GBM_all model constructed based on UAV imaging with all flight altitudes was feasible to accurately detect karst vegetation coverage. The prediction models constructed based on data from different flight altitudes had a certain similarity in the distribution of vegetation index importance. Combined with the method of visual interpretation, the karst green vegetation predicted by the best model was in good agreement with the ground truth, and other land types including hay, rock, and soil were well predicted. This study provided a methodological reference for the detection of karst vegetation coverage in eastern China.

Abstract Background Asthma is an important non-communicable disease worldwide. DNA methylation is associated with the occurrence and development of asthma. We are aimed at assuring differential expressed genes (DEGs) modified by aberrantly methylated genes (DMGs) and pathways related to asthma by integrating bioinformatics analysis. Methods One mRNA dataset (GSE64913) and one gene methylation dataset (GSE137716) were selected from the Gene Expression Omnibus (GEO) database. Functional enrichment analysis was performed using GeneCodies 4.0 database. All gene expression matrices were analyzed by Gene set enrichment analysis (GSEA) software. STRING was applied to construct a protein-protein interaction (PPI) network to find the hub genes. Then, electronic validation was performed to verify the hub genes, followed by the evaluation of diagnostic value. Eventually, quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to detect the expression of hub genes. Results In total, 14 hypomethylated/high-expression genes and 10 hypermethylated/low-expression genes were obtained in asthma. Among them, 10 hub genes were identified in the PPI network. Functional analysis demonstrated that the differentially methylated/expressed genes were primarily associated with the lung development, cytosol and protein binding. Notably, HLA-DOA was enriched in asthma. FKBP5, WNT5A, TM4SF1, PDK4, EPAS1 and GMPR had potential diagnostic value for asthma. Conclusion The project explored the pathogenesis of asthma, which may provide a research basis for the prediction and the drug development of asthma.

Objectives To evaluate the safety and efficacy of high-dose amoxicillin-proton pump inhibitor dual therapy, and to provide a new eradication regimen as a first-line option for patients with H. pylori infection. Methods A total of 971 H. pylori positive patients who received initial treatment were recruited from March to August 2020, and randomly divided into treatment group and control group. The treatment group received of 20 mg esomeprazole four times daily and 750 mg amoxicillin four times daily for 14 days. Control group received of 220 mg bismuth potassium citrate twice daily, 20 mg esomeprazole twice daily, 1000 mg amoxicillin twice daily and 250 mg clarithromycin capsule twice daily for 14 days. Four weeks after the end of treatment, the urea breath test was reviewed to detect whether H. pylori was eradicated. Results There were no statistical differences in age, gender, the total clinical symptom scores before and after initial treatment, the compliance, and the degree of remission of symptoms before and after initial treatment between the two groups. The eradication rates of H. pylori between dual therapy and quadruple therapy were 88.31% and 85.26% (p=.158) by intention-to-treat (ITT) analysis, 88.66% and 85.44% (p=.186) by modified intention-to-treat (mITT) analysis, and 91.63% and 90.60% (p=.116) by PP analysis, respectively. Adverse events in dual therapy group were significantly lower than quadruple therapy group (13.3% vs. 28.2% (p

Glycans are among the most important cell molecular components. However, given their structural diversity, their functions have not been fully explored. Glycosylation is a vital post-translational modification for various proteins. Many bacteria and viruses rely on N-linked and O-linked glycosylation to perform critical biological functions. The diverse functions of glycosylation on viral proteins during viral infections, including Dengue, Zika, influenza, and human immunodeficiency viruses as well as coronaviruses have been reported. N-linked glycosylation is the most common form of protein modification, and it modulates folding, transportation and receptor binding. Compared to N-linked glycosylation, the functions of O-linked viral protein glycosylation have not been comprehensively evaluated. In this review, we summarize findings on viral protein glycosylation, with particular attention to studies on N-linked glycosylation in viral life cycles. This review informs the development of virus-specific vaccines or inhibitors.

Deltamethrin, an important pyrethroid insecticide, is frequently detected in human samples. This study aims to assess the potential effects of deltamethrin on human health and investigate the patterns of residue enrichment and elimination in 112 healthy laying hens. These hens were administered 20 mg·kg−1 deltamethrin based on their body weight. Gas chromatography-mass spectrometry (GC-MS) was used to investigate the residue enrichment pattern and elimination pattern of deltamethrin in the hens. The results indicated a significant increase in the concentration of deltamethrin in chicken manure during the treatment period. By the 14th day of administration, the concentration of deltamethrin in the stool reached 13,510.9 ± 172.24 μg·kg−1, with a fecal excretion rate of 67.56%. The pulmonary deltamethrin concentration was the second highest at 3844.98 ± 297.14 μg·kg−1. These findings suggest that chicken feces contain substantial amounts of deltamethrin after 14 days of continuous administration, and that it can easily transfer to the lungs. After 21 days of drug withdrawal, the residual concentration of deltamethrin in the fat of laying hens was 904.25 ± 295.32 μg·kg−1, with a half-life of 17 days and a slow elimination rate. In contrast, the lungs showed relatively low elimination half-lives of 0.2083 days, indicating faster elimination of deltamethrin in this tissue. These results highlight differences in the rate of deltamethrin elimination in different tissues during drug withdrawal. The fat of laying hens exhibited the highest residue of deltamethrin and the slowest elimination rate, while the lungs showed the fastest elimination rate. Moreover, deltamethrin was found to accumulate in the edible tissues of eggs and laying hens, suggesting that humans may be exposed to deltamethrin through food.

Abstract This research work proposes an equivalent approach modelling the peculiar hysteretic behavior of passive variable friction damper, for engineers who call for a simplified way to simulate such damper in anti-earthquake engineering practice with acceptable accuracy. This approach models the special nonlinear behavior of the damper via paralleling 3 basic link elements that commonly built-in commercially available structural analysis software, instead of developing direct hysteretic model that demands for both post development functionality on software side and programming skill on engineer side. The mathematical derivation and analytical geometric equating work are comprehensively conducted. The numerical accuracy of analysis output yielded using equivalent model is digitally verified against the one yielded using generic FEM simulation of the same damper subject to several loading cases. Code-automated optimization workflow for yielding product-wise modelling parameters is developed that is convenient and straightforward for application by engineers without requirement of high expertise, which is demonstrated by generating optimized parameters to equivalently model tested specimen. Article highlights Passive variable friction damper can be modelled by assembling friction spring, elastic spring and wen model into parallel. Code-automated optimization process can locate the most ideal modelling parameters combination in predefined numeral fields. Hysteretic behaviors yielded from equivalent modelling approach match well corresponding ones from generic FEA simulation.

The emerging two-dimensional monoelemental materials (2D Xenes) have been commonly supposed as promising drug delivery carriers, photothermal and photodynamic therapeutic agents, biosensors, theranostics, and some other candidates for biomedical applications. Here, high-performance and bioactive ultrathin 2D Tellurium nanosheets (Te NSs) are prepared by a simple but efficient liquid-phase exfoliation approach. The as-obtained Te NSs possess a mean size of ∼90 nm and a mean thickness of ∼5.43 nm. The pegylation Te NSs (Te-PEG NSs) possess excellent biocompatibility and stability. The Te-PEG NSs could generate local hyperthermia with a remarkable photothermal conversion efficiency of about 55% under 808 nm laser irradiation. Additionally, Te-PEG NSs exhibit an extremely high loading capacity of chemo drug (∼162%) owing to their ultra-high surface area and tumor microenvironment-triggered drug release superiority. The results of in vivo experiments show that the Te-PEG NSs have higher tumor elimination efficiency via the combination of photothermal and chemotherapy, comparing to any other single therapeutic modalities. Therefore, our work not only highlights the promising potentials of tellurene as an ideal anti-cancer platform but also expands the application of 2D Te for cancer nanomedicine.

Abstract The fish gill is a multifunctional organ involved in numerous physiological processes, such as gas exchange and sensing of hypoxia by respiratory chemoreceptors, called neuroepithelial cells (NECs). Many studies have focused on zebrafish (Danio rerio) to investigate the structure, function and development of the gills, yet the transcriptomic profile of most gill cells remains obscure. We present the results of a comprehensive transcriptomic analysis of the gills of zebrafish using single-cell RNA sequencing (scRNA‐seq). Gill cells from ETvmat2:EGFP zebrafish were individually labelled before scRNA‐seq library construction using 10× Genomics Chromium technology. 12,819 cells were sequenced with an average depth of over 27,000 reads per cell. We identified a median of 485 genes per cell and 16 cell clusters, including NECs, neurons, pavement cells, endothelial cells and mitochondrion-rich cells. The identity of NECs was confirmed by expression of slc18a2, encoding the vesicular monoamine transporter, Vmat2. Highly differentially-expressed genes in NECs included tph1a, encoding tryptophan hydroxylase, sv2 (synaptic vesicle protein), and proteins implicated in O2 sensing (ndufa4l2a, cox8al and epas1a). In addition, NECs and neurons expressed genes encoding transmembrane receptors for serotonergic, cholinergic or dopaminergic neurotransmission. Differential expression analysis showed a clear shift in the transcriptome of NECs following 14 days of acclimation to hypoxia. NECs in the hypoxia group showed high expression of genes involved in cell cycle control and proliferation. The present article provides a complete cell atlas for the zebrafish gill and serves as a platform for future studies investigating the molecular biology and physiology of this organ.

BackgroundSystemic immune-inflammatory index (SII) and prognostic nutritional index (PNI) could evaluate the therapeutic efficacy and prognosis in different tumors. However, no studies investigated the SII-PNI score to predict outcomes in non-small cell lung cancer (NSCLC) patients treated with platinum-doublet chemotherapy. The aim of this study was to investigate the SII-PNI score in predicting outcomes in non-small cell lung cancer (NSCLC) patients treated with platinum-doublet chemotherapy.Materials and methodsOur study retrospectively analyzed clinical data from 124 patients with advanced NSCLC receiving platinum-doublet chemotherapy. The SII and PNI were calculated based on peripheral blood cell counts and serum albumin, and the optimal cut-off values were determined using receiver operating characteristic (ROC). All patients were divided into three groups according to the SII-PNI score. The association between the SII-PNI score and the clinicopathological characteristics of the patients was examined. The Kaplan-Meier and Cox regression models were used to assess progression-free survival (PFS)and overall survival (OS).ResultsThere was no significant correlation between SII, PNI at baseline and chemotherapy response in patients with advanced NSCLC (p>0.05). However, after receiving 4 cycles of platinum-doublet chemotherapy, the SII of the SD group (p=0.0369) and PD group (p=0.0286) was significantly higher than that of the PR group. At the same time, the PNI of the SD group (p=0.0112) and the PD group (p=0.0007) was significantly lower than that of the PR group. The PFS of patients with SII-PNI scores of 0, 1, and 2 were 12.0, 7.0, and 5.0 months, and the OS of patients with SII-PNI scores of 0, 1, and 2 were 34.0, 17.0, and 10.5 months, respectively. There was statistical significance among the three groups (all p

Abstract Background Neuregulin1 (NRG1) plays a role in neuronal migration, regulation of synaptic plasticity, and neural survival, and has been considered to be among the candidate genes for schizophrenia. This study focused on the variations in serum NRG1β1 levels following antipsychotic treatment and the relationship between NRG1β1 levels and improvements in psychotic symptoms among first-episode drug-naïve (FEDN) patients and patients with chronic schizophrenia. Methods A total of 100 patients with schizophrenia were recruited and compared with 79 matched healthy controls. All patients had been drug-naïve for at least four weeks. Serum NRG1β1 levels and positive and negative syndrome scale (PANSS) scores were measured at baseline and after four weeks. Serum NRG1β1 levels were measured using sandwich enzyme-linked immunosorbent assays (ELISAs). Results Baseline NRG1β1 levels were significantly lower in patients with schizophrenia than in healthy controls. NRG1β1 levels increased significantly following antipsychotic treatment. NRG1β1 levels gradually increased with declining PANSS scores and its three subscales during antipsychotic therapy. The levels of NRG1β1 increased significantly in responders after four weeks of treatment, although nonresponders showed no such effect. Correlation analyses showed that the levels of NRG1β1 were negatively correlated with the duration of illness and positively correlated with improvement in symptoms. Conclusion The levels of serum NRG1β1 and the therapeutic effects gradually increased following treatment, indicating that NRG1β1 may be an indicator of therapy, and that it may also be associated with the pathophysiological mechanism causing schizophrenia, although this possible pathway requires further investigation.

Do victims really help their abusive supervisors? Does abusive supervision have any positive consequence? The study aims to address this concern through extending the work by Tröster and Van Quaquebeke (2021). Using subordinates’ self-reports, Tröster and Van Quaquebeke (2021) found that abusive supervision in high-quality leader–member exchange (LMX) relationship motivates subordinates to blame themselves, subsequently making them feel guilty and make up for it by being more helpful. By integrating both subordinates’ and supervisors’ perspectives, and using multi-wave, multi-source, and multi-level data collected in China, we obtain three major findings. First, as a replication of their findings, LMX moderates the direct effect of abusive supervision on workplace self-blame, and the indirect effect of abusive supervision on workplace guilt via workplace self-blame. The positive direct and indirect effects are stronger when LMX quality is higher. Second, different from their findings, LMX moderates the indirect effect of abusive supervision on supervisor-directed helping (evaluated by supervisors) via workplace self-blame and workplace guilt such that the negative indirect effect is stronger when LMX quality is higher. Third, as an extension, supervisor-evaluated LMX (SLMX) moderates the effect of workplace guilt on supervisor-directed helping such that the negative effect is stronger when SLMX is lower-quality. Put together, LMX and SLMX moderate the indirect effect of abusive supervision on supervisor-directed helping via workplace self-blame and workplace guilt. The negative indirect effect is stronger when LMX quality is higher, but SLMX quality is lower. Our study challenges previous speculations on the positive or beneficial consequences of abusive supervision, and thus contributes to the literature on abusive supervision.

To study the aseismic performance after the reinforcement of the mortise-tenon joints of folk houses with traditional Chuan-Dou style wood structure and their steel plate, test specimens of joints—two for Tou mortise-tenon joints, two for Ban mortise-tenon joints, and two for dovetail mortise-tenon joints—were fabricated out of hemlock, and steel plates were utilized to reinforce one of the joint specimens of each type on the middle part of the mortise-tenon joint. By carrying out pseudo-static tests on the joints and building ABAQUS numerical model; the position where the mortise-tenon joints were to be reinforced by the steel plates was optimized for a comparative analysis into the test results on reinforced and unreinforced mortise-tenon joints and the numerically simulated bending moment-turning angle hysteresis curve, skeleton curve, energy-dissipating capacity, and rigidity degeneration curves. The results showed the following: the pulling-out phenomenon of tenons was severe, and the aseismic performance of Tou tenons was superior to Ban tenons and dovetail tenons; reinforcing the middle part of mortise-tenon joints with steel plates could effectively reduce the pulling-out amount of joints and promote the aseismic performance of mortise-tenon joints but have an insignificant promotive effect for the bearing capacity of Tou mortise-tenon joints; the aseismic performance was improved significantly after the flat steel strip reinforced position was moved to the upper and lower ends of mortise-tenon joints, with the ultimate bearing capacities being 1.5∼2.4 times that on the middle part of flat steel strip reinforced joints.

Abstract Background Development of a deep learning method to identify Barrett's esophagus (BE) scopes in endoscopic images. Methods 443 endoscopic images from 187 patients of BE were included in this study. The gastroesophageal junction (GEJ) and squamous-columnar junction (SCJ) of BE were manually annotated in endoscopic images by experts. Fully convolutional neural networks (FCN) were developed to automatically identify the BE scopes in endoscopic images. The networks were trained and evaluated in two separate image sets. The performance of segmentation was evaluated by intersection over union (IOU). Results The deep learning method was proved to be satisfying in the automated identification of BE in endoscopic images. The values of the IOU were 0.56 (GEJ) and 0.82 (SCJ), respectively. Conclusions Deep learning algorithm is promising with accuracies of concordance with manual human assessment in segmentation of the BE scope in endoscopic images. This automated recognition method helps clinicians to locate and recognize the scopes of BE in endoscopic examinations.

Background: The effects of climatic conditions on the prevalence of individual influenza (sub)types are not well understood in the subtropics. This study aims to evaluate the associations between meteorological factors and seasonal epidemics of A(H3N2), A(H1N1)pdm09, and type B influenza viruses, as well as to estimate the interactions between climatic variables in a subtropical basin region. Methods: The seasonality of influenza (sub)types during 2010–2019 were characterized in Chengdu Plain Economic Zone, a densely populated and highly humid plain area in Sichuan Basin in subtropical Southwest China. Generalized additive models were adopted to assess the independent exposure-response relationship between meteorological variables and influenza prevalence. The interactions of meteorological variables were further estimated using bivariate response surface models and strata models. Results: Our analyses indicated that the temperature, relative humidity, and absolute humidity have exhibited a major influence on influenza infection in Chengdu Plain Economic Zone. Low temperature was shown to promote the prevalence of A(H1N1)pdm09 and type B in winter-spring days at all levels of relative humidity. High risk of A(H3N2) infections was observed at low temperature or high temperature, and at higher relative humidity. Moreover, absolute humidity decreased or increased influenza (sub)type infections within different ranges. Conclusions: This study found different nonlinear relationships between meteorological factors and the seasonality of influenza (sub)types, as well as significant interactive effects between climatic variables, contributing to the research on the climate drivers of influenza prevalence in warm-humid basin regions in the subtropics.

BackgroundEsophageal leiomyoma is the most common benign submucosal mesenchymal tumor. Esophageal intraepithelial neoplasia includes low-grade and high-grade intraepithelial neoplasia. The coexistence of epithelial lesions and the subepithelial lesion is rare. We recorded a case of esophageal low-grade intraepithelial neoplasia (LGIN) overlying multiple esophageal leiomyomas and followed with a review of the literature.Case presentationA 49-year-old female patient came for the treatment of esophageal lesions. The submucosal eminences were observed in the right posterior wall and the left anterior wall of the esophagus by Esophagogastroduodenoscopy (EGD). Additionally, we noticed the mucosa of the right wall with brown background color and the dilated, tortuous vessels by narrow-band imaging (NBI). Then we ensured that the submucosal lesions originated from the esophageal mucosal muscle by endoscopic ultrasonography (EUS) and enhanced CT. Subsequently, the submucosal eminence of the right posterior wall and the overlying mucosal lesion were removed together by endoscopic submucosal dissection (ESD). Postoperative pathological diagnosed esophageal submucosal leiomyoma with focal LGIN. Review EGD showed white scars on the right wall of the upper esophagus three months later, while pathological biopsy showed slight squamous epithelial hyperplasia in the left wall. We decided that the left submucosal lesion can be resected at a selective-time operation, and we continue to follow up as planned.ConclusionsThe case of intraepithelial neoplasia overlying the submucosal tumor is rare. Either missed diagnosis or overdiagnosis should be avoided through EGD and pathological biopsy.

BackgroundAs the first step toward building a gatekeeping system in China, the governments have introduced a contracted family doctor service (CFDS) policy in primary healthcare (PHC) facilities. This study was to examine the association between apply of incentive to improve the implementation of CFDS and the performance on diabetes management care.MethodsWe conducted a cross-sectional study in 72 PHC facilities in 6 cities that piloted the CFDS. Multivariate regression models were applied, based on a sample of 827 PHC providers and 420 diabetic patients.ResultsPHC providers who reported the performance being linked with increased income were 168.1 and 78.0% more likely to have good continuity and coordination of diabetes patient management care, respectively. Additional one-point percentage of PHC providers whose performance on CFDS was assessed was associated with 7.192 times higher probability of patients with control of blood glucose.DiscussionInclusion of incentives rewarding better performance on CFDS were associated with better delivery process and outcome performance on diabetes management care.ConclusionDesign and implementation of the incentive should be accompanied with the policy of CFDS, in order to increase the proportion of performance-related income of PHC providers, thereby improving the quality of diabetes management care.

Background: Polycystic ovary syndrome (PCOS) is a complex polygenic disease and is one of the most common endocrinological and reproductive disorders. The purpose of this study was to evaluate the efficacy of acupuncture combined with herbal medicine among infertile females with polycystic ovary syndrome (PCOS). Method: A total of 86 women with PCOS, experiencing infertility, were recruited and randomly assigned to receive either manual acupuncture (MA) or sham acupuncture (SA) twice per week for three menstrual cycles. Both groups received herbal medication. The evaluations were conducted after three menstrual cycles and 24 weeks’ follow-up. Results: The trial was completed by 79 (91.86%) of the 86 randomly selected patients. During this study, the pregnancy rate in the MA group (46.34%) was significantly higher than the SA group (18.42%), with a P-value of 0.008. Moreover, the ovulation rate of the MA group (58.14%) was higher than that of the SA group (45.74%), with a P-value of 0.046. The improvement rate of PCOS score and testosterone level showed a statistical difference between the two groups (P-values were

The molecular perovskite energetic materials (H2dabco)[NH4(ClO4)3] (DAP-4, H2dabco2+ = 1,4-diazabicyclo[2.2.2]octane-1,4-diium), limits its separate application in explosives duo to the severe negative oxygen balance. Therefore, it is of great significance to study the thermal decomposition performance of DAP-4 in the presence of AP oxidant. In this work, the differential scanning calorimetry-thermogravimetry-mass spectrometry-fourier transform infrared spectroscopy (DSC-TG-MS-FTIR) coupling technique, thermal decomposition kinetics, and in-situ FTIR method were used to analyze the thermal decomposition characteristics, and the variation of condensed phase characteristic groups of DAP-4 and the DAP-4/AP mixtures. The results show that AP has negligible effect on thermal decomposition temperature of DAP-4 but can prolong the total decomposition time of DAP-4 by 5.55 min. In addition, thermal decomposition of AP and DAP-4 in the mixture is independent of each other, and the thermal decomposition mechanism of DAP-4/AP mixtures is more complicated than that of DAP-4 alone. Thermal decomposition of DAP-4/AP mixture firstly experiences decomposition of AP at low temperature, the inside crystal transformation of DAP-4, the H+ transfer, and then cage skeleton collapse-induced redox reaction to generate large amount of heat which can shift forward the high-temperature decomposition peak of AP.

Study ObjectivesThe purpose of this study was to determine the effects of daytime transcranial direct current stimulation (tDCS) on sleep electroencephalogram (EEG) in patients with depression.MethodsThe study was a double-blinded, randomized, controlled clinical trial. A total of 37 patients diagnosed with a major depression were recruited; 19 patients (13 females and 6 males mean age 44.79 ± 15.25 years) received tDCS active stimulation and 18 patients (9 females and 9 males; mean age 43.61 ± 11.89 years) received sham stimulation. Ten sessions of daytime tDCS were administered with the anode over F3 and the cathode over F4. Each session delivered a 2 mA current for 30 min per 10 working days. Hamilton-24 and Montgomery scales were used to assess the severity of depression, and polysomnography (PSG) was used to assess sleep structure and EEG complexity. Eight intrinsic mode functions (IMFs) were computed from each EEG signal in a channel. The sample entropy of the cumulative sum of the IMFs were computed to acquire high-dimensional multi-scale complexity information of EEG signals.ResultsThe complexity of Rapid Eye Movement (REM) EEG signals significantly decreased intrinsic multi-scale entropy (iMSE) (1.732 ± 0.057 vs. 1.605 ± 0.046, P = 0.0004 in the case of the C4 channel, IMF 1:4 and scale 7) after tDCS active stimulation. The complexity of the REM EEG signals significantly increased iMSE (1.464 ± 0.101 vs. 1.611 ± 0.085, P = 0.001 for C4 channel, IMF 1:4 and scale 7) after tDCS sham stimulation. There was no significant difference in the Hamilton-24 (P = 0.988), Montgomery scale score (P = 0.726), and sleep structure (N1% P = 0.383; N2% P = 0.716; N3% P = 0.772) between the two groups after treatment.ConclusionDaytime tDCS changed the complexity of sleep in the REM stage, and presented as decreased intrinsic multi-scale entropy, while no changes in sleep structure occurred. This finding indicated that daytime tDCS may be an effective method to improve sleep quality in depressed patients. Trial registration This trial has been registered at the ClinicalTrials.gov (protocol ID: TCHIRB-10409114, in progress).

Abstract Background To measure the effects of using different combinations of multiple informants and the impact score on the estimated prevalence of mental health problems in Chinese schoolchildren. Methods Complete information on the Strengths and Difficulties Questionnaire (SDQ) were obtained from students (S), parents (P), and teachers (T) for 4986 schoolchildren (11–17 years-old). We used 3 criteria to determine the prevalence of mental health problems: SDQ cut-off value (previously established in the United Kingdom), SDQ cut-off value plus an impact score of 1 or more, or plus an impact score of 2 or more. A student was defined as having a mental health problem if any informant (S, P, or T) classified the child as ‘abnormal’. We compared the prevalence of mental health problems determined from 1 informant, 2 informants, and 3 informants. Results The prevalence of overall mental health problems increased with rising number of informants, but decreased with increasing impact score. When the impact score was not considered, the prevalence was 8.2% to 14.2% when rated by 1 informant, 18.8% to 24.7% when rated by 2 informants, and 28.3% when rated by all 3 informants. Failure to measure the impact score led to a two to threefold greater estimate of the prevalence of mental health problems. Conclusions The types, number, and combinations of multiple informants and use of the impact score must be considered when comparing the results of different studies. It is preferable to use multiple informants and have the impact score taken the impact into account to reflect the real burden of mental health burden in children and adolescent.

Abstract Background New therapeutics are urgently needed for infectious diseases, especially for the fungal infection like Fonsecaea monophora. Photodynamic therapy has been showing antimicrobial activity on some pathogens. The combination of antimicrobial medicines and photodynamic therapy (PDT) might be a practical approach. However, whether the treatment of PDT could do benefits to the host immunity remains poorly documented. Results In this study, Galleria mellonella larvae were employed as a model organism to evaluate the activity of PDT, and also to investigate the regulation of humoral immunity by PDT. Photosensitizer 5-aminolevulinic acid (ALA) was applied to the G. mellonella infection model. It was found that ALA-mediated PDT was non-toxic to G. mellonella, and could extend the median survival of infected larvae from 3 days to 5.5 days. We observed that larval hemocytes inhibited the growth of Candida albicans and Staphylococcus aureus, without any contribution by ALA-PDT. Furthermore, the application of ALA-PDT demonstrated the immunomodulation of larval innate immunity as increased hemocyte density counting, cell morphological transformation, and sensitivity to pathogens. Conclusions G. mellonella could be considered as a useful model to study the immunoregulation of PDT. This model revealed that ALA-PDT positively defense against infections through inducing humoral immune responses of larvae.

N6-methyladenosine (m6A) is an abundant mRNA modification and affects many biological processes. However, how m6A levels are regulated during physiological or pathological processes such as virus infections, and the in vivo function of m6A in the intestinal immune defense against virus infections are largely unknown. Here, we uncover a novel antiviral function of m6A modification during rotavirus (RV) infection in small bowel intestinal epithelial cells (IECs). We found that rotavirus infection induced global m6A modifications on mRNA transcripts by down-regulating the m6a eraser ALKBH5. Mice lacking the m6A writer enzymes METTL3 in IECs (Mettl3ΔIEC) were resistant to RV infection and showed increased expression of interferons (IFNs) and IFN-stimulated genes (ISGs). Using RNA-sequencing and m6A RNA immuno-precipitation (RIP)-sequencing, we identified IRF7, a master regulator of IFN responses, as one of the primary m6A targets during virus infection. In the absence of METTL3, IECs showed increased Irf7 mRNA stability and enhanced type I and III IFN expression. Deficiency in IRF7 attenuated the elevated expression of IFNs and ISGs and restored susceptibility to RV infection in Mettl3ΔIEC mice. Moreover, the global m6A modification on mRNA transcripts declined with age in mice, with a significant drop from 2 weeks to 3 weeks post birth, which likely has broad implications for the development of intestinal immune system against enteric viruses early in life. Collectively, we demonstrated a novel host m6A-IRF7-IFN antiviral signaling cascade that restricts rotavirus infection in vivo.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide and has infected more than 250 million people. A typical feature of COVID-19 is the lack of type I interferon (IFN-I)-mediated antiviral immunity in patients. However, the detailed molecular mechanisms by which SARS-CoV-2 evades the IFN-I-mediated antiviral response remain elusive. Here, we performed a comprehensive screening and identified a set of SARS-CoV-2 proteins that antagonize the IFN-I response. Subsequently, we characterized the mechanisms of two viral proteins antagonize IFN-I production and downstream signaling. SARS-CoV-2 membrane protein binds to importin karyopherin subunit alpha-6 (KPNA6) to inhibit interferon regulatory factor 3(IRF3) nuclear translocation. Further, the spike protein interacts with signal transducer and activator of transcription 1 (STAT1) to block its association with Janus kinase 1 (JAK1). This study increases our understanding of SARS-CoV-2 pathogenesis and suggests novel therapeutic targets for the treatment of COVID-19.