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To stimulate economic growth, China has launched multiple economic stimulus plans in recent years, intensifying corporate debt financing and subsequently elevating the leverage levels. Addressing and effectively reducing the leverage levels of our country's enterprises has emerged as a pressing issue in the trajectory of our economic development. This paper primarily investigates the drivers, pathways, and mechanisms for reversing the over-leveraged values of enterprises. Key findings include: (1) Excessive indebtedness exerts a negative impact on corporate value, with the suppressing effect intensifying as the degree of over-leverage increases; (2) Over-leveraged enterprises can effectively decrease their debt levels and enhance their value through private placement. Further research suggests that this mechanism operates by amplifying the operational leverage of over-leveraged enterprises post private placement and alleviating financing constraints, thereby elevating corporate value. (3) Compared to non-state-owned enterprises, state-owned enterprises exhibit higher levels of indebtedness. Among over-leveraged firms, enhancements in corporate governance and increased investment efficiency can positively transform corporate value. This study offers valuable insights for the ongoing supply-side structural reforms and governance guidance from the regulatory bodies.

This study investigates the changes in quantity and cost of bank loans after a private placement of common stocks by A-share listed companies in China from 2011 to 2021. This research is derived from the signaling theory and is based on a difference-in-difference design. Through propensity score matching, the sample comprises companies that placed equity privately in the experiment group and companies that did not place equity privately in the control group. We find evidence that the increase in bank loans slowed down, and the cost of bank loans increased after the private placement. The signaling effect of private placements is robust to various additional tests. Further analysis indicates that when state-owned enterprises place equity privately, their access to bank loans is not affected. When institutional investors participate in the private placement, the company's access to bank credit does not go through significant changes. In addition, private placements by companies located in regions with higher levels of marketization of the financial market do not reduce the cost of bank loans.

The learned helplessness (LH) model is one of the most commonly used acute stress models to explain depression and it has shown good face and predictive validity. However, despite being able to induce depressed-like behaviors and corresponding psychophysiological changes, there is little evidence showing that the LH paradigm can produce anhedonia, a core symptom seen in all forms of depression in humans. So far a couple of studies showed that rodents bred for helplessness develop anhedonic-like behaviors in response to stress; yet, to the best of our knowledge, no similar human research has tried to investigate the direct relationship between the LH model and anhedonia. In the present study, we use a modified version of the original LH task to experimentally and temporarily induce learned helplessness in college students and then examine if the human LH paradigm induces anhedonia. We aim to 1: address the ill-defined connection between the LH model and anhedonia, and 2: directly assess helplessness in humans as opposed to the majority of non-human animal subjects used in the helplessness literature. We believe that our study will fill an important gap in the learned helplessness model literature, and will advance our understanding of the relationship between depression and perceived control, as well as place limitations to what can and cannot be inferred from non-human animal data in this topic.

Spatiotemporal variations in net primary productivity (NPP) reflect the dynamics of water and carbon in the biosphere, and are often closely related to temperature and precipitation. We used the ecosystem model known as the Carnegie-Ames-Stanford Approach (CASA) to estimate NPP of semiarid grassland in northern China counties between 2001 and 2013. Model estimates were strongly linearly correlated with observed values from different counties (slope = 0.76 (p < 0.001), intercept = 34.7 (p < 0.01), R2 = 0.67, RMSE = 35 g C·m-2·year-1, bias = -0.11 g C·m-2·year-1). We also quantified inter-annual changes in NPP over the 13-year study period. NPP varied between 141 and 313 g C·m-2·year-1, with a mean of 240 g C·m-2·year-1. NPP increased from west to east each year, and mean precipitation in each county was significantly positively correlated with NPP-annually, and in summer and autumn. Mean precipitation was positively related to NPP in spring, but not significantly so. Annual and summer temperatures were mostly negatively correlated with NPP, but temperature was positively correlated with spring and autumn NPP. Spatial correlation and partial correlation analyses at the pixel scale confirmed precipitation is a major driver of NPP. Temperature was negatively correlated with NPP in 99% of the regions at the annual scale, but after removing the effect of precipitation, temperature was positively correlated with the NPP in 77% of the regions. Our data show that temperature effects on production depend heavily on recent precipitation. Results reported here have significant and far-reaching implications for natural resource management, given the enormous size of these grasslands and the numbers of people dependent on them.

Cancers from lung and esophagus are the leading causes of cancer-related deaths in China and share many similarities in terms of histological type, risk factors and genetic variants. Recent genome-wide association studies (GWAS) in Chinese esophageal cancer patients have demonstrated six high-risk candidate single nucleotide polymorphisms (SNPs). Thus, the present study aimed to determine the risk of these SNPs predisposing to lung cancer in Chinese population.A total of 1170 lung cancer patients and 1530 normal subjects were enrolled in this study from high-incidence areas for esophageal cancer in Henan, northern China. Five milliliters of blood were collected from all subjects for genotyping. Genotyping of 20 high-risk SNP loci identified from genome-wide association studies (GWAS) on esophageal, lung and gastric cancers was performed using TaqMan allelic discrimination assays. Polymorphisms were examined for deviation from Hardy-Weinberg equilibrium (HWE) using Х2 test. Bonferroni correction was performed to correct the statistical significance of 20 SNPs with the risk of lung cancer. The Pearson's Х2 test was used to compare the distributions of gender, TNM stage, histopathological type, smoking and family history by lung susceptibility genotypes. Kaplan-Meier and Cox regression analyses were carried out to evaluate the associations between genetic variants and overall survival.Four of the 20 SNPs identified as high-risk SNPs in Chinese esophageal cancer showed increased risk for Chinese lung cancer, which included rs3769823 (OR = 1.26; 95% CI = 1.107-1.509; P = 0.02), rs10931936 (OR = 1.283; 95% CI = 1.100-1.495; P = 0.04), rs2244438 (OR = 1.294; 95% CI = 1.098-1.525; P = 0.04) and rs13016963 (OR = 1.268; 95% CI = 1.089-1.447; P = 0.04). All these SNPs were located at 2q33 region harboringgenes of CASP8, ALS2CR12 and TRAK2. However, none of these susceptibility SNPs was observed to be significantly associated with gender, TNM stage, histopathological type, smoking, family history and overall survival.The present study identified four high-risk SNPs at 2q33 locus for Chinese lung cancer and demonstrated the shared susceptibility loci at 2q33 region for Chinese lung and esophageal cancers.

BACKGROUND:Our previous genome-wide association study (GWAS) identified three independent single nucleotide polymorphisms (SNPs) in human major histocompatibility complex (MHC) region showing association with esophageal squamous cell carcinoma (ESCC). In this study, we increased GWAS sample size on MHC region and performed validation in an independent ESCC cases and normal controls with aim to find additional loci at MHC region showing association with an increased risk to ESCC. METHODS:The 1,077 ESCC cases and 1,733 controls were genotyped using Illumina Human 610-Quad Bead Chip, and 451 cases and 374 controls were genotyped using Illumina Human 660W-Quad Bead Chip. After quality control, the selected SNPs were replicated by TaqMan genotyping assay on another 2,026 ESCC cases and 2,384 normal controls. RESULTS:By excluding low quality SNPs in primary GWAS screening, we selected 2,533 SNPs in MHC region for association analysis, and identified 5 SNPs with p

PURPOSE:To investigate the cytokine concentrations in the aqueous humor of patients with refractory polypoidal choroidal vasculopathy (PCV). METHODS:Three separate groups of patients were studied-refractory PCV (Group A, 41 eyes), stable PCV (Group B, 39 eyes) and senile cataract (Group C, 44 eyes). Aqueous humor samples were collected at two time points for Groups A and B-before the first intravitreal ranibizumab injection and before the last injection. Aqueous humor samples were collected prior to phacoemulsification in Group C. The cytokine concentrations of interleukin 2, 6, and 8 (IL-2, IL-6, and IL-8), tumor necrosis factor α (TNF-α), monocyte chemotactic protein 1 (MCP-1), and vascular endothelial growth factor (VEGF) were measured by cytometric bead array and flow cytometry. RESULTS:Before the first treatment, the MCP-1, VEGF, and TNF-α levels in Group A were significantly higher than those in Group C (P < 0.05), and the MCP-1 and VEGF levels in Group A were significantly higher than those in Group B (P < 0.05). Significantly higher MCP-1 and VEGF levels were seen in Group B compared to Group C (P < 0.05). Before the final treatment, the MCP-1, VEGF, and TNF-α concentrations in Group A were significantly higher than those in Group B (P < 0.05) and Group C (P < 0.05). IL-2 levels were significantly lower in Group A compared to Group B (P < 0.05) and Group C (P < 0.05). CONCLUSION:Inflammatory cytokines such as MCP-1, VEGF, and TNF-α may be associated with the pathogenesis of both stable and refractory PCV.

BACKGROUND:The human major histocompatibility complex (MHC) is the most important region in vertebrate genome, and is crucial in innate immunity. Recent studies have demonstrated the possible role of polymorphisms in the MHC region to high risk for esophageal squamous cell carcinoma (ESCC). Our previous genome-wide association study (GWAS) has indicated that the MHC region may confer important risk loci for ESCC, but without further fine mapping. The aim of this study is to further identify the risk loci in the MHC region for ESCC in Chinese population. METHODS:Conditional logistic regression analysis (CLRA) was performed on 24 single nucleotide polymorphisms (SNPs) within the MHC region, which were obtained from the genetically matched 937 cases and 692 controls of Chinese Han population. The identified promising SNPs were further correlated with clinical and clinicopathology characteristics. Immunohistochemistry was performed to explore the protein expression pattern of the related genes in ESCC and neighboring normal tissues. RESULTS:Of the 24 promising SNPs analyzed, we identified three independent SNPs in the MHC region associated with ESCC: rs35399661 (P = 6.07E-06, OR = 1.71, 95%CI = 1.36-2.17), rs3763338 (P = 1.62E-05, OR = 0.63, 95%CI = 0.50-0.78) and rs2844695 (P = 7.60E-05, OR = 0.74, 95%CI = 0.64-0.86). These three SNPs were located at the genes of HLA-DQA1, TRIM27, and DPCR1, respectively. Further analyses showed that rs2844695 was preferentially associated with younger ESCC cases (P = 0.009). The positive immunostaining rates both for HLA-DQA1 and TRIM27 were much higher in ESCC tissues than in neighboring normal tissues (69.4% vs. 26.8% for HLA-DQA1 and 77.6% vs. 47.8% for TRIM27, P

Copy number variations (CNVs) are one of the main contributors to genetic diversity in animals and are broadly distributed in the genomes of swine. Investigating the performance and evolutionary impacts of pig CNVs requires comprehensive knowledge of their structure and function within and between breeds. In the current study, 4 different programs (i.e., GADA, PennCNV, QuantiSNP, and cnvPartition) were used to analyze Porcine SNP60 genotyping data of 585 pigs from one Large White × Minzhu intercross population to detect copy number variant regions (CNVRs). Overlapping CNVRs recalled by at least 2 programs were used to construct a powerful and comprehensive CNVR map, which contained 249 CNVRs (i.e., 70 gains, 43 losses, and 136 gains/losses) and covered 26.22% of the regions in the swine genome. Ten CNVRs, representing different predicted statuses, were selected for validation via quantitative real-time PCR (QPCR); 9/10 CNVRs (i.e., 90%) were validated. When being traced back to the F0 generation, 58 events were identified in only Minzhu F0 parents and 2 events were identified in only Large White F0 parents. A series of CNVR function analyses were performed. Some of the CNVRs functions were predicted, and several interesting CNVRs for meat quality traits and hematological parameters were obtained. A comprehensive and lower false rate genome-wide CNV map was constructed for Large White and Minzhu pig genomes in this study. Our results may provide an important basis for determining the relationship between CNVRs and important qualitative and quantitative traits. In addition, it can help to further understand genetic processes in pigs.

Deubiquitination is a reverse process of cellular ubiquitination important for many biological events. Ubiquitin (Ub)-specific protease 13 (USP13) is an ortholog of USP5 implicated in catalyzing hydrolysis of various Ub chains, but its enzymatic properties and catalytic regulation remain to be explored. Here we report studies of the roles of the Ub-binding domains of USP13 in regulatory catalysis by biochemical and NMR structural approaches. Our data demonstrate that USP13, distinct from USP5, exhibits a weak deubiquitinating activity preferring to Lys63-linked polyubiquitin (K63-polyUb) in a non-activation manner. The zinc finger (ZnF) domain of USP13 shares a similar fold with that of USP5, but it cannot bind with Ub, so that USP13 has lost its ability to be activated by free Ub. Substitution of the ZnF domain with that of USP5 confers USP13 the property of catalytic activation. The tandem Ub-associated (UBA) domains of USP13 can bind with different types of diUb but preferentially with K63-linked, providing a possible explanation for the weak activity preferring to K63-polyUb. USP13 can also regulate the protein level of CD3δ in cells, probably depending on its weak deubiquitinating activity and the Ub-binding properties of the UBA domains. Thus, the non-activating catalysis of USP13 for K63-polyUb chains implies that it may function differently from USP5 in cellular deubiquitination processes. [ABSTRACT FROM AUTHOR]

Homo sapiens J domain protein (HSJ1) is a J-domain containing co-chaperone that is known to stimulate ATPase activity of HSP70 chaperone, while it also harbors two ubiquitin (Ub)-interacting motifs (UIMs) that may bind with ubiquitinated substrates and potentially function in protein degradation. We studied the effects of HSJ1a on the protein levels of both normal and the disease-related polyQ-expanded forms of ataxin-3 (Atx3) in cells. The results demonstrate that the Nterminal J-domain and the C-terminal UIM domain of HSJ1a exert opposite functions in regulating the protein level of cellular overexpressed Atx3. This dual regulation is dependent on the binding of the J-domain with HSP70, and the UIM domain with polyUb chains. The J-domain down-regulates the protein level of Atx3 through HSP70 mediated proteasomal degradation, while the UIM domain may alleviate this process via maintaining the ubiquitinated Atx3. We propose that cochaperone HSJ1a orchestrates the balance of substrates in stressed cells in a Yin-Yang manner. [ABSTRACT FROM AUTHOR]

The ubiquitin-interacting motif (UIM) is a short peptide with dual function of binding ubiquitin (Ub) and promoting ubiquitination. We elucidated the structures and dynamics of the tandem UIMs of ataxin-3 (AT3-UIM12) both in free and Ubbound forms. The solution structure of free AT3-UIM12 consists of two a-helices and a flexible linker, whereas that of the Ub-bound form is much more compact with hydrophobic contacts between the two helices. NMR dynamics indicates that the flexible linker becomes rigid when AT3-UIM12 binds with Ub. Isothermal titration calorimetry and NMR titration demonstrate that AT3-UIM12 binds diUb with two distinct affinities, and the linker plays a critical role in association of the two helices in diUb binding. These results provide an implication that the tandem UIM12 interacts with Ub or diUb in a cooperative manner through an allosteric effect and dynamics change of the linker region, which might be related to its recognitions with various Ub chains and ubiquitinated substrates. [ABSTRACT FROM AUTHOR]

BACKGROUND:The benefits of volatile anesthetics in coronary artery bypass grafting (CABG) patients remain controversial. We aimed to conduct an updated meta-analysis to assess whether the use of volatile anesthetics during CABG could reduce mortality and other outcomes. METHODS:We searched eight databases from inception to June 2019 and included randomized controlled trials (RCTs) comparing the effects of volatile anesthetics versus total intravenous anesthesia (TIVA) in CABG patients. The primary outcomes were operative mortality and one-year mortality. The secondary outcomes included the length of stay in the intensive care unit (ICU) and hospital and postoperative safety outcomes (myocardial infarction, heart failure, arrhythmia, stroke, delirium, postoperative cognitive impairment, acute kidney injury, and the use of intra-aortic balloon pump (IABP) or other mechanical circulatory support). Trial sequential analysis (TSA) was performed to control for random errors. RESULTS:A total of 89 RCTs comprising 14,387 patients were included. There were no significant differences between the volatile anesthetics and TIVA groups in operative mortality (relative risk (RR) = 0.92, 95% confidence interval (CI): 0.68-1.24, p = 0.59, I2 = 0%), one-year mortality (RR = 0.64, 95% CI: 0.32-1.26, p = 0.19, I2 = 51%), or any of the postoperative safety outcomes. The lengths of stay in the ICU and hospital were shorter in the volatile anesthetics group than in the TIVA group. TSA revealed that the results for operative mortality, one-year mortality, length of stay in the ICU, heart failure, stroke, and the use of IABP were inconclusive. CONCLUSIONS:Conventional meta-analysis suggests that the use of volatile anesthetics during CABG is not associated with reduced risk of mortality or other postoperative safety outcomes when compared with TIVA. TSA shows that the current evidence is insufficient and inconclusive. Thus, future large RCTs are required to clarify this issue.

Ubiquitin-specific protease 19 (USP19) is one of the deubiquitinating enzymes (DUBs) involved in regulating the ubiquitination status of substrate proteins. There are two major isoforms of USP19 with distinct C-termini; the USP19_a isoform has a transmembrane domain for anchoring to the endoplasmic reticulum, while USP19_b contains an EEVD motif. Here, we report that the cytoplasmic isoform USP19_b up-regulates the protein levels of the polyglutamine (polyQ)-containing proteins, ataxin-3 (Atx3) and huntingtin (Htt), and thus promotes aggregation of their polyQ-expanded species in cell models. Our data demonstrate that USP19_b may orchestrate the stability, aggregation and degradation of the polyQ-expanded proteins through the heat shock protein 90 (HSP90) chaperone system. USP19_b directly interacts with HSP90 through its N-terminal CS (CHORD and SGT1)/P23 domains. In conjunction with HSP90, the cytoplasmic USP19 may play a key role in triage decision for the disease-related polyQ-expanded substrates, suggesting a function of USP19 in quality control of misfolded proteins by regulating their protein levels.