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Environmental protection talents training (EPTT) is recognized as a key prerequisite for maintaining environmental sustainability, and in order to study the influence of each player on EPTT. This paper innovatively constructs a tripartite evolutionary game model of government, university and enterprise. The equilibrium points and evolutionary stabilization strategies of each participant are solved by replicating the dynamic equations, and the behaviors of each subject in EPTT are analyzed so as to clarify the behavioral characteristics and optimal strategies of the government's participation in EPTT. The results show that enterprises occupy a more important position in influencing government decisions. The government should reduce the financial incentives for enterprises and replace them with greater policy support. Meanwhile, the government should actively promote the cultivation mechanism that integrates universities and enterprises. The results of the study can provide a decision-making basis for the government to promote the sustainable development of EPTT., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: In March 2022, a severe outbreak of COVID-19 broke out in Shanghai, with the virus spreading rapidly. In the most severe two months, more than 50,000 people were diagnosed with COVID-19. For this reason, Shanghai adopted three-district hierarchical management, requiring corresponding people to stay at home to contain the spread of the virus. Due to the requirements of prevention and control management, the diet, exercise and mental health of the corresponding population are affected to a certain extent., Objectives: This article aimed to understand the population in the diet, exercise and psychological changes., Methods: This study carried out the research by distributing the electronic questionnaire and carried out the statistical analysis., Results: People reduced the intake of vegetables and fruits (P = 0.000<0.05), people did about an hour less exercise per week on average (P = 0.000<0.05), the number of steps they took per day decreased by nearly 2000 steps (P = 0.012<0.05), and there were significant changes in the way they exercised., Conclusion: In terms of psychological state, people have some depression, anxiety and easy to feel tired after lockdown. This study can also provide reference for policy adjustment and formulation of normalized epidemic management in the future., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Qiu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

As an important engine for high-quality economic development, the digital economy is gradually integrating with the rural logistics industry. This trend is contributing to making rural logistics a fundamental, strategic, and pioneering industry. However, some valuable topics remain unstudied, such as whether they are coupled and whether there is variability in the coupling system across the provinces. Therefore, this article takes system theory and coupling theory as the analytical framework, aiming to better elaborate the subject's logical relationship and operational structure of the coupled system, which is composed of a digital economy subsystem and a rural logistics subsystem. Furthermore, 21 provinces are seen as the research object in China, and the coupling coordination model is constructed, aiming to verify the coupling and coordination relationship between the two subsystems. The results suggest that two subsystems are coupled and coordinated in the same direction, and they feed back and influence each other. During the same period, four echelons are divided and there is variability in the coupling and coordination between the digital economy and rural logistics, according to the coupling degree (CD) and coupling coordination degree (CCD). Findings presented can serve as a useful reference for the evolutionary laws of the coupled system. The findings presented here can serve as a useful reference for the evolutionary laws of coupled systems. Moreover, it further provides ideas for the development between rural logistics and the digital economy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Shu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Paeonia lactiflora Pall. (Paeonia) has aroused many concerns due to its extensive medicinal value, in which monoterpene glucoside paeoniflorin and its derivatives are the active chemical components. However, little is known in the molecular mechanism of monoterpenoids biosynthesis, and the regulation network between small RNAs and mRNAs in monoterpenoids biosynthesis has not been investigated yet. Herein, we attempted to reveal the tissue-specific regulation network of miRNAs and their targets related to paeoniaflorin and monoterpenoids biosynthesis in Paeonia by combining mRNA and miRNA expression data with degradome analysis. In all, 289 miRNAs and 30177 unigenes were identified, of which nine miRNAs from seven miRNA families including miR396, miR393, miR835, miR1144, miR3638, miR5794 and miR9555 were verified as monoterpenoids biosynthesis-related miRNAs by degradome sequencing. Moreover, the co-expression network analysis showed that four monoterpenoids-regulating TFs, namely AP2, MYBC1, SPL12 and TCP2, were putatively regulated by five miRNAs including miR172, miR828, miR858, miR156 and miR319, respectively. The present study will improve our knowledge of the molecular mechanisms of the paeoniaflorin and monoterpenoids biosynthesis mediated by miRNA to a new level, and provide a valuable resource for further study on Paeonia., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Xu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Five Camellia oleifera Abel seedling substrates were prepared using the conventional formula, but with the peat substituted by the composts of Camellia oleifera shell, pine chips, palm fiber residues, chicken manure, and sheep manure. The physical and chemical properties of the prepared substrates before and after seedling cultivation were determined and their effects on the growth of Camellia oleifera seedling were analyzed. It was found that the survival rates of the one-year-old seedlings produced from stem cuttings on all substrates at 6 months were greater than 97.5%. As compared with the conventional substrate, the substrates formulated with the composts were able to promote the seedling growth based upon height, ground diameter, root length and root volume measurement. The substrate prepared with the compost of Camellia oleifera shell+ palm fiber residue+ chicken manure (A3), vermiculite and perlite (6:3:1) was the most optimal, which gave 100% seedling survival rate, the greatest seedling height, and the largest ground diameter. In particular, the ground diameters and 26.67% of the seedling heights reached the grade 1 standard for two-year-old seedlings., Competing Interests: The authors have declared that no competing interests exist.

[This corrects the article DOI: 10.1371/journal.pone.0020698.].

Contagious ecthyma is a highly contagious disease with worldwide distribution, which is caused by the Orf virus (ORFV) belonging to the Parapoxvirus. To study the alteration of host gene expression in response to ORFV infection at the transcriptional level, several young small-tailed Han sheep were inoculated with ORFV, and their oral mucosa tissue samples (T0, T3, T7 and T15) were collected on day 0, 3, 7 and 15 after ORFV infection respectively. RNA-seq transcriptome comparisons were performed, showing that 1928, 3219 and 2646 differentially expressed genes (DEGs) were identified among T3 vs. T0, T7 vs. T0, and T15 vs. T0 respectively. Gene Ontology (GO) analyses of the DEGs from these comparisons, revealed that ORFV might provoke vigorous immune response of the host cells during the early stage of infection. Moreover, GO and network analysis showed that positive and negative regulative mechanisms of apoptosis were integrated in the host cells through up or down-regulating the expression level of DEGs involved in apoptotic pathways, in order to reach a homeostasis of oral mucosa tissues during the exposure to ORFV infection. In conclusion, our study for the first time describes the direct effects of ORFV on the global host gene expression of its host using high-throughput RNA sequencing, which provides a resource for future characterizing the interaction mechanism between the mammalian host and ORFV.

Background/objective: Inadvertent intraoperative hypothermia (core temperature <36°C) is a frequently preventable complication with several adverse consequences. Our study aimed to determine the overall incidence of inadvertent intraoperative hypothermia and its risk factors associated with clinical outcomes in this national survey in China., Methods: We conducted a national cross-sectional study with 30 days postoperative follow-up from November 2014 through August 2015. A total of 3132 eligible patients underwent general anesthesia were randomly selected from 28 hospitals in the nationwide of China., Results: The overall incidence of intraoperative hypothermia was as high as 44.3%, in which cumulative incidence rates of hypothermia being 17.8%, 36.2%, 42.5% and 44.1% within 1 h, 2 h, 3 h and 4 h respectively following induction of anesthesia. All patients were warmed passively by covering of surgical draping, sheets or cotton blankets, whereas only 14.2% of patients received active warming with space heaters or electric heater or electronic blankets. Compared to normothermic patients, patients with hypothermia is associated with more postoperative ICU admit, longer PACU and more postoperative hospital days, but no difference in surgical site infection (SSI) rates or 30-day mortality. Several factors were shown to be associated with decreased risk of hypothermia. They are active warming (OR = 0.46, 95% CI 0.26-0.81), BMI ≥ 25 (OR = 0.54, 95% CI 0.45-0.65), higher baseline core temperature (OR = 0.04, 95% CI 0.03-0.06), and higher ambient temperature (OR = 0.83, 95% CI 0.78-0.88). Risk factors associated with an increased risk of hypothermia included major-plus surgery (OR = 1.49, 95% CI 1.23-1.79), and long anesthesia (>2 h) (OR = 2.60, 95% CI 2.09-3.24)., Conclusions: The incidence of intraoperative hypothermia in China is high, and the rate of active warming of patients during operation is low. Hypothermia is associated with more postoperative shivering, increased ICU admissions, and longer postoperative hospital days.

Background/objective: The prevalence of type 2 diabetes is increasing rapidly around the world. Work-related stress is thought to be a major risk factor for type 2 diabetes; however, this association has not been widely studied, and the findings that have been reported are inconsistent. Therefore, we conducted a meta-analysis of prospective cohort studies to explore the association between work-related stress and risk for type 2 diabetes., Methods: A systematic literature search and manual search limited to articles published in English were performed to select the prospective cohort studies evaluated the association between work-related stress and risk for type 2 diabetes up to September 2014 from four electronic databases including PubMed, EMBASE, the Cochrane Library and Web of Science. A random-effects model was used to estimate the overall risk., Results: No significant association was found between work-related stress and risk for type 2 diabetes based on meta-analysis of seven prospective cohort studies involving 214,086 participants and 5,511 cases (job demands: relative risk 0.94 [95% confidence interval 0.72-1.23]; decision latitude: relative risk 1.16 [0.85-1.58]; job strain: relative risk 1.12 [.0.95-1.32]). However, an association between work-related stress and risk for type 2 diabetes was observed in women (job strain: relative risk 1.22 [1.01-1.46]) (P = 0.04). A sensitivity analysis conducted by excluding one study in each turn yielded similar results. No publication bias was detected with a funnel plot despite the limited number of studies included in the analysis., Conclusions: The results of this meta-analysis did not confirm a direct association between work-related stress and risk for type 2 diabetes. In subgroup analyses we found job strain was a risk factor for type 2 diabetes in women.

Ischemic stroke is a devastating complication of bone fracture. Bone fracture shortly after stroke enhances stroke injury by augmenting inflammation. We hypothesize that bone fracture shortly before ischemic stroke also exacerbates ischemic cerebral injury. Tibia fracture was performed 6 or 24 hours before permanent middle cerebral artery occlusion (pMCAO) on C57BL/6J mice or Ccr2RFP/+Cx3cr1GFP/+ mice that have the RFP gene knocked into one allele of Ccr2 gene and GFP gene knocked into one allele of Cx3cr1 gene. Behavior was tested 3 days after pMCAO. Infarct volume, the number of CD68+ cells, apoptotic neurons, bone marrow-derived macrophages (RFP+), and microgila (GFP+) in the peri-infarct region were quantified. Compared to mice subjected to pMCAO only, bone fracture 6 or 24 hours before pMCAO increased behavioral deficits, the infarct volume, and the number of CD68+ cells and apoptotic neurons in the peri-infarct area. Both bone marrow-derived macrophages (CCR2+) and microglia (CX3CR1+) increased in the peri-infarct regions of mice subjected to bone fracture before pMCAO compared to stroke-only mice. The mice subjected to bone fracture 6 hours before pMCAO had more severe injury than mice that had bone fracture 24 hours before pMCAO. Our data showed that bone fracture shortly before stroke also increases neuroinflammation and exacerbates ischemic cerebral injury. Our findings suggest that inhibition of neuroinflammation or management of stroke risk factors before major bone surgery would be beneficial for patients who are likely to suffer from stroke.

Background/objective: Inadvertent intraoperative hypothermia (core temperature <360 C) is a recognized risk in surgery and has adverse consequences. However, no data about this complication in China are available. Our study aimed to determine the incidence of inadvertent intraoperative hypothermia and its associated risk factors in a sample of Chinese patients., Methods: We conducted a regional cross-sectional survey in Beijing from August through December, 2013. Eight hundred thirty patients who underwent various operations under general anesthesia were randomly selected from 24 hospitals through a multistage probability sampling. Multivariate logistic regression analyses were applied to explore the risk factors of developing hypothermia., Results: The overall incidence of intraoperative hypothermia was high, 39.9%. All patients were warmed passively with surgical sheets or cotton blankets, whereas only 10.7% of patients received active warming with space heaters or electric blankets. Pre-warmed intravenous fluid were administered to 16.9% of patients, and 34.6% of patients had irrigation of wounds with pre-warmed fluid. Active warming (OR = 0.46, 95% CI 0.26-0.81), overweight or obesity (OR = 0.39, 95% CI 0.28-0.56), high baseline core temperature before anesthesia (OR = 0.08, 95% CI 0.04-0.13), and high ambient temperature (OR = 0.89, 95% CI 0.79-0.98) were significant protective factors for hypothermia. In contrast, major-plus operations (OR = 2.00, 95% CI 1.32-3.04), duration of anesthesia (1-2 h) (OR = 3.23, 95% CI 2.19-4.78) and >2 h (OR = 3.44, 95% CI 1.90-6.22,), and intravenous un-warmed fluid (OR = 2.45, 95% CI 1.45-4.12) significantly increased the risk of hypothermia., Conclusions: The incidence of inadvertent intraoperative hypothermia in Beijing is high, and the rate of active warming of patients during operation is low. Concern for the development of intraoperative hypothermia should be especially high in patients undergoing major operations, requiring long periods of anesthesia, and receiving un-warmed intravenous fluids.

Background: The transcription factor forkhead box D3 (FOXD3) plays important roles in the development of neural crest and has been shown to suppress the development of various cancers. However, the expression and its potential biological roles of FOXD3 in high-grade gliomas (HGGs) remain unknown., Methods: The mRNA and protein expression levels of FOXD3 were examined using real-time quantitative PCR and western blotting in 23 HGG and 13 normal brain samples, respectively. Immunohistochemistry was used to validate the expression FOXD3 protein in 184 HGG cases. The association between FOXD3 expression and the prognosis of HGG patients were analyzed using Kaplan-Meier survival curves and Cox proportional hazards regression models. In addition, we further examined the effects of FOXD3 on the proliferation and serum starvation-induced apoptosis of glioma cells., Results: In comparison to normal brain tissues, FOXD3 expression was significantly decreased in HGG tissues at both mRNA and protein levels. Immunohistochemistry further validated the expression of FOXD3 in HGG tissues. Moreover, low FOXD3 expression was significantly associated with poor prognosis in HGG patients. Depletion of FOXD3 expression promoted glioma cell proliferation and inhibited serum starvation-induced apoptosis, whereas overexpression of FOXD3 inhibited glioma cell proliferation and promoted serum starvation-induced apoptosis., Conclusions: Our results indicated that FOXD3 might serve as an independent prognostic biomarker and a potential therapeutic target for HGGs, which warrant further investigation.

The incidence of obesity is increasing worldwide. It was reported that endoplasmic reticulum stress (ERS) could inhibit insulin receptor signaling by activating c-Jun N-terminal kinase (JNK) in the liver. However, the relationship between ERS and insulin receptor signaling in the brain during obesity remains unclear. The aim of the current study was to assess whether ERS alters insulin receptor signaling through the hyper-activation of JNK in the hippocampus and frontal cortex in the brains of obese rats. Obesity was induced using a high fat diet (HFD). The Morris water maze test was then performed to evaluate decreases in cognitive function, and western blot was used to verify whether abnormal insulin receptor signaling was induced by ERS in HFD rats exhibiting cognitive decline. In addition, to determine whether ERS activated JNK and consequently impaired insulin receptor signaling, SH-SY5Y cells were treated with the JNK inhibitor, SP600125, followed by tunicamycin or thapsigargin, and primary rat hippocampal and cortical neurons were transfected with siRNA against IRE1α and JNK. We found that the expression of phosphorylation of PKR-like kinase (PERK), phosphorylation of α subunit of translation initiation factor 2 (eIF2α), and phosphorylation of inositol-requiring kinase-1α (IRE-1α) were increased in the brains of rats with HFD when compared with control rats. The level of serine phosphorylation of insulin receptor substrate-1 (IRS-1) was also increased, while protein kinase B (PKB/Akt) was reduced. ERS was also found to inhibit insulin receptor signaling via the activation of JNK in SH-SY5Y cells, primary rat hippocampal, and cortical neurons. These results indicate that ERS was increased, thereby resulting in impaired insulin receptor signaling in the hippocampus and frontal cortex of obese rats.

Diabetes related cognitive dysfunction (DACD), one of the chronic complications of diabetes, seriously affect the quality of life in patients and increase family burden. Although the initial stage of DACD can lead to metabolic alterations or potential pathological changes, DACD is difficult to diagnose accurately. Moreover, the details of the molecular mechanism of DACD remain somewhat elusive. To understand the pathophysiological changes that underpin the development and progression of DACD, we carried out a global analysis of metabolic alterations in response to DACD. The metabolic alterations associated with DACD were first investigated in humans, using plasma metabonomics based on high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry and multivariate statistical analysis. The related pathway of each metabolite of interest was searched in database online. The network diagrams were established KEGGSOAP software package. Receiver operating characteristic (ROC) analysis was used to evaluate diagnostic accuracy of metabolites. This is the first report of reliable biomarkers of DACD, which were identified using an integrated strategy. The identified biomarkers give new insights into the pathophysiological changes and molecular mechanisms of DACD. The disorders of sphingolipids metabolism, bile acids metabolism, and uric acid metabolism pathway were found in T2DM and DACD. On the other hand, differentially expressed plasma metabolites offer unique metabolic signatures for T2DM and DACD patients. These are potential biomarkers for disease monitoring and personalized medication complementary to the existing clinical modalities.

Objectives: To describe trends in the availability of biomarker testing in Chinese hospitals and how practice complies with established standards for the diagnosis of acute myocardial infarction (AMI)., Background: Cardiac biomarker testing is standard in high-income countries, but little is known about the availability and use of cardiac biomarker testing in low- and middle-income countries (LMICs) such as China., Methods: Based on a nationally representative sample of Chinese hospitals in 2001, 2006 and 2011, we describe the temporal trends and regional differences in the hospital capability and rates of use of cardiac biomarker testing, as well as the variation in use across hospitals with testing capability, for patients labeled with the diagnosis of AMI., Results: We sampled 175 hospitals (162 participated in the study) and 18,631 AMI admissions. 14,370 patients were included in analysis of biomarker use. The proportion of hospitals with biomarker testing capability was 57.4% in 2001 (25.0% troponin and 32.4% creatine kinase MB fraction (CK-MB) only) and 96.3% (81.4% troponin and 14.9% CK-MB only) in 2011. The proportion of hospitals with troponin testing capability in 2011 was significantly higher in urban compared with rural hospitals (96.8% vs. 71.4%, p< 0.001). In 2011, only 55.9% of hospitals with troponin testing capability (71 out of 127 hospitals) used the assay for more than 80% of their patients with AMI. Among hospitals with either biomarker testing capability, there was marked variation in use in both rural (from 7.1% to 100.0% of patients) and urban hospitals (from 57.9% to 100.0% of patients). In 2011, 36.1% of the patients with AMI did not have troponin tested and 4.9% did not have either biomarker measured., Conclusions: The recommended biomarker tests for AMI diagnosis are not universally available and the testing is not consistently applied when it is available in China., Trial Registration: ClinicalTrials.gov NCT01624883.

Reading is an important part of our daily life, and rapid responses to emotional words have received a great deal of research interest. Our study employed rapid serial visual presentation to detect the time course of emotional noun processing using event-related potentials. We performed a dual-task experiment, where subjects were required to judge whether a given number was odd or even, and the category into which each emotional noun fit. In terms of P1, we found that there was no negativity bias for emotional nouns. However, emotional nouns elicited larger amplitudes in the N170 component in the left hemisphere than did neutral nouns. This finding indicated that in later processing stages, emotional words can be discriminated from neutral words. Furthermore, positive, negative, and neutral words were different from each other in the late positive complex, indicating that in the third stage, even different emotions can be discerned. Thus, our results indicate that in a three-stage model the latter two stages are more stable and universal.

Members of the epidermal growth factor family play important roles in the regulation of cell growth, proliferation, and survival. However, the specific roles of each epidermal growth factor family member with respect to brain injury are not well understood. Gene chip assay screens have revealed drastic increases in the expression of the epidermal growth factor family members amphiregulin and epiregulin following lipopolysaccharide stimulation, which activates an immune response. Both immune activity and endoplasmic reticulum stress are activated during cerebral ischemia. We found that the expression levels of amphiregulin and epiregulin were significantly increased under conditions of cerebral ischemia. Because endoplasmic reticulum stress increased the expression of amphiregulin and epiregulin in glial cells, endoplasmic reticulum stress may be a key mediatory factor of pathophysiological activity. Recombinant epiregulin and amphiregulin proteins effectively inhibited endoplasmic reticulum stress and the subsequent induction of neuronal cell death. Therefore, the upregulation of the epidermal growth factor family members epiregulin and amphiregulin may play a critical role in preventing endoplasmic reticulum stress-induced cell death, thus providing a potential therapy for brain injury.

Background & Aims: Farnesoid X receptor (FXR, NR1H4) is a ligand-activated transcription factor, belonging to the nuclear receptor superfamily. FXR is highly expressed in the liver and is essential in regulating bile acid homeostasis. FXR deficiency is implicated in numerous liver diseases and mice with modulation of FXR have been used as animal models to study liver physiology and pathology. We have reported genome-wide binding of FXR in mice by chromatin immunoprecipitation - deep sequencing (ChIP-seq), with results indicating that FXR may be involved in regulating diverse pathways in liver. However, limited information exists for the functions of human FXR and the suitability of using murine models to study human FXR functions., Methods: In the current study, we performed ChIP-seq in primary human hepatocytes (PHHs) treated with a synthetic FXR agonist, GW4064 or DMSO control. In parallel, RNA deep sequencing (RNA-seq) and RNA microarray were performed for GW4064 or control treated PHHs and wild type mouse livers, respectively., Results: ChIP-seq showed similar profiles of genome-wide FXR binding in humans and mice in terms of motif analysis and pathway prediction. However, RNA-seq and microarray showed more different transcriptome profiles between PHHs and mouse livers upon GW4064 treatment., Conclusions: In summary, we have established genome-wide human FXR binding and transcriptome profiles. These results will aid in determining the human FXR functions, as well as judging to what level the mouse models could be used to study human FXR functions.

TRPV4, one of the TRP channels, is implicated in diverse physiological and pathological processes including cell proliferation. However, the role of TRPV4 in liver fibrosis is largely unknown. Here, we characterized the role of TRPV4 in regulating HSC-T6 cell proliferation. TRPV4 mRNA and protein were measured by RT-PCR and Western blot in patients and rat model of liver fibrosis in vivo and TGF-β1-activated HSC-T6 cells in vitro. Both mRNA and protein of TRPV4 were dramatically increased in liver fibrotic tissues of both patients and CCl4-treated rats. Stimulation of HSC-T6 cells with TGF-β1 resulted in increase of TRPV4 mRNA and protein. However, TGF-β1-induced HSC-T6 cell proliferation was inhibited by Ruthenium Red (Ru) or synthetic siRNA targeting TRPV4, and this was accompanied by downregulation of myofibroblast markers including α-SMA and Col1α1. Moreover, our study revealed that miR-203 was downregulated in liver fibrotic tissues and TGF-β1-treated HSC-T6 cell. Bioinformatics analyses predict that TRPV4 is the potential target of miR-203. In addition, overexpression of miR-203 in TGF-β1-induced HSC significantly reduced TRPV4 expression, indicating TRPV4, which was regulated by miR-203, may function as a novel regulator to modulate TGF-β1-induced HSC-T6 proliferation.

Background: Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear chromatin-associated enzyme involved in several important cellular processes, particularly in the DNA repair system. PARP-1 rs1136410: C>T is among the most studied polymorphisms and likely involved in human carcinogenesis. However, results from previous studies are inconclusive. Thus, a meta-analysis was conducted to derive a more precise estimation of the effects of this enzyme., Methodology and Principal Findings: A comprehensive search was conducted in the PubMed and EMBASE databases until December 9, 2013. A total of 39 studies with 16,783 cancer cases and 23,063 control subjects were included in the meta-analysis on the basis of the inclusion and exclusion criteria. No significant association between the PARP-1 Val762Ala polymorphism and cancer risk was found when all of the studies were pooled into the analysis (VA + AA vs. VV: OR = 1.03, 95% CI = 0.95-1.11). The subgroup analysis of cancer types revealed that the -762Ala allele was associated with increased risk of gastric, cervical, and lung cancers and a decreased risk of glioma. In addition, a significantly increased risk of cancer associated with the polymorphism was observed in Asian descendents (VA + AA vs. VV: OR = 1.17, 95% CI = 1.09-1.25; AA vs. VV: OR = 1.28, 95% CI = 1.08-1.51; VA vs. VV: OR = 1.12, 95% CI = 1.04-1.20; AA vs. VA + VV: OR = 1.09, 95% CI = 1.03-1.39). These results also indicated that a joint effect between PARP-1 Val762Ala and XRCC1 Arg399Gln could be involved in the risk of cancer development (OR = 3.53, 95% CI = 1.30-9.59)., Conclusion: The present meta-analysis provides evidence that the PARP-1 Val762Ala may be involved in cancer development at least in some ethnic groups (Asian) or some specific cancer types (gastric, cervical, and lung cancers, and glioma).

Multiple organ systems, including the brain, which undergoes changes that may increase the risk of cognitive decline, are adversely affected by diabetes mellitus (DM). Here, we demonstrate that type 2 diabetes mellitus (T2DM) db/db mice exhibited hippocampus-dependent memory impairment, which might associate with a reduction in dendritic spine density in the pyramidal neurons of brain, Aβ1-42 deposition in the prefrontal cortex (PFC) and hippocampus, and a decreased expression of neurostructural proteins including microtubule-associated protein (MAP2), a marker of dendrites, and postsynaptic density 95 (PSD95), a marker of excitatory synapses. To investigate the effects of the ZiBuPiYin recipe (ZBPYR), a traditional Chinese medicine recipe, on diabetes-related cognitive decline (DACD), db/db mice received daily administration of ZBPYR over an experimental period of 6 weeks. We then confirmed that ZBPYR rescued learning and memory performance impairments, reversed dendritic spine loss, reduced Aβ1-42 deposition and restored the expression levels of MAP2 and PSD95. The present study also revealed that ZBPYR strengthened brain leptin and insulin signaling and inhibited GSK3β overactivity, which may be the potential mechanism or underlying targets of ZBPYR. These findings conclude that ZBPYR prevents DACD, most likely by improving dendritic spine density and attenuating brain leptin and insulin signaling pathway injury. Our findings provide further evidence for the effects of ZBPYR on DACD.

Objectives: Sarcoplasmic reticulum (SR) Ca(2+)-handling proteins play an important role in myocardial dysfunction after acute ischemia/reperfusion injury. We hypothesized that nitrite would improve postresuscitation myocardial dysfunction by increasing nitric oxide (NO) generation and that the mechanism of this protection is related to the modulation of SR Ca(2+)-handling proteins., Methods: We conducted a randomized prospective animal study using male Sprague-Dawley rats. Cardiac arrest was induced by intravenous bolus of potassium chloride (40 µg/g). Nitrite (1.2 nmol/g) or placebo was administered when chest compression was started. No cardiac arrest was induced in the sham group. Hemodynamic parameters were monitored invasively for 90 minutes after the return of spontaneous circulation (ROSC). Echocardiogram was performed to evaluate cardiac function. Myocardial samples were harvested 5 minutes and 1 hour after ROSC., Results: Myocardial function was significantly impaired in the nitrite and placebo groups after resuscitation, whereas cardiac function (i.e., ejection fraction and fractional shortening) was significantly greater in the nitrite group than in the placebo group. Nitrite administration increased the level of nitric oxide in the myocardium 5 min after resuscitation compared to the other two groups. The levels of phosphorylated phospholamban (PLB) were decreased after resuscitation, and nitrite increased the phosphorylation of phospholamban compared to the placebo. No significant differences were found in the expression of sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) and ryanodine receptors (RyRs)., Conclusions: postresuscitation myocardial dysfunction is associated with the impairment of PLB phosphorylation. Nitrite administered during resuscitation improves postresuscitation myocardial dysfunction by preserving phosphorylated PLB protein during resuscitation.

Objective: Xeroderma pigmentosum group D (XPD) is an essential gene involved in the nucleotide excision repair (NER) pathway. Two commonly studied single nucleotide polymorphisms (SNPs) of XPD (Lys751Gln, A>C, rs13181; Asp312Asn, G>A, rs1799793) are implicated in the modulation of DNA repair capacity, thus related to the responses to platinum-based chemotherapy. Here we performed a meta-analysis to better evaluate the association between the two XPD SNPs and clinical outcome of platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients., Methods: A comprehensive search of PubMed database was conducted to identify relevant articles. Primary outcomes included objective response (i.e., complete response + partial response vs. stable disease + progressive disease), progression-free survival (PFS) and overall survival (OS). The pooled and 95% confidence intervals (CIs) of ORs (odds ratios) and HRs (hazard ratios) were estimated using the fixed or random effect model., Results: Twenty-four studies were eligible according to the inclusion criteria. None of the XPD Lys751Gln/Asp312Asn polymorphisms was associated with objective response, PFS or OS in NSCLC patients treated with platinum drugs. However, in stratified analysis by ethnicity, the XPD Lys751Gln (A>C) polymorphism was not significantly associated with increased response in Caucasians (OR=1.35, 95%CI=1.0-1.83, P=0.122 for heterogeneity) but was associated with decreased PFS in Asians (HR=1.39, 95%CI=1.07-1.81, P=0.879 for heterogeneity). Furthermore, a statistically significant difference existed in the estimates of effect between the two ethnicities (P=0.014 for TR; P<0.001 for PFS)., Conclusions: XPD Lys751Gln (A>C) may have inverse predictive and prognostic role in platinum-based treatment of NSCLC according to different ethnicities. Further studies are needed to validate our findings.

Our previous work established that DNA is naturally transferable on agar plates through a new transformation system which is regulated by the stationary phase master regulator RpoS in Escherichia coli. In this transformation system, neither additional Ca(2+) nor heat shock is required. Instead, transformation is stimulated by agar. The membrane protein OmpA, a gated pore permeable to ions and larger solutes, serves as a receptor for DNA transfer during bacteriophage infection and conjugation. However, it remains unknown how DNA transfers across membranes and whether OmpA is involved in transformation of E. coli. Here, we explored potential roles of OmpA in natural and chemical transformation of E. coli. We observed that ompA inactivation significantly improved natural transformation on agar plates, indicating that OmpA blocks DNA transfer. Transformation promotion by ompA inactivation also occurred on soft plates, indicating that OmpA blocks DNA transfer independent of agar. By contrast, compared with the wild-type strain, chemical transformation of the ompA mutant was lower, indicating that OmpA has a role in DNA transfer. Inactivation of ompA also reduced chemical transformation in solution containing less Ca(2+) or with a shortened time for heat shock, suggesting that the promotion effect of OmpA on DNA transfer does not solely rely on Ca(2+) or heat shock. We conclude that OmpA plays opposite roles in natural and chemical transformation: it blocks DNA uptake on agar plates but promotes DNA transfer in the liquid Ca(2+) solution. Considering that no single factor was identified to reverse the function of OmpA, we propose that multiple factors may cooperate in the functional reversal of OmpA during natural and artificial transformation of E. coli. Finally, we observed that ompA transcription was not affected by the expression of RpoS, excluding the possibility that RpoS regulates DNA transfer by suppressing ompA transcription.

Cytosolic aggregation of the nuclear RNA-binding protein TDP-43 is a histopathologic signature of degenerating neurons in amyotrophic lateral sclerosis (ALS), and mutations in the TARDBP gene encoding TDP-43 cause dominantly inherited forms of this condition. To understand the relationship between TDP-43 misregulation and neurotoxicity, we and others have used Drosophila as a model system, in which overexpression of either wild-type TDP-43 or its ALS-associated mutants in neurons is sufficient to induce neurotoxicity, paralysis, and early death. Using microarrays, we have examined gene expression patterns that accompany TDP-43-induced neurotoxicity in the fly system. Constitutive expression of TDP-43 in the Drosophila compound eye elicited widespread gene expression changes, with strong upregulation of cell cycle regulatory genes and genes functioning in the Notch intercellular communication pathway. Inducible expression of TDP-43 specifically in neurons elicited significant expression differences in a more restricted set of genes. Genes that were upregulated in both paradigms included SpindleB and the Notch target Hey, which appeared to be a direct TDP-43 target. Mutations that diminished activity of Notch or disrupted the function of downstream Notch target genes extended the lifespan of TDP-43 transgenic flies, suggesting that Notch activation was deleterious in this model. Finally, we showed that mutation of the nucleoporin Nup50 increased the lifespan of TDP-43 transgenic flies, suggesting that nuclear events contribute to TDP-43-dependent neurotoxicity. The combined findings identified pathways whose deregulation might contribute to TDP-43-induced neurotoxicity in Drosophila.

Background: Farnesoid X Receptor (FXR) is a member of the nuclear receptor superfamily and is a ligand-activated transcription factor essential for maintaining liver and intestinal homeostasis. FXR is protective against carcinogenesis and inflammation in liver and intestine as demonstrated by the development of inflammation and tumors in the liver and intestine of FXR knock-out mice. However, mechanisms for the protective effects of FXR are not completely understood. This study reports a novel role of FXR in regulating expression of Sqstm1, which encodes for p62 protein. p62 plays an important role in maintaining cellular homeostasis through selective autophagy and activating signal transduction pathways, such as NF-κB to support cell survival and caspase-8 to initiate apoptosis. FXR regulation of Sqstm1 may serve as a protective mechanism., Methods and Results: This study showed that FXR bound to the Sqstm1 gene in both mouse livers and ileums as determined by chromatin immunoprecipitation. In addition, FXR activation enhanced transcriptional activation of Sqstm1 in vitro. However, wild-type mice treated with GW4064, a synthetic FXR ligand, showed that FXR activation induced mRNA and protein expression of Sqstm1/p62 in ileum, but not in liver. Interestingly, FXR-transgenic mice showed induced mRNA expression of Sqstm1 in both liver and ileum compared to wild-type mice., Conclusions: Our current study has identified a novel role of FXR in regulating the expression of p62, a key factor in protein degradation and cell signaling. Regulation of p62 by FXR indicates tissue-specific and gene-dosage effects. Furthermore, FXR-mediated induction of p62 may implicate a protective mechanism of FXR.

Oxidative stress plays a critical role in the pathophysiology of cardiac failure, including the modulation of neovascularization following myocardial infarction (MI). Redox molecules thioredoxin (Trx) and glutaredoxin (Grx) superfamilies actively maintain intracellular thiol-redox homeostasis by scavenging reactive oxygen species. Among these two superfamilies, the pro-angiogenic function of Trx-1 has been reported in chronic MI model whereas similar role of Grx-1 remains uncertain. The present study attempts to establish the role of Grx-1 in neovascularization and ventricular remodeling following MI. Wild-type (WT) and Grx-1 transgenic (Grx-1(Tg/+)) mice were randomized into wild-type sham (WTS), Grx-1(Tg/+) Sham (Grx-1(Tg/+)S), WTMI, Grx-1(Tg/+)MI. MI was induced by permanent occlusion of the LAD coronary artery. Sham groups underwent identical time-matched surgical procedures without LAD ligation. Significant increase in arteriolar density was observed 7 days (d) after surgical intervention in the Grx-1(Tg/+)MI group as compared to the WTMI animals. Further, improvement in myocardial functional parameters 30 d after MI was observed including decreased LVIDs, LVIDd, increased ejection fraction and, fractional shortening was also observed in the Grx-1(Tg/+)MI group as compared to the WTMI animals. Moreover, attenuation of oxidative stress and apoptotic cardiomyocytes was observed in the Grx-1(Tg/+)MI group as compared to the WTMI animals. Increased expression of p-Akt, VEGF, Ang-1, Bcl-2, survivin and DNA binding activity of NF-κB were observed in the Grx-1(Tg/+)MI group when compared to WTMI animals as revealed by Western blot analysis and Gel-shift analysis, respectively. These results are the first to demonstrate that Grx-1 induces angiogenesis and diminishes ventricular remodeling apparently through neovascularization mediated by Akt, VEGF, Ang-1 and NF-κB as well as Bcl-2 and survivin-mediated anti-apoptotic pathway in the infarcted myocardium., (© 2012 Adluri et al.)

The identification and quantitative analysis of protein-protein interactions are essential to the functional characterization of proteins in the post-proteomics era. The methods currently available are generally time-consuming, technically complicated, insensitive and/or semi-quantitative. The lack of simple, sensitive approaches to precisely quantify protein-protein interactions still prevents our understanding of the functions of many proteins. Here, we develop a novel dual luciferase reporter pull-down assay by combining a biotinylated Firefly luciferase pull-down assay with a dual luciferase reporter assay. The biotinylated Firefly luciferase-tagged protein enables rapid and efficient isolation of a putative Renilla luciferase-tagged binding protein from a relatively small amount of sample. Both of these proteins can be quantitatively detected using the dual luciferase reporter assay system. Protein-protein interactions, including Fos-Jun located in the nucleus; MAVS-TRAF3 in cytoplasm; inducible IRF3 dimerization; viral protein-regulated interactions, such as MAVS-MAVS and MAVS-TRAF3; IRF3 dimerization; and protein interaction domain mapping, are studied using this novel assay system. Herein, we demonstrate that this dual luciferase reporter pull-down assay enables the quantification of the relative amounts of interacting proteins that bind to streptavidin-coupled beads for protein purification. This study provides a simple, rapid, sensitive, and efficient approach to identify and quantify relative protein-protein interactions. Importantly, the dual luciferase reporter pull-down method will facilitate the functional determination of proteins.

The experimental infection of a mouse lung with influenza A virus has proven to be an invaluable model for studying the mechanisms of viral adaptation and virulence. The mouse adaption of human influenza A virus can result in mutations in the HA and other proteins, which is associated with increased virulence in mouse lungs. In this study, a mouse-adapted seasonal H1N1 virus was obtained through serial lung-to-lung passages and had significantly increased virulence and pathogenicity in mice. Genetic analysis indicated that the increased virulence of the mouse-adapted virus was attributed to incremental acquisition of three mutations in the HA protein (T89I, N125T, and D221G). However, the mouse adaption of influenza A virus did not change the specificity and affinity of receptor binding and the pH-dependent membrane fusion of HA, as well as the in vitro replication in MDCK cells. Notably, infection with the mouse adapted virus induced severe lymphopenia and modulated cytokine and chemokine responses in mice. Apparently, mouse adaption of human influenza A virus may change the ability to replicate in mouse lungs, which induces strong immune responses and inflammation in mice. Therefore, our findings may provide new insights into understanding the mechanisms underlying the mouse adaption and pathogenicity of highly virulent influenza viruses.

The novel pandemic A (H1N1) virus was first identified in Mexico in April 2009 and quickly spread worldwide. Like all influenzas, the H1N1 strain-specific properties of replication, virulence, and pathogenicity are a result of the particular genomic sequence and concerted expression of multiple genes. Thus, specific mutations may support increased virulence and may be useful as biomarkers of potential threat to human health. We performed comparative genomic analysis of ten strains of the 2009 pandemic A (H1N1) influenza viruses to determine whether genotypes associated with clinical phenotypes, which ranged from mild to severe illness and up to lethal. Virus replication capacity was tested for each strain in vitro using cultured epithelial cells, while virulence and pathogenicity were investigated in vivo using the BALB/c mouse model. The results indicated that A/Sichuan/1/2009 strain had significantly higher replication ability and virulence than the other strains, and five unique non-synonymous mutations were identified in important gene-encoding sequences. These mutations led to amino acid substitutions in HA (L32I), PA (A343T), PB1 (K353R and T566A), and PB2 (T471M), and may be critical molecular determinants for replication, virulence, and pathogenicity. Our results suggested that the replication capacity in vitro and virulence in vivo of the 2009 pandemic A (H1N1) viruses were not associated with the clinical phenotypes. This study offers new insights into the transmission and evolution of the 2009 pandemic A (H1N1) virus.

Activating transcription factor 1 (ATF1) and the closely related proteins CREB (cyclic AMP resonse element binding protein) and CREM (cyclic AMP response element modulator) constitute a subfamily of bZIP transcription factors that play critical roles in the regulation of cellular growth, metabolism, and survival. Previous studies demonstrated that CREB is phosphorylated on a cluster of conserved Ser residues, including Ser-111 and Ser-121, in response to DNA damage through the coordinated actions of the ataxia-telangiectasia-mutated (ATM) protein kinase and casein kinases 1 and 2 (CK1/2). Here, we show that DNA damage-induced phosphorylation by ATM is a general feature of CREB and ATF1. ATF1 harbors a conserved ATM/CK cluster that is constitutively and stoichiometrically phosphorylated by CK1 and CK2 in asynchronously growing cells. Exposure to DNA damage further induced ATF1 phosphorylation on Ser-51 by ATM in a manner that required prior phosphorylation of the upstream CK residues. Hyperphosphorylated ATF1 showed a 4-fold reduced affinity for CREB-binding protein. We further show that PP2A, in conjunction with its targeting subunit B56gamma, antagonized ATM and CK1/2-dependent phosphorylation of CREB and ATF1 in cellulo. Finally, we show that CK sites in CREB are phosphorylated during cellular growth and that phosphorylation of these residues reduces the threshold of DNA damage required for ATM-dependent phosphorylation of the inhibitory Ser-121 residue. These studies define overlapping and distinct modes of CREB and ATF1 regulation by phosphorylation that may ensure concerted changes in gene expression mediated by these factors.