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Li-Chao Ma,1,2 Shi-Ning Lou,3 Xiao-Li Zhu,3 Ruo-Lan Zhang,1 Lin Wu,1 Jiang-Yuan Xu,1 Xiao-Juan Ding,1 Juan Liu,4 Yan Wang1 1School of Nursing, Hebei University, Baoding, Hebei, 071000, People’s Republic of China; 2Operating Room, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China; 3Department of Traditional Chinese Medicine, Work’s Hospital of China Lucky Group Corporation, Baoding, Hebei, 07100, People’s Republic of China; 4Department of Rehabilitation Medicine, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, People’s Republic of ChinaCorrespondence: Juan Liu, Department of Rehabilitation Medicine, Affiliated Hospital of Hebei University, No. 212 of Yuhua East Road, Lianchi District, Baoding City, Hebei Province, 071000, People’s Republic of China, Tel +86 13582292161, Email juanliulj07@126.com Yan Wang, School of Nursing, Hebei University, No. 342 of Yuhua East Road, Lianchi District, Baoding City, Hebei Province, 071000, People’s Republic of China, Tel +86 13833258628, Email ywang_dr06@163.comObjective: This study aimed to explore the needs and constraints to cardiac rehabilitation (CR) among patients diagnosed with coronary heart disease (CHD) in a community-based setting, and thereby facilitating the implementation of effective CR programs for this population.Methods: Focus group interviews were used as the primary research methodology. A total of 11 community-dwelling individuals diagnosed with CHD were selected from a community hospital to participate in in-depth interviews, aiming to discern and analyze their requirements and constraints experienced concerning medical resources and healthcare agency. The textual data underwent examination using Colaizzi’s method of descriptive data analysis.Results: Deficits existed in the perceptions of patients with CHD within a community-based setting about their condition and CR, and in the social support for this disease. Patients expressed expectations for professional guidance during CR, gained an understanding about the beneficial effects of emotional stability on cognitive function. Patients expressed their thoughts and feelings regarding the diversity of physical exercise options. Two main themes and seven sub-themes were identified: (a) “Insufficient CR resources for patients”: Lack of awareness about CHD; inadequate knowledge about secondary prevention/CR; insufficient support from family and friends. (b) “Patient CR initiative”: Patient self-adjustment; expectation of professional rehabilitation guidance; stable emotions improving cognition; diverse attitudes and awareness of exercise.Conclusion: For more effective CR, community-based medical teams should provide more comprehensive and individualized rehabilitation programs. They should focus on individual variations and preferences of patients, as well as enhance the autonomy of patients and improve their self-care ability through effective empowerment measures.Keywords: coronary heart disease, cardiac rehabilitation, community sanitation service, self-care, patient needs

The objective of this study is to assess the influence of blended education methodologies, utilizing an online education platform, among stage III cardiac rehabilitation (CR) patients diagnosed with coronary heart disease (CHD). Between June and August 2021, a cohort of 90 patients diagnosed with CHD, previously discharged from a second-class hospital 1 year earlier, were randomly allocated into 2 groups: the experimental and control groups, with each comprising 45 patients. Patients in the control group received out-of-hospital CR education via WeChat, while those in the experimental group received blended CR education utilizing an online education platform. Following a 24-week period, the self-management behavior and negative emotions of both groups were compared before and after the intervention. The final count of patients in the control and experimental groups was 39 and 37, respectively. Post the intervention, in terms of self-management behavior, the control group achieved an average score of 90.69 ± 7.13, while the experimental group scored 96.11 ± 5.42 (P < .05). Concerning negative emotions, the anxiety scores for the control and experimental groups were 3.03 ± 2.63 and 1.86 ± 1.80, respectively, and the depression scores were 3.00 (3.00) and 2.00 (3.00), respectively (P < .05). The differences in the outcomes mentioned above were statistically significant. The implementation of a blended educational approach utilizing an online platform has resulted in notable improvements in self-management skills and the reduction of negative emotions among patients with CHD. As a result, this educational strategy has demonstrated effectiveness in providing post-discharge CR education for patients with CHD., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Type 2 diabetes mellitus (T2DM) is a metabolic syndrome characterized by chronic inflammation, insulin resistance, and islet cell damage. The prevention of T2DM and its associated complications is an urgent public health issue that affects hundreds of millions of people globally. Numerous studies suggest that disturbances in gut metabolites are important driving forces for the pathogenesis of diabetes. However, the functions and mechanisms of action of most commensal bacteria in T2DM remain largely unknown., Methods: The quantification of bile acids (BAs) in fecal samples was performed using ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS). The anti-diabetic effects of Bacteroides uniformis ( B. uniformis ) and its metabolites cholic acid (CA) and chenodeoxycholic acid (CDCA) were assessed in T2DM mice induced by streptozocin (STZ) plus high-fat diet (HFD)., Results: We found that the abundance of B. uniformis in the feces and the contents of CA and CDCA were significantly downregulated in T2DM mice. B. uniformis was diminished in diabetic individuals and this bacterium was sufficient to promote the production of BAs. Colonization of B. uniformis and intragastric gavage of CA and CDCA effectively improved the disorder of glucose and lipid metabolism in T2DM mice by inhibiting gluconeogenesis and lipolysis in the liver. CA and CDCA improved hepatic glucose and lipid metabolism by acting on the Takeda G protein-coupled receptor 5 (TGR5)/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway since knockdown of TGR5 minimized the benefit of CA and CDCA. Furthermore, we screened a natural product-vaccarin (VAC)-that exhibited anti-diabetic effects by promoting the growth of B. uniformis in vitro and in vivo. Gut microbiota pre-depletion abolished the favorable effects of VAC in diabetic mice., Conclusions: These data suggest that supplementation of B. uniformis may be a promising avenue to ameliorate T2DM by linking the gut and liver.

The microbiome encompasses the genomes of the microorganisms that inhabit specific environments. One Health is an emerging concept, recognised as a cohesive, harmonising approach aimed at sustainably improving the well-being of humans, animals, and the environment. The microbiome plays a crucial role in the One Health domain, facilitating interactions among humans, animals, and the environment, along with co-evolution, co-development, co-metabolism, and co-regulation with their associated humans and animals. In addition, the microbiome regulates environmental health through interactions with plant microbiota, which actively participate in substance cycling (particularly the carbon and nitrogen cycles) and influence the overall energy flow in the biosphere. Moreover, antibiotic resistance genes present in microbiota can lead to widespread drug resistance in both humans and animals. This review explores the impact of the microbiome on humans, animals, and the environment, highlighting the significance of focusing on this field in One Health research., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Aim: To investigate the factors affecting hemodialysis patients' self-management ability at a dialysis center in Taiwan., Background: Taiwan has the highest incidence and prevalence of end-stage kidney disease (ESKD) in the world. Over 90% of patients with ESKD receiving hemodialysis (HD) and self-management behaviors are critical among these patients. Failure to adhere to self-managed care increases the cost of medical care and the risk of morbidity and mortality., Methods: In this cross-sectional study, a total of 150 HD patients were observed for their self-management behaviors and the factors influencing these behaviors including education level, comorbid conditions, biochemical analysis, depression, and social support, etc., were analyzed., Results: Self-management behaviors in HD patients were significantly impaired in the presence of diabetes mellitus, hypertension, anemia, hypoalbuminemia, and depression. The major predictor of patients' self-management was depression, explaining 14.8% of the total variance. Further addition of social support, hypertension, and diabetes mellitus into the regression model increased the total explained variance to 28.6%. Of the various domains of self-management, the partnership domain received the highest score, whereas emotional processing received the lowest score., Conclusions: This study found the important factors influencing self-management behaviors; through this acknowledgement and early correction of these factors, we hope to improve HD patients' individual life quality and further decrease their morbidity and mortality.

Background: Recent literature reported the biological role of C-peptide, but this role is still controversial and unclear. The primary aim of this study was to investigate associations between C-peptide and cardiovascular biomarkers as well as events., Methods: A total of 55636 participants who had a health examination from 2017 to 2021 were included. Of them, 6727 participants visited the hospital at least twice. Cardiovascular biomarkers like high-sensitivity C-reactive protein (hs-CRP) and high-sensitivity cardiac troponin T (hs-cTnT) were measured and their relationships with fasting C-peptide were evaluated for all participants. Cardiovascular events were obtained during the last visit and their associations with C-peptide were evaluated for those participants who visited the hospital at least twice., Results: Among the included participants, 11.1% had a previous type 2 diabetes mellitus (T2DM). In the participants without previous T2DM, the relationships between fasting C-peptide and hs-CRP and hs-cTnT were negative if the value of fasting C-peptide was < 1.4 ng/mL and positive if the value was ≥ 1.4 ng/mL. These relationships remained significant after adjusting for hemoglobin A1c, insulin resistance index, and its interaction with C-peptide, even if the participants were stratified by glucose metabolism status or levels of insulin resistance index. Hazard ratios of cardiovascular events were first decreased and then increased with the increasing of baseline C-peptide levels, though these associations became unsignificant using the multivariate Cox regression model. Unlike the participants without previous T2DM, the associations of C-peptide with cardiovascular biomarkers and events were not significant in the patients with previous T2DM., Conclusions: The associations of C-peptide with cardiovascular biomarkers and events were different between the participants without previous T2DM and those with previous T2DM. The effect of C-peptide on cardiovascular risk may be bidirectional, play a benefit role at a low level, and play a harmful role at a high level in the nondiabetic adults and the patients with newly diagnosed T2DM., (© 2022. The Author(s).)

Background: The association of vitamin D with all-cause mortality remains controversial and longitudinal evidence exploring the potential effects of change in vitamin D status is limited in the oldest old (aged ≥ 80 years old). We aimed to study the relationship between vitamin D change and all-cause mortality among older Chinese adults including the oldest old., Methods: The data of Chinese Longitudinal and Health Longevity Study in 2012 and 2014 wave was used for baseline data. Mortality was assessed in the subsequent 2018 survey waves. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% confidence interval (CI) of all-cause mortality related to vitamin D change, including maintaining deficiency or no deficiency, deficiency to no deficiency, and no deficiency to deficiency, using below 50 nmol/L as definition of deficiency., Results: The mean age of the total 1362 participants was 84.4 ± 12.1(60-113) years. The prevalence of vitamin D deficiency was 67.5% and 68.4% in 2012 and 2014 wave respectively, and significantly differed by sex and age at baseline. Cox regression showed that participants with deficiency to no deficiency and maintaining no deficiency of vitamin D status had decreased HR for all-cause mortality, compared to the maintaining deficiency group. The HRs for mortality were 0.70(95%CI: 0.50-0.96, p = 0.028) and 0.47(95%CI: 0.33-0.68, p < 0.001) respectively in the adjusted model. Also, females and the oldest old had a greatest reduction in mortality risk. And no significant difference in mortality in the no deficiency to deficiency group., Conclusions: Not only maintaining no deficiency, but also the change from deficiency to no deficiency of vitamin D status were associated with lower risk of all-cause mortality, especially in the female and oldest-old participants initially with low vitamin D level., (© 2022. The Author(s).)

The prevalence of type 2 diabetes increases with age-associated increased susceptibility of islet β-cells and altered dietary patterns, in part because of insufficient compensation of β-cell functional mass in the face of increasing insulin resistance. However, the underlying mechanisms have not been fully elucidated. In the present study, we investigated the effects of a long-term calorie-restricted (CR) or high-fat (HF) diet compared to a normal ad libitum diet on β-cell structure-function relationships and autophagy in the islets of 3- and 24-month-old Fischer 344 rats. Aging and the HF diet decreased the β-cell-to-islet area ratio, disorganized the islet structure, and increased the expression of senescence markers. Aging and the long-term HF diet also decreased autophagy-related proteins, which suggests compromised autophagic function. These findings were further corroborated by increased p62 accumulation and polyubiquitin aggregates observed with aging and the HF diet intervention; these are cardinal markers of attenuated autophagic function. It is important to note that the 24-month-old rats maintained on the CR diet closely mimicked the 3-month-old rats, which indicates that a long-term CR diet can delay islet aging and prevent the decline in the autophagic function of islets during the aging process. Taken together, our results indicate an autophagy-dependent mechanism responsible for islet function in older people or those with altered dietary patterns and lay the foundations for future research leading to novel therapeutic strategies for treating diabetes., (Copyright © 2021. Published by Elsevier Inc.)

Billions of neurons in the human brain form neural networks with oscillation rhythms. Infra-slow oscillation (ISO) presents three main physiological sources: endogenic, neurogenic, and myogenic vasomotions. Having an in vivo methodology for the absolute quantification of ISO from the human brain can facilitate the detection of brain abnormalities in cerebral hemodynamic and metabolic activities. In this study, we introduced a novel measurement-plus-analysis framework for the non-invasive quantification of prefrontal ISO by (1) taking dual-channel broadband near infrared spectroscopy (bbNIRS) measurements from 12 healthy humans during a 6-min rest and 4-min post transcranial photobiomodulation (tPBM) and (2) performing wavelet transform coherence (WTC) analysis on the measured time series data. The WTC indexes (IC, between 0 and 1) enabled the assessment of ipsilateral hemodynamic-metabolic coherence and bilateral functional connectivity in each ISO band of the human prefrontal cortex. At rest, bilateral hemodynamic connectivity was consistent across the three ISO bands (IC ≅ 0.66), while bilateral metabolic connectivity was relatively weaker. For post-tPBM/sham comparison, our analyses revealed three key findings: 8-min, right-forehead, 1064-nm tPBM (1) enhanced the amplitude of metabolic oscillation bilaterally, (2) promoted the bilateral metabolic connectivity of neurogenic rhythm, and (3) made the main effect on endothelial cells, causing alteration of hemodynamic-metabolic coherence on each side of the prefrontal cortex.

Proximal pulmonary artery masses are exceedingly rare, and their diagnosis and therapy are important and challenging for clinicians. This study reviews our experience exploring the value of a combination of transthoracic echocardiography and contrast echocardiography for the differential diagnosis of proximal pulmonary artery masses. Between January 2018 and June 2021, 44 patients diagnosed with a mass attached to the major pulmonary artery and straddling the bilateral pulmonary arteries or pulmonary valve on transthoracic echocardiography were referred to this study. Contrast echocardiography was performed in 17 patients. Masses were diagnosed based on their site of attachment, shape, size, mobility, hemodynamic consequences on transthoracic echocardiography, and tissue perfusion on contrast echocardiographic perfusion imaging. Pathological data were collected from medical records and analyzed. The most frequent location of proximal pulmonary artery masses was the major pulmonary artery trunk. Twelve patients underwent complete mass resection, whereas nine patients underwent percutaneous pulmonary artery biopsy puncture and had a pathological diagnosis. Another 24 patients were confirmed with the validation methods. Contrast echocardiography has good sensitivity and specificity for differentiating thrombi from pulmonary artery sarcomas (PAS). The mass types were distributed as follows: thrombi (19, 43%), PAS (15, 34%), metastatic tumors (6, 14%), vegetations (3, 7%), and primary benign lesions (1, 2%). The majority of proximal pulmonary artery masses were thrombi or PAS. A combination of transthoracic echocardiography and contrast echocardiography offers advantages in the early identification of proximal pulmonary masses and provides clinically important information about the characteristics of masses, especially for differentiating thrombi from PAS., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

The extraterminal (ET) domain of BRD3 is conserved among BET proteins (BRD2, BRD3, BRD4), interacting with multiple host and viral protein-protein networks. Solution NMR structures of complexes formed between the BRD3 ET domain and either the 79-residue murine leukemia virus integrase (IN) C-terminal domain (IN 329-408 ) or its 22-residue IN tail peptide (IN 386-407 ) alone reveal similar intermolecular three-stranded β-sheet formations. 15 N relaxation studies reveal a 10-residue linker region (IN 379-388 ) tethering the SH3 domain (IN 329-378 ) to the ET-binding motif (IN 389-405 ):ET complex. This linker has restricted flexibility, affecting its potential range of orientations in the IN:nucleosome complex. The complex of the ET-binding peptide of the host NSD3 protein (NSD3 148-184 ) and the BRD3 ET domain includes a similar three-stranded β-sheet interaction, but the orientation of the β hairpin is flipped compared with the two IN:ET complexes. These studies expand our understanding of molecular recognition polymorphism in complexes of ET-binding motifs with viral and host proteins., Competing Interests: Declaration of interests G.T.M. is a founder of Nexomics Biosciences, Inc. G.L. is chief scientific officer and director of Nexomics Biosciences, Inc. The remaining authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The slab-coupled optical fiber sensor (SCOS) is an innovative electric field detector with an ultrawide measuring range and a millimeter-level package size. The core sensing part of the SCOS is a fiber-waveguide evanescent coupler (FWEC) that directly determines the device's main performance specifications. This paper presents an investigation of the spectrum characteristics of FWECs with various structural and curing parameters. Methods for fabricating an FWEC with higher resonant depth, narrower free spectral range, and sharper spectrum slope are determined based on the experimental results. Z-cut lithium-niobate FWEC and Z-cut lithium-tantalate FWEC of about ${{1}} \times {0.5} \times {0.3}\;{\rm{mm}}^3$ are fabricated on this basis. Excellent coupling characteristics are achieved in both, according to the relevant spectra. Electric field tests indicate that the peak wavelengths shift linearly with the external AC field amplitude by 0.11 nm/(kV/cm) and 0.24 nm/(kV/cm), respectively. Three optimization methods are proposed to enhance performance: optimizing material selection, adding an antenna structure, and adjusting the calibration method. The results of this work may provide workable guidance for developing miniature, all-dielectric electric field sensors.

Annexin A1 (AnxA1, also known as lipocortin-1), is a calcium-dependent phospholipid binding protein with diverse functions. Previous studies have indicated that AnxA1 is associated with age-related β-cell dysfunction and aging, which lead to decreased β-cell proliferation capacity. However, it has been uncertain whether AnxA1 affects the proliferation of pancreatic beta (β) cells. In the present study, we reduced AnxA1 expression in the MIN6 islet β-cell line using small interfering RNA (AnxA1-siRNA), then measured cell cycle distribution and cellular proliferation. We also measured the expression levels of cell cycle-related proteins such as cyclin D1, cyclin E, and cyclin-dependent kinase 2 (CDK2) by Western blot analysis. We investigated the phosphatidylinositol 3-kinase (PI3K)/ serine/threonine protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway to explore the potential mechanism underlying the observed effects. Knockdown of AnxA1 expression using siRNA reduced the rates of MIN6 cell proliferation. The proportions of cells in S and G2/M phases also decreased upon inhibition of AnxA1. Moreover, AnxA1 protein expression in MIN6 cells was positively related to the protein levels of cyclin D1, cyclin E, and CDK2. Activation of the PI3K/Akt/mTOR signaling pathway by AnxA1 may be involved in the signaling cascade to regulate cell proliferation. This study identified a positive correlation between AnxA1 protein and pancreatic β-cell proliferation. AnxA1 protein expression might affect the proliferation of MIN6 cells via regulation of cyclin D1, cyclin E, and CDK2 proteins, as well as the PI3K/Akt/mTOR signaling pathway., (Copyright 2020 Biolife Sas. www.biolifesas.org.)

Background: Many studies have found that large tumor suppressor kinase 1 (LATS1) and LATS2 play important roles in many diseases, but studies have been rare on the relationship between these genes and non-cardia gastric cancer (GC). We performed a case-control association study to investigate the associations between single nucleotide polymorphisms (SNPs) in LATS1 and LATS2 genes and Helicobacter pylori (H. pylori) infection as well as the risk of non-cardia GC., Methods: First, H. pylori infection was determined by the serological test using enzyme-linked immunoassay. Then genotyping of SNPs was performed for 808 samples by the Taqman method. Finally, unconditional logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age and gender, for the association of each SNP with the infection of H. pylori, the risk of non-cardia gastric cancer, as well as the expression of LATS1 and LATS2 proteins in non-cardia GC tissues, using the codominant, dominant, recessive, overdominant, and log-additive inheritance models, respectively., Results: The statistical results showed that LATS2 rs9552315 was associated with H. pylori infection, and the CC + CT genotype could reduce the risk of H. pylori infection (odds ratio [OR]: 0.549, 95% confidence interval [CI]: 0.339-0.881, P < 0.05) compared with the TT genotype in a dominant model. LATS1 rs9393175 was associated with the risk of non-cardia GC, and the AG genotype reduced the risk of non-cardia GC (OR: 0.702, 95% CI: 0.516-0.952, P < 0.05) compared with the GG + AA genotype in an overdominant model. LATS2 rs9509492 was associated with the risk of GC in an log-additive model. No associations were found between five SNPs and expression of LATS1 and LATS2 proteins in non-cardia GC tissue., Conclusions: LATS2 rs9552315 CT genotype may be a protective factor against infection of H. pylori. LATS1 rs9393175 AG genotype and LATS2 rs9509492 GG genotype may be protective factors for non-cardia GC.

The structure and anisotropic magnetization of One-dimensional (1D) Nd/Co/PA66 coaxial nanocables prepared by a low cost physical infiltration and electrodeposition methods are investigated. The preparation of Co nanotubes, Co/PA66 two-layer nanotubes and Nd/Co/PA66 three-layer nanocales is described, respectively. The structure, chemical composition and magnetic properties of various nanomaterials were investigated. The results show that the magnetic properties were affected by the rare earth metal Nd and the structural properties. The residual magnetization ratio of Nd/Co/PA66 nanocables is the biggest due to the synergistic effect of Nd and Co. In addition, the magnetization processes of the nanostructure were discussed in detail. We believe that these methods may provide an idea for ferromagnetic alloys and permanent magnet material and suitable for future applications in perpendicular recording media.

Influenza A viruses cause widespread human respiratory disease. The viral multifunctional NS1 protein inhibits host antiviral responses. This inhibition results from the binding of specific cellular antiviral proteins at various positions on the NS1 protein. Remarkably, binding of several proteins also requires the two amino-acid residues in the NS1 N-terminal RNA-binding domain (RBD) that are required for binding double-stranded RNA (dsRNA). Here we focus on the host restriction factor DHX30 helicase that is countered by the NS1 protein, and establish why the dsRNA-binding activity of NS1 is required for its binding to DHX30. We show that the N-terminal 152 amino-acid residue segment of DHX30, denoted DHX30N, possesses all the antiviral activity of DHX30 and contains a dsRNA-binding domain, and that the NS1-DHX30 interaction in vivo requires the dsRNA-binding activity of both DHX30N and the NS1 RBD. We demonstrate why this is the case using bacteria-expressed proteins: the DHX30N-NS1 RBD interaction in vitro requires the presence of a dsRNA platform that binds both NS1 RBD and DHX30N. We propose that a similar dsRNA platform functions in interactions of the NS1 protein with other proteins that requires these same two amino-acid residues required for NS1 RBD dsRNA-binding activity., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Objective: To explore the influence of micro ribonucleic acid (miR)-154 on myocardial apoptosis in rats with acute myocardial infarction (AMI), and to analyze whether Wnt/β-catenin signaling pathway was involved in the regulation., Materials and Methods: The Sprague-Dawley (SD) rat model of AMI was established via ligation of left anterior descending artery. Rats were randomly divided into model group (M group, n=12) and ICG-001 intervention group (I group, n=12). At the same time, sham operation group (S group, n=12) was established. In I group, ICG-001 (5 mg/kg) was intraperitoneally injected every day after operation. Meanwhile, an equal amount of normal saline was injected in rats of S group and M group. 21 d after operation, the cardiac function of rats in each group was detected via echocardiography. After that, the rats were immediately executed. MI area in each group was detected via 2,3,5-triphenyltetrazolium chloride (TTC) staining. Myocardial apoptosis level in each group was detected via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Moreover, the changes of apoptotic proteins in rat myocardial cells were detected via Western blotting. Moreover, the expression level of miR-154 in myocardial cells of rats was detected via quantitative polymerase chain reaction (qPCR). Furthermore, the influence of miR-154 on Wnt/β-catenin signaling pathway was detected via Western blotting., Results: Compared with S group, left ventricular ejection fraction (LVEF, %) and left ventricular fractional shortening (LVFS, %) were significantly decreased in M group (p<0.01). However, left ventricular internal diameter at end-diastole (LVIDd) and left ventricular internal diameter at end-systole (LVIDs) were significantly increased (p<0.01). In I group, LVEF (%) and LVFS (%) were significantly higher than those of M group (p<0.05), whereas LVIDs and LVIDd were significantly lower (p<0.05). MI area in M group was remarkably larger than that of S group (p<0.01). Meanwhile, MI area in I group was significantly smaller than that of M group (p<0.01). Compared with S group, the number of apoptotic myocardial cells and the protein expression level of cleaved caspase-3 were significantly increased in M group (p<0.01). However, the expression level of B-cell lymphoma-2/Bcl-2 associated X protein (Bcl-2/Bax) was significantly decreased (p<0.01). The number of apoptotic myocardial cells and the protein expression level of cleaved caspase-3 were significantly declined in I group when compared with those of M group (p<0.01). However, the expression level of Bcl-2/Bax was significantly increased in I group (p<0.01). The expression level of miR-154 in myocardial cells of M group and I group was remarkably increased when compared with that of S group (p<0.01). Furthermore, the expression levels of β-catenin and Cyclin D1 in myocardial cells of M group were remarkably higher than those of S group and I group (p<0.01)., Conclusions: AMI significantly increases the expression level of miR-154. Moreover, miR-154 can activate Wnt/β-catenin signaling pathway, eventually promoting myocardial apoptosis.

For over 2 decades, there have been debates, sometimes contentious, about the efficacy and safety of antidepressants. Growing awareness of the difficulty some patients have when discontinuing these medications has intensified these debates. Recently, Cipriani and colleagues published the largest meta-analysis to date that assessed the efficacy and tolerability of antidepressants. They concluded that all were more efficacious than placebo, and they also synthesized the trial results from head-to-head studies in an effort to guide pharmacologic treatment for major depressive disorder in adults. Although the researchers acknowledged many limitations in their analysis, including the fact that effect sizes were modest at best, the media overstated the results of the study. Both the meta-analysis and the news stories reinvigorated the debates about whether or not antidepressants "work." Unfortunately, however, the key question-how can this meta-analysis help physicians in assisting their patients with a difficult decision about depression treatment options?-was lost in the controversy. In this commentary, we identify the questions and challenges that were not addressed in the current debate and offer specific suggestions for enhancing shared decision making for physicians working in primary care settings., Competing Interests: Conflict of interest: none declared., (© Copyright 2019 by the American Board of Family Medicine.)

We present a novel method to trap nanoparticles in double nanohole (DNH) nanoapertures integrated on top of solid-state nanopores (ssNP). The nanoparticles were propelled by an electrophoretic force from the cis towards the trans side of the nanopore but were trapped in the process when they reached the vicinity of the DNH-ssNP interface. The self-induced back action (SIBA) plasmonic force existing between the tips of the DNH opposed the electrophoretic force and enabled simultaneous optical and electrical sensing of a single nanoparticle for seconds. The novel SIBA actuated nanopore electrophoresis (SANE) sensor was fabricated using two-beam GFIS FIB. Firstly, Ne FIB milling was used to create the DNH features and was combined with end pointing to stop milling at the metal-dielectric interface. Subsequently, He FIB was used to drill a 25 nm nanopore through the center of the DNH. Proof of principle experiments to demonstrate the potential utility of the SANE sensor were performed with 20 nm silica and Au nanoparticles. The addition of optical trapping to electrical sensing extended translocation times by four orders of magnitude. The extended electrical measurement times revealed newly observed high frequency charge transients that were attributed to bobbing of the nanoparticle driven by the competing optical and electrical forces. Frequency analysis of this bobbing behavior hinted at the possibility of distinguishing single from multi-particle trapping events. We also discuss how SANE sensor measurement characteristics differ between silica and Au nanoparticles due to differences in their physical properties and how to estimate the charge around a nanoparticle. These measurements show promise for the SANE sensor as an enabling tool for selective detection of biomolecules and quantification of their interactions.

Lop Nor potash deposit is the largest sulfate-type liquid potassium salt deposit in China, consisting of three areas: Xinqing platform, Luobei depression, and Tenglong platform. In this study, the geological background, basin structure, and fracture system of the deposit, along with the brine storage size of the three ore bodies are introduced in detail, using underground brine elevation models of the mining areas. We collected 91 samples of brine from long-term observation boreholes in the Lop Nor ore district, and analyzed their ion contents. The KCl content of the brine varies from 1% to 1.45% and that of B 2 O 3 varies from 1900 to 4500 mg/L, which are higher than the cut-off for Chinese industrial mining grades. The spatial distributions of KCl and B 2 O 3 contents in different ore beds were plotted, and the distributions of different grades of K + and B 3+ were revealed.

One-dimensional (1D) Nd/Fe/polyamide 66 (Nd/Fe/PA66) three-layer coaxial nanocable arrays with high aspect ratio and highly anisotropic magnetization were successfully prepared via layer-by-layer deposition in the anodic aluminum oxide template. The morphology, chemical composition, and magnetic properties of Nd/Fe/PA66 nanocables were characterized by scanning electron microscopy, transmission electron microscopy, X-ray diffraction, and vibrating sample magnetometry . The effects of 1D nanocables on the magnetic properties of the assembled ordered arrays have been systematically investigated. The structural properties of these nanostructures are investigated as a function of the geometrical parameters. The magnetic anisotropy of Nd/Fe/PA66 nanocables has been significantly enhanced owing to the doped Nd that possesses a larger spin-orbital coupling and leads to a synergistic effect with Fe to enhance anisotropy energy., Competing Interests: The authors declare no competing financial interest.

A strategy for acquiring structural information from sparsely isotopically labeled large proteins is illustrated with an application to the E. coli heat-shock protein, HtpG (high temperature protein G), a 145 kDa dimer. It uses 13 C-alanine methyl labeling in a perdeuterated background to take advantage of the sensitivity and resolution of Methyl-TROSY spectra, as well as the backbone-centered structural information from 1 H- 13 C residual dipolar couplings (RDCs) of alanine methyl groups. In all, 40 of the 47 expected crosspeaks were resolved and 36 gave RDC data. Assignments of crosspeaks were partially achieved by transferring assignments from those made on individual domains using triple resonance methods. However, these were incomplete and in many cases the transfer was ambiguous. A genetic algorithm search for consistency between predictions based on domain structures and measurements for chemical shifts and RDCs allowed 60% of the 40 resolved crosspeaks to be assigned with confidence. Chemical shift changes of these crosspeaks on adding an ATP analog to the apo-protein are shown to be consistent with structural changes expected on comparing previous crystal structures for apo- and complex- structures. RDCs collected on the assigned alanine methyl peaks are used to generate a new solution model for the apo-protein structure.

Importance: Little is known about the association between bicuspid aortic valve (BAV) morphologic findings and the degree of valvular dysfunction, presence of aortopathy, and complications, including aortic valve surgery, aortic dissection, and all-cause mortality., Objective: To investigate the association between BAV morphologic findings (raphe vs nonraphe) and the degree of valve dysfunction, presence of aortopathy, and prognosis (including need for aortic valve surgery, aortic dissection, and all-cause mortality)., Design, Setting, and Participants: In this large international multicenter registry of patients with BAV treated at tertiary referral centers, 2118 patients with BAV were evaluated. Patients referred for echocardiography from June 1, 1991, through November 31, 2015, were included in the study., Exposures: Clinical and echocardiographic data were analyzed retrospectively. The morphologic BAV findings were categorized according to the Sievers and Schmidtke classification. Aortic valve function was divided into normal, regurgitation, or stenosis. Patterns of BAV aortopathy included the following: type 1, dilation of the ascending aorta and aortic root; type 2, isolated dilation of the ascending aorta; and type 3, isolated dilation of the sinus of Valsalva and/or sinotubular junction., Main Outcomes and Measures: Association between the presence and location of raphe and the risk of significant (moderate and severe) aortic valve dysfunction and aortic dilation and/or dissection., Results: Of the 2118 patients (mean [SD] age, 47 [18] years; 1525 [72.0%] male), 1881 (88.8%) had BAV with fusion raphe, whereas 237 (11.2%) had BAV without raphe. Bicuspid aortic valves with raphe had a significantly higher prevalence of valve dysfunction, with a significantly higher frequency of aortic regurgitation (622 [33.1%] vs 57 [24.1%], P < .001) and aortic stenosis (728 [38.7%] vs 51 [21.5%], P < .001). Furthermore, aortic valve replacement event rates were significantly higher among patients with BAV with raphe (364 [19.9%] at 1 year, 393 [21.4%] at 2 years, and 447 [24.4%] at 5 years) vs patients without raphe (30 [14.0%] at 1 year, 32 [15.0%] at 2 years, and 40 [18.0%] at 5 years) (P = .02). In addition, the all-cause mortality event rates were significantly higher among patients with BAV with raphe (77 [5.1%] at 1 year, 87 [6.2%] at 2 years, and 110 [9.5%] at 5 years) vs patients without raphe (2 [1.8%] at 1 year, 3 [3.0%] at 2 years, and 5 [4.4%] at 5 years) (P = .03). However, on multivariable analysis, the presence of raphe was not significantly associated with all-cause mortality., Conclusions and Relevance: In this large multicenter, international BAV registry, the presence of raphe was associated with a higher prevalence of significant aortic stenosis and regurgitation. The presence of raphe was also associated with increased rates of aortic valve and aortic surgery. Although patients with BAV and raphe had higher mortality rates than patients without, the presence of a raphe was not independently associated with increased all-cause mortality.

Palladium-based catalytic membrane reactors (CMRs) effectively remove H₂ to induce higher conversions in methane steam reforming (MSR) and water-gas-shift reactions (WGS). Within such a context, this work evaluates the technical performance of a novel CMR, which utilizes two catalysts in series, rather than one. In the process system under consideration, the first catalyst, confined within the shell side of the reactor, reforms methane with water yielding H₂, CO and CO₂. After reforming is completed, a second catalyst, positioned in series, reacts with CO and water through the WGS reaction yielding pure H₂O, CO₂ and H₂. A tubular composite asymmetric Pd/Au/Pd membrane is situated throughout the reactor to continuously remove the produced H₂ and induce higher methane and CO conversions while yielding ultrapure H₂ and compressed CO₂ ready for dehydration. Experimental results involving (i) a conventional packed bed reactor packed (PBR) for MSR, (ii) a PBR with five layers of two catalysts in series and (iii) a CMR with two layers of two catalysts in series are comparatively assessed and thoroughly characterized. Furthermore, a comprehensive 2D computational fluid dynamics (CFD) model was developed to explore further the features of the proposed configuration. The reaction was studied at different process intensification-relevant conditions, such as space velocities, temperatures, pressures and initial feed gas composition. Finally, it is demonstrated that the above CMR module, which was operated for 600 h, displays quite high H₂ permeance and purity, high CH₄ conversion levels and reduced CO yields., Competing Interests: The authors declare no conflict of interest.

Influenza viruses cause a highly contagious respiratory disease in humans. The NS1 proteins of influenza A and B viruses (NS1A and NS1B proteins, respectively) are composed of two domains, a dimeric N-terminal domain and a C-terminal domain, connected by a flexible polypeptide linker. Here we report the 2.0-Å X-ray crystal structure and nuclear magnetic resonance studies of the NS1B C-terminal domain, which reveal a novel and unexpected basic RNA-binding site that is not present in the NS1A protein. We demonstrate that single-site alanine replacements of basic residues in this site lead to reduced RNA-binding activity, and that recombinant influenza B viruses expressing these mutant NS1B proteins are severely attenuated in replication. This novel RNA-binding site of NS1B is required for optimal influenza B virus replication. Most importantly, this study reveals an unexpected RNA-binding function in the C-terminal domain of NS1B, a novel function that distinguishes influenza B viruses from influenza A viruses., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Fermi-Dirac electron thermal excitation is an intrinsic phenomenon that limits functionality of various electron systems. Efforts to manipulate electron thermal excitation have been successful when the entire system is cooled to cryogenic temperatures, typically <1 K. Here we show that electron thermal excitation can be effectively suppressed at room temperature, and energy-suppressed electrons, whose energy distribution corresponds to an effective electron temperature of ~45 K, can be transported throughout device components without external cooling. This is accomplished using a discrete level of a quantum well, which filters out thermally excited electrons and permits only energy-suppressed electrons to participate in electron transport. The quantum well (~2 nm of Cr2O3) is formed between source (Cr) and tunnelling barrier (SiO2) in a double-barrier-tunnelling-junction structure having a quantum dot as the central island. Cold electron transport is detected from extremely narrow differential conductance peaks in electron tunnelling through CdSe quantum dots, with full widths at half maximum of only ~15 mV at room temperature.

Background: Young people in Taiwan have become more liberal and active toward sex. Despite heavy investments of money, time, and effort, sexual education programs have generally lagged expectations., Purpose: Personality traits such as sexual sensation seeking are found to be significantly associated with risky sexual behaviors. This study, therefore, attempts to explore the link of sexual sensation seeking to acceptance by Taiwanese college students of cybersex, multiple sexual partners, and one-night stands., Methods: A cross-sectional study was conducted using the multistage cluster sampling method. Five hundred sixteen students recruited from eight universities/colleges in Taiwan participated in this study, and 507 completed the self-report questionnaire. The valid response rate was 98.26%., Results: The results reveal that high-sexual-sensation seekers were more likely than low-sexual-sensation seekers to accept cybersex, multiple sexual partners, and one-night stands., Conclusions/implications for Practice: This study suggests that the designers of campus-based health prevention campaigns should target campaign messages on high-sexual-sensation seekers using novel, thrilling, and complex messages to achieve safe sex educational campaign goals.

Climate changes within Cenozoic extreme climate events such as the Paleocene-Eocene Thermal Maximum and the First Oligocene Glacial provide good opportunities to estimate the global climate trends in our present and future life. However, quantitative paleotemperatures data for Cenozoic climatic reconstruction are still lacking, hindering a better understanding of the past and future climate conditions. In this contribution, quantitative paleotemperatures were determined by fluid inclusion homogenization temperature (Th) data from continental halite of the first member of the Shahejie Formation (SF1; probably late Eocene to early Oligocene) in Bohai Bay Basin, North China. The primary textures of the SF1 halite typified by cumulate and chevron halite suggest halite deposited in a shallow saline water and halite Th can serve as an temperature proxy. In total, one-hundred-twenty-one Th data from primary and single-phase aqueous fluid inclusions with different depths were acquired by the cooling nucleation method. The results show that all Th range from 17.7°C to 50.7°C,with the maximum homogenization temperatures (ThMAX) of 50.5°C at the depth of 3028.04 m and 50.7°C at 3188.61 m, respectively. Both the ThMAX presented here are significantly higher than the highest temperature recorded in this region since 1954 and agree with global temperature models for the year 2100 predicted by the Intergovernmental Panel on Climate Change.

Alpha-dystroglycanopathies are a group of diseases due to reduced glycosylation of alpha-dystroglycan, which commonly result from mutations in POMT1, POMT2, and POMGnT1. Patients with alpha-dystroglycanopathies present with muscular, cerebral, and ocular involvements with differing severities. We reported a boy who presented with muscular dystrophy, developmental delay, and non-specific white matter lesions. Mutation analysis of POMT1 was performed and revealed two novel mutations, a substitution mutation (c.176T>G) and a duplication mutation (c.2059dupC) which results in premature termination of translation. In-silico prediction in five different platforms concurred that the substitution is damaging, and functional studies by immunofluorescence revealed lack of staining in the carbohydrate moiety of alpha-dystroglycan, confirming the molecular findings in a functional manner. In conclusion, we reported the first case of genetically confirmed alpha-dystroglycanopathy due to mutations in POMT1 in Chinese., (Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Nonstructural protein 1 of influenza A virus (NS1A) is a conserved virulence factor comprised of an N-terminal double-stranded RNA (dsRNA)-binding domain and a multifunctional C-terminal effector domain (ED), each of which can independently form symmetric homodimers. Here we apply (19)F NMR to NS1A from influenza A/Udorn/307/1972 virus (H3N2) labeled with 5-fluorotryptophan, and we demonstrate that the (19)F signal of Trp187 is a sensitive, direct monitor of the ED helix:helix dimer interface. (19)F relaxation dispersion data reveal the presence of conformational dynamics within this functionally important protein:protein interface, whose rate is more than three orders of magnitude faster than the kinetics of ED dimerization. (19)F NMR also affords direct spectroscopic evidence that Trp187, which mediates intermolecular ED:ED interactions required for cooperative dsRNA binding, is solvent exposed in full-length NS1A at concentrations below aggregation. These results have important implications for the diverse roles of this NS1A epitope during influenza virus infection., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Cyanobacterial phycobiliproteins have evolved to capture light energy over most of the visible spectrum due to their bilin chromophores, which are linear tetrapyrroles that have been covalently attached by enzymes called bilin lyases. We report here the crystal structure of a bilin lyase of the CpcS family from Thermosynechococcus elongatus (TeCpcS-III). TeCpcS-III is a 10-stranded β barrel with two alpha helices and belongs to the lipocalin structural family. TeCpcS-III catalyzes both cognate as well as noncognate bilin attachment to a variety of phycobiliprotein subunits. TeCpcS-III ligates phycocyanobilin, phycoerythrobilin, and phytochromobilin to the alpha and beta subunits of allophycocyanin and to the beta subunit of phycocyanin at the Cys82-equivalent position in all cases. The active form of TeCpcS-III is a dimer, which is consistent with the structure observed in the crystal. With the use of the UnaG protein and its association with bilirubin as a guide, a model for the association between the native substrate, phycocyanobilin, and TeCpcS was produced.

We report an uncommon mitochondrial variant in a baby girl with congenital hyperlactataemia and Leigh syndrome. The patient presented with a single episode of generalised clonic convulsion at day 19, and was found to have isolated and persistent hyperlactataemia ranging from 3.34 to 9.26 mmol/L. She had elevated serum lactate-to-pyruvate ratios of up to 35 and high plasma alanine concentration, indicative of a respiratory chain defect. At the age of 8 months, she developed evolving neurological and imaging features compatible with Leigh syndrome. Genetic testing for common mitochondrial DNA mutations, large mitochondrial DNA deletions, and selected nuclear genes was negative. Further analysis of lymphocyte mitochondrial DNA by sequencing revealed an uncommon heteroplasmic variant, NC&#95;012920.1(MT-ND5):m.13094T>C (p.Val253Ala), which was previously shown to reduce complex I activity. In patients in whom there was a high suspicion of mitochondrial disorder, entire mitochondrial DNA analysis may be warranted if initial screening of common mitochondrial DNA mutations is negative.

With the advancement of ophthalmological genetics, the molecular basis for more and more eye diseases can be elucidated. Congenital fibrosis of extraocular muscle (CFEOM) is an example. It is characterised by a congenital non-progressive restrictive ophthalmoplegia and ptosis. It is an autosomal dominant disease, caused by mutations of the KIF21A gene. With positive family history and typical ophthalmological findings, mutational analysis of KIF21A gene should be performed, not only to confirming the diagnosis, but also to offer a prognosis, for genetic counselling, and the possibility of prenatal diagnosis. Here we report the first KIF21A mutation associated with CFEOM1A in Hong Kong.

This cross-sectional research study explored differences in health-promoting behavior and resilience among three groups of chronic kidney disease patients (high-risk, early chronic kidney disease; early CKD and pre-end stage renal disease; pre-ESRD) treated at the Nephrology outpatient clinic in northern Taiwan. A total of 150 CKD outpatients were interviewed using structured questionnaires including a CKD Health to Promote Lifestyle Scale, and resilience scale. We found that the pre-ESRD group had lower resilience than either high-risk or early CKD groups. Factors affecting pre-ESRD resilience were gender, occupational status, diabetes and health-promoting behaviors. Factors affecting resilience of the high-risk group included level of education and health-promoting behaviors while factors affecting resilience in the early CKD group involved whether they are employed and health promoting behaviors. A significant positive correlation was found between health promoting behavior and resilience in all study subjects. Multiple regression analysis found that factors which could effectively predict resilience in patients at high-risk for CKD were gender, whether the patient had a job, nutrition, self-actualization, and stress level, accounting for 69.7% of the variance. Therefore, nursing education should focus on health promotion advocacy throughout the life of not only patients but also their families.

Aim: The aim of this study was to evaluate the self-help behaviour of individuals with eating disorders in an Internet-based self-help programme developed in the Asia-Pacific region and to determine their compliance with the programme., Background: Eating disorders represent a growing health problem affecting both Western and Asian countries. Without timely and adequate treatment, individuals with eating disorders are at risk of premature death. Self-help approaches for treating eating disorders offer therapeutic promise., Design: An open trial design was used., Method: This study, conducted from August 2006-July 2011, included 280 participants recruited from outpatient eating disorder clinics and treatment units and through a university student newspaper and Internet websites. This open trial evaluated an Internet-based self-help programme, which included components on healthy eating, family education, health assessment, motivation enhancement, self-help strategies, and psychological health promotion. The progress of participants was followed up via monthly e-mails. A tracking system was implemented to determine their compliance with the programme., Findings: A small majority of the participants (56·9%) were already undergoing treatment for their eating disorders. About 63% (n = 176) demonstrated self-help behaviour, as manifested by their completion of health assessment questionnaires, involvement in motivation enhancement exercises, or the use of self-help strategies such as monitoring, normalizing eating behaviour, and stress management. Improvements were observed in their eating disorder psychopathology, motivational stage of change and psychological health from baseline to the 1-month follow up., Conclusion: Internet-based self-help programmes for eating disorders are helpful adjuncts to professional treatment., (© 2012 Blackwell Publishing Ltd.)

The ribosome consists of small and large subunits each composed of dozens of proteins and RNA molecules. However, the functions of many of the individual protomers within the ribosome are still unknown. In this article, we describe the solution NMR structure of the ribosomal protein RP-L35Ae from the archaeon Pyrococcus furiosus. RP-L35Ae is buried within the large subunit of the ribosome and belongs to Pfam protein domain family PF01247, which is highly conserved in eukaryotes, present in a few archaeal genomes, but absent in bacteria. The protein adopts a six-stranded anti-parallel β-barrel analogous to the "tRNA binding motif" fold. The structure of the P. furiosus RP-L35Ae presented in this article constitutes the first structural representative from this protein domain family., (Copyright © 2012 Wiley Periodicals, Inc.)

The expression of genes specific to floral organ is important for the floral organ formation and development in Medicago truncatula. Screening of the genes specifically expressed in M. truncatula flowers and comparing the expression patterns of their orthologous homologous genes among different model plants can provide novel insights into the functions of these genes in controlling the floral organ development in M. truncatula. According to the expression profile data of PISTILLATA (PI), we screened 97 genes specifically expressed in M. truncatula floral organs (ratio≥10 and Z≥7.9). Their homolog genes were also identified in Arabidopsis thaliana, soybean (Glycine max L.), Lotus japonicus, and rice (Oryza sativa L.). The results of comparing the gene expression levels, the gene expression patterns, and the gene functions among these species indicated that the expression variation of the orthologous homolog genes was small in the kindred species and was great in distant species. Furthermore, we compared the cis-acting regulatory elements of the genes, which had large expression variation among different plants. These results suggest that the great discrepancy of the orthologous homolog gene expression caused by the different character of cis-element in the promoter region.

This article describes the development of a simple and robust fluorescence polarization (FP)-based binding assay and adaptation to high-throughput identification of small molecules blocking dsRNA binding to NS1A protein (nonstructural protein 1 from type A influenza strains). This homogeneous assay employs fluorescein-labeled 16-mer dsRNA and full-length NS1A protein tagged with glutathione S-transferase to monitor the changes in FP and fluorescence intensity simultaneously. The assay was optimized for high-throughput screening in a 384-well format and achieved a z' score greater than 0.7. Its feasibility for high-throughput screening was demonstrated using the National Institutes of Health clinical collection. Six of 446 small molecules were identified as possible ligands in an initial screening. A series of validation tests confirmed epigallocatechine gallate (EGCG) to be active in the submicromolar range. A mechanism of EGCG inhibition involving interaction with the dsRNA-binding motif of NS1A, including Arg38, was proposed. This structural information is anticipated to provide a useful basis for the modeling of antiflu therapeutic reagents. Overall, the FP-based binding assay demonstrated its superior capability for simple, rapid, inexpensive, and robust identification of NS1A inhibitors and validation of their activity targeting NS1A.

Human interferon-stimulated gene 15 protein (ISG15), also called ubiquitin cross-reactive protein (UCRP), is the first identified ubiquitin-like protein containing two ubiquitin-like domains fused in tandem. The active form of ISG15 is conjugated to target proteins via the C-terminal glycine residue through an isopeptide bond in a manner similar to ubiquitin. The biological role of ISG15 is strongly associated with the modulation of cell immune function, and there is mounting evidence suggesting that many viral pathogens evade the host innate immune response by interfering with ISG15 conjugation to both host and viral proteins in a variety of ways. Here we report nearly complete backbone (1)H(N), (15)N, (13)C', and (13)C(α), as well as side chain (13)C(β), methyl (Ile-δ1, Leu, Val), amide (Asn, Gln), and indole N-H (Trp) NMR resonance assignments for the 157-residue human ISG15 protein. These resonance assignments provide the basis for future structural and functional solution NMR studies of the biologically important human ISG15 protein.

Interferon-induced ISG15 conjugation plays an important antiviral role against several viruses, including influenza viruses. The NS1 protein of influenza B virus (NS1B) specifically binds only human and nonhuman primate ISG15s and inhibits their conjugation. To elucidate the structural basis for the sequence-specific recognition of human ISG15, we determined the crystal structure of the complex formed between human ISG15 and the N-terminal region of NS1B (NS1B-NTR). The NS1B-NTR homodimer interacts with two ISG15 molecules in the crystal and also in solution. The two ISG15-binding sites on the NS1B-NTR dimer are composed of residues from both chains, namely residues in the RNA-binding domain (RBD) from one chain, and residues in the linker between the RBD and the effector domain from the other chain. The primary contact region of NS1B-NTR on ISG15 is composed of residues at the junction of the N-terminal ubiquitin-like (Ubl) domain and the short linker region between the two Ubl domains, explaining why the sequence of the short linker in human and nonhuman primate ISG15s is essential for the species-specific binding of these ISG15s. In addition, the crystal structure identifies NS1B-NTR binding sites in the N-terminal Ubl domain of ISG15, and shows that there are essentially no contacts with the C-terminal Ubl domain of ISG15. Consequently, NS1B-NTR binding to ISG15 would not occlude access of the C-terminal Ubl domain of ISG15 to its conjugating enzymes. Nonetheless, transfection assays show that NS1B-NTR binding of ISG15 is responsible for the inhibition of interferon-induced ISG15 conjugation in cells.

Non-structural protein 1 from influenza A virus, NS1A, is a key multifunctional virulence factor composed of two domains: an N-terminal double-stranded RNA (dsRNA)-binding domain and a C-terminal effector domain (ED). Isolated RNA-binding and effector domains of NS1A both exist as homodimers in solution. Despite recent crystal structures of isolated ED and full-length NS1A proteins from different influenza virus strains, controversy remains over the actual biologically relevant ED dimer interface. Here, we report the biophysical properties of the NS1A ED from H3N2 influenza A/Udorn/307/1972 (Ud) virus in solution. Several lines of evidence, including (15)N NMR relaxation, NMR chemical shift perturbations, static light scattering, and analytical sedimentation equilibrium, demonstrate that Ud NS1A ED forms a relatively weak dimer in solution (K(d) = 90 ± 2 μm), featuring a symmetric helix-helix dimer interface. Mutations within and near this interface completely abolish dimerization, whereas mutations consistent with other proposed ED dimer interfaces have no effect on dimer formation. In addition, the critical Trp-187 residue in this interface serves as a sensitive NMR spectroscopic marker for the concentration-dependent dimerization of NS1A ED in solution. Finally, dynamic light scattering and gel shift binding experiments demonstrate that the ED interface plays a role in both the oligomerization and the dsRNA binding properties of the full-length NS1A protein. In particular, mutation of the critical tryptophan in the ED interface substantially reduces the propensity of full-length NS1A from different strains to oligomerize and results in a reduction in dsRNA binding affinity for full-length NS1A.

A library of quinoxaline derivatives were prepared to target non-structural protein 1 of influenza A (NS1A) as a means to develop anti-influenza drug leads. An in vitro fluorescence polarization assay demonstrated that these compounds disrupted the dsRNA-NS1A interaction to varying extents. Changes of substituent at positions 2, 3 and 6 on the quinoxaline ring led to variance in responses. The most active compounds (35 and 44) had IC(50) values in the range of low micromolar concentration without exhibiting significant dsRNA intercalation. Compound 44 was able to inhibit influenza A/Udorn/72 virus growth., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: To investigate the effects of long-term high-protein, low-carbohydrate diet on body weight and the expression of gastrointestinal hormones in diet-induced obesity rats., Methods: Twenty-four diet-induced obesity rat models were established by feeding fat-enriched diet, then were randomly divided into two groups by stratified sampling method by weight: the high-protein diet group (HP, 36.7% of energy from protein), and the normal chow group (NC, 22.4% of energy from protein), 12 rats in each group. The total calorie intake of each rat per day was similar and was maintained for 24 weeks, then body weight, visceral fat mass, fasting plasma ghrelin and glucagon-like peptide-1 (GLP-1) were determined, as well as protein expression of ghrelin in stomach, GLP-1 in ileum were detected by immunohistochemistry., Results: After 24 weeks, body weight of HP, NC groups were (490.92 ± 39.47) g and (545.55 ± 31.08) g, respectively (t = -3.664, P < 0.01); visceral fat mass were (22.42 ± 7.04) g and (32.33 ± 9.27) g, respectively (t = -2.503, P < 0.05); plasma ghrelin level were (2.36 ± 0.82) and (1.95 ± 0.64) ng/ml, respectively (t = 1.337, P > 0.05), and plasma ghrelin level was negatively correlated to body weight (r = -0.370, t = -1.899, P < 0.05), visceral fat mass (r = -0.454, t = -2.52, P < 0.01); plasma GLP-1 concentration were (0.52 ± 0.13) and (0.71 ± 0.19) ng/ml, respectively(t = -2.758, P < 0.05); ghrelin protein expression in stomach were 25 473 ± 8701 and 10 526 ± 6194, respectively (t = 2.501, P < 0.05); GLP-1 protein expression in ileum were 27 431 ± 5813 and 36 601 ± 5083, respectively (t = -1.833, P = 0.081)., Conclusion: Long-term isocaloric high-protein, low-carbohydrate diet can reduce body weight and visceral fat, increase the expression of ghrelin, and decline GLP-1 expression in diet-induced obesity rats.

Phosphatidylinositol 3-kinase (PI3K) proteins actively trigger signaling pathways leading to cell growth, proliferation and survival. These proteins have multiple isoforms and consist of a catalytic p110 subunit and a regulatory p85 subunit. The iSH2 domain of the p85β isoform has been implicated in the binding of nonstructural protein 1 (NS1) of influenza A viruses. Here, the crystal structure of human p85β iSH2 determined to 3.3 Å resolution is reported. The structure reveals that this domain mainly consists of a coiled-coil motif. Comparison with the published structure of the bovine p85β iSH2 domain bound to the influenza A virus nonstructural protein 1 indicates that little or no structural change occurs upon complex formation. By comparing this human p85β iSH2 structure with the bovine p85β iSH2 domain, which shares 99% sequence identity, and by comparing the multiple conformations observed within the asymmetric unit of the bovine iSH2 structure, it was found that this coiled-coil domain exhibits a certain degree of conformational variability or `plasticity' in the interhelical turn region. It is speculated that this plasticity of p85β iSH2 may play a role in regulating its functional and molecular-recognition properties.

We describe the core Protein Production Platform of the Northeast Structural Genomics Consortium (NESG) and outline the strategies used for producing high-quality protein samples. The platform is centered on the cloning, expression and purification of 6X-His-tagged proteins using T7-based Escherichia coli systems. The 6X-His tag allows for similar purification procedures for most targets and implementation of high-throughput (HTP) parallel methods. In most cases, the 6X-His-tagged proteins are sufficiently purified (>97% homogeneity) using a HTP two-step purification protocol for most structural studies. Using this platform, the open reading frames of over 16,000 different targeted proteins (or domains) have been cloned as>26,000 constructs. Over the past 10 years, more than 16,000 of these expressed protein, and more than 4400 proteins (or domains) have been purified to homogeneity in tens of milligram quantities (see Summary Statistics, http://nesg.org/statistics.html). Using these samples, the NESG has deposited more than 900 new protein structures to the Protein Data Bank (PDB). The methods described here are effective in producing eukaryotic and prokaryotic protein samples in E. coli. This paper summarizes some of the updates made to the protein production pipeline in the last 5 years, corresponding to phase 2 of the NIGMS Protein Structure Initiative (PSI-2) project. The NESG Protein Production Platform is suitable for implementation in a large individual laboratory or by a small group of collaborating investigators. These advanced automated and/or parallel cloning, expression, purification, and biophysical screening technologies are of broad value to the structural biology, functional proteomics, and structural genomics communities.

Background: It has been shown that the β3-adrenergic receptor (β3-AR) gene Trp64Arg mutation was closely related to obesity and insulin resistance, and may be related to the prevalence of metabolic syndrome (MS). The aim of this study was to investigate the relationship between the β3-AR gene mutation and the prevalence of MS., Methods: A seven-year follow-up study was initiated in 2000, with 496 samples of simplex obese subjects (body mass index ≥ 25 kg/m(2)) and 248 normal-weight subjects. According to the β3-AR genotypes, the subjects were classified as Trp64 homozygote group and Arg64 carrier group and after 7 years the prevalence of MS was determined., Results: According to the baseline profile, there were no significant differences in the adiposity, blood pressure, lipid profile, fasting plasma glucose and fasting insulin between Trp64 homozygote group and Arg64 carrier group either in obesity or normal-weight subjects. The results of follow-up study indicated that in obese men the prevalence rate of MS was much higher in Arg64 carrier group than that in Trp64 homozygote group (54.76% vs. 40.85%, P < 0.05), but there was no statistical difference in women of the above groups. The prevalence rate of MS in obese men of both Trp64 homozygote group and Arg64 carrier obese group were obviously higher than that in women of the above groups (40.85% vs. 18.27% and 54.76% vs 21.28%, all P < 0.005). Differences were not statistically significant in the prevalence of MS for normal weight Trp64 homozygote group and normal weight Arg64 carrier group, either between men, between women, or between men and women. Comparison of populations indicated that no matter with the β3-AR gene mutation or not, the prevalence of MS in obese subjects was significantly higher than normal weight subjects (χ(2) = 28.240 and χ(2) = 15.586, all P < 0.005). Logistic analysis showed that the mutation of β3-AR gene was associated with the prevalence of MS in men., Conclusion: The mutation of β3-AR gene is the independent risk factor for the prevalence of MS in men.

The world is currently undergoing a pandemic caused by an H1N1 influenza A virus, the so-called 'swine flu'. The H5N1 ('bird flu') influenza A viruses, now circulating in Asia, Africa and Europe, are extremely virulent in humans, although they have not so far acquired the ability to transfer efficiently from human to human. These health concerns have spurred considerable interest in understanding the molecular biology of influenza A viruses. Recent structural studies of influenza A virus proteins (or fragments) help enhance our understanding of the molecular mechanisms of the viral proteins and the effects of drug resistance to improve drug design. The structures of domains of the influenza RNA-dependent RNA polymerase and the nonstructural NS1A protein provide opportunities for targeting these proteins to inhibit viral replication.