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Iterative homology search has been widely used in identification of remotely related proteins. Our previous study has found that the query-seeded sequence iterative search can reduce homologous over-extension errors and greatly improve selectivity. However, iterative homology search remains challenging in protein functional prediction. More sensitive scoring models are highly needed to improve the predictive performance of the alignment methods, and alignment annotation with better visualization has also become imperative for result interpretation. Here we report an open-source application PSISearch2D that runs query-seeded iterative sequence search for remotely related protein detection. PSISearch2D retrieves domain annotation from Pfam, UniProtKB, CDD and PROSITE for resulting hits and demonstrates combined domain and sequence alignments in novel visualizations. A scoring model called C-value is newly defined to re-order hits with consideration of the combination of sequence and domain alignments. The benchmarking on the use of C-value indicates that PSISearch2D outperforms the original PSISearch2 tool in terms of both accuracy and specificity. PSISearch2D improves the characterization of unknown proteins in remote protein detection. Our evaluation tests show that PSISearch2D has provided annotation for 77 695 of 139 503 unknown bacteria proteins and 140 751 of 352 757 unknown virus proteins in UniProtKB, about 2.3-fold and 1.8-fold more characterization than the original PSISearch2, respectively. Together with advanced features of auto-iteration mode to handle large-scale data and optional programs for global and local sequence alignments, PSISearch2D enhances remotely related protein search.

Aim To emphasize the mechanism of the effect of exercise on lipid droplet (LD) metabolism disorder in nonalcoholic fatty liver disease (NAFLD). Main methods C57BL/6J mice were randomly divided into three groups: The first group was fed with a normal diet (CON), the second group was fed a high-fat diet (HF), and finally group with a high-fat diet intervention and swim training (HF-EX). The total intervention period was 16 weeks. RT-PCR and Western blot were performed to evaluate the effect of exercise on LDs metabolism and the AMPK pathway. Histopathological examinations and immunofluorescence were performed to evaluate the lipid deposition and lipophagy in the liver. Key findings Exercise reduced liver steatosis and insulin resistance along with the stimulation of AMPK/SIRT1 signaling and downstream regulation of lipid metabolism. In addition, exercise increased the expression of autophagy marker and colocalization of LC3 and LAMP1 with LDs. Significance Exercise stimulated AMPK/SIRT1 and activated lipophagy in NAFLD. Enhancing lipophagy may be one of the key mechanisms of regulation and resolution of NAFLD by exercise.

While variants of noncoding RNAs (ncRNAs) have been experimentally validated as a new class of biomarkers and drug targets, the discovery and interpretation of relationships between ncRNA variants and human diseases become important and challenging. Here we present ncRNAVar (http://www.liwzlab.cn/ncrnavar/), the first database that provides association data between validated ncRNA variants and human diseases through manual curation on 2650 publications and computational annotation. ncRNAVar contains 4565 associations between 711 human disease phenotypes and 3112 variants from 2597 ncRNAs. Each association was reviewed by professional curators, incorporated with valuable annotation and cross references, and designated with an association score by our refined score model. ncRNAVar offers web applications including association prioritization, network visualization, and relationship mapping. ncRNAVar, presenting a landscape of ncRNA variants in human diseases and a useful resource for subsequent software development, will improve our insight of relationships between ncRNA variants and human health.

The Financial requirements of the investigation and the specific design techniques for Web applications in the financial services industry Web Embedded Systems (WES) of. In discussing some of the financial services industry has decision-making technology, using data mining motives are related to the basic challenge of some typical applications using embedded design, after the realization of prompt analysis and user behavior online risks Accounting Oversight Internet control, early warning accounting software module risk In the monitoring system and embedded, the construction of interest rate risk, currency risk, accounting for risk prediction of the network, warning the Multiple of supervision of discriminant analysis model, accounting for boot loader in accordance with the classification Improve internet controls and requirements, real-time early tracking alert payment network and information on the efficiency of various fees and interest, corporate accounting fees business operations and regular financial reporting system. Internet financial analysis and risk measurement receivers. As a result, to achieve real-time risk-aware network can use the Internet shows that the supervision of accounting, risk management capabilities and improve prevention.

Purpose To determine possible impacts on retinal microvasculature in healthy young adults during exercise with a face mask, using optical coherence tomography angiography (OCTA). Methods Twenty-three healthy participants (23 eyes, 17 women and 6 men) performed the incremental continuous running test (ICRT) with different masks. OCTA of the macula and optic nerve head were performed before and after ICRT to detect changes in retinal vessel density (VD). All participants were in groups A, B, and C (before ICRT) and groups A′, B′, and C′ (after ICRT), which comprised data from volunteers without a mask, with a surgical mask, and with an N95 mask, respectively. Results Before ICRT, group C showed significantly reduced VD in the superficial plexus (SP), except foveal VD, compared with group A (P < 0.05). After ICRT, groups B′ and C′ showed significantly shorter maximum running time, lower oxygen saturation, and lower perifoveal VD of SP compared with group A′ (P < 0.05). Conclusions Use of an N95 mask reduced VD in SP even under quiescent conditions, which might have clinical implications for protecting healthy workers and indoor manual labor workers from potential risks of retinal damage due to long-term mask use. Moreover, mask use while exercising might lead to attenuated exercise ability and lower VD in SP, which should be investigated in additional studies. Translational Relevance Retina vascular perfusion dynamics could be monitored in vivo by OCTA, which would be valuable to study physiologic retinal blood flow redistribution and potential impacts on retinal vascular perfusion during exercise with face masks.

Background: Oxidative stress plays a crucial role in the development of alcoholic liver disease (ALD), however effective pharmacological treatment for oxidative injury is still lacking. The objective of this study was to determine whether inhibition of NADPH oxidase activity could reverse alcohol-induced liver injury via protecting mitochondrial functions. Methods: C57BL/6J mice were pair-fed with Lieber-DeCarli control or ethanol diet for four week with or without administration with 30 mg/kg/d GKT137831, a NOX4 inhibitor for the last two weeks. H4IIEC3 cells were transfected with scrambled or NOX4 shRNA. Cells were then treated with 200 mM ethanol for 48 h. Results: Alcohol exposure induced NOX4 expression in the liver and mitochondrial fraction. GKT137831 partially reversed alcohol-induced liver injury and elevation of serum H2O2. The levels of mitochondrial ROS, mitochondrial DNA, respiratory chain complex IV, and hepatic ATP were partially reversed by GKT137831 after alcohol exposure. Furthermore GKT137831 ameliorated alcohol-induced lipid accumulation and increased HNF-4α and β-oxidation enzymes. GKT137831 also decreased alcohol-induced apoptosis coupled with decreased insertion of Bax into mitochondria and decreased activation of cleaved caspase-9 and cleaved PARP. Mechanistic study shows that ethanol induced expression of NOX4 in H4IIEC3 cells. Knockdown of NOX4 caused an increased mitochondrial membrane potential, decreased mitochondrial superoxide levels, reduced number of apoptotic cells, decreased lipid accumulation, and improved ATP levels and NAD +/NADH ratio after ethanol treatment. Conclusion: Pharmacological inhibition of NOX4 activity protects against alcohol-induced fat accumulation and activation of intrinsic apoptosis via improving mitochondrial function. General significance: Pharmacological inhibition of NOX4 could be a promising treatment for ALD.

Mounting evidence has firmly established that increased exercise capacity (EC) is associated with considerable improvements in the survival of patients with cardiovascular disease (CVD) and that antistress capacity is a prognostic predictor of adverse cardiovascular events in patients with CVD. Previous studies have indicated that aerobic exercise (AE) and supplementation withRhodiola sacra(RS), a natural plant pharmaceutical, improve EC and enable resistance to stress; however, the underlying mechanism remains unclear. This study explored the ability of AE and RS, alone or combined, to improve EC and ameliorate exhaustive exercise- (EE-) induced stress and elucidate the mechanism involved. We found that AE and RS significantly increased EC in mice and ameliorated EE-induced stress damage in skeletal and cardiac muscles (SCM); furthermore, a synergistic effect was detected for the first time. To our knowledge, the present work is the first to report that AE and RS activate mitophagy, mitochondrial dynamics, and biogenesis in SCM, both in the resting state and after EE. These data indicate that AE and RS synergistically improve EC in mice and protect SCM from EE-induced stress by enhancing mitochondrial quality control, including the activation of mitophagy, mitochondrial dynamics, and biogenesis, both at rest and after EE.

Porous carbon nanosheets (aCS) formed by carbonization and chemical activation of biomass cornstalk are presented for capacitive energy storage. The obtained carbon possesses a two-dimensional (2D) sheet-like structure which is mainly composed of abundant micropores. Depending on the amount of KOH used in the activation step, the specific surface area of the carbon sheets varies from 388 to 1736 m2 g−1, whereas the lateral size is in the range of 50–100 μm, and sheet thickness is around 100 nm. The capacitive performance of aCS-5 in both KOH and Na2SO4 aqueous electrolytes is investigated. The aCS-5 electrode in KOH electrolyte exhibits a remarkable high-rate capability due to the dramatically shortened ion pathway and more exposed external surface. While, in Na2SO4 it shows relatively lower capacitance retention but a stable and extended voltage window (0–1.6 V), thus delivering a specific energy of 20.2 W h kg−1 at a power density of 398 W kg−1. The aCS-5 with a large aspect ratio (200–500) can also serve as an electrode for assembling a solid-state capacitor (SSC) using PVA/KOH gel as a polymer electrolyte. The SSC retains the normal capacitive performance under bent and twisted states and exhibit an unusual rate capability with an areal capacitance of 136 mF cm−2 at 0.5 mA cm−2.

Pro-inflammatory cytokines play a vital role in the pathogenesis of alcoholic steatohepatitis. The present study was to determine the role of alcohol-induced oxidative stress in modulating cytokine production. A rat model of alcohol consumption was used to determine alcohol-induced hepatic cytokine expression. Chronic alcohol exposure caused lipid accumulation, oxidative stress, and inflammation in the livers of Wistar rats. The role of oxidative stress in regulating cell type-specific cytokine production was further dissected in vitro. Lipopolysaccharide (LPS) dose-dependently upregulated TNF-α, MIP-1α, MCP-1, and CINC-1 in Kupffer cells-SV40, whereas TNF-α dose-dependently induced CINC-1, IP-10, and MIP-2 expression in H4IIEC3 hepatoma cells. An addictive effect on cytokine production was observed in both Kupffer cells-SV40 and hepatocytes when combined hydrogen peroxide with LPS or TNF-α, respectively, which was associated with NF-κB activation and histone H3 hyper-acetylation. Unexpectedly, an inhibiting effect of 4-hydroxynonenal on cytokine production was revealed in LPS-treated Kupffer cells-SV40. Mechanistic study showed that 4-hydroxynonenal significantly enhanced mRNA degradation of TNF-α, MCP-1, and MIP-1α, and decreased the protein levels of MCP-1 in LPS-stimulated Kupffer cells-SV40 through reducing the phosphorylation of mRNA binding proteins. This study suggests that Kupffer cells and hepatocytes express distinct pro-inflammatory cytokines/chemokines in response to alcohol intoxication, and oxidative products (4-hydroxynonenal) differentially modulate pro-inflammatory cytokine/chemokine production via NF-κB signaling, histone acetylation, and mRNA stability.

Background Overproduction of reactive oxygen species is associated with the development of alcoholic liver disease (ALD). Plant polyphenols have been used as dietary interventions for multiple diseases including ALD. The objective of this study was to determine whether dietary supplementation with fisetin, a novel flavonoid, exerts beneficial effect on alcohol-induced liver injury. Methods C57BL/6J mice were pair-fed with the Lieber-DeCarli control or ethanol (EtOH) diet for 4 weeks with or without fisetin supplementation at 10 mg/kg/d. Results Alcohol feeding induced lipid accumulation in the liver and increased plasma alanine aminotransferase and aspartate aminotransferase activities, which were attenuated by fisetin supplementation. The EtOH concentrations in the plasma and liver were significantly elevated by alcohol exposure but were reduced by fisetin supplementation. Although fisetin did not affect the protein expression of alcohol metabolism enzymes, the aldehyde dehydrogenase activities were significantly increased by fisetin compared to the alcohol alone group. In addition, fisetin supplementation remarkably reduced hepatic NADPH oxidase 4 levels along with decreased plasma hydrogen peroxide and hepatic superoxide and 4-hydroxynonenal levels after alcohol exposure. Alcohol-induced apoptosis and up-regulation of Fas and cleaved caspase-3 in the liver were prevented by fisetin. Moreover, fisetin supplementation attenuated alcohol-induced hepatic steatosis through increasing plasma adiponectin levels and hepatic protein levels of p-AMPK, ACOX1, CYP4A, and MTTP. Conclusions This study demonstrated that the protective effect of fisetin on ALD is achieved by accelerating EtOH clearance and inhibition of oxidative stress. The data suggest that fisetin has a therapeutical potential for treating ALD.

To survive and replicate within a host, many viruses have evolved strategies that target crucial components within the apoptotic cascade, leading to either inhibition or induction of cell apoptosis. Enterovirus 71 (EV71) infections have been demonstrated to impact the mitochondrial apoptotic pathway and induce apoptosis in many cell lines. However, the detailed mechanism of EV71-induced apoptosis remains to be elucidated. In this study, we report that EV71 2B protein (2B) localized to the mitochondria and induced cell apoptosis by interacting directly with and activating the proapoptotic protein Bax. 2B recruited Bax to the mitochondria and induced Bax conformational activation. In addition, mitochondria isolated from 2B-expressing cells that were treated with a recombinant Bax showed increased Bax interaction and cytochrome c (Cyt c ) release. Importantly, apoptosis in cells with either EV71 infection or 2B expression was dramatically reduced in Bax knockdown cells but not in Bak knockdown cells, suggesting that Bax played a pivotal role in EV71- or 2B-induced apoptosis. Further studies indicate that a hydrophobic region of 18 amino acids (aa) in the C-terminal region of 2B (aa 63 to 80) was responsible for the location of 2B in the mitochondria. A hydrophilic region of 14 aa in the N-terminal region of 2B was functional in Bax interaction and its subsequent activation. Moreover, overexpression of the antiapoptotic protein Bcl-X L abrogates 2B-induced release of Cyt c and caspase activation. Therefore, this study provides direct evidence that EV71 2B induces cell apoptosis and impacts the mitochondrial apoptotic pathway by directly modulating the redistribution and activation of proapoptotic protein Bax. IMPORTANCE EV71 infections are usually accompanied by severe neurological complications. It has also been postulated that the induction of cell apoptosis resulting from tissue damage is a possible process of EV71-related pathogenesis. In this study, we report that EV71 2B protein (2B) localized to the mitochondria and induced cell apoptosis by interacting directly with and activating the proapoptotic protein Bax. This study provides evidence that EV71 induces cell apoptosis by modulating Bax activation and reveals important clues regarding the mechanism of Cyt c release and mitochondrial permeabilization during EV71 infection.

Accumulating evidences indicate that poly C binding protein (PCBP1) is downregulated in various carcinomas as a tumor suppressor, but the underlying mechanism in suppression of tumorigenesis still remains elusive. Here, we found that PCBP1 overexpression attenuates tumor cell growth upon serum-free starvation. Notably, the autophagic degradation inhibitor, chloroquine, could mimic this suppressive effect in tumor cell growth. Autophagy analyses demonstrated that PCBP1 overexpression blocked autophagic flux of tumor cells under starvation conditions, while PCBP1 downregulation in turn refueled this autophagic flux, protecting cells from death. Mechanistically, PCBP1 overexpression attenuated microtubule-associated protein Light chain 3 (LC3B) mRNA stability to repress LC3B expression, resulting in the autophagy inhibition. Consequently, PCBP1 overexpression strongly triggered the caspase 3 and 8-mediated apoptosis of tumor cells and downregulated anti-apoptotic Bcl-2 expression upon starvation, which could be further synergized by autophagic inhibitor, indicating that PCBP1 not only inhibits tumor cell autophagy, but also renders them to apoptosis. Taken together, our results uncovered a novel mechanism of PCBP1 in repressing autophagy-mediated cell survival and indicated that inhibition of tumor cell autophagy by PCBP1 upregulation or with autophagic inhibitors could be an effective therapeutical strategy to colon and ovary tumors with low PCBP1 expression.

Previously we identified and deorphaned G-protein-coupled receptor 31 (GPR31) as the high-affinity 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] receptor (12-HETER1). Here we have determined its distribution in prostate cancer tissue and its role in prostate tumorigenesis using in vitro and in vivo assays. Data-mining studies strongly suggest that 12-HETER1 expression positively correlates with the aggressiveness and progression of prostate tumors. This was corroborated with real-time PCR analysis of human prostate tumor tissue arrays that revealed the expression of 12-HETER1 positively correlates with the clinical stages of prostate cancers and Gleason scores. Immunohistochemistry analysis also proved that the expression of 12-HETER1 is positively correlated with the grades of prostate cancer. Knockdown of 12-HETER1 in prostate cancer cells markedly reduced colony formation and inhibited tumor growth in animals. To discover the regulatory factors, 5 candidate 12-HETER1 promoter cis elements were assayed as luciferase reporter fusions in Chinese hamster ovary (CHO) cells, where the putative cis element required for gene regulation was mapped 2 kb upstream of the 12-HETER1 transcriptional start site. The data implicate 12-HETER1 in a critical new role in the regulation of prostate cancer progression and offer a novel alternative target for therapeutic intervention.—Honn, K. V., Guo, Y., Cai, Y., Lee, M.-J., Dyson, G., Zhang, W., Tucker, S. C. 12-HETER1/GPR31, a high-affinity 12(S)-hydroxyeicosatetraenoic acid receptor, is significantly up-regulated in prostate cancer and plays a critical role in prostate cancer progression.

Background: Analysis of emerging data shows that miRNAs, including miR-155, play important roles in tumorigenesis. Several studies have indicated that miR-155 and MIR155HG polymorphisms may be related to cancer risk, but the association was controversial. Therefore, we conducted this first-reported comprehensive meta-analysis of the association of miR-155 and MIR155HG polymorphisms with cancer risk. Materials and Methods: We searched several databases, including PubMed, Embase, and Web of Science, to identify the eligible studies reporting the association of miR-155 and MIR155HG polymorphisms with cancer risk. We calculated the pooled odds ratios (ORs) and 95% confidence intervals (CIs) to analyze the association. Stata software (version 16.0) was used to analyze the data we collected. Results: After being carefully and strictly screened, eight articles reporting on six common single-nucleotide polymorphisms consisting of 6184 cases and 6896 controls were included in this meta-analysis. The six polymorphisms included were rs767649 (T>A), rs928883 (A>G), rs2829803 (G>A), rs1893650 (T>C), rs4143370 (G>C), and rs12482371 (T>C). Our results showed that, in the overall analysis, heterozygotes increased cancer risk, with a marginal P value, compared with wild-type (OR = 1.06, 95% CI = 1.00–1.12, P = 0.062). Subsequent analyses showed that only rs767649 was associated with an increased risk of non-small-cell lung cancer (NSCLC) in an allele model (T vs. A: OR = 1.15, 95% CI = 1.04–1.26, P = 0.007), a homozygote model (TT vs. AA: OR = 1.31, 95% CI = 1.06–1.60, P = 0.011), and a recessive model (TT vs. AT + AA: OR = 1.30, 95% CI = 1.08–1.55, P = 0.005). Conclusion: The present meta-analysis indicates that the rs767649 polymorphism might be a potential factor for NSCLC risk; however, more studies should be conducted to confirm these findings.

Timely and accurately obtaining the strength of pouring material, e.g., concrete, cement mortar, is of great significance for engineering construction. In this paper, a non-destructive, economical and accurate strength detection method that suites for on-site using is proposed for the steel bar cement mortar material. The method based on the relationship between the vibration frequency of the steel bar and the properties of the mortar material, which is obtained by solving the Euler-Bernoulli beam problem. Both Particle Flow Code (PFC) software simulation (calibrated) and Split Hopkinson pressure Bar experiment on test samples of cement mortar and steel bar were performed to verify the theoretically obtained relationship. Studies on samples of various aggregate ratio further confirmed such correspondence. Results show that the dynamic stiffness of the cement mortar material dominates the calculation of the vibration frequency of steel bar, while the combined effect of the density, length, elastic modulus, inertia moment of the steel bar can be safely ignored. A single-valued mapping relation exists in between the dynamic stiffness coefficient and the Uniaxial Compressive Strength (UCS) of the cement mortar sample, i.e., increased dynamic stiffness coefficient with increasing UCS. Both experimental and predicted results showed a linear relationship between the vibration frequency of the steel bar and the strength of the mortar material. Fitted linear relations were proposed with coefficients depending on sample size and aggregate ratio and might serve as a good indicator for the strength of the mortar material. Further studies on the effect of internal defects of the mortar materials as well as on samples of more size and aggregate ratio are required to make the proposed method a practical tool.

We have systematically studied physical properties of Ba(Fe_{0.97}Cr_{0.03})_{2}(As_{1-x}P_{x})_{2}, where superconductivity in BaFe_{2}(As_{1-x}P_{x})_{2} is fully suppressed by just 3% of Cr substitution of Fe. A quantum critical point is revealed at x∼0.42, where non-Fermi-liquid behaviors similar to those in BaFe_{2}(As_{1-x}P_{x})_{2} are observed. Neutron diffraction and inelastic neutron scattering measurements suggest that the quantum critical point is associated with the antiferromagnetic order, which is not of conventional spin-density-wave type as evidenced by the ω/T scaling of spin excitations. On the other hand, no divergence of low-temperature nematic susceptibility is observed when x is decreased to 0.42 from higher doping level, demonstrating that there are no nematic quantum critical fluctuations. Our results suggest that non-Fermi-liquid behaviors in iron-based superconductors can be solely resulted from the antiferromagnetic quantum critical fluctuations, which cast doubts on the role of nematic fluctuations played in the normal-state properties in iron-based superconductors.

To explore the effects of trimetazidine combined with exercise on EC and anti-fatal stress ability, and illustrate the underlying mechanism.C57BL/6 mice were randomly assigned to four groups (n = 11 in each group): the control, exercise, trimetazidine and trimetazidine + exercise (TE) groups. Mice were accordingly given saline (ig), Aerobic exercise (AE), trimetazidine (ig), or a combination of trimetazidine (ig) and AE for five weeks. After the intervention, each group was randomly subdivided into rest and exhaustive exercise (EE) subgroups. The mice in the control-EE and TE-EE subgroups underwent fatal stress experiments. EC and anti-fatal stress ability were assessed respectively. Mitochondrial quality control (MQC) in skeletal muscle were measured at the protein level and the organelle level.A significantly increased exhaustive swimming time was observed in exercise (39.10 ± 12.58 min vs 14.18 ± 4.37 min), trimetazidine (33.73 ± 8.45 min vs 14.18 ± 4.37 min) and TE groups (73.78 ± 18.95 min vs 14.18 ± 4.37 min) compared with that in the control group, and a synergistic effect was detected (P 0.05). Fatal stress experiments successfully induced skeletal muscle damage, including increased creatine kinase activity, myofibrosis, and impaired antioxidative enzyme system, all those were significantly alleviated by trimetazidine supplementation combined with AE precondition (P 0.05). Meanwhile, AE and trimetazidine alone or combined, significantly enhanced the MQC in normal mice by activating mitochondrial biogenesis, dynamics and mitophagy, and that in mice underwent fatal stress stimulus (P 0.05).This study for the first time found that trimetazidine and AE have synergistic effects on improving EC. Moreover, the combination of both interventions enhances anti-fatal stress ability. Enhancing MQC may be a key mechanism of AE combined with trimetazidine that improves EC and anti-fatal stress ability.

Let $R$ be an $F$-finite Noetherian regular ring containing an algebraically closed field $k$ of positive characteristic, and let $M$ be an $\F$-finite $\F$-module over $R$ in the sense of Lyubeznik (for example, any local cohomology module of $R$). We prove that the $\mathbb{F}_p$-dimension of the space of $\F$-module morphisms $M \rightarrow E(R/\fm)$ (where $\fm$ is any maximal ideal of $R$ and $E(R/\fm)$ is the $R$-injective hull of $R/\fm$) is equal to the $k$-dimension of the Frobenius stable part of $\Hom_R(M,E(R/\fm))$. This is a positive-characteristic analogue of a recent result of Hartshorne and Polini for holonomic $\D$-modules in characteristic zero. We use this result to calculate the $\F$-module length of certain local cohomology modules associated with projective schemes., Comment: Minor changes to improve exposition. Comments welcome!

We have systematically studied physical properties of Ba(Fe_{0.97}Cr_{0.03})_{2}(As_{1-x}P_{x})_{2}, where superconductivity in BaFe_{2}(As_{1-x}P_{x})_{2} is fully suppressed by just 3% of Cr substitution of Fe. A quantum critical point is revealed at x∼0.42, where non-Fermi-liquid behaviors similar to those in BaFe_{2}(As_{1-x}P_{x})_{2} are observed. Neutron diffraction and inelastic neutron scattering measurements suggest that the quantum critical point is associated with the antiferromagnetic order, which is not of conventional spin-density-wave type as evidenced by the ω/T scaling of spin excitations. On the other hand, no divergence of low-temperature nematic susceptibility is observed when x is decreased to 0.42 from higher doping level, demonstrating that there are no nematic quantum critical fluctuations. Our results suggest that non-Fermi-liquid behaviors in iron-based superconductors can be solely resulted from the antiferromagnetic quantum critical fluctuations, which cast doubts on the role of nematic fluctuations played in the normal-state properties in iron-based superconductors.

Understanding magnetic interactions in the parent compounds of high-temperature superconductors forms the basis for determining their role for the mechanism of superconductivity. For parent compounds of iron pnictide superconductors such as $A{\mathrm{Fe}}_{2}{\mathrm{As}}_{2}$ ($A=\mathrm{Ba}$, Ca, Sr), although spin excitations have been mapped out throughout the entire Brillouin zone, the respective measurements were carried out on twinned samples and did not allow for a conclusive determination of the spin dynamics. Here we use inelastic neutron scattering to completely map out spin excitations of $\ensuremath{\sim}100%$ detwinned ${\mathrm{BaFe}}_{2}{\mathrm{As}}_{2}$. By comparing observed spectra with theoretical calculations, we conclude that the spin excitations can be well described by an itinerant model when taking into account moderate electronic correlation effects.

Let $R$ be a polynomial or power series ring over a field $k$. We study the length of local cohomology modules $H^j_I(R)$ in the category of $D$-modules and $F$-modules. We show that the $D$-module length of $H^j_I(R)$ is bounded by a polynomial in the degree of the generators of $I$. In characteristic $p>0$ we obtain upper and lower bounds on the $F$-module length in terms of the dimensions of Frobenius stable parts and the number of special primes of local cohomology modules of $R/I$. The obtained upper bound is sharp if $R/I$ is an isolated singularity, and the lower bound is sharp when $R/I$ is Gorenstein and $F$-pure. We also give an example of a local cohomology module that has different $D$-module and $F$-module lengths., 30 pages, final version

Understanding magnetic interactions in the parent compounds of high-temperature superconductors forms the basis for determining their role for the mechanism of superconductivity. For parent compounds of iron pnictide superconductors such as AFe_{2}As_{2} (A=Ba, Ca, Sr), although spin excitations have been mapped out throughout the entire Brillouin zone, the respective measurements were carried out on twinned samples and did not allow for a conclusive determination of the spin dynamics. Here we use inelastic neutron scattering to completely map out spin excitations of ∼100% detwinned BaFe_{2}As_{2}. By comparing observed spectra with theoretical calculations, we conclude that the spin excitations can be well described by an itinerant model when taking into account moderate electronic correlation effects.

Although the CSP algorithm has been extensively studied, little has been known about its relatively low accuracy and efficiency. Based on the evident advantage of S transform in feature extraction, including more obvious characteristic of time, frequency and phase, it is applied to preprocess the data for a better classification. The experiment result on the motion imagery indicates that the combined algorithm achieve an accuracy of 92.8%, far higher than the accuracy of applying CSP algorithm only. What is more, the time cost could be diminished to 0.85s after sampling, 31% less than the original method, and could still achieve the accuracy of 89.8%. In conclusion, the combination of CSP and S transform algorithm is a feasible and applicable one with data and technical support.

We extend a result by Huneke and Watanabe bounding the multiplicity of $F$-pure local rings of prime characteristic in terms of their dimension and embedding dimensions to the case of $F$-injective, generalized Cohen-Macaulay rings. We then produce an upper bound for the multiplicity of any local Cohen-Macaulay ring of prime characteritic in terms of their dimensions, embedding dimensions and HSL numbers. Finally, we extend the upper bounds for the multiplicity of generalized Cohen-Macaulay rings in characteristic zero which have dense $F$-injective type.

Chinese hamster ovary (CHO) cells are the famous expression system for industrial production of recombinant proteins, such as therapeutic antibodies. However, there still remain bottlenecks in protein quality and weakness in expression efficiency because of the intrinsic genetic properties of the cell. Here we have enhanced biosynthesis performance of heterologous proteins in CHO-K1 cells using CRISPR-Cas9 by editing the genome precisely with two genes for improving ER microenvironment and reinforcing antiapoptotic ability. A linear donor plasmid harboring eGFP-HsQSOX1b and Survivin genes was knocked in specific locus in CHO-K1 genome by the CRISPR-Cas9 RNA guided nucleases via NHEJ with efficiencies of up to 3.85% in the CHO-K1 cell pools following FACS, and the hQSOX1 and hSurvivin genes were integrated into expected genome locus successfully. Compared with control, the antiapoptotic viability of edited CHO-K1 cells was increased by 6.40 times, and the yield has been raised by 5.55 times with GLuc as model protein. The possible molecular mechanisms and pathways of remarkable antiapoptotic ability and protein biosynthesis in modified CHO-K1 cells have been elucidated reasonably. In conclusion, the novel ideas and reliable techniques for obtaining foreign proteins more efficiently in engineered animal cells were very valuable to meet large clinical needs.

SummaryKif5b-driven anterograde transport and clathrin-mediated endocytosis (CME) are responsible for opposite intracellular trafficking, contributing to plasma membrane homeostasis. However, whether and how the two trafficking processes coordinate remain unclear. Here, we show that Kif5b directly interacts with clathrin heavy chain (CHC) at a region close to that for uncoating catalyst (Hsc70) and preferentially localizes on large clathrin-coated vesicles (CCVs). Uncoatingin vitrois decreased for CCVs from the cortex ofkif5bconditional knockout (mutant) mouse and facilitated by adding CHC-binding Kif5b fragments, while cell peripheral distribution of CHC or Hsc70 keeps unaffected by Kif5b depletion. Furthermore, cellular entry of vesicular stomatitis virus that internalized into large CCV is inhibited in cells by Kif5b depletion or introducing a dominant-negative Kif5b fragment. These findings showed a new role of Kif5b in CCV uncoating and CME, indicating Kif5b as a molecular knot connecting anterograde transport to CME.

To survive and replicate within a host, many viruses have evolved strategies that target crucial components within the apoptotic cascade, leading to either inhibition or induction of cell apoptosis. Enterovirus 71 (EV71) infections have been demonstrated to impact the mitochondrial apoptotic pathway and induce apoptosis in many cell lines. However, the detailed mechanism of EV71-induced apoptosis remains to be elucidated. In this study, we report that EV71 2B protein (2B) localized to the mitochondria and induced cell apoptosis by interacting directly with and activating the proapoptotic protein Bax. 2B recruited Bax to the mitochondria and induced Bax conformational activation. In addition, mitochondria isolated from 2B-expressing cells that were treated with a recombinant Bax showed increased Bax interaction and cytochrome c (Cyt c) release. Importantly, apoptosis in cells with either EV71 infection or 2B expression was dramatically reduced in Bax knockdown cells but not in Bak knockdown cells, suggesting that Bax played a pivotal role in EV71- or 2B-induced apoptosis. Further studies indicate that a hydrophobic region of 18 amino acids (aa) in the C-terminal region of 2B (aa 63 to 80) was responsible for the location of 2B in the mitochondria. A hydrophilic region of 14 aa in the N-terminal region of 2B was functional in Bax interaction and its subsequent activation. Moreover, overexpression of the antiapoptotic protein Bcl-XEV71 infections are usually accompanied by severe neurological complications. It has also been postulated that the induction of cell apoptosis resulting from tissue damage is a possible process of EV71-related pathogenesis. In this study, we report that EV71 2B protein (2B) localized to the mitochondria and induced cell apoptosis by interacting directly with and activating the proapoptotic protein Bax. This study provides evidence that EV71 induces cell apoptosis by modulating Bax activation and reveals important clues regarding the mechanism of Cyt c release and mitochondrial permeabilization during EV71 infection.

The characteristics of intrinsically disordered proteins depend on their length. An obvious fact is that the composition of amino acid sequences is different for different length disordered regions. In order to improve the performance of the predicting model, a new method was proposed to predict disordered regions of diverse length disordered regions in proteins by using different feature teams. Taking into account the relevance between their characteristics and length of intrinsically disordered proteins, different feature teams were constructed for different length disordered regions. In every feature team, the selection of window sizes and features could meet the demand of the corresponding length disordered region. Comparing with the traditional method, this method could consider not only the influence of the window sizes but also the effect of the feature information. According to every feature team, a basic predictor was required to built by SVM. By integrating these basic predictors, the final decision could be made by the majority voting method. Subsequent simulation suggests that the proposed method can consider the information from the long and short disordered regions simultaneously and get a good predicting accuracy for IDPs, especially for short disordered regions.

Morphological and functional alterations of hepatic mitochondria have been documented in patients with alcoholic liver disease (ALD). Our recent study demonstrated that zinc level was decreased in whole liver and mitochondria by chronic alcohol feeding. The present study was undertaken to determine whether zinc deficiency mediates alcohol-induced mitochondrial electron transport chain (ETC) defect and whether defective ETC function may lead to generation of reactive oxygen species (ROS). Male Wistar rats were pair fed with the Lieber-DeCarli control or ethanol diet for 5 mo. Chronic alcohol exposure increased hepatic triglyceride, free fatty acid, and 4-hydroxynonenal (4HNE) levels; meanwhile hepatic mitochondrial 4HNE level was also increased. Moreover, hepatic mitochondrial respiratory complexes I, III, IV, and V and hepatic ATP production were decreased by chronic alcohol exposure. Chronic alcohol feeding decreased peroxisome proliferator-activated receptor gamma coactivator-1-alpha (PGC1α), nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), and mitochondrial DNA. HepG2 cells were treated with N, N, N′, N′-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) for 6 h. Zinc deficiency significantly decreased mitochondrial respiratory complexes I, III, and IV. In addition, PGC1α, NRF1, and TFAM levels as well as mitochondrial DNA were significantly decreased by TPEN treatment. Knockdown of mitochondrial respiratory complexes I, III, or IV by shRNA caused a decrease in mitochondrial membrane potential and an increase in ROS production. These results suggest that alcohol-induced hepatic zinc deficiency could inactivate mitochondrial biogenesis pathway and decrease mitochondrial DNA replication, which, in turn, decreases mitochondrial complex protein expression. The defect of mitochondrial respiratory complexes may worsen alcohol-induced ROS production.

The metastasis-associated phosphatase of regenerating liver-3 (PRL-3) plays multiple roles in progression of various human cancers; however, significance of its role during development has not been addressed. Here we cloned and characterized the expression pattern of zebrafish prl-3 transcript and showed that it is ubiquitiously expressed in the first 24 h of development with both maternal and zygotic expressions. The transcripts become progressively restricted to the notochord, vessels and the intestine by 96 h post-fertilization. Notably, overexpression of zebrafish Prl-3 (zPrl-3) and human PRL-3 induces notochord malformation in zebrafish. This phenotype resembles chordoma and is confirmed by associated misexpression of notochord-specific markers. Clinical significance of the PRL-3 in chordoma is strongly suggested by detection of PRL-3 antigen in clinical chordoma specimens. Collectively, our results uncovered that aberrant overexpression of PRL-3 could initiate chordoma in early development and suggest the use of PRL-3 could be used as a predictor and a therapeutic target for chordoma.

Aims/Introduction Heart rate recovery (HRR) after exercise is considered to be a new index of autonomic dysfunction associated with cardiovascular disease and mortality. The present study aimed to investigate the risk factors of HRR and the effects of exercise on the abnormal HRR in type 2 diabetes. Materials and Methods A total of 123 type 2 diabetes patients were recruited, and the oral glucose tolerance test and exercise test were carried out to analyze the risk factors associated with abnormal HRR. Among these patients, 42 patients with abnormal HRR were further randomized to either the conventional therapy group (CT group; n = 20) or the intensive therapy group (IT group; n = 22). The CT group patients underwent metformin and diet control, whereas the IT group additionally underwent a combined moderate intensity aerobic and resistance training three times per week for 12 weeks. The results of blood sample analysis and HRR were recorded before and after the training. Results Abnormal HRR was related to fasting blood glucose, glycosylated hemoglobin, low-density lipoprotein cholesterol, and resting and maximum heart rates (P < 0.05 for both). After training, the IT group had significantly lower levels of fasting blood glucose, glycosylated hemoglobin and resting heart rate than the CT group (all P < 0.01 or P < 0.005). Significant improvement in HRR and metabolic equivalents was observed in the IT group compared with the CT group (P < 0.05). Conclusions These data suggested that combined aerobic and resistance training improved cardiac autonomic dysfunction as measured by HRR in type 2 diabetes patients. This might be due to better improvement of glycemic control, resting heart rate and physical fitness.

1. introductionR. Hartshorneprovedin [Har62, Proposition2.1]that, if (R,m) is anoetherianlo-cal ring whose depth is at least 2, then the punctured spectrum (i.e. Spec(R)\{m})is connected. In this note we partially extend this result to the case depth ≥ 3. Weexpress our extension in terms of a simplicial complex (which already appeared in[Lyu07, Theorem 1.1]) defined as follows.Definition 1.1. Let Rbe a noetherian commutative ring and let {p

Background & Aims Effective therapies for alcoholic liver disease are currently unavailable. The present study tested the efficacy of Alda-1, a specific aldehyde dehydrogenase 2 (ALDH2) activator, in treating alcoholic liver disease. Methods Male C57BL/6J mice were exposed to alcohol for a time-course study on aldehyde metabolism. The specificity and efficacy of Alda-1 on activating hepatic ALDH2 and aldehyde clearance were determined by acute treatments. Then, mice were fed alcohol for 8weeks with Alda-1 administration for the last 10days to test the therapeutic potential of Alda-1. Lastly, H4IIEC3 cells were treated with ethanol, acetaldehyde, or 4-hydroxynonenal to define the link between aldehydes and hepatotoxicity. Results Alcohol feeding for 8weeks induced hepatic ALDH2 dysfunction and aldehyde accumulation. One dose of Alda-1 administration elevated hepatic ALDH activity, which was blocked by the specific ALDH2 inhibitor, daidzin. Alda-1 accelerated acetaldehyde clearance after acute alcohol intoxication. Alda-1 treatment in the 8-week alcohol feeding model reversed liver damage along with reduction of hepatic aldehydes. Alda-1 re-activated transcription factors, upregulated fatty acid oxidation enzymes, and reversed steatosis. Alcohol-induced endoplasmic reticulum stress and apoptotic cell death were also attenuated by Alda-1. Acetaldehyde or 4-hydroxynonenal treatment to H4IIEC3 cells inactivated transcription factors and induced endoplasmic reticulum stress and apoptosis, while ethanol per se showed limited effects. Conclusions Pharmacological activation of ALDH2 by Alda-1 reversed alcoholic steatosis and apoptosis through accelerating aldehyde clearance. This study indicates that ALDH2 is a promising molecular target and Alda-1 has therapeutic potential for treating alcoholic liver disease.

Excessive fatty acid release from the white adipose tissue (WAT) contributes to the development of alcoholic liver disease (ALD). Lipin1 (LPIN1), as a co-regulator of DNA-bound transcription factors and a phosphatidic acid (PA) phosphatase (PAP) enzyme that dephosphorylates PA to form diacylglycerol (DAG), is dramatically reduced by alcohol in the WAT. This study aimed at determining the role of adipose LPIN1 in alcohol-induced lipodystrophy and the development of ALD. Transgenic mice overexpressing LPIN1 in adipose tissue (LPIN1-Tg) and wild type (WT) mice were fed a Lieber-DeCarli alcohol or isocaloric maltose dextrin control liquid diet for 8 weeks. Alcohol feeding to WT mice resulted in significant liver damage, which was significantly alleviated in the LPIN1-Tg mice. Alcohol feeding significantly reduced epididymal WAT (EWAT) mass, inhibited lipogenesis, and increased lipolysis in WT mice, which were attenuated in the LPIN1-Tg mice. LPIN1 overexpression also partially reversed alcohol-reduced plasma leptin levels. In WT mice, alcohol feeding induced hepatic lipid accumulation and down-regulation of beta-oxidation genes, which were dramatically alleviated in the LPIN1-Tg mice. LPIN1 overexpression also significantly attenuated alcohol-induced hepatic ER stress. These results suggest that overexpression of LPIN1 in adipose tissue restores WAT lipid storage function and secretive function to alleviate alcohol-induced liver injury.

Figure S9. Relationship of PCBP1 to p27 mRNA level in tumor samples. (A). Semiquantitative RT-PCR detection of PCBP1, p27 mRNA expression in conlon tumor tissues. GAPDH was used as control. p27 mRNA level is correlated to PCBP1 level in the paired normal (N) and tumor (T) samples of colon tissues. (B). p27 mRNA level as well as its ubiquitin ligase Skp2 in ovarian epithelia. GEO ID is shown. (C). TCGA gene profile of Skp2 in tumors indicates the relative low amplification in ovary and colon tumors. (PPT 2633 kb)

Figure S4. Colonies induced by A2780 or DLD-1 cells overexpressing PCBP1. PCBP1, PCBP1-p27 KD and GFP control cells were analyzed by soft agar assay for anchorage-independent growth. Colonies were stained with Trypan Blue and photographed. (PPT 609 kb)

Figure S7. Expression of PCBP1 and p27 in ovary cancer samples compared to that in the normal tissues. The indicated protein expression level was defined based on the staining intensity under the same robust IHC staining condition. (PPT 1277 kb)

Figure S1. PCBP1 increased p27 mRNA stability in A2780, DLD-1 and MDA-MB-231 cells. (A). Schematic procedure of isolation and identification of PCBP1-bound RNA transcripts. (B). Semi-quantitative RT-PCR detection of p27 mRNA levels in the indicated cell lines. A positive correlation between PCBP1 and p27 mRNA level is observed in these cell lines. (PPT 740 kb)

Figure S5. p27 mRNA stabilized by PCBP1. The half-life of p27 mRNA was derived from the decay curve plotted from the Fig. 6g and h. Linear regression equation in A: PCBP1, y = − 0.0096× + 0.998,R2 = 0.99; GFP, y = − 0.058× + 0.9844, R2 = 0.9865; B: PCBP1 KD, y = − 0.0749× + 0.965, R2 = 0.9607; GFP, y = − 0.0749× + 0.9677, R2 = 0.9387. (PPT 309 kb)

Figure S6. No effect of PCBP2 on p27 expression on both mRNA and protein levels. (A). RT-PCR analysis of PCBP2 knockdown efficiency by 2 specific siRNAs in A2780 GFP control cells or GFP-PCBP1 overexpressing cells. (B). Immunoblot analysis of p27 expression upon PCBP2 knockdown in A2780 GFP control cells or GFP-PCBP1 overexpressing cells. GAPDH was used as a loading control. (PPT 2665 kb)

Supplementary Experimental Procedures. (DOCX 19 kb)

Figure S2. PCBP1 overexpression inhibits cell cycle progression. (A). Representative immunofluorescence staining of A2780 and DLD-1 cells with EdU and Hoechst in cells with endogenous PCBP1 knockdown (PCBP1 KD), GFP-PCBP1 overexpression (PCBP1) and the additional p27KD in PCBP1-overexpressing cells (PCBP1-p27KD). (B). Statistical analyses of EdU positive cells in A. The EdU positive cells were counted randomly in 3 views and analyzed. (mean ± SEM, n = 3 per group). (C). Representative flow cytometry analysis of A2780 and DLD-1 cells with PCBP1 overexpression after EDU staining. Ratios of EdU + GFP-positive cells to GFP positive cells or GFP-PCBP1-positive cells are shown in the right-upper quadrant of each diagram. (PPT 2149 kb)