Cryo-EM structure of the polyphosphate polymerase VTC reveals coupling of polymer synthesis to membrane transit.

The eukaryotic vacuolar transporter chaperone (VTC) complex acts as a polyphosphate (polyP) polymerase that synthesizes polyP from adenosine triphosphate (ATP) and translocates polyP across the vacuolar membrane to maintain an intracellular phosphate (Pi ) homeostasis. To discover how the VTC complex performs its function, we determined a cryo-electron microscopy structure of an endogenous VTC complex (Vtc4/Vtc3/Vtc1) purified from Saccharomyces cerevisiae at 3.1 Å resolution. The structure reveals a heteropentameric architecture of one Vtc4, one Vtc3, and three Vtc1 subunits. The transmembrane region forms a polyP-selective channel, likely adopting a resting state conformation, in which a latch-like, horizontal helix of Vtc4 limits the entrance. The catalytic Vtc4 central domain is located on top of the pseudo-symmetric polyP channel, creating a strongly electropositive pathway for nascent polyP that can couple synthesis to translocation. The SPX domain of the catalytic Vtc4 subunit positively regulates polyP synthesis by the VTC complex. The noncatalytic Vtc3 regulates VTC through a phosphorylatable loop. Our findings, along with the functional data, allow us to propose a mechanism of polyP channel gating and VTC complex activation.

Differential Association of Serum BDNF With Poststroke Depression and Poststroke Anxiety.

OBJECTIVES: To investigate the correlation between brain-derived neurotrophic factor (BDNF) and risk factors, as well as functional outcome in poststroke depression (PSD) or poststroke anxiety (PSA). DESIGN: Cohort study. SETTING: Stroke patients admitted to an urban rehabilitation hospital. PARTICIPANTS: Stroke patients (N=162) without any previous history of depression and anxiety. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Sociodemographic information and comorbidities were recorded during hospital admission. Functional outcomes were assessed using FIM scores at time of admission and discharge. The influence of various factors such as BDNF and patient characteristics on functional outcome was investigated. Single-factor effect was examined using simple logistic regression, as was multi-factor effect using multiple logistic regression. The goodness-of-fit of those regression models was evaluated by the integrated area under ROC curve. RESULTS: PSD was diagnosed in 61 (37.7%) patients, and PSA was diagnosed in 40 (24.7%). Multiple logistic analysis showed that BDNF, divorce or separation, and history of smoking were significantly associated with the occurrence of PSD but not with the occurrence of PSA. The model combining low BDNF level and divorce or separation improved the prediction for PSD. Among the variables analyzed for prediction of functional outcome, serum BDNF had a minimum correlation with motor FIM scores in PSD but no significant correlation with motor FIM scores in PSA. CONCLUSIONS: BDNF is a valuable prediction for the occurrence of PSD but not for PSA. More strikingly, ischemic stroke patients who are divorced or separated with low serum BDNF have a much higher risk for PSD. BDNF has a minimum correlation with motor function outcome in PSD but no significant correlation with motor outcome in PSA.

PYCR1 interference inhibits cell growth and survival via c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathway in hepatocellular cancer.

BACKGROUND: Liver cancer is the second leading causes of cancer-related death globally. Pyrroline-5-carboxylate reductase 1 (PYCR1) plays a critical role in metabolic profiles of tumors. Therefore, it is necessary to explore the mechanisms of PYCR1 on cell growth and survival in hepatocellular carcinoma (HCC). METHODS: Protein and mRNA expression levels of PYCR1 in 140 pairs of tumor and adjacent normal liver tissues of HCC patients were analyzed by immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). Expressions of PYCR1 were inhibited in BEL-7404 cells and SMMC-7721 cells using gene interference technology. The cell proliferation was detected by Celigo and MTT assay. The colony formation assay was also performed. The cell apoptosis was measured by flow cytometric assay. The effect of PYCR1 interference on tumor growth was observed by xenograft nude mice assay in vivo. The downstream pathway of PYCR1 interference was searched by microarray and bioinformatics analysis, and validated by qRT-PCR and western blot. RESULTS: PYCR1 levels were significantly up-regulated in HCC tumor tissues than adjacent normal liver tissues in both protein and mRNA levels (P < 0.01). In vitro, the cell proliferation was significantly slower in shPYCR1 group than shCtrl group in BEL-7404 and SMMC-7721 cells (P < 0.001). The colony number was significantly smaller after PYCR1 interference (P < 0.01). The percentage of apoptosis cells significantly increased in shPYCR1 group (P < 0.01). In vivo, PYCR1 interference could obviously suppress tumor growth in xenograft nude mice. The volume and weight of tumors were significantly smaller via PYCR1 interference. The c-Jun N-terminal kinase (JNK) signaling pathway significantly altered, and insulin receptor substrate 1 (IRS1) were significantly down-regulated by PYCR1 interference in both mRNA and protein levels (P < 0.001). CONCLUSION: PYCR1 interference could inhibit cell proliferation and promote cell apoptosis in HCC through regluting JNK/IRS1 pathway. Our study will provide a drug target for HCC therapy and a potential biomarker for its diagnosis or prognosis.

Folate intake, serum folate levels, and prostate cancer risk: a meta-analysis of prospective studies.

BACKGROUND: Studies have reported inconsistent results concerning the existence of associations of folate intake and serum folate levels with prostate cancer risk. This study sought to summarise the evidence regarding these relationships using a dose-response meta-analysis approach. METHODS: In January 2014, we performed electronic searches of PubMed, Embase, and the Cochrane Library to identify studies examining the effect of folate on the incidence of prostate cancer. Only prospective studies that reported effect estimates with 95% confidence intervals (CIs) of the incidence of prostate cancer for more than 2 categories of folate were included. RESULTS: Overall, we included 10 prospective studies reporting data on 202,517 individuals. High dietary folate intake had little or no effect on prostate cancer risk (risk ratio [RR] = 1.02; 95% CI = 0.95-1.09; P = 0.598). The dose-response meta-analysis suggested that a 100 µg per day increase in dietary folate intake has no significant effect on the risk of prostate cancer (RR = 1.01; 95% CI = 0.99-1.02; P = 0.433). However, high serum folate levels were associated with an increased risk of prostate cancer (RR = 1.21; 95% CI = 1.05-1.39; P = 0.008). The dose-response meta-analysis indicated that a 5 nmol/L increment of serum folate levels was also associated with an increased risk of prostate cancer (RR = 1.04; 95% CI = 1.00-1.07; P = 0.042). CONCLUSIONS: Our study indicated that dietary folate intake had little or no effect on prostate cancer risk. However, increased serum folate levels have potentially harmful effects on the risk of prostate cancer.

The effect of body weight-supported Tai Chi Yunshou on upper limb motor function in stroke survivors based on neurobiomechanical analysis: a four-arm, parallel-group, assessors-blind randomized controlled trial protocol.

Introduction: A series of functional disorders commonly occur after stroke, of which upper limb dysfunction is the most difficult to recover. The upper limb rehabilitation effect of Tai Chi Yunshou(TCY) in the later stage of stroke has been confirmed by research. Body weight support-Tai Chi Yunshou (BWS-TCY) is based on TCY exercise and robotic exoskeletons offers most flexibility in deweighting and control strategy. This study is aimed to explore the effect of BWS-TCY on upper limb motor function in stroke based on neurobiomechanics. Methods and analysis: A single-blind randomized controlled trial will be conducted on 36 stroke survivors who will be randomly assigned to three groups: experimental group, control group A and control group B. In addition, 12 healthy elderly people will be recruited into the healthy control group. Those in the experimental group will receive 20 min of CRT and 20 min of BWS-TCY training, while participants in the control group A will receive 20 min of CRT and 20 min of Robot-assisted training. Participants in the control group B will undergo 40 min of Conventional rehabilitation training (CRT) daily. All interventions will take place 5 days a week for 12 weeks, with a 12-week follow-up period. No intervention will be carried out for the healthy control group. Upper limb function will be assessed before and after the intervention using various rating scales (Fugl-Meyer Assessment, Wolf Motor Function Test, etc.), as well as neurobiomechanical analyses (surface electromyography, functional near-infrared brain function analysis system, and Xsens maneuver Capture System). Additionally, 10 healthy elderly individuals will be recruited for neurobiomechanical analysis, and the results will be compared with those of stroke survivors. Discussion: The results of this study will offer initial evidence on the effectiveness and feasibility of BWS-TCY as an early intervention for stroke rehabilitation. Positive findings from this study could contribute to the development of guidelines for the use of BWS-TCY in the early stages of stroke. Ethics and dissemination: This study has been approved by the Research Ethics Committees of the seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (Study ID: 2022-7th-HIRB-022). The results of the study will be published in a peer-reviewed journal and presented at scientific conferences. Clinical trial registration: https://clinicaltrials.gov/, ChiCTR 2200063150.

Structure of human GPR119-Gs complex binding APD597 and characterization of GPR119 binding agonists.

The rhodopsin-like receptor GPR119 plays a crucial role in glucose homeostasis and is an emerging target for the treatment of type 2 diabetes mellitus. In this study, we analyzed the structure of GPR119 with the agonist APD597 bound and in complex with the downstream G protein trimer by single particle cryo-electron microscopy (cryo-EM). Structural comparison in combination with function assay revealed the conservative and specific effects of different kinds of GPR119 agonists. The activation mechanism of GPR119 was analyzed by comparing the conformational changes between the inactive and active states. The interaction between APD597 derivatives and synthetic agonists with GPR119 was analyzed by molecular docking technique, and the necessary structural framework was obtained. The above conclusions can provide structural and theoretical basis for the development of therapeutic drugs for type 2 diabetes mellitus.

Association of interleukin-6 with sarcopenia and its components in older adults: a systematic review and meta-analysis of cross-sectional studies.

BACKGROUND: Observational studies have documented increased serum IL-6 levels in elderly individuals afflicted with sarcopenia. Nevertheless, the relationship between serum IL-6 concentrations and sarcopenia prevalence in the aging population is yet to be defined. METHODS: We executed a systematic review and meta-analysis of cross-sectional studies that scrutinized serum IL-6 levels in older adults with and without sarcopenia. Relevant studies were sourced from PubMed, Scopus, Embase, Cochrane Library, and Web of Science from inception until 10 September 2023. The standard mean differences (SMDs) in serum IL-6 levels between studies were synthesized using a random-effects model. To examine the influence of demographic and clinical factors on these outcomes, we performed subgroup analyses and meta-regression, focusing on variables such as sex, age, and body mass index (BMI). We also assessed the relationship between serum IL-6 levels and the defining components of sarcopenia: muscle mass, muscle strength, and physical performance. We used Fisher's Z transformation to standardize the interpretation of effect sizes from these relationships. The transformed values were then converted to summary correlation coefficients (r) for a clear and unified summary of the results. RESULTS: We included twenty-one cross-sectional studies involving 3,902 participants. Meta-analysis revealed significantly elevated serum IL-6 levels in older adults with sarcopenia compared with those without sarcopenia (SMD = 0.31; 95% CI 0.18, 0.44). The difference was highly pronounced in the subgroups of male and those with female percentage below 50% or a mean BMI below 24 kg/m2. Serum IL-6 levels were inversely correlated with muscle mass (summary r = -0.18; 95% CI -0.30, -0.06), but not with handgrip strength (summary r = -0.10; 95%CI: -0.25, 0.05) or gait speed (summary r = -0.09; 95%CI: -0.24, 0.07). CONCLUSIONS: This meta-analysis establishes a link between increased serum IL-6 levels and sarcopenia in the elderly, particularly in relation to decreased muscle mass.

Several studies have demonstrated elevated serum IL-6 levels in elderly individuals with sarcopenia, while the relationship between serum IL-6 levels and sarcopenia remains unclear.This is a systematic review and meta-analysis of 21 cross-sectional studies for the relationship between serum IL-6 levels and sarcopenia.Elevated serum IL-6 levels appear to be associated with sarcopenia in older adults, especially in relation to reduced muscle mass.

Comprehensive review on sexual dimorphism to improve scalp acupuncture in nervous system disease.

BACKGROUND: With the development of modern medicine, the Traditional Chinese Medicine (TCM) combined with western medicine began to be produced and applied. Scalp acupuncture (SA) as a Chinese medicine based on neurological theory, has a great advantage compared with TCM in the treatment of nervous system diseases. METHOD: In this paper, we analyze the physiological and pathological manifestations of sexual dimorphism (SD) to illustrate the necessity of SD treatment. In addition, we review the factors that can affect SD and analyze in physiological structure, function, and pathological neurons. Diseases (pathological basis, pathological manifestations, and incidence) and factors leading to gender differences, which to analyze the possibility of gender differences in SA. RESULT: Furthermore, we creatively a new insight of SD-SA and provide the complete SD treatment cases on the basis of the existing SA in different kinds of diseases including stroke, migraine, attention deficit hyperactivity disorder (ADHD), and depression. CONCLUSION: In summary, we believe that it is feasible to improve the clinical effectiveness of SA, which is able to promote the development of SA, and then provides an actionable evidence for the promotion of precision medicine in the future.

Efficacy of hip abductors exercise training combined with repetitive transcranial magnetic stimulation on knee osteoarthritis: A randomized controlled trial.

BACKGROUND: Knee osteoarthritis is a common degenerative joint disease where a single treatment method often fails to fully alleviate symptoms. Hence, finding effective non-invasive combined treatment approaches is particularly crucial. OBJECTIVE: The efficacy of treating knee osteoarthritis with hip abductors exercise training combined with repetitive transcranial magnetic stimulation was assessed through functional scales and objective evaluation methods. METHODS: In this four-week randomized clinical trial, 160 patients meeting inclusion criteria were randomly assigned 1:1 to group A to receive oral celecoxib and group B to receive a combination of hip abductors exercise training and repeated transcranial magnetic stimulation. The primary outcome was the western Ontario and McMaster universities osteoarthritis index. The secondary outcomes include Visual Analogue Scale, knee outcome survey activities of daily living scale, Active Range of Motion, and the Quadriceps Angle, the tibiofemoral angle, peak adductor moment, the integrated electromyography and root mean square of the surface electromyography of the lower extremity muscles. Paired sample t test was used for Within-Group comparison of outcome indicators, and independent sample t test was used for Between-Group comparison. RESULTS: Of the 160 randomly assigned patients, 150 completed the study. After 4 weeks, the WOMAC index decreased from 61 ± 10.83 to 40.55 ± 7.58 in the combined treatment group and from 60.97 ± 10.18 to 47.7 ± 10.13 in the celecoxib group. The effect of the combined treatment group was significantly higher than that in the celecoxib group (P< 0.001). In the combined treatment group, the score of knee joint daily living scale increased (P< 0.001), the active range of motion increased (P< 0.001), the quadriceps angle decreased (P< 0.001), the tibiofemoral angle increased (P< 0.001), and the peak adduction moment decreased (P< 0.001), integrated electromyography and root mean square increased (P< 0.001), and the effect was better than that of celecoxib group (P< 0.001). The visual analog scale score in celecoxib group was lower (P< 0.001) and knee outcome survey activities of daily living scale was higher (P< 0.001). The incidence of treatment-related adverse events was 10% in the celecoxib group and 2.5% in the combined treatment group, all of which were mild. CONCLUSIONS: Hip abductors exercise training combined with repetitive transcranial magnetic stimulation can enhance abduction muscle strength, improve mobility, reduce joint pain, and enhance quality of life. This combined approach shows superior clinical effectiveness compared to oral celecoxib.

Effect of Tai Chi Yunshou training on the balance and motor functions of stroke patients: a systematic review and meta-analysis of randomized controlled trials.

Background: There is insufficient evidence on the effect of Tai Chi Yunshou on improving balance and motor function in stroke survivors. Therefore, this systematic review and meta-analysis aimed to evaluate the effect of Tai Chi Yunshou on improving balance and motor function in stroke patients through a comprehensive literature search. Methods: English and Chinese databases were searched from inception to February 10, 2023, to collect randomized controlled trials (RCTs) investigating the effects of Tai Chi Yunshou on balance and motor function in stroke survivors. Two reviewers independently selected studies meeting eligibility criteria, extracted required data, and assessed the risk of bias using methods recommended by the Cochrane Reviewers' Handbook. Primary outcomes were balance function and motor function, while secondary outcomes included walking gait and activities of daily living. Review Manager software (version 5.4.1) was used for data analysis. Results: Among the 1,400 identified records, 12 eligible randomized controlled trials were finally included, with a total of 966 subjects. The results of the meta-analysis showed that the balance function of the experimental group and the control group was assessed using the Berg Balance Scale (MD = 4.87, p < 0.001, I2 = 90, 95% CI = 4.46-5.28). The motor function assessment of the experimental group and the control group used the Fugl-Meyer Motor Assessment (SMD = 1.11, p < 0.001, I2 = 94, 95% CI = 0.94-1.28) and Simple Test of Extremity Function (MD = 10.28, p < 0.001, I2 = 0, 95% CI = 7.89-12.68). Walking ability was measured using the Time-Up and Go Test (MD = -3.22, p < 0.001, I2 = 83, 95% CI = -3.71--2.73). Activities of daily living were measured using the Modified Bathel Index (MD = 4.61, p < 0.001, I2 = 81, 95% CI = 3.61-5.61). Conclusion: Initial evidence seems to show that Tai Chi Yunshou training can improve the balance and motor function of stroke survivors and further improve walking ability and daily living ability, and the rehabilitation effect may be better than that of conventional rehabilitation training. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=376969, identifier [CRD42022376969].

Structural Insight into the Mechanism of σ32-Mediated Transcription Initiation of Bacterial RNA Polymerase.

Bacterial RNA polymerases (RNAP) form distinct holoenzymes with different σ factors to initiate diverse gene expression programs. In this study, we report a cryo-EM structure at 2.49 Å of RNA polymerase transcription complex containing a temperature-sensitive bacterial σ factor, σ32 (σ32-RPo). The structure of σ32-RPo reveals key interactions essential for the assembly of E. coli σ32-RNAP holoenzyme and for promoter recognition and unwinding by σ32. Specifically, a weak interaction between σ32 and -35/-10 spacer is mediated by T128 and K130 in σ32. A histidine in σ32, rather than a tryptophan in σ70, acts as a wedge to separate the base pair at the upstream junction of the transcription bubble, highlighting the differential promoter-melting capability of different residue combinations. Structure superimposition revealed relatively different orientations between ßFTH and σ4 from other σ-engaged RNAPs and biochemical data suggest that a biased σ4-ßFTH configuration may be adopted to modulate binding affinity to promoter so as to orchestrate the recognition and regulation of different promoters. Collectively, these unique structural features advance our understanding of the mechanism of transcription initiation mediated by different σ factors.

Patients with advanced pancreatic and biliary cancer appear vulnerable to SARS-CoV-2 Omicron variant: An observational study during the COVID-19 outbreak in Shanghai.

Background: The COVID-19 pandemic has spread rapidly across the globe. Cancer patients have a higher risk of severe infections and associated mortality than the general population. However, the lethal effect of Omicron-variant affection on advanced pancreatic and biliary cancer patients is still not clear. Herein, we designed an observational study to shed light on the influence of the Omicron variant on this so-called "King of Cancer" and improve management of these patients with COVID-19 in the future. Methods: Omicron-infected patients with advanced pancreatic and biliary cancer were enrolled from 15 April to 31 May 2022. Four groups were set up in this study: Group 1, Omicron-infected cancer patients (N = 4); Group 2, non-infected cancer patients (N = 4); Group 3, infected non-cancer-afflicted subjects (N = 4); Group 4, non-infected non-cancer-afflicted subjects (N = 4). On Days 0, 7, and 14 after infection, the blood samples were collected dynamically from all subjects. The primary endpoints were disease severity and survival. Results: At the endpoint of this observational study, Patient Nos. 2, 3, and 4 died separately on Days 11, 25, and 13 after viral infection. All of them had advanced cancer, with a death rate of up to 75%. Group 1 presented an overall T-cell exhaustion status compared with other groups. Group 1 had obviously lower T-cell populations and higher B-cell percentages and CD4+T/CD8+T ratios (P <0.05). Time-course cytokine monitoring results showed that IL-1ß was significantly decreased in Group 1 (P <0.05) and generally kept at a low level without obvious fluctuation. IL-6 was markedly increased in infected cancer patients (P <0.01) but remained at a low level and had no apparent change during the whole infection process in non-cancer-afflicted subjects. Furthermore, several inflammatory parameter indexes indicated a tight association of Omicron infection with the disease course and prognosis of Omicron-infected cancer patients. Conclusions: Advanced pancreatic and biliary cancer patients with Omicron infection have severe symptoms and poor outcomes. More attention, protective measures, and routine healthcare services should be recommended to these vulnerable populations in clinical practice during the pandemic in the foreseeable future.

[Practice and exploration on clinical evaluations of hospital-made Chinese herbal formulas in the Pudong new area of Shanghai].

Chinese herbal formulas can well present the characteristics of traditional Chinese medicine (TCM) with their simple, convenient, inexpensive and effective uses. However, due to the high cost of production, manufacturing pharmacies inside the hospital closed down one after another, which rendered the difficult situation of developing preparation of Chinese herbal formulas. The Pudong New Area of Shanghai, as a pilot region for comprehensive reforms on national development of TCM, vigorously explores the standardized research on and application of hospital-made Chinese herbal formulas. The Health Bureau of the Pudong New Area, based on the Shuguang Hospital, has established a clinical evaluation center for hospital-made Chinese herbal formulas. Through screening, manufacturing, quality control, unified allocation, and standardized clinical evaluation, the clinical evaluation center has summarized its experience on these processes.

microRNA-605 promotes cell proliferation, migration and invasion in non-small cell lung cancer by directly targeting LATS2.

[This retracts the article DOI: 10.3892/etm.2017.4538.].

MicroRNA-495 suppresses cell proliferation and invasion of hepatocellular carcinoma by directly targeting insulin-like growth factor receptor-1.

[This retracts the article DOI: 10.3892/etm.2017.5467.].

Activation and signaling mechanism revealed by GPR119-Gs complex structures.

Agonists selectively targeting cannabinoid receptor-like G-protein-coupled receptor (GPCR) GPR119 hold promise for treating metabolic disorders while avoiding unwanted side effects. Here we present the cryo-electron microscopy (cryo-EM) structures of the human GPR119-Gs signaling complexes bound to AR231453 and MBX-2982, two representative agonists reported for GPR119. The structures reveal a one-amino acid shift of the conserved proline residue of TM5 that forms an outward bulge, opening up a hydrophobic cavity between TM4 and TM5 at the middle of the membrane for its endogenous ligands-monounsaturated lipid metabolites. In addition, we observed a salt bridge between ICL1 of GPR119 and Gßs. Disruption of the salt bridge eliminates the cAMP production of GPR119, indicating an important role of Gßs in GPR119-mediated signaling. Our structures, together with mutagenesis studies, illustrate the conserved binding mode of the chemically different agonists, and provide insights into the conformational changes in receptor activation and G protein coupling.

Generalized atmospheric turbulence MTF for wave propagating through non-Kolmogorov turbulence.

A generalized exponential spectrum model is derived, which considers finite turbulence inner and outer scales and has a general spectral power law value between the range 3 to 5 instead of standard power law value 11/3. Based on this generalized spectrum model, a new generalized long exposure turbulence modulation transfer function (MTF) is obtained for optical plane and spherical wave propagating through horizontal path in weak fluctuation turbulence. When the inner scale and outer scale are set to zero and infinite, respectively, the new generalized MTF is reduced to the classical generalized MTF derived from the non-Kolmogorov spectrum.

P4HB modulates epithelial-mesenchymal transition and the ß-catenin/Snail pathway influencing chemoresistance in liver cancer cells.

The aim of the present study was to investigate the role of prolyl 4-hydroxylase beta polypeptide (P4HB) in the chemoresistance of liver cancer. Drug-resistant liver cancer cell lines, such as HepG2/adriamycin (ADR) cells, were treated and screened using adriamycin. Gene interference was used to silence the expression of P4HB in liver cancer cells. Cell viability, invasiveness and migration were assessed using CCK8, Transwell and wound healing assays, respectively. In addition, changes to key genes and proteins in the epithelial-mesenchymal transition (EMT) and ß-catenin/Snail pathway were analyzed using reverse transcription-quantitative PCR and western blotting. Drug-resistant HepG2/ADR cells were successfully cultivated; the IC50 to ADR for HepG2/ADR and HepG2 cell lines was 4.85 and 0.61 µM, respectively. HepG2/ADR cells exhibited higher invasion and migration abilities compared with HepG2 cells (P<0.05). E-cadherin mRNA and protein expression levels in HepG2/ADR cells were decreased significantly, whereas P4HB, N-cadherin and vimentin mRNA and protein levels were significantly increased compared with HepG2 cells (all P<0.05). Knockdown of P4HB significantly decreased cell viability and the invasion and migration ability of HepG2/ADR cells. In addition, P4HB knockdown enhanced E-cadherin mRNA and protein expression levels, whereas N-cadherin, vimentin, total ß-catenin, nuclear ß-catenin and Snail mRNA and protein levels were significantly decreased (all P<0.05). Overall, the present study demonstrated that EMT and ß-catenin/Snail pathway influence P4HB modulation in liver cancer chemoresistance.

BDNF Met allele Is Associated With Lower Cognitive Function in Poststroke Rehabilitation.

Background and purpose. The identification of a genetic role for cognitive outcome could influence the design of individualized treatment in poststroke rehabilitation. The aim of this study is to determine whether brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is independently associated with poststroke functional outcome. Methods. A total of 775 stroke patients with genomic data were identified from the Partners HealthCare Biobank, which contains a large number of genotypes from Biobank's consented patients. Of 775 stroke patients who met the inclusion/exclusion criteria, 86 were enrolled. Functional outcomes were assessed using the Functional Independence Measure scores at the time of admission and discharge. Logistic and linear regression models adjusted for covariate variables, including age, sex, and medical conditions, were used to evaluate the association between BDNF Val66Met and functional outcome. Results. We detected a significant correlation between Met alleles and lower cognitive function at discharge in both ischemic and hemorrhagic stroke patients. Genotyping findings confirmed that BDNF Met allele frequency was higher in contrast to Val/Val allele frequency in lower cognitive functional recovery. Furthermore, after adjusting for covariate variables, BDNF Met alleles were found to be associated with lower cognitive outcome [P = .003; odds ratio (OR) = 5.95 (1.81-19.52)] and recovery [P = .006; OR = 3.16 (1.4-7.15)], especially with lower problem solving, expression, and social recovery in all stroke patients. Conclusions. Met allele carriers exhibited impaired poststroke cognitive function. The BDNF genotype may be a useful predictor of cognitive function in inpatient poststroke rehabilitation.

P4HB knockdown induces human HT29 colon cancer cell apoptosis through the generation of reactive oxygen species and inactivation of STAT3 signaling.

Colon cancer is the second most lethal malignancy worldwide. A better understanding of colon cancer at the molecular level may increase overall survival rates. Previous studies have indicated that prolyl 4­hydroxylase, ß polypeptide (P4HB) is associated with tumorigenesis in colon cancer; however, its role and molecular mechanisms in colon cancer remain unclear. In the present study, the cellular responses to P4HB in human colon cancer cell lines were investigated by proliferation and apoptosis assays, western blotting, and immunohistochemistry. The results showed that expression of P4HB was higher in colon cancer tissues compared within adjacent normal tissues. P4HB knockdown increased the apoptosis of human HT29 cells. Furthermore, P4HB knockdown reduced the activation of signal transducer and activator of transcription 3 (STAT3) and promoted accumulation of reactive oxygen species (ROS). Inhibiting the accumulation of ROS abrogated the increased cell apoptosis induced by P4HB knockdown. Notably, decreased ROS levels effectively antagonized the effects of P4HB on STAT3 inactivation. In conclusion, these findings suggested that P4HB knockdown may induce HT29 human colon cancer cell apoptosis through the generation of ROS and inactivation of the STAT3 signaling pathway.