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Abstract Background Regular physical activity has been shown to ameliorate cognitive decline associated with aging, and to improve autonomic nervous function. However, the effect of active housework, a form of light to moderate physical activity, on postoperative cognitive function in the elderly remain unknown. The aim of this study is to investigate whether active housework exerts a protective effect against delayed neurocognitive recovery (dNCR), and to explore the role of vagal activity in this relationship. Methods This is a prospective nested case-control study that enrolled 152 elderly patients scheduled for elective knee replacement surgery. The neuropsychological assessments were conducted to evaluate dNCR both preoperatively and one week postoperatively. Physical activity levels were quantified based on the Physical Activity Scale for the Elderly and categorized into active housework and sedentary behavior groups using hierarchical clustering. High-frequency spectral analysis of heart rate variability was used to assess vagal activity. Multivariable logistic regression analysis was employed to examine the association between active housework, vagal activity, and dNCR. Additionally, mediation analysis was performed to explore the possible mediating effect of vagal activity. Results dNCR occurred in 33/141 (23.4%) patients. Active housework was associated with 84.7% lower odds of developing dNCR [OR = 0.153, 95% CI (0.042 to 0.550), p = 0.004]. There was significant interaction between vagal activity and dNCR [OR = 0.003, 95% CI (0.001 to 0.052), p

Abstract Background Osteoarthritis (OA) is a common degenerative joint disease that significantly impacts the quality of life, especially among older adults. Testosterone, a critical hormone for musculoskeletal health, has been suggested to influence OA pathogenesis. However, the relationship between low testosterone levels and OA risk remains underexplored in large, representative populations. This study aimed to investigate the association between low testosterone levels and OA risk using data from the National Health and Nutrition Examination Survey (NHANES, 2011–2016). Methods This cross-sectional analysis included 4,548 participants from NHANES, a nationally representative U.S. dataset. Testosterone levels were categorized as low or normal, with low testosterone defined as

Abstract Background Diabetic kidney disease (DKD) is a complication caused by end-stage diabetes mellitus and usually results in glomerular podocyte injury. Exosomes are important for intercellular information exchange. However, the effect of podocyte exosomes on DKD has not been elucidated. Methods GEO, PROMO, and GSE1009 databases were used to identify the gene APOC1 and transcription factor HOXD9. qRT-PCR, western blot, and transmission electron microscopy (TEM) were investigated to confirm APOC1 change in high glucose-treated podocytes and exosomes. Flow cytometry, immunofluorescence, qPCR, immunoblotting, wound healing, Transwell invasion assays, dual luciferase assay, and ChIP-PCR assay were performed to detect the effect of APOC1 and HOXD9 on macrophage polarization in high glucose-treated podocytes and exosomes. qRT-PCR and immunoblotting assays were employed to assess the impact of APOC1 knockdown on the M1 polarization of macrophages in response to liraglutide treatment. Results The results suggested that the expression of APOC1 in human podocytes (HPC) and exosomes was elevated. High glucose-treated HPC exosomes promoted macrophage M1-type polarization, which was reversed by adding sh-APOC1. Afterward, HOXD9 was identified as a potential transcription factor for APOC1. Knockdown of HOXD9 led to macrophage M2 polarization, and overexpression of APOC1 polarized macrophage M1. In addition, enhanced p65 phosphorylation verified that HOXD9/APOC1 induced macrophage M1-type polarization by activating the NF-κB signaling pathway. Knocking down APOC1 enhanced the inhibitory effect of liraglutide on macrophage M1 polarization. Conclusion Our findings highlighted that HOXD9/APOC1 was a key player in causing podocyte injury in diabetic kidney disease and led to macrophage M1 polarization through the NF-κB signaling pathway.

Abstract Background Advance care planning (ACP) is pivotal in mitigating end-of-life suffering and ensuring healthcare congruence with the values of older adults and dignity in death. Despite its paramount importance, the current readiness for ACP among community-dwelling older adults and the intricate influencing factors have yet to be explored. Objective To review the literature focusing on ACP readiness among community-dwelling older adults and the influencing factors. Methods A scoping review conducted using the Arksey and O’Malley (2005) framework. Electronic databases (PubMed, CINAHL, Cochrane, Web of Science, PsycINFO), as well as grey literature databases (OpenGrey and GreyLit.org) were searched to identify studies published in English between January 2012 and March 2023. Results 19 studies were selected, comprising 3 qualitative, 13 quantitative, 2 mixed-methods, and 1 review article. The study evaluated the readiness of older adults for ACP by examining their knowledge and attitudes. It categorizes influencing factors into intrinsic and extrinsic levels. This review revealed that the knowledge about ACP among older adults across all settings was limited. However, they had positive attitudes toward it. In addition, intrinsic factors including sociodemographic characteristics, psychological factors, and family relationships, along with extrinsic factors including health care professionals’ attitudes and experience, as well as policies and laws, influenced the ACP readiness among older adults. Conclusions This study established the groundwork for future ACP intervention trials, providing a theoretical framework to guide their design and implementation. operationalization.

Abstract Background Thoracotomy is considered one of the most painful surgical procedures and can cause debilitating chronic post-surgical pain lasting months or years postoperatively. Aggressive management of acute pain resulting from thoracotomy may reduce the likelihood of developing chronic pain. This trial compares the two most commonly used modes of acute analgesia provision at the time of thoracotomy (thoracic epidural blockade (TEB) and paravertebral blockade (PVB)) in terms of their clinical and cost-effectiveness in preventing chronic post-thoracotomy pain. Methods TOPIC 2 is a multi-centre, open-label, parallel group, superiority, randomised controlled trial, with an internal pilot investigating the use of TEB and PVB in 1026 adult (≥ 18 years old) patients undergoing thoracotomy in up to 20 thoracic centres throughout the UK. Patients (N = 1026) will be randomised in a 1:1 ratio to receive either TEB or PVB. During the first year, the trial will include an integrated QuinteT (Qualitative Research Integrated into Trials) Recruitment Intervention (QRI) with the aim of optimising recruitment and informed consent. The primary outcome is the incidence of chronic post-surgical pain at 6 months post-randomisation defined as ‘worst chest pain over the last week’ equating to a visual analogue score greater than or equal to 40 mm indicating at least a moderate level of pain. Secondary outcomes include acute pain, complications of regional analgesia and surgery, health-related quality of life, mortality and a health economic analysis. Discussion Both TEB and PVB have been demonstrated to be effective in the prevention of acute pain following thoracotomy and nationally practice is divided. Identification of which mode of analgesia is both clinically and cost-effective in preventing chronic post-thoracotomy pain could ameliorate the debilitating effects of chronic pain, improving health-related quality of life, facilitating return to work and caring responsibilities and resulting in a cost saving to the NHS. Trial registration NCT03677856 [ClinicalTrials.gov] registered September 19, 2018. https://clinicaltrials.gov/ct2/show/NCT03677856 . First patient recruited 8 January 2019.

Abstract Background Infertility affects approximately 10–15% of reproductive-age men worldwide, and genetic causes play a role in one-third of cases. As a Bin-Amphiphysin-Rvs (BAR) domain protein, protein interacting with C-kinase 1 (PICK1) deficiency could lead to impairment of acrosome maturation. However, its effects on auxiliary germ cells such as Sertoli cells are unknown. Purpose The present work was aimed to use multi-omics analysis to research the effects of PICK1 deficiency on Sertoli cells and to identify effective biomarkers to distinguish fertile males from infertile males caused by PICK1 deficiency. Methods Whole-exome sequencing (WES) was performed on 20 infertility patients with oligozoospermia to identify pathogenic PICK1 mutations. Multi-omics analysis of a PICK1 knockout (KO) mouse model was utilized to identify pathogenic mechanism. Animal and cell function experiments of Sertoli cell-specific PICK1 KO mouse were performed to verify the functional impairment of Sertoli cells. Results Two loss-of-function deletion mutations c.358delA and c.364delA in PICK1 resulting in transcription loss of BAR functional domain were identified in infertility patients with a specific decrease in serum inhibin B, indicating functional impairment of Sertoli cells. Multi-omics analysis of PICK1 KO mouse illustrated that targeted genes of differentially expressed microRNAs and mRNAs are significantly enriched in the negative regulatory role in the vesicle trafficking pathway, while metabolomics analysis showed that the metabolism of amino acids, lipids, cofactors, vitamins, and endocrine factors changed. The phenotype of PICK1 KO mouse showed a reduction in testis volume, a decreased number of mature spermatozoa and impaired secretory function of Sertoli cells. In vitro experiments confirmed that the expression of growth factors secreted by Sertoli cells in PICK1 conditional KO mouse such as Bone morphogenetic protein 4 (BMP4) and Fibroblast growth factor 2 (FGF2) were decreased. Conclusions Our study attributed male infertility caused by PICK1 deficiency to impaired vesicle-related secretory function of Sertoli cells and identified a variety of significant candidate biomarkers for male infertility induced by PICK1 deficiency.

Abstract Background A cost-effective pretreatment and saccharification process is a necessary prerequisite for utilizing lignocellulosic biomass (LCB) in biofuel and biomaterials production. Utilizing a multifunctional enzyme with both pretreatment and saccharification functions in a single step for simultaneous biological pretreatment and saccharification process (SPS) will be a green method of low cost and high efficiency. Manganese peroxidase (MnP, EC 1.11.1.13), a well-known lignin-degrading peroxidase, is generally preferred for the biological pretreatment of biomass. However, exploring the role and performance of MnP in LCB conversion will promote the application of MnP for lignocellulose-based biorefineries. Results In this study, we explored the ability of an MnP from Moniliophthora roreri, MrMnP, in LCB degradation. With Mn2+ and H2O2, MrMnP decomposed 5.0 g/L carboxymethyl cellulose to 0.14 mM of reducing sugar with a conversion yield of 5.0 mg/g, including 40 μM cellobiose, 70 μM cellotriose, 20 μM cellotetraose, and 10 μM cellohexaose, and degraded 1.0 g/L mannohexaose to 0.33 μM mannose, 4.08 μM mannotriose, and 4.35 μM mannopentaose. Meanwhile, MrMnP decomposed 5.0 g/L lichenan to 0.85 mM of reducing sugar with a conversion yield of 30.6 mg/g, including 10 μM cellotriose, 20 μM cellotetraose, and 80 μM cellohexose independently of Mn2+ and H2O2. Moreover, the versatility of MrMnP in LCB deconstruction was further verified by decomposing locust bean gum and wheat bran into reducing sugars with a conversion yield of 54.4 mg/g and 29.5 mg/g, respectively, including oligosaccharides such as di- and tri-saccharides. The catalytic mechanism underlying MrMnP degraded lignocellulose was proposed as that with H2O2, MrMnP oxidizes Mn2+ to Mn3+. Subsequently, it forms a complex with malonate, facilitating the degradation of CMC and mannohexaose into reducing sugars. Without H2O2, MrMnP directly oxidizes malonate to hydroperoxyl acetic acid radical to form compound I, which then attacks the glucosidic bond of lichenan. Conclusion This study identified a new function of MrMnP in the hydrolysis of cellulose and hemicellulose, suggesting that MrMnP exhibits its versatility in the pretreatment and saccharification of LCB. The results will lead to an in-depth understanding of biocatalytic saccharification and contribute to forming new enzymatic systems for using lignocellulose resources to produce sustainable and economically viable products and the long-term development of biorefinery, thereby increasing the productivity of LCB as a green resource.

Abstract Objectives To explore the impact of visceral obesity (VO) measured by preoperative abdominal computed tomography (CT) on postoperative infectious complications for colorectal cancer (CRC) patients and establish a predictive model. Methods Patients who underwent resection for colorectal cancer between January 2015 and January 2021 were enrolled in this study. All patients were measured for body mass index (BMI) and visceral fat area (VFA) preoperatively. Infectious complications were compared between the different groups according to BMI and VO categories. Univariate and multivariate logistic regression were used to analyze whether VO was an independent risk factor for postoperative infectious complications. According to the results of logistic regression, six machine learning approaches were used to establish predictive models and perform internal validation. The best-performing model was interpreted by the SHAPley Additive exPlanations value. Results Approximately 64.81% of 520 patients had VO. VO was significantly connected with postoperative infectious complications (P

Abstract Background Acute lung injury (ALI) is a common and serious complication of sepsis with high mortality. Ferroptosis, categorized as programmed cell death, contributes to the development of lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is an endogenous lipid mediator that exerts protective effects against multiorgan injury. However, the role of PCTR1 in the ferroptosis of sepsis-related ALI remains unknown. Methods A pulmonary epithelial cell line and a mouse model of ALI stimulated with lipopolysaccharide (LPS) were established in vitro and in vivo. Ferroptosis biomarkers, including ferrous (Fe2+), glutathione (GSH), malondialdehyde (MDA) and 4-Hydroxynonenal (4-HNE), were assessed by relevant assay kits. Glutathione peroxidase 4 (GPX4) and prostaglandin-endoperoxide synthase 2 (PTGS2) protein levels were determined by western blotting. Lipid peroxides were examined by fluorescence microscopy and flow cytometry. Cell viability was determined by a CCK-8 assay kit. The ultrastructure of mitochondria was observed with transmission electron microscopy. Morphology and inflammatory cytokine levels predicted the severity of lung injury. Afterward, related inhibitors were used to explore the potential mechanism by which PCTR1 regulates ferroptosis. Results PCTR1 treatment protected mice from LPS-induced lung injury, which was consistent with the effect of the ferroptosis inhibitor ferrostatin-1. PCTR1 treatment decreased Fe2+, PTGS2 and lipid reactive oxygen species (ROS) contents, increased GSH and GPX4 levels and ameliorated mitochondrial ultrastructural injury. Administration of LPS or the ferroptosis agonist RSL3 resulted in reduced cell viability, which was rescued by PCTR1. Mechanistically, inhibition of the PCTR1 receptor lipoxin A4 (ALX), protein kinase A (PKA) and transcription factor cAMP-response element binding protein (CREB) partly decreased PCTR1 upregulated GPX4 expression and a CREB inhibitor blocked the effects ofPCTR1 on ferroptosis inhibition and lung protection. Conclusion This study suggests that PCTR1 suppresses LPS-induced ferroptosis via the ALX/PKA/CREB signaling pathway, which may offer promising therapeutic prospects in sepsis-related ALI.

Abstract Background Exosomes have emerged as vital biomarkers of multiple cancers and contain abundant circular RNAs (circRNAs). However, the potential for exosomal circRNAs to be used in diagnostics and their molecular mechanism of action in colorectal cancer (CRC) remain unclear. Methods CRC-specific exosomal circRNAs were identified by RNA sequencing, exoRBase database and a tissue microarray. The diagnostic performance of plasma exosomal circRNAs was evaluated among cancer-free controls, precancer individuals, CRC patients, and patients with other types of cancer. The corresponding biological functions were mainly assessed using circRNA pull-down, proteomic analysis, and RNA immunoprecipitation assay underlying cellular and mouse models. Results CircLPAR1 was encapsulated in exosomes with high stability and detectability, and its expression in plasma exosomes was remarkably decreased during CRC development but recovered after surgery. Exosomal circLPAR1 showed cancer specificity in CRC diagnosis and increased the diagnostic performance to an area under the receiver operating characteristic curve of 0.875, as determined by analysing its performance in combination with common clinical biomarkers CEA and CA19–9. Additionally, circLPAR1 was downregulated in CRC tissues and was associated with overall survival. Mechanistically, exosomal circLPAR1 was internalized by CRC cells, and it suppressed tumor growth, likely because exosomal circLPAR1 directly bound with eIF3h specifically suppressed the METTL3-eIF3h interaction, decreasing the translation of oncogene BRD4. Conclusions This comprehensive study highlights plasma exosomal circLPAR1 as a promising predictor in CRC diagnosis and describes its biological regulation of colorectal tumorigenesis. This study provides a new perspective on early diagnosis in the clinic and pathogenesis in disease development.

Abstract Background Although randomized controlled trials (RCTs) have suggested a non-significant increased risk of stroke among proton pump inhibitor (PPI) users, the association has not been confirmed. We evaluated the association between regular use of PPIs and incident stroke and identified population groups at high net risk. Methods This is a prospective analysis of 492,479 participants free of stroke from the UK biobank. Incident stroke was identified through linkage to hospital admission and death registries using the International Classification of Diseases (ICD)-10 codes (I60, I61, I63, and I64). We evaluated hazard ratios (HRs) adjusting for demographic factors, lifestyle habits, prevalent comorbidities, concomitant use of medications, and indications of PPIs. We assessed the risk differences (RDs) according to the baseline Framingham Stroke Risk Score. In the meta-analysis, we searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (from 1988 to 1 June 2020) for randomized trials comparing PPIs with other interventions, placebo, or no treatment on stroke risk. Results were combined using a fix-effect meta-analysis (Mantel-Haenszel method). Results We documented 5182 incident strokes over 3,935,030 person-years of follow-up. Regular PPI users had a 16% higher risk of stroke than non-users (HR 1.16, 95% CI 1.06 to 1.27). The estimated effect was similar to our meta-analysis of nine RCTs (case/participants 371/26,642; RR 1.22, 95% CI 1.00 to 1.50; quality of evidence: moderate). The absolute effect of PPI use on stroke increased with the baseline Framingham Stroke Risk Score, with an RD of 1.34‰, 3.32‰, 4.83‰, and 6.28‰ over 5 years for the lowest, quartile 2, quartile 3, and the highest quartile, respectively. Conclusions Regular use of PPIs was associated with an increased risk of stroke, with a higher absolute risk observed in individuals with high baseline stroke risk. Physicians should therefore exercise caution when prescribing PPIs. An assessment of the underlying stoke risk is recommended for individualized use of PPIs.

Abstract Long noncoding RNAs (lncRNAs), are transcripts longer than 200 nucleotides that are considered to be vital regulators of many cellular processes, particularly in tumorigenesis and cancer progression. long intergenic non-protein coding RNA 261 (LINC00261), a recently discovered lncRNA, is abnormally expressed in a variety of human malignancies, including pancreatic cancer, gastric cancer, colorectal cancer, lung cancer, hepatocellular carcinoma, breast cancer, laryngeal carcinoma, endometrial carcinoma, esophageal cancer, prostate cancer, choriocarcinoma, and cholangiocarcinoma. LINC00261 mainly functions as a tumor suppressor that regulates a variety of biological processes in the above-mentioned cancers, such as cell proliferation, apoptosis, motility, chemoresistance, and tumorigenesis. In addition, the up-regulation of LINC00261 is closely correlated with both favorable prognoses and many clinical characteristics. In the present review, we summarize recent research documenting the expression and biological mechanisms of LINC00261 in tumor development. These findings suggest that LINC00261, as a tumor suppressor, has bright prospects both as a biomarker and a therapeutic target.

Abstract Background Treatment of hepatocellular carcinoma (HCC) using antibody-based targeted therapies, such as antibody conjugates and chimeric antigen receptor T (CAR-T) cell therapy, shows potent antitumor efficacy. Glypican-3 (GPC3) is an emerging HCC therapeutic target; therefore, antibodies against GPC3 would be useful tools for developing immunotherapies for HCC. Methods We isolated a novel human monoclonal antibody, 32A9, by phage display technology. We determined specificity, affinity, epitope and anti-tumor activity of 32A9, and developed 32A9-based immunotherapy technologies for evaluating the potency of HCC treatment in vitro or in vivo. Results 32A9 recognized human GPC3 with potent affinity and specificity. The epitope of 32A9 was located in the region of the GPC3 protein core close to the modification sites of the HS chain and outside of the Wnt-binding site of GPC3. The 32A9 antibody significantly inhibited HCC xenograft tumor growth in vivo. We then pursued two 32A9-based immunotherapeutic strategies by constructing an immunotoxin and CAR-T cells. The 32A9 immunotoxin exhibited specific cytotoxicity to GPC3-positive cancer cells, while 32A9 CAR-T cells efficiently eliminated GPC3-positive HCC cells in vitro and caused HCC xenograft tumor regressions in vivo. Conclusions Our study provides a rationale for 32A9 as a promising GPC3-specific antibody candidate for HCC immunotherapy.

Abstract 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

Abstract Background Acute respiratory distress syndrome (ARDS) is characterized by alveolar epithelial disruption. Lipoxins (LXs), as so-called “braking signals” of inflammation, are the first mediators identified to have dual anti-inflammatory and inflammatory pro-resolving properties. Methods In vivo, lipoxinA4 was administrated intraperitoneally with 1 μg/per mouse after intra-tracheal LPS administration (10 mg/kg). Apoptosis, proliferation and epithelial–mesenchymal transition of AT II cells were measured by immunofluorescence. In vitro, primary human alveolar type II cells were used to model the effects of lipoxin A4 upon proliferation, apoptosis and epithelial–mesenchymal transition. Results In vivo, lipoxin A4 markedly promoted alveolar epithelial type II cells (AT II cells) proliferation, inhibited AT II cells apoptosis, reduced cleaved caspase-3 expression and epithelial–mesenchymal transition, with the outcome of attenuated LPS-induced lung injury. In vitro, lipoxin A4 increased primary human alveolar epithelial type II cells (AT II cells) proliferation and reduced LPS induced AT II cells apoptosis. LipoxinA4 also inhibited epithelial mesenchymal transition in response to TGF-β1, which was lipoxin receptor dependent. In addition, Smad3 inhibitor (Sis3) and PI3K inhibitor (LY294002) treatment abolished the inhibitory effects of lipoxinA4 on the epithelial mesenchymal transition of primary human AT II cells. Lipoxin A4 significantly downregulated the expressions of p-AKT and p-Smad stimulated by TGF-β1 in primary human AT II cells. Conclusion LipoxinA4 attenuates lung injury via stimulating epithelial cell proliferation, reducing epithelial cell apoptosis and inhibits epithelial–mesenchymal transition.

Abstract Porcine circovirus type 2 (PCV2) is an economically important swine pathogen but some extra trigger factors are required for the development of PCV2-associated diseases. By evaluating cap protein expression, viral DNA copies and the number of infected cells, the present study further confirmed that oxidative stress can promote PCV2 replication. The results showed that oxidative stress induced autophagy in PCV2-infected PK15 cells. Blocking autophagy with inhibitor 3-methyladenine or ATG5-specific siRNA significantly inhibited oxidative stress-promoted PCV2 replication. Importantly, autophagy inhibition significantly increased apoptosis in oxidative stress-treated PK15 cells. Suppression of apoptosis by benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone in conditions of autophagy inhibition restored PCV2 replication. Taken together, autophagy protected host cells against potential apoptosis and then contributed to PCV2 replication promotion caused by oxidative stress. Our findings can partly explain the pathogenic mechanism of PCV2 related to the oxidative stress-induced autophagy.

Abstract Background Acute kidney injury (AKI) refers to a broad spectrum of kidney damage and is attributed a high morbidity and mortality rate at all degrees of severity. Obesity increases the risk for developing AKI. However, some studies have shown that obesity at onset of AKI is paradoxically associated with greater survival. The aim of this review is to explore the relationship between body mass index and survival in patients with AKI. Methods An electronic search will be conducted using MEDLINE, EMBASE, CINAHL and CENTRAL using predefined search strategies. The cited and citing references of selected key studies will also be searched for relevant articles. Risk of bias will be assessed using a modified Quality in Prognosis Studies (QUIPS) tool. The primary outcome will be an exploration of the association between BMI and mortality in patients presenting with AKI. Two authors will independently select, data extract, and risk of bias assess articles. Any discrepancies will be resolved by consensus or by consulting a third author. A narrative synthesis of the findings from the included studies will be presented. Meta-analyses will be conducted where the data is available from clinically and methodologically similar studies and in the same format. Heterogeneity in such analyses, beyond that expected by chance, will be quantified using the I 2 statistic. Sub-group analyses will be performed to determine the influence of gender, AKI duration, underlying aetiology, and intervening treatments, on pooled results. Discussion Body mass index may be an important modifiable risk factor for mortality in patients presenting with AKI. The proposed systematic review will help to elucidate the association between all categories of BMI and survival in this patient group. Systematic review registration PROSPERO CRD42017071124.

Abstract Background Calcineurin (CaN) having a high expression in hippocampal neurons is closely related to apoptosis. Pretreatment with nimodipine can lower the apoptosis rate of hippocampal neuron to reduce the incidence of postoperative cognitive dysfunction (POCD). However, the relationship between cerebral protective effect of pretreatment with nimodipine and CaN is controversial in the literature. The aim of this study is to evaluate the relationship between neuroprotective effect of nimodipine and CaN on POCD in aged rats. Methods Ninety-six 18-month-old male Sprague-Dawley rats were randomly assigned into 4 groups (n = 24 each): control group (Group C), nimodipine group (Group N), surgery group (Group S) and nimodipine + surgery group (Group N + S). In Group N and Group N + S, nimodipine 1 mg/kg was intraperitoneally injected, while the equal volume of normal saline was given instead in Group S. 30 min later, Group N and Group C inhaled pure oxygen for 2 h, and Group S and N + S inhaled 3% sevoflurane for 2 h when exploratory laparotomy was performed. Morris water maze test was performed on 1 day before operation and 1, 3 and 7 days after operation. After the end of Morris water maze test at 1 day before operation and 1 and 7 days after operation, 8 rats were sacrificed, brains were removed and hippocampal tissues were obtained for detection of apoptosis in hippocampal neurons, cytoplasmic calcium ([Ca2+]i), and hippocampal CaN and caspase-3 expression. Results Compared with the 1st day before operation, the escape latency, apoptosis rate, [Ca2+]i, expression of CaN and caspase-3 increased significantly, but the frequency of crossing the original platform decreased dramatically in Group S and N + S(P

Abstract Background Sepsis is a common condition which kills between 36,000 and 64,000 people every year in the UK. Early recognition and management of sepsis has been shown to reduce mortality and improve the health and well-being of people with sepsis. Paramedics frequently come into contact with patients with sepsis and are well placed to provide early diagnosis and treatment. We aim to determine the feasibility of undertaking a fully powered randomised controlled trial (RCT) to test the clinical and cost-effectiveness of paramedics obtaining blood cultures from and administering IV antibiotics to patients with sepsis, so we can make a decision about whether to proceed to a fully powered randomised controlled trial, which will answer questions regarding safety and effectiveness for patients and benefit to the National Health Service (NHS). Methods/design This is an individually randomised, two-arm feasibility study for a randomised controlled trial with a 1:1 ratio. Sixty paramedics will receive training to assist them to recognise sepsis using a screening tool, obtain blood cultures, and provide IV antibiotics. If sepsis is suspected, paramedics will randomly allocate patients to intervention or usual care using their next sequential individually issued scratch card. Patients will be followed up at 90 days using linked anonymised data to capture length of hospital admission and mortality. We will also collect self-reported health-related quality of life (using SF-12) at this time. We will interview ten patients by telephone and hold a focus group with paramedics, to find out what they think about the intervention. Discussion At the end of this study, we will make a recommendation about whether a full randomised controlled trial of paramedics obtaining blood cultures and administering IV antibiotics for sepsis is warranted, and if so, we will develop a proposal for research funding in order to take the work forward. Trial registration ISRCTN, ISRCTN36856873

Abstract Porcine circovirus type 2 (PCV2) is recognized as the causative agent of porcine circovirus-associated diseases. PCV2 replication could be promoted by low doses of ochratoxin A (OTA) as in our previous study and selenium has been shown to attenuate PCV2 replication. However, the underlying mechanism remains unclear. The aim of the study was to investigate the effects of selenomethionine (SeMet), the major component of organic selenium, on OTA-induced PCV2 replication promotion and its potential mechanism. The present study demonstrates that OTA could promote PCV2 replication as measured by cap protein expression, viral titer, viral DNA copies and the number of infected cells. In addition, OTA could activate autophagy as indicated by up-regulated light chain 3 (LC3)-II and autophagy-related protein 5 expressions and autophagosome formation. Further, OTA could down-regulate p-AKT and p-mTOR expressions and OTA-induced autophagy was inhibited when insulin was applied. SeMet at 2, 4 and 6 μM had significant inhibiting effects against OTA-induced PCV2 replication promotion. Furthermore, SeMet could attenuate OTA-induced autophagy and up-regulate OTA-induced p-AKT and p-mTOR expression inhibition. Rapamycin, an inhibitor of AKT/mTOR, could reverse the effects of SeMet on OTA-induced autophagy and the PCV2 replication promotion. In conclusion, SeMet could block OTA-induced PCV2 replication promotion by inhibiting autophagy by activating the AKT/mTOR pathway. Therefore, SeMet supplementation could be an effective prophylactic strategy against PCV2 infections and autophagy may be a potential marker to develop novel anti-PCV2 drugs.

Abstract Background We have engaged in an international program designated the Bank On A Cure, which has established DNA banks from multiple cooperative and institutional clinical trials, and a platform for examining the association of genetic variations with disease risk and outcomes in multiple myeloma. We describe the development and content of a novel custom SNP panel that contains 3404 SNPs in 983 genes, representing cellular functions and pathways that may influence disease severity at diagnosis, toxicity, progression or other treatment outcomes. A systematic search of national databases was used to identify non-synonymous coding SNPs and SNPs within transcriptional regulatory regions. To explore SNP associations with PFS we compared SNP profiles of short term (less than 1 year, n = 70) versus long term progression-free survivors (greater than 3 years, n = 73) in two phase III clinical trials. Results Quality controls were established, demonstrating an accurate and robust screening panel for genetic variations, and some initial racial comparisons of allelic variation were done. A variety of analytical approaches, including machine learning tools for data mining and recursive partitioning analyses, demonstrated predictive value of the SNP panel in survival. While the entire SNP panel showed genotype predictive association with PFS, some SNP subsets were identified within drug response, cellular signaling and cell cycle genes. Conclusion A targeted gene approach was undertaken to develop an SNP panel that can test for associations with clinical outcomes in myeloma. The initial analysis provided some predictive power, demonstrating that genetic variations in the myeloma patient population may influence PFS.

Abstract Background Gene clustering plays an important role in the organization of the bacterial chromosome and several mechanisms have been proposed to explain its extent. However, the controversies raised about the validity of each of these mechanisms remind us that the cause of this gene organization remains an open question. Models proposed to explain clustering did not take into account the function of the gene products nor the likely presence or absence of a given gene in a genome. However, genomes harbor two very different categories of genes: those genes present in a majority of organisms – persistent genes – and those present in very few organisms – rare genes. Results We show that two classes of genes are significantly clustered in bacterial genomes: the highly persistent and the rare genes. The clustering of rare genes is readily explained by the selfish operon theory. Yet, genes persistently present in bacterial genomes are also clustered and we try to understand why. We propose a model accounting specifically for such clustering, and show that indispensability in a genome with frequent gene deletion and insertion leads to the transient clustering of these genes. The model describes how clusters are created via the gene flux that continuously introduces new genes while deleting others. We then test if known selective processes, such as co-transcription, physical interaction or functional neighborhood, account for the stabilization of these clusters. Conclusion We show that the strong selective pressure acting on the function of persistent genes, in a permanent state of flux of genes in bacterial genomes, maintaining their size fairly constant, that drives persistent genes clustering. A further selective stabilization process might contribute to maintaining the clustering.

Abstract Background The objective of this study was to evaluate the safety of twice daily, intra-vaginal use of 0.5% PRO 2000 Gel for fourteen days in HIV un-infected women at lower as well as higher risk for HIV acquisition, in Pune, India. Methods Forty-two eligible volunteers (30 low-risk and 12 high-risk) were given 0.5% PRO 2000 Gel for intra-vaginal application twice daily for 14 consecutive days. Results Twenty-four participants (57%, 95% CI 41%–72%) experienced at least one adverse event (AE) judged to be possibly related to the product use. There were 17 (40%, 95% CI 26%–57%) mild AEs and 7 (17%, 95% CI 7%–31%) moderate AEs. There were no serious adverse events and no AEs judged probably or definitely related to product use. Genitourinary discomfort was reported by 2/30 (6.67%) participants in the low-risk cohort as compared to 4/12 (33.3%) women in the high-risk cohort (p = 0.03). Intermenstrual bleeding was reported in 2/30 (6.7%, 95% CI 1.0–22.1) women from the low risk cohort and 3/12 (25%, 95% CI 5.5–57.2) women from the high-risk cohort. One participant showed mild elevation of blood gamma glutamyl transferase and two showed mild elevations in total bilirubin. None of the participants showed detectable PRO 2000 in their blood after 14 days of product use. Conclusion 0.5% PRO 2000 Gel appeared to be safe when used twice-daily by sexually active HIV-uninfected women from Pune, India. Although genitourinary discomfort and metrorrhagia were more common in the high-risk cohort, ongoing Phase II/IIb trial would provide data for generalization of this finding.

Abstract Background Two putative methionine aminopeptidase genes, map (essential) and yflG (non-essential), were identified in the genome sequence of Bacillus subtilis. We investigated whether they can function as methionine aminopeptidases and further explored possible reasons for their essentiality or dispensability in B. subtilis. Results In silico analysis of MAP evolution uncovered a coordinated pattern of MAP and deformylase that did not correlate with the pattern of 16S RNA evolution. Biochemical assays showed that both MAP (MAP_Bs) and YflG (YflG_Bs) from B. subtilis overproduced in Escherichia coli and obtained as pure proteins exhibited a methionine aminopeptidase activity in vitro. Compared with MAP_Bs, YflG_Bs was approximately two orders of magnitude more efficient when assayed on synthetic peptide substrates. Both map and yflG genes expressed in multi-copy plasmids could complement the function of a defective map gene in the chromosomes of both E. coli and B. subtilis. In contrast, lacZ gene transcriptional fusions showed that the promoter activity of map was 50 to 100-fold higher than that of yflG. Primer extension analysis detected the transcription start site of the yflG promoter. Further work identified that YvoA acted as a possible weak repressor of yflG expression in B. subtilis in vivo. Conclusion Both MAP_Bs and YflG_Bs are functional methionine aminopeptidases in vitro and in vivo. The high expression level of map and low expression level of yflG may account for their essentiality and dispensality in B. subtilis, respectively, when cells are grown under laboratory conditions. Their difference in activity on synthetic substrates suggests that they have different protein targets in vivo.

Abstract Background The enormous amount of genome sequence data asks for user-oriented databases to manage sequences and annotations. Queries must include search tools permitting function identification through exploration of related objects. Methods The GenoList package for collecting and mining microbial genome databases has been rewritten using MySQL as the database management system. Functions that were not available in MySQL, such as nested subquery, have been implemented. Results Inductive reasoning in the study of genomes starts from "islands of knowledge", centered around genes with some known background. With this concept of "neighborhood" in mind, a modified version of the GenoList structure has been used for organizing sequence data from prokaryotic genomes of particular interest in China. GenoChore http://bioinfo.hku.hk/genochore.html, a set of 17 specialized end-user-oriented microbial databases (including one instance of Microsporidia, Encephalitozoon cuniculi, a member of Eukarya) has been made publicly available. These databases allow the user to browse genome sequence and annotation data using standard queries. In addition they provide a weekly update of searches against the world-wide protein sequences data libraries, allowing one to monitor annotation updates on genes of interest. Finally, they allow users to search for patterns in DNA or protein sequences, taking into account a clustering of genes into formal operons, as well as providing extra facilities to query sequences using predefined sequence patterns. Conclusion This growing set of specialized microbial databases organize data created by the first Chinese bacterial genome programs (ThermaList, Thermoanaerobacter tencongensis, LeptoList, with two different genomes of Leptospira interrogans and SepiList, Staphylococcus epidermidis) associated to related organisms for comparison.