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Abstract T‐bet, encoded by TBX21, is extensively expressed across various immune cell types, and orchestrates critical functions in their development, survival, and physiological activities. However, the role of T‐bet in non‐immune compartments, notably the epithelial cells, remains obscure. Herein, a Tet‐O‐T‐bet transgenic mouse strain is generated for doxycycline‐inducible T‐bet expression in adult animals. Unexpectedly, ubiquitous T‐bet overexpression causes acute diarrhea, intestinal damage, and rapid mortality. Cell‐type‐specific analyses reveal that T‐bet‐driven pathology is not attributable to its overexpression in CD4+ T cells or myeloid lineages. Instead, inducible T‐bet overexpression in the intestinal epithelial cells is the critical determinant of the observed lethal phenotype. Mechanistically, T‐bet overexpression modulates ion channel and transporter profiles in gut epithelial cells, triggering profound fluid secretion and subsequent lethal dehydration. Furthermore, ectopic T‐bet expression enhances gut epithelial cell apoptosis and markedly suppresses colon cancer development in xenograft models. Collectively, the findings unveil a previously unrecognized role of T‐bet in intestinal epithelial cells for inducing apoptosis, diarrhea, and local inflammation, thus implicating its potential as a therapeutic target for the treatment of cancer and inflammatory diseases.

Background Glucocorticoids have been widely used in perioperative period for postoperative pain relief after total knee arthroplasty (TKA). However, the optimal administration protocols of glucocorticoids remain controversial. This study aims to compare the efficacy of glucocorticoids between intravenous and periarticular injection on clinical outcomes. Methods A total of 114 patients were randomly assigned to intravenous (IV) group ( n = 57) and periarticular injection (PI) group ( n = 57). The IV group received 10 mg dexamethasone intravenously and the PI group received periarticular injection of 10 mg dexamethasone during the procedure. The clinical outcomes were assessed using visual analogue scale (VAS), knee society score (KSS), range of motion (ROM), knee swelling, inflammation markers and complications after TKA. Results The VAS score during walking at 2nd day postoperatively was lower in the PI group compared with the IV group (2.08 ± 1.45 vs 2.73 ± 1.69, p = .039), and there was no significant difference at the other time points of VAS score in two groups. The inflammation markers, knee swelling, knee ROM and KSS score were not statistically different. Vomiting and other complications occurrence were not significantly different between the two groups. Conclusions Intraoperative periarticular injection of glucocorticoids has similar analgesic effect compared to intravenous in the postoperative period following TKA and may be even more effective on the second postoperative day. In addition, periarticular injection of glucocorticoids does not impose an excess risk or complication on patients.

Abstract Carbapenem-resistant Escherichia coli (CREC) poses a severe global public health risk. This study reveals the worldwide geographic spreading patterns and spatiotemporal distribution characteristics of resistance genes in 7918 CREC isolates belonging to 497 sequence types (ST) and originating from 75 countries. In the last decade, there has been a transition in the prevailing STs from highly virulent ST131 and ST38 to higher antibiotic-resistant ST410 and ST167. The rise of multi-drug resistant strains of CREC carrying plasmids with extended-spectrum beta-lactamase (ESBL) resistance genes could be attributed to three important instances of host-switching events. The spread of CREC was associated with the changing trends in bla NDM-5, bla KPC-2, and bla OXA-48, as well as the plasmids IncFI, IncFII, and IncI. There were intercontinental geographic transfers of major CREC strains. Various crucial transmission hubs and patterns have been identified for ST131 in the United Kingdom, Italy, the United States, and China, ST167 in India, France, Egypt, and the United States, and ST410 in Thailand, Israel, the United Kingdom, France, and the United States. This work is valuable in managing CREC infections and preventing CREC occurrence and transmission inside healthcare settings and among diverse hosts.

Abstract Background Adolescent aggression has long been of interest to researchers. However, few studies have examined the influencing factors and mechanisms of aggression among violent juvenile offenders. This study tests a moderated mediation model with Chinese male violent juvenile offenders as subjects. Specifically, it explores the relationship between early adversity and aggression, as well as the mechanisms of life history strategy and meaning in life in this relationship. Methods A total of 537 Chinese male violent juvenile offenders completed the Childhood Environment Scale, the Life History Strategy Short Form Scale, the Aggression Questionnaire, and the Meaning in Life Questionnaire. After controlling for socioeconomic status (SES), the current cross-sectional study used structural equation modeling (SEM) to examine a moderated mediation model. Results The results showed that life history strategy mediated the relationship between early adversity and aggression, and early adversity affected individuals’ aggression by accelerating their life history strategies. The results also showed that meaning in life moderated the relationship between early adversity and life history strategy. For individuals with high meaning in life scores, the negative predictive effect of early adversity on life history strategy was stronger than that for individuals with low meaning in life scores. Conclusion The results of this study can advance the understanding of how early adversity affects aggression among violent juvenile offenders and provide theoretical support for prison staff to develop educational strategies and subsequent interventions.

Abstract Ventilator-associated pneumonia (VAP) and pyogenic liver abscess (PLA) due to Klebsiella pneumoniae infection can trigger life-threatening malignant consequences, however, there are few studies on the strain-associated clinical pathogenic mechanisms between VAP and PLA. A total of 266 patients consist of 129 VAP and 137 PLA were included for analysis in this study. We conducted a comprehensive survey for the two groups of K. pneumoniae isolates, including phenotypic experiments, clinical epidemiology, genomic analysis, and instrumental analysis, i.e., to obtain the genomic differential profile of K. pneumoniae strains responsible for two distinct infection outcomes. We found that PLA group had a propensity for specific underlying diseases, especially diabetes and cholelithiasis. The resistance level of VAP was significantly higher than that of PLA (78.57% vs. 36%, P

Common-signal-induced synchronization of semiconductor lasers with optical feedback inspired a promising physical-layer key distribution with information-theoretic security and potential in high rate. A significant challenge is the requirement to shorten the synchronization recovery time for increasing the key rate without sacrificing the operation parameter space for security. Here, open-loop synchronization of wavelength-tunable multi-section distributed Bragg reflector lasers is proposed as a solution for physical-layer key distribution. Experiments show that the synchronization is sensitive to two operation parameters, i.e., currents of grating section and phase section. Furthermore, fast wavelength-shift keying synchronization can be achieved by direct modulation on one of the two currents. The synchronization recovery time is shortened by one order of magnitude compared to close-loop synchronization. An experimental implementation is demonstrated with a final key rate of 5.98 Mbit/s over 160 km optical fiber distance. It is thus believed that fast-tunable multi-section semiconductor lasers open a new avenue for a high-rate physical-layer key distribution using laser synchronization.

IntroductionAutism spectrum disorder (ASD) is a multifaceted developmental condition that commonly appears during early childhood. The etiology of ASD remains multifactorial and not yet fully understood. The identification of biomarkers may provide insights into the underlying mechanisms and pathophysiology of the disorder. The present study aimed to explore the causes of ASD by investigating the key biomedical markers, trace elements, and microbiota factors between children with autism spectrum disorder (ASD) and control subjects.MethodsMedline, PubMed, ProQuest, EMBASE, Cochrane Library, PsycINFO, Web of Science, and EMBSCO databases have been searched for publications from 2012 to 2023 with no language restrictions using the population, intervention, control, and outcome (PICO) approach. Keywords including “autism spectrum disorder,” “oxytocin,” “GABA,” “Serotonin,” “CRP,” “IL-6,” “Fe,” “Zn,” “Cu,” and “gut microbiota” were used for the search. The Joanna Briggs Institute (JBI) critical appraisal checklist was used to assess the article quality, and a random model was used to assess the mean difference and standardized difference between ASD and the control group in all biomedical markers, trace elements, and microbiota factors.ResultsFrom 76,217 records, 43 studies met the inclusion and exclusion criteria and were included in this meta-analysis. The pooled analyses showed that children with ASD had significantly lower levels of oxytocin (mean differences, MD = −45.691, 95% confidence interval, CI: −61.667, −29.717), iron (MD = −3.203, 95% CI: −4.891, −1.514), and zinc (MD = −6.707, 95% CI: −12.691, −0.722), lower relative abundance of Bifidobacterium (MD = −1.321, 95% CI: −2.403, −0.238) and Parabacteroides (MD = −0.081, 95% CI: −0.148, −0.013), higher levels of c-reactive protein, CRP (MD = 0.401, 95% CI: 0.036, 0.772), and GABA (MD = 0.115, 95% CI: 0.045, 0.186), and higher relative abundance of Bacteroides (MD = 1.386, 95% CI: 0.717, 2.055) and Clostridium (MD = 0.281, 95% CI: 0.035, 0.526) when compared with controls. The results of the overall analyses were stable after performing the sensitivity analyses. Additionally, no substantial publication bias was observed among the studies.InterpretationChildren with ASD have significantly higher levels of CRP and GABA, lower levels of oxytocin, iron, and zinc, lower relative abundance of Bifidobacterium and Parabacteroides, and higher relative abundance of Faecalibacterium, Bacteroides, and Clostridium when compared with controls. These results suggest that these indicators may be a potential biomarker panel for the diagnosis or determining therapeutic targets of ASD. Furthermore, large, sample-based, and randomized controlled trials are needed to confirm these results.

Abstract Background Based on its objective characteristics, laboratory markers have always been the research direction of clinical diagnosis and assessment of mental disorders including Alzheimer's disease. Methods MTT Colorimetric Assay, ELISA, and quantitative PCR were used to investigate the responsiveness of peripheral blood mononuclear cells (PBMCs) to mitogen Lipopolysaccharides (LPS) and Phytohemagglutinin (PHA), PBMCs genomic methylation and hydroxymethylation levels, nuclear DNA and mitochondrial DNA damage, respiratory chain enzyme activities, and circulating cell-free mitochondrial DNA levels were detected in 90 patients with Alzheimer's disease. Results In the Alzheimer's disease group, LPS stimulated PBMCs viability, TNF-α secretion, PHA stimulated IL-10 secretion, genomic DNA methylation levels, circulating cell-free mitochondrial DNA copies, citrate synthase activity were reduced compared to the control; while the LPS stimulated PBMCs IL-1α secretion, PHA stimulated IL-1α and IFN-γ secretion, plasma IL-6 and TNF-α, mitochondrial DNA damages were increased compared to the control. Conclusions The reactivity of peripheral blood mononuclear cells to mitogens, mitochondrial DNA integrity characteristics, and cell-free mitochondrial DNA copies may be used as candidate laboratory biomarkers to help clinical management of Alzheimer's disease.

Abstract Background Accurate localization of pulmonary nodules is the main difficulty experienced in wedge resection. Commonly used localization methods have their own advantages and disadvantages. However, clinical work has demonstrated that intraoperative indocyanine green localization under electromagnetic navigation bronchoscopy/virtual navigation bronchoscopy (VNB) is more advantageous than conventional methods for patients with multiple pulmonary nodules undergoing simultaneous surgery, especially for those undergoing bilateral lung surgery. Methods Data of patients undergoing simultaneous surgery for multiple pulmonary nodules with preoperative methylene blue localization by computed tomography (CT)‐guided percutaneous lung puncture (methylene blue group) or intraoperative indocyanine green localization under VNB (virtual navigation group) were retrospectively analyzed. Patient characteristics, pulmonary nodule features, localization time, preoperative location time, location success rate, operation time, complication incidence, visceral pleural staining rate after localization, and pulmonary nodule primary resection success rate were compared between the two groups. Results The methylene blue and virtual navigation groups comprised 39 and 20 patients with 119 and 67 pulmonary nodules resected, respectively. Sex, age, number of pulmonary nodules resected simultaneously, unilateral/bilateral lung surgery, pulmonary nodule size, distance between pulmonary nodules and the visceral pleura, pulmonary nodule consolidation‐to‐tumor ratio, location of pulmonary nodules in the pulmonary lobe, postoperative pathology, visceral pleura staining rate, primary pulmonary nodule resection success rate, and surgical duration did not differ significantly between the groups (p > 0.05). The localization time of the virtual navigation group was significantly shorter than that of the methylene blue group (p

Abstract Severe peripheral nerve injury leads to the irreparable disruption of nerve fibers. This leads to disruption of synapses with the designated muscle, which consequently go through progressive atrophy and damage of muscle function. The molecular mechanism that underlies the re-innervation process has yet to be evaluated using proteomics or transcriptomics. In the present study, multi-dimensional data were therefore integrated with transcriptome and proteome profiles in order to investigate the mechanism of re-innervation in muscles. Two simulated nerve injury muscle models in the rat tibial nerve were compared: the nerve was either cut (denervated, DN group) or crushed but with the nerve sheath intact (re-innervated, RN group). The control group had a preserved and intact tibial nerve. At 4 weeks, the RN group showed better tibial nerve function and recovery of muscle atrophy compared to the DN group. As the high expression of Myh3, Postn, Col6a1 and Cfi, the RN group demonstrated superior re-innervation as well. Both differentially expressed genes (DEGs) and proteins (DEPs) were enriched in the peroxisome proliferator-activated receptors (PPARs) signaling pathway, as well as the energy metabolism. This study provides basic information regarding DEGs and DEPs during re-innervation-induced muscle atrophy. Furthermore, the crucial genes and proteins can be detected as possible treatment targets in the future.

Bacteriophages (phages) are nanostructured viruses with highly selective antibacterial properties that have gained attention beyond eliminating bacteria. Specifically, M13 phages are filamentous phages that have recently been studied in various aspects of nanomedicine due to their biological advantages and more compliant engineering capabilities over other phages. Having nanofiber-like morphology, M13 phages can reach varied target sites and self-assemble into multidimensional scaffolds in a relatively safe and stable way. In addition, genetic modification of the coat proteins enables specific display of peptides and antibodies on the phages, allowing for precise and individualized medicine. M13 phages have also been subjected to novel engineering approaches, including phage-based bionanomaterial engineering and phage-directed nanomaterial combinations that enhance the bionanomaterial properties of M13 phages. In view of these features, researchers have been able to utilize M13 phages for therapeutic applications such as drug delivery, biodetection, tissue regeneration, and targeted cancer therapy. In particular, M13 phages have been utilized as a novel bionanomaterial for precisely mimicking natural tissue environment in order to overcome the shortage in tissue and organ donors. Hence, in this review, we address the recent studies and advances of using M13 phages in the field of nanomedicine as therapeutic agents based upon their characteristics as novel bionanomaterial with biomolecules displayed. This paper also emphasizes the novel engineering approach that enhances M13 phage's bionanomaterial capabilities. Current limitations and future approaches are also discussed to provide insight in further progress for M13 phage-based clinical applications.

[This corrects the article DOI: 10.1371/journal.pgen.1004524.].

Sepsis-induced acute kidney injury (AKI) is one of the important causes of increased mortality in sepsis patients. Long non-coding RNA (lncRNA) is believed to play a vital function in the progression of AKI. However, the mechanism of nuclear enriched abundant transcript 1 (NEAT1) has not been fully elucidated. NEAT1 was overexpressed and miR-22-3p was underexpressed in sepsis patients and lipopolysaccharide (LPS)-induced AKI cell models. Knockdown of NEAT1 could promote viability and suppress apoptosis and the inflammatory response in LPS-induced HK2 cells. MiR-22-3p could be sponged by NEAT1, and its inhibitor reversed the inhibition effect of NEAT1 silencing on LPS-induced HK2 cell injury. CXCL12 could be targeted by miR-22-3p, and its overexpression reversed the suppression effect of miR-22-3p on LPS-induced HK2 cell injury. Silenced NEAT1 could restrain the activity of the NF-B signaling pathway, and miR-22-3p inhibitor or CXCL12 overexpression could reverse this effect. In addition, NEAT1 knockdown alleviated the inflammation response of cecal ligation and puncture (CLP) mouse models. In summary, our data showed that NEAT1 promoted LPS-induced HK2 cell injury via regulating the miR-22-3p/CXCL12/NF-B signaling pathway, suggesting that NEAT1 knockdown might be a potential pathway for alleviating sepsis-induced AKI.

Abstract Background Escherichia coli peritonitis (EP) is a serious complication of peritoneal dialysis (PD). Gut microbiota alterations occur in end-stage renal disease (ESRD) patients. The relationship between the gut microbiota and PD-related peritonitis is still poorly understood. It is unclear whether the intestinal flora is involved in the pathogenesis of EP. Methods We collected fecal samples from EP patients and normal group (NG) PD patients. 16S rRNA sequencing was used to analyze the gut microbiota of EP and NG patients. The demographic data and clinical indicators of all patients were collected. Results Six EP patients and 28 NG patients were recruited for this study. The analysis of fecal community diversity with 16S rDNA sequencing showed an obvious change in the microbial structure of EP patients, where Bacteroidetes and Synergistetes were upregulated at different levels, while Bacilli and Lactobacillus were downregulated at different levels compared to the NG group. Additionally, decreased gene function associated with metabolic pathways was observed in EP patients. Conclusions The altered composition of the gut microbiota in EP patients provided deeper insights into the pathogenesis of EP, and these biomarkers might be established as potential therapeutic targets that deserve further exploration.

Abstract Background Treatment of avascular necrosis of the femoral head (ANFH) in young patients remains a clinical challenge. A current controversy is whether hip-preserving surgery results in better outcomes. The adverse effects of hip-preserving surgery are associated with the fill material for the necrotic areas. This study aims to evaluate the early effects of autologous bone marrow buffy coat (BBC) and angioconductive bioceramic rod (ABR) grafting with advanced core decompression (ACD) on early ANFH. Methods Forty-four (57 hips) patients with early ANFH from 2015 to 2020 were recruited for this study. They were randomized into two groups: group A received ACD, BBC, and ABR grafting; group B received treatment of ACD with β-tricalcium phosphate (β-TCP) granules and ABR grafting. The outcomes were assessed using the Harris Hip Scores (HHS) and survival rate analysis. The follow-up endpoint was defined as conversion to total hip arthroplasty (THA). Results Forty patients (51 hips) were ultimately included in this study for analysis. Compared with group B, patients in group A had higher postoperative function score (P = 0.032) and postoperative Harris Hip Scores (HHS) (P = 0.041). Kaplan-Meier analysis showed a trend that the survivorship of the femoral head was higher in group A than in group B. Conclusion The short-term follow-up results showed that the autologous bone marrow buffy coat and angioconductive bioceramic rod grafting with advanced core decompression is effective in the treatment of early ANFH. Trial registration Chictr.org.cn , ChiCTR2000039595. Retrospectively registered on 11 February 2015.

This preliminary research determines whether a combination of reverse end-to-side neurorrhaphy and rapamycin treatment achieves a better functional outcome than a single application after prolonged peripheral nerve injury. We found that the tibial nerve function of the reverse end-to-side + rapamycin group recovered better, with a higher tibial function index value, higher amplitude recovery rate, and shorter latency delay rate (P < 0.05). The reverse end-to-side + rapamycin group better protected the gastrocnemius muscle with more forceful contractility, tetanic tension, and a higher myofibril cross-sectional area (P < 0.05). Combining reverse end-to-side neurorrhaphy with rapamycin treatment is a practical approach to promoting the recovery of chronically denervated muscle atrophy after peripheral nerve injury.

Carbapenem-resistant Klebsiella pneumoniae (CRKP), a pathogen that causes severe nosocomial infections and yields a high mortality rate, poses a serious threat to global public health due to its high antimicrobial resistance. Bacteriophages encode polysaccharide-degrading enzymes referred to as depolymerases that cleave the capsular polysaccharide (CPS), one of the main virulence factors of K. pneumoniae. In this study, we identified and characterized a new capsule depolymerase K19-Dpo41 from K. pneumoniae bacteriophage SH-KP156570. Our characterization of K19-Dpo41 demonstrated that this depolymerase showed specific activities against K19-type K. pneumoniae. K19-Dpo41-mediated treatments promoted the sensitivity of a multidrug-resistant K19-type K. pneumoniae strain to the bactericidal effect of human serum and significantly increased the survival rate of Galleria mellonella infected with K19-type K. pneumoniae. Our results provided strong primary evidence that K19-Dpo41 was not only effective in capsular typing of K19-type K. pneumoniae but promising in terms of developing new alternative therapeutic strategies against K19-type CRKP infections in the future.

With increasing attention paid to the concept of the microbiota–gut–brain axis, mounting evidence reveals that the gut microbiota is involved in a variety of neurological and psychiatric diseases. However, gut microbiota changes in major depressive disorder (MDD) patients and their association with disease mechanisms remain undefined. Fifty MDD patients and sixty healthy controls were recruited from the Shanghai Healthy Mental Center, China. Fecal samples were collected, and the compositional characteristics of the intestinal flora were determined in MDD patients by MiSeq sequencing. Venous blood was collected for the detection of plasma indoleamine-2,3-dioxygenase (Ido), kynurenine (Kyn) and tryptophan (Trp) levels. Stool samples of bacterial 16S sequencing was carried out. A total of 2,705,809 optimized sequences were obtained, with an average of 54,116 per sample. More unique OTUs were observed at the family, genus and species levels in the control group compared with the MDD cases. Further analysis showed significant changes in the α- and β-diversities and relative abundance levels of gut microbial entities in MDD patients, as well as elevated amounts of Ido and Kyn indicating Kyn pathway activation, KEGG bacterial 16S function prediction analysis shows a variety of amino acids and metabolic (including Ido, Trp and Kyn) changes in the body of patients with MDD. These may result in increased neurotoxic metabolites and reduced generation of serotonin in the disease process. These changed factors may potentially be utilized as biomarkers for MDD in the future, playing more important roles in the disease course.

Abstract Background Although medical intervention of periprosthetic bone loss in the immediate postoperative period was recommended, not all the patients experienced periprosthetic bone loss after total hip arthroplasty (THA). Prediction tools that enrolled all potential risk factors to calculate an individualized prediction of postoperative periprosthetic bone loss were strongly needed for clinical decision-making. Methods Data of the patients who underwent primary unilateral cementless THA between April 2015 and October 2017 in our center were retrospectively collected. Candidate variables included demographic data and bone mineral density (BMD) in spine, hip, and periprosthetic regions that measured 1 week after THA. Outcomes of interest included the risk of postoperative periprosthetic bone loss in Gruen zone 1, 7, and total zones in the 1st postoperative year. Nomograms were presented based on multiple logistic regressions via R language. One thousand Bootstraps were used for internal validation. Results Five hundred sixty-three patients met the inclusion criteria were enrolled, and the final analysis was performed in 427 patients (195 male and 232 female) after the exclusion. The mean BMD of Gruen zone 1, 7, and total were decreased by 4.1%, 6.4%, and 1.7% at the 1st year after THA, respectively. 61.1% of the patients (261/427) experienced bone loss in Gruen zone 1 at the 1st postoperative year, while there were 58.1% (248/427) in Gruen zone 7 and 63.0% (269/427) in Gruen zone total. Bias-corrected C-index for risk of postoperative bone loss in Gruen zone 1, 7, and total zones in the 1st postoperative year were 0.700, 0.785, and 0.696, respectively. The most highly influential factors for the postoperative periprosthetic bone loss were primary diagnosis and BMD in the corresponding Gruen zones at the baseline. Conclusions To the best of our knowledge, our study represented the first time to use the nomograms in estimating the risk of postoperative periprosthetic bone loss with adequate predictive discrimination and calibration. Those predictive models would help surgeons to identify high-risk patients who may benefit from anti-bone-resorptive treatment in the early postoperative period effectively. It is also beneficial for patients, as they can choose the treatment options based on a reasonable expectation following surgery.

Biofilms are complex microbial microcolonies consisting of planktonic and dormant bacteria bound to a surface. The bacterial cells within the biofilm are embedded within the extracellular polymeric substance (EPS) consisting mainly of exopolysaccharides, secreted proteins, lipids, and extracellular DNA. This structural matrix poses a major challenge against common treatment options due to its extensive antibiotic-resistant properties. Because biofilms are so recalcitrant to antibiotics, they pose a unique challenge to patients in a nosocomial setting, mainly linked to lower respiratory, urinary tract, and surgical wound infections as well as the medical devices used during treatment. Another unique property of biofilm is its ability to adhere to both biological and man-made surfaces, allowing growth on human tissues and organs, hospital tools, and medical devices, etc. Based on prior understanding of bacteriophage structure, mechanisms, and its effects on bacteria eradication, leading research has been conducted on the effects of phages and its individual proteins on biofilm and its role in overall biofilm removal while also revealing the obstacles this form of treatment currently have. The expansion in the phage host-species range is one that urges for improvement and is the focus for future studies. This review aims to demonstrate the advantages and challenges of bacteriophage and its components on biofilm removal, as well as potential usage of phage cocktail, combination therapy, and genetically modified phages in a clinical setting.

Background Schizophrenia is a serious mental illness affecting approximately 20 million individuals globally. Both genetic and environmental factors contribute to the illness. If left undiagnosed and untreated, schizophrenia results in impaired social function, repeated hospital admissions, reduced quality of life and decreased life expectancy. Clinical diagnosis largely relies on subjective evidence, including self-reported experiences, and reported behavioural abnormalities followed by psychiatric evaluation. In addition, psychoses may occur along with other conditions, and the symptoms are often episodic and transient, posing a significant challenge to the precision of diagnosis. Therefore, objective, specific tests using biomarkers are urgently needed for differential diagnosis of schizophrenia in clinical practice.Aims We aimed to provide evidence-based and consensus-based recommendations, with a summary of laboratory measurements that could potentially be used as biomarkers for schizophrenia, and to discuss directions for future research.Methods We searched publications within the last 10 years with the following keywords: ‘schizophrenia’, ‘gene’, ‘inflammation’, ‘neurotransmitter’, ‘protein marker’, ‘gut microbiota’, ‘pharmacogenomics’ and ‘biomarker’. A draft of the consensus was discussed and agreed on by all authors at a round table session.Results We summarised the characteristics of candidate diagnostic markers for schizophrenia, including genetic, inflammatory, neurotransmitter, peripheral protein, pharmacogenomic and gut microbiota markers. We also proposed a novel laboratory process for diagnosing schizophrenia in clinical practice based on the evidence summarised in this paper.Conclusions Further efforts are needed to identify schizophrenia-specific genetic and epigenetic markers for precise diagnosis, differential diagnosis and ethnicity-specific markers for the Chinese population. The development of novel laboratory techniques is making it possible to use these biomarkers clinically to diagnose disease.

Abstract Background A method that can accurately predict the outcome of surgery can give patients timely feedback. In addition, to some extent, an objective evaluation method can help the surgeon quickly summarize the patient’s surgical experience and lessen dependence on the long wait for follow-up results. However, there was still no precise tool to predict clinical outcomes of total knee arthroplasty (TKA). This study aimed to develop a scoring system to predict clinical results of TKA and then grade the quality of TKA. Methods We retrospectively reviewed 98 primary TKAs performed between April 2013 and March 2017 to determine predictors of clinical outcomes among lower-extremity angles of alignment. Applying multivariable linear-regression analysis, we built Models (i) and (ii) to predict detailed clinical outcomes which were evaluated using the Knee Society Score (KSS). Multivariable logistic-regression analysis was used to establish Model (iii) to predict probability of getting a good clinical outcome (PGGCO) which was evaluated by Knee Injury and Osteoarthritis Outcome Score (KOOS) score. Finally, we designed a new scoring system consisting of 3 prediction models and presented a method of grading TKA quality. Thirty primary TKAs between April and December 2017 were enrolled for external validation. Results We set up a scoring system consisting of 3 models. The interpretations of Model (i) and (ii) were good (R2 = 0.756 and 0.764, respectively). Model (iii) displayed good discrimination, with an area under the curve (AUC) of 0.936, and good calibration according to the calibration curve. Quality of surgery was stratified as follows: “A” = PGGCO ≥0.8, “B” = PGGCO ≤0.6 but

Abstract Background Avascular necrosis of the femoral head (ANFH) is a severely disabling disease of the hip. Several clinical trials have shown promising outcomes on the use of mesenchymal stem cells for the treatment of ANFH, but long-term clinical assessments are lacking. Previously, we reported the 2-year follow-up results of a prospective, double-blinded, randomized, controlled study on autologous bone marrow buffy coat grafting combined with core decompression in patients with ANFH. Here, we report the 10-year follow-up results of this study. Methods We recruited 43 (53 hips) patients from 2009 to 2010. The hips were randomly allocated to code decompression (CD) with or without bone marrow buffy coat (BBC) grafting. Participants underwent follow-up at 24, 60, and 120 months postoperatively. The visual analogue scale (VAS), Lequesne algofunctional index, and Western Ontario and McMaster Universities Arthritis Index (WOMAC) osteoarthritis scores were recorded. Survival rate analysis and prognostic factor analysis were performed. The endpoint was defined as progression to Ficat stage IV or conversion to hip arthroplasty. Results A total of 31 patients (41 hips) were included in the final analysis. The CD + BBC group had better subjective assessment scores than the CD group. The average survival times were 102.3 months and 78.1 months in the CD + BBC group and CD group, respectively (log-rank test, P = 0.029). In the univariate Cox proportional hazards regression model, age [hazard ratio (HR) = 1.079, P = 0.047] and preoperative Ficat stage (HR = 3.283, P = 0.028) indicated a high risk for progression, while the use of BBC (HR = 0.332, P = 0.042) indicated a low risk. Preoperative Ficat stage III was isolated as an independent risk factor for clinical failure in the multivariate model (HR = 3.743, P = 0.018). Conclusion The 10-year follow-up results of this prospective, double-blinded, randomized, controlled study showed that the use of autologous BBC in combination with core decompression was more effective than the use of core decompression alone. Trial registration ClinicalTrials.gov, NCT01613612 . Registered on 13 December 2011—retrospectively registered

Abstract Background Strength deficits, muscle imbalances, and quadriceps inhibition are common after the total knee arthroplasty (TKA). It was suggested that theoretically single radius (SR) femoral protheses could provide longer extensor moment arm compared to the multiple radius (MR) design. However, quantitative evidence has not yet been reported. Thus, the aim of the study was to investigate the differences in isokinetic data and to compare the patient-reported outcome scores between TKA SR and MR design. Method The present retrospective study included 36 TKA involving 16 knees (9 patients) using SR design implant and 20 knees (11 patients) using MR design implant. The mean follow-up time was longer than 1 year. Isokinetic knee flexion and extension torques of the operated leg were evaluated at 60°/s and 180°/s. Quadriceps and hamstring torques and ratios, work and power were recorded. Angle-specific torques were also collected at different extension or flexion angles. Results Both groups showed improvement in knee society scores (KSS) and knee injury, and osteoarthritis outcome score (KOOS) after operation. Patients in SR group had significantly higher scores in KSS-knee, symptoms and activities of daily living KOOS sub-score than those in the MR group at the end of the follow-up. The peak knee flexion torque, peak knee extension torque and maximum knee flexion work were greater in SR group at 180°/s and 60°/s. At 60°/s, and SR group had higher average knee flexion power and average knee extension power than MR group. In the isometric contraction test, the knee extension torque was higher in SR group than in MR group. At 180°/s, SR group showed higher flexion torques at 30°, 40°, 50°, 60° compared with MR group. At 60°/s, SR group showed higher flexion torques at 30°, 40°, 50°, 60°, 80° when compared with MR group. Additionally, SR group also provided higher extension torques at 40°, 50°, 60° than the MR group. There were no differences in other isokinetic and isometric parameters between the two groups. Conclusion Femoral design exerted an influence on quadriceps and hamstring strength after TKA, and SR design shows advantages, in terms of higher extension and flexion strength, over MR design.

Multilayer hexagonal boron nitride (hBN) is a desirable dielectric substrate for 2D electronics but its controllable synthesis is challenging. Here, the authors report a vapor–liquid–solid growth method to achieve uniform multilayer hBN by using a molten Fe82B18 alloy and N2 as reactants.

Abstract Background Total hip arthroplasty is the most common orthopaedic procedure for the end-stage hip diseases. Periprosthetic bone loss is closely related to the increased risk of implant loosening and periprosthetic fractures, but the predictive value of periprosthetic bone mineral density (BMD) measured immediately after surgery has not yet been investigated. Methods From April 2015 to October 2017, 64 patients with femoral neck fracture, hip osteoarthritis, femoral head necrosis, or developmental dysplasia of the hip underwent unilateral total hip arthroplasty. Demographic data, bone mineral density of the hip and spine, periprosthetic BMD of 7 Gruen zones, and radiographic parameters measured preoperatively, 1 week, 3 months, and 12 months after surgery were collected. A p value

This study explored the relationship between teacher job stress and job burnout using a sample of 558 primary and secondary school teachers, who were administered with a teacher job stress scale, teacher job burnout scale, work–family conflict questionnaire, and general self-efficacy scale. The results showed that: (1) job stress had a significant predictive effect on work–family conflict and job burnout; (2) work–family conflict played a mediating role in the relationship between job stress and job burnout; (3) self-efficacy was found to play a moderating role in work–family conflict and job burnout. However, this indirect effect was stronger for teachers with high self-efficacy, which means that the protective effects of self-efficacy were limited. These findings add to research on the relationship between teacher job stress and job burnout, and provide ideas for teachers to balance work–family relationships and reduce job burnout.

Abstract Background Revision total hip arthroplasty (THA) with large acetabular defect remains a challenge. Though trabecular metal (TM) cup and augments have been introduced in defect reconstruction with good result, the accurate positioning of implant is important to avoid complications. Therefore, we aimed to evaluate the usefulness of three-dimensional (3D) simulation and 3D model in assisting implant positioning during complex revision THA. Methods Sixteen patients (18 hips) who underwent revision THA with a Paprosky type III acetabular defect were analyzed retrospectively. Placement of acetabular cup and TM augments was simulated with 3D simulation software and 3D model preoperatively. Cup anteversion, abduction angle, and hip center were measured in each case preoperatively and postoperatively. Primary outcome was the percentage of outliers according to Lewinnek safe zone and Harris hip score (HHS). Secondary outcome was the correlation between the 3D planned and the postoperative value. Results The percentage of outliers was significantly corrected from 77.78% (14/18) preoperatively to 38.88% (7/18) postoperatively (p = 0.04). There was a significant correlation between mean planned cup anteversion and postoperative value (13.39 vs 11.99, r = 0.894; p < 0.001). There was a significant correlation between mean planned abduction and postoperative value (42.67 vs 44.91, r = 0.921, p < 0.001). The number of planned and used augments was the same in all the cases. In 15 cases (83.33%), the size of planned and used TM augments was the same. The HHS was significantly improved at final follow-up (80.94 vs 27.50, p < 0.001). No cases presented dislocation or radiological signs of loosening. Conclusion Preoperative 3D simulation and model were considered the useful method to assist implant positioning in revision THA with complex acetabular defect, with moderate to high accuracy and satisfied clinical outcome.

Abstract Background Major depressive disorder (MDD) is related to human’s immune status, and immunological indicators such as mitogen stimulated cell proliferation and cytokines may become candidate biomarkers for disease diagnosis. Methods One hundred diagnosed major depressive disorder subjects and 100 health controls were enrolled in this study. Phytohaemagglutinin and lipopolysaccharide stimulated cell proliferations and cytokine concentrations were detected in peripheral blood mononuclear cells from both groups. The corresponding stimulated responses were conducted and confirmed in chronic unpredictable mild stress (CUMS) mice. Results Compared to the people in control group, there were lower cell proliferations and lower TNF-α produced in lipopolysaccharide stimulated peripheral blood mononuclear cells in depression patients, lower IL-2 and IL-10 produced in phytohaemagglutinin stimulated peripheral blood mononuclear cells in depression patients, higher IL-6, IL-10 and lower IL-2 secretions were detected in peripheral plasma in depression patients. In CUMS mice we found lower splenocyte proliferations, lower IL-1α productions and higher IL-6 secretions in lipopolysaccharide stimulated splenocytes. It seems lipopolysaccharide stimulated cell proliferation activities were inhibited in depressive states. Conclusions Lower lipopolysaccharide stimulated cell proliferation and phytohaemagglutinin stimulated or plasma cytokine IL-2 decreases should be potential monitoring indices in the depressive state assessment for major depressive disorder patients.

The increasing prevalence of infections caused by multidrug-resistant Klebsiella pneumoniae necessitates the development of alternative therapies. Here, we isolated, characterized, and sequenced a K. pneumoniae bacteriophage (SH-KP152226) that specifically infects and lyses K. pneumoniae capsular type K47. The phage SH-KP152226 contains a genome of 41,420 bp that encodes 48 predicted proteins. Among these proteins, Dep42, the gene product of ORF42, is a putative tail fiber protein and hypothetically possesses depolymerase activity. We demonstrated that recombinant Dep42 showed specific enzymatic activities in the depolymerization of the K47 capsule of K. pneumoniae and was able to significantly inhibit biofilm formation and/or degrade formed biofilms. We also showed that Dep42 could enhance polymyxin activity against K. pneumoniae biofilms when used in combination with antibiotics. These results suggest that combination of the identified novel depolymerase Dep42, encoded by the phage SH-KP152226, with antibiotics may represent a promising strategy to combat infections caused by drug-resistant and biofilm-forming K. pneumoniae.

The ubiquitin-proteasome system regulates cellular reprogramming by degradation of key pluripotency factors. Here the authors report that the post-translational regulation of PRC1 components CBX4 and CBX6 by ubiquitination influences reprogramming.

Abstract Background Prunus triloba Lindl. is a naturally salt-alkaline-tolerant plant with several unique characteristics, and it can be used as the rootstock of Chinese plum (Prunus salicina Lindl.) in saline-alkaline soils. To comprehensively investigate the alkaline acclimation mechanisms in P. triloba, a series of analyses were conducted under alkaline stress, including analyses of the kinetics of molecular and physiological changes, and leaf microstructure. Results To understand the kinetics of molecular changes under short-term alkaline stress, we used Illumina HiSeq 2500 platform to identify alkaline stress-related differentially expressed genes (DEGs) in P. triloba. Approximately 53.0 million high-quality clean reads were generated from 59.6 million raw reads, and a total of 124,786 unigenes were obtained after de novo assembly of P. triloba transcriptome data. After alkaline stress treatment, a total of 8948 unigenes were identified as DEGs. Based on these DEGs, a Gene Ontology (GO) enrichment analysis was conducted, suggesting that 28 genes may play an important role in the early alkaline stress response. In addition, analysis of DEGs with the Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed that pathways were significant at different treatment time points. A significant positive correlation was found between the quantitative real-time PCR (qRT-PCR) results and the RNA-Seq data for seven alkaline-related genes, confirming the reliability of the RNA-Seq results. Based on physiological analysis of P. triloba in response to long-term alkaline stress, we found that the internal microstructures of the leaves of P. triloba changed to adapt to long-term alkaline stress. Various physiological indexes indicated that the degree of membrane injury increased with increasing duration of alkaline stress, affecting photosynthesis in P. triloba seedlings. Conclusions This represents the first investigation into the physiology and transcriptome of P. triloba in response to alkaline stress. The results of this study can enrich the genomic resources available for P. triloba, as well as deepening our understanding of molecular and physiological alkaline tolerance mechanisms in P. triloba. This will also provide new insights into our understanding of alkaline acclimation mechanisms in Chinese plum (Prunus salicina) trees.

Little is known regarding differences in the gut microbiomes of rheumatoid arthritis (RA) patients and healthy cohorts in China. This study aimed to identify differences in the fecal microbiomes of 66 Chinese patients with RA and 60 healthy Chinese controls. The V3-V4 variable regions of bacterial 16S rRNA genes were sequenced with the Illumina system to define the bacterial composition. The alpha-diversity index of the microbiome of the RA patients was significantly lower than that of the control group. The bacterial genera Bacteroides (p = 0.02202) and Escherichia-Shigella (p = 0.03137) were more abundant in RA patients. In contrast, Lactobacillus (p = 0.000014), Alloprevotella (p = 0.0000008615), Enterobacter (p = 0.000005759), and Odoribacter (p = 0.0000166) were less abundant in the RA group than in the control group. Spearman correlation analysis of blood physiological measures of RA showed that bacterial genera such as Dorea and Ruminococcus were positively correlated with RF-IgA and anti-CCP antibodies. Furthermore, Alloprevotella and Parabacteroides were positively correlated with the erythrocyte sedimentation rate, and Prevotella-2 and Alloprevotella were positively correlated with C-reactive protein, both biomarkers of inflammation. These findings suggest that the gut microbiota may contribute to RA development via interactions with the host immune system.

Aim: In this study, Staphylococcus phage JD007 bactericidal activity and induced immune responses during treatment were assessed in a dermal abscess model.Materials and Methods: Dermal abscesses in nude mice were established by injecting a clinical isolate of S. aureus SA325 isolated from the back under-dermal abscess of an in-patient.Results: Phage JD007 was able to inhibit the growth of S. aureus SA325 at MOI = 1 or 10, significantly preventing the formation of dermal abscesses. Moderate immune responses were observed in the prevention group through detection of cytokines.Conclusion: Phage JD007 inhibits the formation of dermal abscesses caused by a clinical S. aureus strain in nude mice without robust immune responses.

In some areas of cultivation, a lack of salt tolerance severely affects plant productivity. Apple, Malus x domestica Borkh., is sensitive to salt, and, as a perennial woody plant the mechanism of salt stress adaption will be different from that of annual herbal model plants, such as Arabidopsis. Malus zumi is a salt tolerant apple rootstock, which survives high salinity (up to 0.6% NaCl). To examine the mechanism underlying this tolerance, a genome-wide expression analysis was performed, using a cDNA library constructed from salt-treated seedlings of Malus zumi. A total of 15,000 cDNA clones were selected for microarray analysis. In total a group of 576 cDNAs, of which expression changed more than four-fold, were sequenced and 18 genes were selected to verify their expression pattern under salt stress by semi-quantitative RT-PCR. Our genome-wide expression analysis resulted in the isolation of 50 novel Malus genes and the elucidation of a new apple-specific mechanism of salt tolerance, including the stabilization of photosynthesis under stress, involvement of phenolic compounds, and sorbitol in ROS scavenging and osmoprotection. The promoter regions of 111 genes were analyzed by PlantCARE, suggesting an intensive cross-talking of abiotic stress in Malus zumi. An interaction network of salt responsive genes was constructed and molecular regulatory pathways of apple were deduced. Our research will contribute to gene function analysis and further the understanding of salt-tolerance mechanisms in fruit trees.

Objective: Activation of nuclear factor kappaB by diverse bacteria regulates the secretion of chemokines and cytokines. Staphylococcus aureus (S. aureus)-infected osteoblasts can significantly increase the secretion of interleukin-6 and monocyte chemoattractant protein-1. The aim of this study was to investigate whether S. aureus can activate nuclear factor kappaB in human osteoblasts, and whether the activation of nuclear factor kappaB by S. aureus regulates the secretion of interleukin-6 and monocyte chemoattractant protein-1. Methods: Immunoblot and electrophoretic mobility shift assay were used to detect the degradation of IκBa and activation of nuclear factor kappaB in human osteoblasts in response to S. aureus, respectively. Enzyme-linked immunosorbent assay was used to measure the secretion of interleukin-6 and monocyte chemoattractant protein-1 in the supernatants. Lastly, carbobenzoxyl-l-leucinyl-l-leucinyl-l-leucinal, an inhibitor of the nuclear factor kappaB, was used to determine if activation of nuclear factor kappaB by S. aureus in human osteoblasts regulates the secretions of interleukin-6 and monocyte chemoattractant protein-1. Results: Our results for the first time demonstrated that S. aureus can induce the degradation of IκBa and activation of nuclear factor kappaB in human osteoblasts in a time and dose-dependent manner. In addition, inhibition of nuclear factor kappaB by carbobenzoxyl-l-leucinyl-l-leucinyl-l-leucinal suppressed the secretion of interleukin-6 and monocyte chemoattractant protein-1 in the supernatants of S. aureus-infected human osteoblasts in a dose-dependent manner. Conclusions: These findings suggest that S. aureus can activate nuclear factor kappaB in human osteoblasts, and subsequently regulate the secretion of interleukin-6 and monocyte chemoattractant protein-1. The nuclear factor kappaB transcription factor regulates a number of genes involved in a wide variety of biological processes. Further study of the effects of nuclear factor kappaB activation on S. aureus-infected human osteoblast may provide us new insights into discovery of the immune mechanisms in osteomyelitis. Keywords: Staphylococcus aureus, osteoblasts, NF-kappaB, interleukin-6, chemokine CCL2

The nuclear receptor coactivator-6 (NCOA6, AIB3, PRIP, ASC-2, TRBP, RAP250 or NRC) is a co-activator for nuclear hormone receptors and certain other transcription factors. NCOA6 plays an important role in embryonic development, adipocyte differentiation, metabolism and breast carcinogenesis. The human and mouse NCOA6 genes had 15 and 14 previously identified exons, respectively. This study further identified an alternatively spliced exon 11b (E11b) in human or E10b in mouse, which codes a short polypeptide and a Stop codon, resulting in splicing variants lacking the last four exon-coded polypeptide. Analyses of mouse testis NCOA6 mRNAs identified four alternatively spliced variants, NCOA6-α (without E10b), -β (without E10a and E10b), -γ (with E10a and E10b) and -δ (without E10a but with E10b). These isoforms were detected in multiple mouse tissues and in MDA-MB-435 human cells. NCOA6-α and -β are mainly located in the nucleus; NCOA6-γ is located in both cytoplasm and nucleus; and NCOA6-δ is mainly located in mitochondria. The C-terminus coded by the last four exons was responsible for locating NCOA6-α and -β into the nucleus. The human E11a or mouse E10a-coded region is responsible for distributing NCOA6-γ in both cytoplasm and nucleus, while the region coded by E8-E9 in human or E7-E8 in mouse is responsible for directing NCOA6-δ to mitochondria. Our assays also demonstrated that NCOA6-α and -β could significantly enhance estrogen receptor α-mediated transcription, but NCOA6-γ and -δ were unable to do so. These results suggest that the diverse physiological function of NCOA6 may be mediated by multiple isoforms expressed in different tissues and localized in different subcellular compartments.

Plants are unavoidably subjected to various abiotic stressors, including high salinity, drought and low temperature, which results in water deficit and even death. Water uptake and transportation play a critical role in response to these stresses. Many aquaporin proteins, localized at different tissues, function in various transmembrane water movements. We targeted at the key aquaporin in charge of both water uptake in roots and radial water transportation from vascular tissues through the whole plant.The MzPIP2;1 gene encoding a plasma membrane intrinsic protein was cloned from salt-tolerant apple rootstock Malus zumi Mats. The GUS gene was driven by MzPIP2;1 promoter in transgenic Arabidopsis. It indicated that MzPIP2;1 might function in the epidermal and vascular cells of roots, parenchyma cells around vessels through the stems and vascular tissues of leaves. The ectopically expressed MzPIP2;1 conferred the transgenic Arabidopsis plants enhanced tolerance to slight salt and drought stresses, but sensitive to moderate salt stress, which was indicated by root length, lateral root number, fresh weight and K+/Na+ ratio. In addition, the possible key cis-elements in response to salt, drought and cold stresses were isolated by the promoter deletion experiment.The MzPIP2;1 protein, as a PIP2 aquaporins subgroup member, involved in radial water movement, controls water absorption and usage efficiency and alters transgenic plants drought and salt tolerance.

Histone demethylases have emerged as important players in developmental processes. Jumonji domain containing-3 (Jmjd3) has been identified as a key histone demethylase that plays a critical role in the regulation of gene expression; however, the in vivo function of Jmjd3 in embryonic development remains largely unknown. To this end, we generated Jmjd3 global and conditional knockout mice. Global deletion of Jmjd3 induces perinatal lethality associated with defective lung development. Tissue and stage-specific deletion revealed that Jmjd3 is dispensable in the later stage of embryonic lung development. Jmjd3 ablation downregulates the expression of genes critical for lung development and function, including AQP-5 and SP-B. Jmjd3-mediated alterations in gene expression are associated with locus-specific changes in the methylation status of H3K27 and H3K4. Furthermore, Jmjd3 is recruited to the SP-B promoter through interactions with the transcription factor Nkx2.1 and the epigenetic protein Brg1. Taken together, these findings demonstrate that Jmjd3 plays a stage-dependent and locus-specific role in the mouse lung development. Our study provides molecular insights into the mechanisms by which Jmjd3 regulates target gene expression in the embryonic stages of lung development.

Mammalian β-defensins are small cationic peptides that have been implicated in mediating innate immune defenses against microbial infection. Mouse β-defensin-14 (MBD-14), based on structural and functional similarities, appears to be an ortholog of human β-defensin-3 (HBD-3). Previous studies identified signaling pathway p38 mitogen-activated protein kinase (MAPK) that contributed to the expression of MBD-14 in mouse osteoblasts upon contacted with methicillin-resistance Staphylococcus aureus (MRSA) supernatant, which provided a theoretical basis as a promising therapeutic target in the treatment of intramedullary infection with MRSA in vivo. In this study, the medullary cavities of tibiae were contaminated with MRSA 10(3) colony forming units and different doses of p38 MAPK agonists anisomycin were followed as group III or IV in 30 mice. Fifteen animals that received phosphate- buffered saline served as group II and 15 mice were not contaminated with MRSA and received phosphate-buffered saline served as controls (group I). Follow-up was 7 days. In day 1, day 4 and day 7 postoperatively, infection was evaluated by blood routine, microbiological and histological analyses after sacrifice. All animals of group II developed microbiological and histological signs of infection. Histological signs of infection, white blood counts and cultures of group III and IV showed significantly reduced bacterial growth compared to cultures of group II. Simultaneously, different doses of anisomycin significantly induced the expression of osteoblast-associated genes, including alkaline phosphatase, osteocalcin and collagen type I. In addition, the expression of HBD-3 in human interfacial membranes around infected periprosthetic joint by staphylococcus contaminated was evaluated, and the expression pattern changed with significant induction of HBD-3 in infected periprosthetic joint compared with aseptic loosening under inflammatory conditions. Our primary study indicated that the potential antibacterial role of increased MBD-14 in the osteomyelitis mouse model.

BACKGROUND: A large number of human tumor-associated antigens that are recognized by CD8(+) T cells in a human leukocyte antigen class I (HLA-I)-restricted fashion have been identified. Special AT-rich sequence binding protein 1 (SATB1) is highly expressed in many types of human cancers as part of their neoplastic phenotype, and up-regulation of SATB1 expression is essential for tumor survival and metastasis, thus this protein may serve as a rational target for cancer vaccines. METHODOLOGY/PRINCIPAL FINDINGS: Twelve SATB1-derived peptides were predicted by an immuno-informatics approach based on the HLA-A*02 binding motif. These peptides were examined for their ability to induce peptide-specific T cell responses in peripheral blood mononuclear cells (PBMCs) obtained from HLA-A*02(+) healthy donors and/or HLA-A*02(+) cancer patients. The recognition of HLA-A*02(+) SATB1-expressing cancer cells was also tested. Among the twelve SATB1-derived peptides, SATB1(565-574) frequently induced peptide-specific T cell responses in PBMCs from both healthy donors and cancer patients. Importantly, SATB1(565-574)-specific T cells recognized and killed HLA-A*02(+) SATB1(+) cancer cells in an HLA-I-restricted manner. CONCLUSIONS/SIGNIFICANCE: We have identified a novel HLA-A*02-restricted SATB1-derived peptide epitope recognized by CD8(+) T cells, which, in turn, recognizes and kills HLA-A*02(+) SATB1(+) tumor cells. The SATB1-derived epitope identified may be used as a diagnostic marker as well as an immune target for development of cancer vaccines.

Prostate cancer is the most common cancer among elderly men in the US, and immunotherapy has been shown to be a promising strategy to treat patients with metastatic castration-resistant prostate cancer. Efforts to identify novel prostate specific tumor antigens will facilitate the development of effective cancer vaccines against prostate cancer. Prostate-specific G-protein coupled receptor (PSGR) is a novel antigen that has been shown to be specifically over-expressed in human prostate cancer tissues. In this study, we describe the identification of PSGR-derived peptide epitopes recognized by CD8(+) T cells in an HLA-A2 dependent manner.Twenty-one PSGR-derived peptides were predicted by an immuno-informatics approach based on the HLA-A2 binding motif. These peptides were examined for their ability to induce peptide-specific T cell responses in peripheral blood mononuclear cells (PBMCs) obtained from either HLA-A2(+) healthy donors or HLA-A2(+) prostate cancer patients. The recognition of HLA-A2 positive and PSGR expressing LNCaP cells was also tested. Among the 21 PSGR-derived peptides, three peptides, PSGR3, PSGR4 and PSGR14 frequently induced peptide-specific T cell responses in PBMCs from both healthy donors and prostate cancer patients. Importantly, these peptide-specific T cells recognized and killed LNCaP prostate cancer cells in an HLA class I-restricted manner.We have identified three novel HLA-A2-restricted PSGR-derived peptides recognized by CD8(+) T cells, which, in turn, recognize HLA-A2(+) and PSGR(+) tumor cells. The PSGR-derived peptides identified may be used as diagnostic markers as well as immune targets for development of anticancer vaccines.

OBJECTIVE: Activation of nuclear factor kappaB by diverse bacteria regulates the secretion of chemokines and cytokines. Staphylococcus aureus (S. aureus)-infected osteoblasts can significantly increase the secretion of interleukin-6 and monocyte chemoattractant protein-1. The aim of this study was to investigate whether S. aureus can activate nuclear factor kappaB in human osteoblasts, and whether the activation of nuclear factor kappaB by S. aureus regulates the secretion of interleukin-6 and monocyte chemoattractant protein-1. METHODS: Immunoblot and electrophoretic mobility shift assay were used to detect the degradation of IκBa and activation of nuclear factor kappaB in human osteoblasts in response to S. aureus, respectively. Enzyme-linked immunosorbent assay was used to measure the secretion of interleukin-6 and monocyte chemoattractant protein-1 in the supernatants. Lastly, carbobenzoxyl-l-leucinyl-l-leucinyl-l-leucinal, an inhibitor of the nuclear factor kappaB, was used to determine if activation of nuclear factor kappaB by S. aureus in human osteoblasts regulates the secretions of interleukin-6 and monocyte chemoattractant protein-1. RESULTS: Our results for the first time demonstrated that S. aureus can induce the degradation of IκBa and activation of nuclear factor kappaB in human osteoblasts in a time and dose-dependent manner. In addition, inhibition of nuclear factor kappaB by carbobenzoxyl-l-leucinyl-l-leucinyl-l-leucinal suppressed the secretion of interleukin-6 and monocyte chemoattractant protein-1 in the supernatants of S. aureus-infected human osteoblasts in a dose-dependent manner. CONCLUSION: These findings suggest that S. aureus can activate nuclear factor kappaB in human osteoblasts, and subsequently regulate the secretion of interleukin-6 and monocyte chemoattractant protein-1. The nuclear factor kappaB transcription factor regulates a number of genes involved in a wide variety of biological processes. Further study of the effects of nuclear factor kappaB activation on S. aureus-infected human osteoblast may provide us new insights into discovery of the immune mechanisms in osteomyelitis.

Polymyxins are a last-resort treatment option for multidrug-resistant gram-negative bacterial infections, but they are associated with nephrotoxicity. Gelofusine was previously shown to reduce polymyxin-associated kidney injury in an animal model. However, the mechanism(s) of renal protection has not been fully elucidated. Here, we report the use of a cell culture model to provide insights into the mechanisms of renal protection. Murine epithelial proximal tubular cells were exposed to polymyxin B. Cell viability, lactate dehydrogenase (LDH) release, polymyxin B uptake, mitochondrial superoxide production, nuclear morphology, and apoptosis activation were evaluated with or without concomitant gelofusine. A megalin knockout cell line was used as an uptake inhibition control. Methionine was included in selected experiments as an antioxidant control. A polymyxin B concentration-dependent reduction in cell viability was observed. Increased viability was observed in megalin knockout cells following comparable polymyxin B exposures. Compared with polymyxin B exposure alone, concomitant gelofusine significantly increased cell viability as well as reduced LDH release, polymyxin B uptake, mitochondrial superoxide, and apoptosis. Gelofusine and methionine were more effective at reducing renal cell injury in combination than either agent alone. In conclusion, the mechanisms of renal protection by gelofusine involve decreasing cellular drug uptake, reducing subsequent oxidative stress and apoptosis activation. These findings would be valuable for translational research into clinical strategies to attenuate drug-associated acute kidney injury. NEW & NOTEWORTHY Gelofusine is a gelatinous saline solution with the potential to attenuate polymyxin-associated nephrotoxicity. We demonstrated that the mechanisms of gelofusine renal protection involve reducing polymyxin B uptake by proximal tubule cells, limiting subsequent oxidative stress and apoptosis activation. In addition, gelofusine was more effective at reducing cellular injury than a known antioxidant control, methionine, and a megalin knockout cell line, indicating that gelofusine likely has additional pharmacological properties besides only megalin inhibition. [ABSTRACT FROM AUTHOR]