The clinical impact of preoperative physiotherapy on recovery after joint replacement remains controversial. This systematic review aimed to assess the clinical impact of prehabilitation before joint replacement.

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease affecting predominantly females. To discover additional genetic risk variants for SLE on the X chromosome, we performed a follow-up study of our previously published genome-wide association study (GWAS) data set in this study.

Recent research has shown that pathogen virulence can be altered by exposure to antibiotics, even when the growth rate is unaffected. Investigating this phenomenon provides new insights into understanding the virulence mechanisms of bacterial pathogens. This study investigates the phenotypic and transcriptomic responses of the rice pathogenic bacterium Acidovorax avenae subsp. avenae (Aaa) strain RS-1 to ß-lactam antibiotics especially Ampicillin (Amp). Our results indicate that exposure to Amp does not influence bacterial growth and biofilm formation, but alters the virulence, colonization capacity, composition of extracellular polymeric substances and secretion of Type VI secretion system (T6SS) effector Hcp. This attenuation in virulence is linked to unique or differential expression of known virulence-associated genes based on genome-wide transcriptomic analysis. The reliability of expression data generated by RNA-Seq was verified with quantitative real-time PCR of 21 selected T6SS genes, where significant down-regulation in expression of hcp gene, corresponding to the reduction in secretion of Hcp, was observed under exposure to Amp. Hcp is highlighted as a potential target for Amp, with similar changes observed in virulence-associated phenotypes between exposure to Amp and mutation of hcp gene. In addition, Hcp secretion is reduced in knockout mutants of 4 differentially expressed T6SS genes.

Endothelial cells (ECs) form blood vessels through angiogenesis that is regulated by coordination of vascular endothelial growth factor (VEGF), Notch, transforming growth factor β, and other signals, but the detailed molecular mechanisms remain unclear.

Lysine acetylated modification was indicated to impact colorectal cancer (CRC)'s distant metastasis. However, the global acetylated proteins in CRC and the differential expressed acetylated proteins and acetylated sites between CRC primary and distant metastatic tumor remains unclear. Our aim was to construct a complete atlas of acetylome in CRC and paired liver metastases. Combining high affinity enrichment of acetylated peptides with high sensitive mass spectrometry, we identified 603 acetylation sites from 316 proteins, among which 462 acetylation sites corresponding to 243 proteins were quantified. We further classified them into groups according to cell component, molecular function and biological process and analyzed the metabolic pathways, domain structures and protein interaction networks. Finally, we evaluated the differentially expressed lysine acetylation sites and revealed that 31 acetylated sites of 22 proteins were downregulated in CRC liver metastases compared to that in primary CRC while 40 acetylated sites of 32 proteins were upregulated, of which HIST2H3AK19Ac and H2BLK121Ac were the acetylated histones most changed, while TPM2 K152Ac and ADH1B K331Ac were the acetylated non-histones most altered. These results provide an expanded understanding of acetylome in CRC and its distant metastasis, and might prove applicable in the molecular targeted therapy of metastatic CRC.

Marrow mesenchymal stem cells (MSCs) can differentiate into specific phenotypes, including chondrocytes, and have been widely used for cartilage tissue engineering. However, cartilage grafts from MSCs exhibit phenotypic alternations after implantation, including matrix calcification and vascular ingrowth.

Epithelial-mesenchymal transition (EMT) plays a pivotal role in the development of cancer. Has-miR-200b-3p is generally recognized as one of the fundamental regulators of EMT. In this study, we found that the expression of miR-200b-3p was downregulated in glioma tissues and human glioma cells U87 and U251. Meanwhile, Up-regulating miR-200b-3p enhanced E-cadherin, reduced mesenchymal markers, and decreased cell proliferation, migration, and invasion in vitro. In vivo, the xenograft mouse model also unveiled the suppressive effects of miR-200b-3p on tumor growth. Additionally, The extracellular-regulated protein kinase 5 (ERK5) was confirmed as a direct target gene of miR-200b-3p. The direct suppression of ERK5 expressions by miR-200b-3p was revealed by luciferase reporter assay, quantitative RT-PCR analysis, and western blot. Moreover, we observed an inverse correlation between miR-200b-3p and ERK5 in human glioma tissues. In summary, our findings demonstrated that miR-200b-3p suppresses glioma tumor growth, invasion, and reverses EMT through downregulated its target ERK5.

IκBβis an inhibitor of nuclear factor kappa B(NF-κB) and participates in the cardiac response to sepsis. However, the role of the hypo-phosphorylated form of IκBβ at Ser313, which can be detected during sepsis, is unknown. Here, we examined the effects of IκBβ with a mutation at Ser313→Ala313 on cardiac damage induced by sepsis. Transgenic (Tg) mice were generated to overexpress IκBβ, in which Ser-313 is replaced with alanine ubiquitously, in order to mimic the hypo-phosphorylated form of IκBβ. Survival analysis showed that Tg mice exhibited decreased inflammatory cytokine levels and decreased rates of mortality in comparison to wild type (WT) mice, after sepsis in a cecal-ligation and puncture model (CLP). Compared to WT septic mice, sepsis in Tg mice resulted in improved cardiac functions, lower levels of troponin I and decreased rates of cardiomyocyte apoptosis, compared to WT mice. The increased formation of autophagicvacuoles detected with electron microscopy demonstrated the enhancement of cardiac autophagy. This phenomenon was further confirmed by the differential expression of genes related to autophagy, such as LC3, Atg5, Beclin-1, and p62. The increased expression of Cathepsin L(Ctsl), a specific marker for mitochondrial stress response, may be associated with the beneficial effects of the hypo-phosphorylated form of IκBβ. Our observations suggest that the hypo-phosphorylated form of IκBβ at Ser313 is beneficial to the heart in sepsis through inhibition of apoptosisand enhancement of autophagy in mutated IκBβ transgenic mice.

Seawater aspiration‑induced acute lung injury (ALI) is a syndrome associated with a high mortality rate, which is characterized by severe hypoxemia, pulmonary edema and inflammation. The present study is the first, to the best of our knowledge, to analyze gene expression profiles from a rat model of seawater aspiration‑induced ALI. Adult male Sprague‑Dawley rats were instilled with seawater (4 ml/kg) in the seawater aspiration‑induced ALI group (S group) or with distilled water (4 ml/kg) in the distilled water negative control group (D group). In the blank control group (C group) the rats' tracheae were exposed without instillation. Subsequently, lung samples were examined by histopathology; total protein concentration was detected in bronchoalveolar lavage fluid (BALF); lung wet/dry weight ratios were determined; and transcript expression was detected by gene sequencing analysis. The results demonstrated that histopathological alterations, pulmonary edema and total protein concentrations in BALF were increased in the S group compared with in the D group. Analysis of differential gene expression identified up and downregulated genes in the S group compared with in the D and C groups. A gene ontology analysis of the differential gene expression revealed enrichment of genes in the functional pathways associated with neutrophil chemotaxis, immune and defense responses, and cytokine activity. Kyoto Encyclopedia of Genes and Genomes analysis revealed that the cytokine‑cytokine receptor interaction pathway was one of the most important pathways involved in seawater aspiration‑induced ALI. In conclusion, activation of the cytokine‑cytokine receptor interaction pathway may have an essential role in the progression of seawater aspiration‑induced ALI, and the downregulation of tumor necrosis factor superfamily member 10 may enhance inflammation. Furthermore, IL‑6 may be considered a biomarker in seawater aspiration‑induced ALI.

Excessive accumulation of DNA damage will generate chromosome stress, leading to various chromosome abnormalities such as chromatin bridge and result in genomic instability. Orchestra procession and regulation of DNA damage repair are vital for keeping genome stability. Despite of the key role of HDAC1/2 in double strand break (DSB) repair, the regulation for their mode of action is less well understood. In this study, we found that deubiquitination enzymes USP19 physically interacts with HDAC1/2 and specifically regulate their K63-linked ubiquitination, which might be crucial for regulation of HDAC1/2 activity in DNA damage repair. Notably, we found that USP19 trans-locate into nucleus upon IR irradiation and is indispensable for normally DNA damage response. In addition, we showed that USP19 play critical role in preventing anaphase bridge formation through regulating DNA damage repair process. Furthermore, the expression level of USP19 is commonly lower or deleted in several types of tumor. These results indicated that USP19 is a key factor in modulating DNA damage repair by targeting HDAC1/2 K63-linked ubiquitination, cells with deletion or decreased expression of USP19 might cause genome instability and even contribute to tumorigenesis.

The expression of BRDT, a member of the BET sub-family of double bromodomain-containing proteins, is restricted to the male germ line, specifically to pachytene-diplotene spermatocytes and early spermatids. We previously showed that loss of the first bromodomain of BRDT by targeted mutagenesis (Brdt(ΔBD1) ) resulted in sterility and abnormalities in spermiogenesis, but little is known about BRDT's function at the molecular level. As part of studies designed to identify BRDT-interacting proteins we stably introduced a FLAG-tagged BRDT cDNA into 293T cells, which do not normally express BRDT. Affinity-purification of FLAG-tagged BRDT complexes indicated that BRDT has novel interactions with the histone deacetylase HDAC1, the arginine-specific histone methyltransferase 5 PRMT5, and the Tripartite motif-containing 28 protein TRIM28. Immunofluorescent microscopy revealed that BRDT co-localized with each of these proteins in round spermatids and co-immunoprecipitation of testicular extracts showed that these proteins interact with BRDT. Furthermore, they bind the promoter of H1t, a putative target of BRDT-containing complexes. This binding of H1t was lost in mice expressing the Brdt(ΔBD1) mutant protein and concomitantly, H1t expression was elevated in round spermatids. Our study reveals a role for BRDT-containing complexes in the repression of gene expression in vivo that correlates with dramatic effects on chromatin remodeling and the progression of spermiogenesis.

The regulation of stability is particularly crucial for unstable proteins in cells. However, a convenient and unbiased method of identifying regulators of protein stability remains to be developed. Recently, a genome-scale CRISPR-Cas9 library has been established as a genetic tool to mediate loss-of-function screening. Here, we developed a protein stability regulators screening assay (Pro-SRSA) by combining the whole-genome CRISPR-Cas9 library with a dual-fluorescence-based protein stability reporter and high-throughput sequencing to screen for regulators of protein stability. Using Cdc25A as an example, Cul4B-DDB1(DCAF8) was identified as a new E3 ligase for Cdc25A. Moreover, the acetylation of Cdc25A at lysine 150, which was acetylated by p300/CBP and deacetylated by HDAC3, prevented the ubiquitin-mediated degradation of Cdc25A by the proteasome. This is the first study to report that acetylation, as a novel posttranslational modification, modulates Cdc25A stability, and we suggest that this unbiased CRISPR-Cas9 screening method at the genome scale may be widely used to globally identify regulators of protein stability.

The MBW complex, comprised by R2R3-MYB, basic helix-loop-helix (bHLH) and WD40, is a single regulatory protein complex that drives the evolution of multiple traits such as flavonoid biosynthesis and epidermal cell differentiation in plants. In this study, two IIIf Clade-bHLH regulator genes, FhGL3L and FhTT8L, were isolated and functionally characterized from Freesia hybrida. Different spatio-temporal transcription patterns were observed showing diverse correlation with anthocyanin and proanthocyanidin accumulation. When overexpressed in Arabidopsis, FhGL3L could enhance the anthocyanin accumulation through up-regulating endogenous regulators and late structural genes. Unexpectedly, trichome formation was inhibited associating with the down-regulation of AtGL2. Comparably, only the accumulation of anthocyanins and proanthocyanidins was strengthened in FhTT8L transgenic lines. Furthermore, transient expression assays demonstrated that FhGL3L interacted with AtPAP1, AtTT2 and AtGL1, while FhTT8L only showed interaction with AtPAP1 and AtTT2. In addition, similar activation of the AtDFR promoter was found between AtPAP1-FhGL3L/FhTT8L and AtPAP1- AtGL3/AtTT8 combinations. When FhGL3L was fused with a strong activation domain VP16, it could activate the AtGL2 promoter when co-transfected with AtGL1. Therefore, it can be concluded that the functionality of bHLH factors may have diverged, and a sophisticated interaction and hierarchical network might exist in the regulation of flavonoid biosynthesis and trichome formation.

To investigate the thymic regenerative potential in adults accepting chemotherapy for lymphoma. The dynamics of thymic activity in 54 adults from baseline to 12 mo post-chemotherapy was analyzed by assessing thymic structural changes with serial computed tomography (CT) scans, and correlating these with measurements of thymic output by concurrent analysis of single-joint (sj) T-cell receptor excision circles (sjTREC) and CD31(+) recent thymic emigrants (RTE) in peripheral blood. Furthermore, the consequence of thymic renewal on peripheral CD4(+) T cell recovery after chemotherapy was evaluated. Time-dependent changes of thymic size and thymic output assessed by both sjTREC levels and CD31(+) RTE counts in peripheral blood were observed during and after chemotherapy. Enlargement of thymus over baseline following chemotherapy regarded as rebound thymic hyperplasia (TH) was identified in 20 patients aged 18-53 y (median 33 y). By general linear models repeated measure analysis, it was found that, patients with TH (n = 20) had a faster recovery of sjTREC levels and CD31(+) RTE counts after chemotherapy than patients with comparable age, gender, diagnosis, disease stage, thymic volume and output function at baseline but without TH (n = 18) (p = 0.035, 0.047); besides, patients with TH had a faster repopulation of both naïve CD4(+) T cell and natural regulatory CD4(+) T cell subsets than those without TH (p = 0.042, 0.038). These data suggested that adult thymus retains the capacity of regeneration after chemotherapy, especially in young adults. The presence of TH could contribute to the renewal of thymopoiesis and the replenishment of peripheral CD4(+) T cell pool following chemotherapy in adults.

PI3Kδ has been found to be over-expressed in B-Cell-related malignancies. Despite the clinical success of the first selective PI3Kδ inhibitor, CAL-101, inhibition of PI3Kδ itself did not show too much cytotoxic efficacy against cancer cells. One possible reason is that PI3Kδ inhibition induced autophagy that protects the cells from death. Since class III PI3K isoform PIK3C3/Vps34 participates in autophagy initiation and progression, we predicted that a PI3Kδ and Vps34 dual inhibitor might improve the anti-proliferative activity observed for PI3Kδ-targeted inhibitors. We discovered a highly potent ATP-competitive PI3Kδ/Vps34 dual inhibitor, PI3KD/V-IN-01, which displayed 10-1500 fold selectivity over other PI3K isoforms and did not inhibit any other kinases in the kinome. In cells, PI3KD/V-IN-01 showed 30-300 fold selectivity between PI3Kδ and other class I PI3K isoforms. PI3KD/V-IN-01 exhibited better anti-proliferative activity against AML, CLL and Burkitt lymphoma cell lines than known selective PI3Kδ and Vps34 inhibitors. Interestingly, we observed FLT3-ITD AML cells are more sensitive to PI3KD/V-IN-01 than the FLT3 wt expressing cells. In AML cell inoculated xenograft mouse model, PI3KD/V-IN-01 exhibited dose-dependent anti-tumor growth efficacies. These results suggest that dual inhibition of PI3Kδ and Vps34 might be a useful approach to improve the PI3Kδ inhibitor's anti-tumor efficacy.

There is considerable interest in the use of drugs and other methods for protecting implanted neural stem cells (NSCs) from the adverse environment of injured tissue for successful cell therapy. Resveratrol can modify cardiac stem cells to enhance their survival and differentiation, however, its effect and the mechanism underlying its neuroprotective effect on NSCs following stroke remain to be fully elucidated. Nuclear factor erythroid 2‑related factor 2 (Nrf‑2) signaling is important in antioxidative stress, and the role of Nrf‑2 signaling in the enhanced neuroprotection of NSCs by resveratrol following stroke also remains to be elucidated. In the present study, NSCs were pretreated with resveratrol prior to oxygen‑glucose deprivation/reoxygenation (OGD/R) in vitro. The survival, apoptosis and proliferation of the NSCs were assessed using an MTT assay, Hoechst 33258 staining of nuclei and flow cytometry, respectively. In addition, the activity of superoxide dismutase (SOD), level of malondiadehyde (MDA) and content of glutathione (GSH) were determined. The protein expressions levels of Nrf‑2, NAD(P)H:quinone oxidoreductase 1 (NQO‑1), and heme oxygenase 1 (HO‑1) were detected using western blot analysis. It was found that resveratrol markedly enhanced NSC survival and proliferation, decreased apoptosis and the levels of MDA, and increased the activity of SOD and content of GSH in a concentration‑dependent manner following OGD/R injury in vitro. In addition, the protein expression levels of Nrf2, HO‑1 and NQO1 were significantly upregulated. These findings suggested that resveratrol attenuated injury and promoted proliferation of the NSCs, at least in part, by upregulating the expression of Nrf2, HO‑1 and NQO1 following OGD/R injury in vitro.

The coordinating atoms in polydentate chelates are primarily heteroatoms. We present the first examples of pentadentate chelates with all binding atoms of the chelating agent being carbon atoms, denoted as CCCCC chelates. Having up to five metal-carbon bonds in the equatorial plane has not been previously observed in transition metal chemistry. Density functional theory calculations showed that the planar metallacycle has extended Craig-Möbius aromaticity arising from 12-center-12-electron dπ-pπ π-conjugation. These planar chelates have broad absorption in the ultraviolet-visible-near-infrared region and, thus, notable photothermal performance upon irradiation by an 808-nm laser, indicating that these chelates have potential applications in photothermal therapy. The combination of facile synthesis, high stability, and broad absorption of these complexes could make the polydentate carbon chain a novel building block in coordination chemistry.

It has been suggested that 1,25-dihydroxyvitamin D3 (vitamin D) plays a protective role against inflammation and insulin resistance (IR) in type 2 diabetes mellitus (T2DM). The present study investigate the hypothesis that vitamin D may exert beneficial effects on the liver in a rat model of T2DM by regulating the expression of inflammation-related cytokines and ameliorating IR induced by inflammation. Normal control group rats were fed a basic diet (NC). Experimental rats received a high-fat diet for 8 weeks and were then injected with streptozotocin (STZ) to induce T2DM. Half of the T2DM model rats received vitamin D (0.03 µg/kg/day) for 8 weeks (vitamin D-treated group; VD; n=11), while the other (T2DM group; DM; n=10) and NC group received an equivalent quantity of peanut oil. Following sacrifice, fasting plasma glucose (FPG) and fasting insulin (FINS) were recorded and homeostasis model assessment of IR (HOMA-IR) was calculated. Liver histopathology was examined using hematoxylin and eosin staining. The levels of the inflammatory cytokines C-Jun N-terminal kinase, C-Jun, tumor necrosis factor-α and interleukin-1β were measured using immunohistology, quantitative polymerase chain reaction and western blot analyses. The results revealed that treatment with vitamin D markedly alleviated the pathological alterations of liver and reduced the expression of inflammatory cytokines at the protein and mRNA levels. Furthermore, decreased levels of FPG, HOMA-IR and increased FINS were detected. In conclusion, the results of the present study indicate that vitamin D has therapeutic effects on diabetes-induced liver complications in T2DM model rats, which may involve the modulation of the inflammatory response, attenuating the crosstalk' between inflammation and IR and ameliorating hyperglycemic state.

The CD4(+) and CD8(+) T cell dichotomy is essential for effective cellular immunity. How individual T cell identity is established remains poorly understood. Here we show that the high-mobility group (HMG) transcription factors Tcf1 and Lef1 are essential for repressing CD4(+) lineage-associated genes including Cd4, Foxp3 and Rorc in CD8(+) T cells. Tcf1- and Lef1-deficient CD8(+) T cells exhibit histone hyperacetylation, which can be ascribed to intrinsic histone deacetylase (HDAC) activity in Tcf1 and Lef1. Mutation of five conserved amino acids in the Tcf1 HDAC domain diminishes HDAC activity and the ability to suppress CD4(+) lineage genes in CD8(+) T cells. These findings reveal that sequence-specific transcription factors can utilize intrinsic HDAC activity to guard cell identity by repressing lineage-inappropriate genes.

Several genome-wide association studies of primary biliary cirrhosis (PBC) in European and Japanese origins have shown significant association of dozens of genetic loci contributive to the susceptibility of PBC. Most of the loci were related to immune response pathway. In this study, we tested whether the lipid metabolic gene HELZ2 was associated with the pathogenesis of PBC.