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Platelets are generated from the cytoplasm of megakaryocytes (MKs) via actin cytoskeleton reorganization. Zyxin is a focal adhesion protein and wildly expressed in eukaryotes to regulate actin remodeling. Zyxin is upregulated during megakaryocytic differentiation; however, the role of zyxin in thrombopoiesis is unknown. Here we show that zyxin ablation results in profound macrothrombocytopenia. Platelet lifespan and thrombopoietin level were comparable between wild-type and zyxin-deficient mice, but MK maturation, demarcation membrane system formation, and proplatelet generation were obviously impaired in the absence of zyxin. Differential proteomic analysis of proteins associated with macrothrombocytopenia revealed that glycoprotein (GP) Ib-IX was significantly reduced in zyxin-deficient platelets. Moreover, GPIb-IX surface level was decreased in zyxin-deficient MKs. Knockdown of zyxin in a human megakaryocytic cell line resulted in GPIbα degradation by lysosomes leading to the reduction of GPIb-IX surface level. We further found that zyxin was colocalized with vasodilator-stimulated phosphoprotein (VASP), and loss of zyxin caused diffuse distribution of VASP and actin cytoskeleton disorganization in both platelets and MKs. Reconstitution of zyxin with VASP binding site in zyxin-deficient hematopoietic progenitor cell-derived MKs restored GPIb-IX surface expression and proplatelet generation. Taken together, our findings identify zyxin as a regulator of platelet biogenesis and GPIb-IX surface expression through VASP-mediated cytoskeleton reorganization, suggesting possible pathogenesis of macrothrombocytopenia.

Quercetin and kaempferol are flavonoids widely present in fruits, vegetables, and medicinal plants. They have attracted much attention due to their antioxidant, anti-inflammatory, anticancer, antibacterial, and neuroprotective properties. As the guarantee cells in direct contact with germ cells, Sertoli cells exert the role of support, nutrition, and protection in spermatogenesis. In the current study, network pharmacology was used to explore the targets and signaling pathways of quercetin and kaempferol in treating spermatogenic disorders. In vitro experiments were integrated to verify the results of quercetin and kaempferol against heat stress-induced Sertoli cell injury. The online platform was used to analyze the GO biological pathway and KEGG pathway. The results of the network pharmacology showed that quercetin and kaempferol intervention in spermatogenesis disorders were mostly targeting the oxidative response to oxidative stress, the ROS metabolic process and the NFκB pathway. The results of the cell experiment showed that Quercetin and kaempferol can prevent the decline of cell viability induced by heat stress, reduce the expression levels of HSP70 and ROS in Sertoli cells, reduce p-NF-κB-p65 and p-IκB levels, up-regulate the expression of occludin, vimentin and F-actin in Sertoli cells, and protect cell structure. Our research is the first to demonstrate that quercetin and kaempferol may exert effects in resisting the injury of cell viability and structure under heat stress.

Survival of motor neuron (SMN) functions in diverse biological pathways via recognition of symmetric dimethylarginine (Rme2s) on proteins by its Tudor domain, and deficiency of SMN leads to spinal muscular atrophy. Here we report a potent and selective antagonist with a 4-iminopyridine scaffold targeting the Tudor domain of SMN. Our structural and mutagenesis studies indicate that both the aromatic ring and imino groups of compound 1 contribute to its selective binding to SMN. Various on-target engagement assays support that compound 1 specifically recognizes SMN in a cellular context and prevents the interaction of SMN with the R1810me2s of RNA polymerase II subunit POLR2A, resulting in transcription termination and R-loop accumulation mimicking SMN depletion. Thus, in addition to the antisense, RNAi and CRISPR/Cas9 techniques, potent SMN antagonists could be used as an efficient tool to understand the biological functions of SMN.

BACKGROUND Leukaemias comprise a heterogenous group of haematological malignancies. In CONCORD-3, we analysed data for children (aged 0-14 years) and adults (aged 15-99 years) diagnosed with a haematological malignancy during 2000-14 in 61 countries. Here, we aimed to examine worldwide trends in survival from leukaemia, by age and morphology, in young patients (aged 0-24 years). METHODS We analysed data from 258 population-based cancer registries in 61 countries participating in CONCORD-3 that submitted data on patients diagnosed with leukaemia. We grouped patients by age as children (0-14 years), adolescents (15-19 years), and young adults (20-24 years). We categorised leukaemia subtypes according to the International Classification of Childhood Cancer (ICCC-3), updated with International Classification of Diseases for Oncology, third edition (ICD-O-3) codes. We estimated 5-year net survival by age and morphology, with 95% CIs, using the non-parametric Pohar-Perme estimator. To control for background mortality, we used life tables by country or region, single year of age, single calendar year and sex, and, where possible, by race or ethnicity. All-age survival estimates were standardised to the marginal distribution of young people with leukaemia included in the analysis. FINDINGS 164 563 young people were included in this analysis: 121 328 (73·7%) children, 22 963 (14·0%) adolescents, and 20 272 (12·3%) young adults. In 2010-14, the most common subtypes were lymphoid leukaemia (28 205 [68·2%] patients) and acute myeloid leukaemia (7863 [19·0%] patients). Age-standardised 5-year net survival in children, adolescents, and young adults for all leukaemias combined during 2010-14 varied widely, ranging from 46% in Mexico to more than 85% in Canada, Cyprus, Belgium, Denmark, Finland, and Australia. Individuals with lymphoid leukaemia had better age-standardised survival (from 43% in Ecuador to ≥80% in parts of Europe, North America, Oceania, and Asia) than those with acute myeloid leukaemia (from 32% in Peru to ≥70% in most high-income countries in Europe, North America, and Oceania). Throughout 2000-14, survival from all leukaemias combined remained consistently higher for children than adolescents and young adults, and minimal improvement was seen for adolescents and young adults in most countries. INTERPRETATION This study offers the first worldwide picture of population-based survival from leukaemia in children, adolescents, and young adults. Adolescents and young adults diagnosed with leukaemia continue to have lower survival than children. Trends in survival from leukaemia for adolescents and young adults are important indicators of the quality of cancer management in this age group. FUNDING Children with Cancer UK, the Institut National du Cancer, La Ligue Contre le Cancer, Centers for Disease Control and Prevention, Swiss Re, Swiss Cancer Research foundation, Swiss Cancer League, Rossy Family Foundation, US National Cancer Institute, and the American Cancer Society.

Jie Xia,1– 4,* Lina Sun,5,* Suqin Xu,1– 4 Qiu Xiang,1– 4 Jianping Zhao,1– 4 Weining Xiong,1– 4 Yongjian Xu,1– 4 Shuyuan Chu1– 4,6 1Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, People’s Republic of China; 2Wuhan Clinical Medical Research Center for Chronic Airway Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, People’s Republic of China; 3Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, People’s Republic of China; 4Key Site of National Clinical Research Center for Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, People’s Republic of China; 5Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, People’s Republic of China; 6Laboratory of Respiratory Disease, Affiliated Hospital of Guilin Medical University, Guilin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuyuan Chu; Jie XiaDepartment of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, People’s Republic of ChinaTel +8613978345180; +8627-83665520Email emilyyuanchu@163.com; xiajhzu1215@126.comPurpose: Patients with chronic obstructive pulmonary disease (COPD) would have a poor prognosis if they were not continuously managed according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. We aim to develop a model to classify whether COPD patients have been continuously managed according to GOLD in the previous year.Methods: The Managed group were COPD patients from a prospectivecohort from November 2017 to November 2019, who have been continuously managed according to GOLD for 1 year. The Control group were COPD patients who were not continuously managed according to GOLD. They were from a retrospective cohort from October 2016 to October 2017 in the same hospitals as the Managed group. A synthetic minority over-sampling technique (SMOTE) algorithm was used to up-sample the Managed group in a training dataset. Features for classification were selected using a support vector machine recursive feature elimination (SVM-RFE) algorithm. The classification model was developed using LibSVM, and its performance was assessed on the testing dataset.Results: The final analysis included 15 subjects in the Managed group and 191 in the Control group. SVM-RFE selects nine features including smoking history, post-bronchodilator (post-)FVC before management, and those after 1-year follow-up (BMI, moderate and severe AECOPD frequency in previous 12 months, mMRC score, post-FEV1, post-FEV1%pred, post-FVC, and post-FEV1/FVC). For our model, positive predictive value is 66.7%, F1 score is 0.978, and AUC is 0.987.Conclusion: SVM classifier combined with SVM-REF feature selection algorithm could achieve good classification between COPD patients who are or are not continuously managed. This model could be applied in clinical practice to help doctors make decisions and enhance COPD patients’ compliance with standard treatment.Keywords: COPD, GOLD, continuous management, support vector machine

Phostensin (PTS) encoded by KIAA1949 is a protein phosphatase 1 (PP1)-binding protein. In order to explore the cellular functions of PTS, we have searched PTS-binding proteins by using co-immunoprecipitation in combination with shotgun proteomics. Here, we report two novel PTS-binding proteins, Eps 15 homology domain-containing protein 1 (EHD1) and EHD4. PTS associated with EHD proteins was also observed in GST pull-down assays. Immunofluorescence microscopy demonstrated that the complex was co-localized at the endocytic vesicles. EHD proteins have been known to play a critical role in regulation of endocytic transport. Overexpression of PTS-β can attenuate the endocytic trafficking of transferrin.

Rheumatoid arthritis (RA) is a persistent autoimmune disease. Fibroblast-like synoviocytes (FLS) are a key component of invasive pannus and a pathogenetic mechanism in RA. Expression of bone morphogenetic protein 3 (BMP3) mRNA is reportedly decreased in the arthritic synovium. We previously showed that BMP3 expression is significantly downregulated in the synovial tissues of RA patients and models of adjuvant-induced arthritis (AIA). In the present study, we explored the association between BMP3 and FLS migration and secretion of proinflammatory factors in RA. We found that inhibition of BMP3 expression using BMP3 siRNA increased the proinflammatory chemokines and migration of FLS stimulated with TNF-α. Inhibition of BMP3 expression also increased expression of IL-6, IL-1β, IL-17A, CCL-2, CCL-3, VCAM-1, MMP-3, and MMP-9, but not TIMP-1, in AIA and RA FLS. Correspondingly, induction of BMP3 overexpression through intra-articular injection of ad-BMP3 diminished arthritis severity in AIA rats. We also found that BMP3 may inhibit activation of TGF-β1/Smad signaling. These data indicate that BMP3 may suppress the proliferation and migration of FLS via the TGF-β1/Smad signaling pathway.

Rheumatoid arthritis is a chronic systemic autoimmune disease characterized by synovial hyperplasia, inflammatory cell infiltration, and proliferation of inflammatory tissue (angiogranuloma). The destruction of joints and surrounding tissues eventually causes joint deformities and dysfunction or even loss. The S100 protein family is one of the biggest subtribes in the calcium-binding protein family and has more than 20 members. The overexpression of most S100 proteins in rheumatoid arthritis is closely related to its pathogenesis. This paper reviews the relationship between S100 proteins and the occurrence and development of rheumatoid arthritis. It will provide insights into the development of new clinical diagnostic markers and therapeutic targets for rheumatoid arthritis.

The best time window of percutaneous coronary intervention (PCI) is within 12 hours for ST-segment elevation myocardial infarction (STEMI). However, there is limited evidence about the proper time of PCI for delayed STEMI patients. From June 2014 to June 2015, a total of 268 patients receiving PCI with second-generation drug-eluting stent in a Chinese hospital after 3 days of STEMI onset were enrolled in this retrospective study, who were divided into the early group (3–14 days) and the late group (>14 days). A propensity score match was conducted to reduce the baseline difference. The primary endpoint of all-cause death and secondary endpoints of major adverse cardiac and cerebrovascular event (myocardial infarction [MI], stroke, emergent revascularization, and rehospitalization due to heart failure) were compared using survival analysis. At last, 182 cases were matched after propensity score match, with no statistical difference in baseline characteristics and PCI data. Kaplan-Meier survival curve demonstrated no difference in all-cause death of the 2 groups (P = .512). However, the early group presented a higher incidence of MI than the late group (P = .036). The multivariate Cox regression analysis also demonstrated that the early PCI was an independent risk factor for MI compared with late PCI (hazard ratio = 3.83, 95%CI [1.91–8.82], P = .001). There was no statistical difference in other major adverse cardiac and cerebrovascular event, including stroke, emergent revascularization, and rehospitalization due to heart failure. Using the 2nd drug-eluting stent, early PCI (3–14 days) and late PCI (>14 days) have comparable efficacy and outcomes. However, patients receiving early PCI are subjected to a relatively higher risk of recurrent MI.

Background and Objectives: Ankylosing spondylitis (AS) is a chronic inflammatory disease and is highly linked with the expression of the human leukocytic antigen-B*27 (HLA-B*27) genotype. HLA-B*27 heavy chain (B*27-HC) has an innate characteristic to slowly fold, resulting in the accumulation of the misfolded B*27-HC and the formation of homo-oligomeric B*27-HC molecules. The homo-oligomeric B*27-HC can act as a ligand of KIR3DL2. Interaction of the homo-oligomeric B*27-HC molecules with KIR3DL2 will trigger the survival and activation of KIR3DL2-positive NK cells. However, the effects of homo-oligomeric B*27-HC molecules associated with KIR3DL2 on the cytotoxic activity of NK cells and their cytokine expressions remain unknown. Materials and Methods: HLA-B*-2704-HC was overexpressed in the HMy2.C1R (C1R) cell line. Western blotting and quantitative RT-PCR were used to analyze the protein expression and cytokine expression, respectively, when C1R-B*-2704 cells that overexpress B*2704-HC were co-cultured with NK-92MI cells. Flow cytometry was used to analyze the cytotoxicity mediated by NK-92MI cells. Results: Our results revealed that NK-92MI cells up-regulated the expression of perforin and enhanced the cytotoxic activity via augmentation of PI3K/AKT signaling after co-culturing with C1R-B*2704 cells. Suppression of the dimerized B*27-HC formation or treatment with an inhibitor of PI3K, LY294002, or with an anti-B*27-HC monoclonal antibody can reduce the perforin expression of NK-92MI after co-culturing with C1R-B*-2704. Co-culturing with C1R-B*-2704 cells suppressed the TNF-α and IL6 expressions of NK-92MI cells. Conclusion: Stimulation of NK cell-mediated cytotoxicity by homo-oligomeric B*27-HC molecules may contribute to the pathogenesis of AS.

Targeted analysis of sequential window acquisition of all theoretical mass spectra (SWATH-MS) requires the spectral library, which can be generated by shotgun mass spectrometry (MS) or by the pseudo-spectra files directly obtained from SWATH-MS data. The external library generated by shotgun MS is employed in most SWATH-MS research. However, performance of the internal library, which is constructed by pseudo-spectra files, in the targeted analysis of SWATH-MS has not been systemically evaluated. Here, we show that up to 40% of the peptides detected by the internal library were not overlapped with those detected by the external library for most SWATH-MS data sets. However, the internal library did not identify extra phosphopeptides compared with the external library for phosphoproteomic SWATH-MS data. Therefore, the internal library should be incorporated into the external library for targeted analysis of nonphosphoproteomic SWATH-MS, given that it can significantly increase the number of peptides of SWATH-MS without requiring additional instrument measurement time.

MLL3 and MLL4 are two closely related members of the SET1/MLL family of histone H3K4 methyltransferases and are responsible for monomethylating histone H3K4 on enhancers, which are essential in regulating cell-type-specific gene expression. Mutations of MLL3 or MLL4 have been reported in different types of cancer. Recently, the PHD domains of MLL3/4 have been reported to recruit the MLL3/4 complexes to their target genes by binding to histone H4 during the NT2/D1 stem cell differentiation. Here we show that an extended PHD domain (ePHD6) involving the sixth PHD domain and its preceding zinc finger in MLL3 and MLL4 specifically recognizes an H4H18-containing histone H4 fragment and that modifications of residues surrounding H4H18 modulate H4 binding to MLL3/4. Our in vitro methyltransferase assays and cellular experiments further reveal that the interaction between ePHD6 of MLL3/4 and histone H4 is required for their nucleosomal methylation activity and MLL4-mediated neuronal differentiation of NT2/D1 cells., MLL3 and MLL4 are members of the SET1/MLL family of histone H3K4 methyltransferases, which are responsible for monomethylating histone H3K4 on enhancers. Here the authors show that an extended PHD domain (ePHD6) in MLL3 and MLL4 specifically recognizes an H4H18-containing fragment of histone H4, and that modifications of residues surrounding H4H18 modulate H4 binding to MLL3/4.

The corticotropin-releasing hormone (CRH) family is widely distributed among the central nervous system and peripheral tissues, such as the digestive, cardiovascular, immune, reproductive, endocrine systems. The CRH family members are widely involved in the regulation of human cell biological processes, immune response, and regulation of inflammatory processes that can affect the occurrence and development of tumors. At present, CRH family members and their receptors can be detected in many tumor tissues, and some people think that members of the CRH family may be potential tumor treatment targets as they can affect cellular processes, such as proliferation, migration, invasion, and apoptosis. However currently, there is no systematic introduction to the relationship between the CRH family and various tumors. This review introduces the molecular regulation of the CRH family in tumor formation and seeks further targeted therapy.

Ankylosing spondylitis (AS) is a chronic inflammatory disease that mainly affects the spine. AS is highly associated with the expression of HLA-B27. Up to 95% AS patients are HLA-B27-positive. However, only 1%–2% of the HLA-B27-positive carriers suffer from AS, implying that other factors may also govern the development of AS. Long non-coding RNAs (lncRNAs) can regulate the immune response via their binding proteins. In the present study, we have identified that the levels of lncRNA, LOC645166, in T cells of AS patients were reduced. Overexpression of LOC645166 in Jurkat cells down-regulated the IL-23p19 expression and suppressed the JAK2/STAT3 signaling in response to stimulation by phorbol 12-myristate 13-acetate. Suppression of STAT3 activation by LOC645166 was also observed when Jurkat cells or T cells of AS patient were treated with anti-CD3/CD28 antibodies. In order to explore the role of LOC645166 in the pathogenesis of AS, RNA pull-down assay plus proteomic approach and western blotting were performed and identified that LOC645166 prefers binding the K63-linked polyubiquitin chains. LOC645166 can suppress recruitment of the IKK complex to K63-linked polyubiquitin chains and diminish IKK2 activation, leading to down-regulation of NF-κB activation. Down-regulation of LOC645166 expression in T cells of AS patients up-regulates NF-kB activation via decreasingly impeding recruitment of the IKK complex to K63-linked polyubiquitin chains, allowing AS patients to exhibit more sensitivity to stimulation by the proinflammatory cytokines or by TLR ligands.

International audience; Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations,and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR= 25, P=2.9 x 10-14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10-8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

The PWWP domain was first identified in the HDGF protein family and named after the conserved Proline-Tryptophan-Tryptophan-Proline motif in WHSC1. The PWWP domain-containing proteins play important roles in different biological processes, such as DNA replication, transcription, DNA repair, pre-mRNA processing by recognizing methylated histone and dsDNA simultaneously. Recently, how the HDGF family of PWWP domains recognize histone H3K36me3-modified nucleosome has been reported. In order to better understand the interactions between the PWWP domain and dsDNA, we carried out family-wide characterization of dsDNA binding abilities of human PWWP domains. Our binding assays confirmed that PWWP domains bind to dsDNA without sequence selectivity. Our crystal structure of the BRPF2 PWWP domain in complex with a 12-mer dsDNA reveals that the PWWP domain interacts with dsDNA by binding to its major groove, instead of the minor groove observed in the HDGF family of PWWP domains. Our study indicates that PWWP domains could bind to dsDNA in different modes.

To investigate the inducing effect of PKA inhibitor H89 of different concentrations on platelet apoptosis and its mechanism.Platelets were isolated from peripheral venous blood of healthy volunteers. Different concentrations gradient PKA inhibitor H89 were co-incubated with washing platelets, and the effects of PKA inhibitor H89 at different concentrations on platelet mitochondrial membrane potential, phosphatidylserine and reactive oxygen species(ROS) were determined by ELISA and flow cytometry.Different concentration of PKA inhibitor H89 could induce the depolarization of mitochondrial membrane potential and PS exposure of platelet. However, high concentration(100 μmol/L) PKA inhibitor H89 could induce the production of ROS in platelets, but medium and low concentrations did not induce the production of ROS in platelets. And several ROS inhibitors could inhibit the apoptosis induced by high concentration PKA inhibitor H89.High concentration H89 can induce platelet apoptosis, however the mechanism of platelet apoptosis caused by H89 of high concentration is different from H89 at medium and low concentrations.不同浓度PKA抑制剂对血小板凋亡的诱导作用及机制.探讨不同浓度PKA抑制剂H89对血小板凋亡的诱导作用和机制.取健康志愿者外周静脉血分离血小板，选择不同浓度梯度的PKA抑制剂H89与经洗涤的血小板共同孵育，应用酶联免疫吸附试验、流式细胞术等检测不同浓度PKA抑制剂H89对血小板线粒体膜电位（Mitochondrial membrane potential，Δψm）、磷脂酰丝氨酸（Phosphatidylserine，PS）和活性氧（Reactive oxygen species，ROS）的影响.不同浓度PKA抑制剂H89均能诱导血小板发生Δψm去极化和PS暴露，但高浓度（100 μmol/L）PKA抑制剂H89可诱导血小板产生ROS，而中低浓度则不会诱导血小板内ROS的产生，并且多种ROS抑制剂均可抑制高浓度H89诱导的凋亡.高浓度的PKA抑制剂H89能诱导血小板凋亡，但是作用机制不同于中低浓度.

Fluorescent brighteners, illegally used to whitening wheat flour, are detrimental to people health. The aim was to establish a rapid and direct method to identify and quantify fluorescent whitening agent OB-1 (FWA OB-1) in wheat flour by using multi-molecular infrared (MM-IR) spectroscopy combined with stereomicroscopy. Characteristic peak profile of FWA OB-1 used as a judgment basis was spatially revealed by stereomicroscopy with group-peak matching of MM-IR at 1614 cm−1, 1501 cm−1 and 893 cm−1 and were further unveiled by the second derivative infrared spectroscopy (SD-IR) and its two-dimensional correlation infrared (SD-2DCOS IR) spectroscopy for higher resolution, and were validated by high-performance liquid chromatography (HPLC). Moreover, a quantitative prediction model based on IR spectra was established by partial least squares 1 (PLS1) (R2, 98.361; SEE, 5.032; SEP, 5.581). The developed method was applicable for rapid and direct analysis of FWA OB-1 (low to 10 ppm) in flour with relative standard deviation (RSD) of 5%. The capabilities of MM-IR with spectral qualitative and quantitative analysis would be applicable to direct identification and quantitation of fluorescent whitening agents or other IR-active compounds in powder objects.

We developed a label-free, real-time, and highly sensitive nucleic acid biosensor based on fiber optic particle plasmon resonance (FOPPR). The biosensor employs a single-strand deoxyoligonucleotides (ssDNA) probe, conjugated to immobilized gold nanoparticles on the core surface of an optical fiber. We explore the steric effects on hybridization affinity and limit of detection (LOD), by using different ssDNA probe designs and surface chemistries, including diluent molecules of different lengths in mixed self-assembled monolayers, ssDNA probes of different oligonucleotide lengths, ssDNA probes in different orientations to accommodate target oligonucleotides with a hybridization region located unevenly in the strand. Based on the optimized ssDNA probe design and surface chemistry, we achieved LOD at sub-nM level, which makes detection of target oligonucleotides as low as 1 fmol possible in the 10-μL sensor chip. Additionally, the FOPPR biosensor shows a good correlation in determining HLA-B27 mRNA, in extracted blood samples from patients with ankylosing spondylitis (AS), with the clinically accepted real-time reverse transcription-polymerase chain reaction (RT-PCR) method. The results from this fundamental study should guide the design of ssDNA probe for anti-sense sensing. Further results through application to HLA-B27 mRNA detection illustrate the feasibility in detecting various nucleic acids of chemical and biological relevance.

Summary The CDY (chromodomain on the Y) proteins play an essential role in normal spermatogenesis and brain development. Dysregulation of their expression has been linked to male infertility and various neurological diseases. Like the chromodomains of HP1 and Polycomb, the CDY chromodomains also recognize the lysine-methylated ARKS motif embedded in histone and non-histone proteins. Interestingly, the CDY chromodomains exhibit different binding preferences for the lysine-methylated ARKS motif in different sequence contexts. Here, we present the structural basis for selective binding of CDY1 to H3K9me3 and preferential binding of CDYL2 to H3tK27me3 over H3K27me3. In addition, we use a CDYL1/2-selective compound, UNC4850, to gain further insight into the molecular mechanisms underlying CDYL2 binding specificity. Our work also provides critical implications that CDYL1b's role in the regulation of neural development is dependent on its recognition of the lysine-methylated ARKS motif.

The mixed-lineage leukemia (MLL)-AF10 fusion oncoprotein recruits DOT1L to the homeobox A (HOXA) gene cluster through its octapeptide motif leucine zipper (OM-LZ), thereby inducing and maintaining the MLL-AF10-associated leukemogenesis. However, the recognition mechanism between DOT1L and MLL-AF10 is unclear. Here, we present the crystal structures of both apo AF10OM-LZ and its complex with the coiled-coil domain of DOT1L. Disruption of the DOT1L–AF10 interface abrogates MLL-AF10-associated leukemic transformation. We further show that zinc stabilizes the DOT1L–AF10 complex and may be involved in the regulation of the HOXA gene expression. Our studies may also pave the way for the rational design of therapeutic drugs against MLL-rearranged leukemia.

Background: One-lung ventilation (OLV) is a common ventilation technology during thoracic surgery that can cause serious clinical problems. We aimed to conduct a meta-analysis to compare oxygenation and intrapulmonary shunt during OLV in adults undergoing thoracic surgery with dexmedetomidine (Dex) versus placebo to assess the influence and safety of using Dex. Methods: Randomized controlled trials comparing lung protection in patients who underwent thoracic surgery with Dex or a placebo were retrieved from PubMed, EMBASE, MEDLINE, Cochrane Library, and China CNKI database. The following information was extracted from the paper: arterial oxygen partial pressure (PaO2), PaO2/inspired oxygen concentration (PaO2/FiO2, oxygenation index [OI]), intrapulmonary shunt (calculated as Qs/Qt), mean arterial pressure (MAP), heart rate (HR), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, superoxide dismutase (SOD), and malondialdehyde (MDA). Results: Fourteen randomized controlled trials were included containing a total of 625 patients. Compared with placebo group, Dex significantly increased PaO2/FiO2 (standard mean difference [SMD] = 0.98, 95% confidence interval [CI] [0.72, 1.23], P < 0.00001). Besides, Qs/Qt (SMD= −1.22, 95% CI [−2.20, −0.23], P = 0.020), HR (SMD= −0.69, 95% CI [−1.20, 0.17], P = 0.009), MAP (SMD= −0.44, 95% CI [−0.84, 0.04], P = 0.030), the concentrations of TNF-α (SMD = −1.55, 95% CI [−2.16, −0.95], P

Hepatic fibrosis induced by schistosomes is regulated by a complex network of cytokines. T helper type 9 (Th9) cells are a new type of effector T helper cells, which mainly secrete the specific cytokine interleukin-9 (IL-9). Interleukin-9 has been shown to contribute to liver fibrosis in patients with chronic hepatitis B and in a mouse model due to carbon tetrachloride. However, the role of IL-9 in schistosomiasis fibrosis remains unknown. In this study, we investigated the roles of IL-9 in schistosomiasis through in vivo and in vitro studies. The in vivo studies found that neutralization of IL-9 reduced liver granulomatous inflammation and collagen deposition around parasite eggs. The in vitro studies found that the treatment of primary hepatic stellate cells with IL-9 induced a significant increase of collagen and α-smooth-muscle actin. Moreover, we also described the dynamics and relevance of IL-9 and IL-4 in mice infected with Schistosoma japonicum. We found that IL-9 might appear more quickly and at higher levels than IL-4. Hence, our findings indicated that IL-9 might play a role in regulating hepatic fibrosis in early-stage schistosomiasis and become a promising approach for regulating hepatic fibrosis caused by S. japonicum.

Supplemental Digital Content is available in the text, Background: To compare the clinical efficacy and safety of phloroglucinol (PHL) and magnesium sulfate (MS) in the treatment of threatened abortion through systematic review. Methods: Foreign databases, such as the Cochrane Library, PubMed and EMBASE, and Chinese databases, including the China Biology Medicine disc (SinoMed), China National Knowledge Infrastructure (CNKI), Chongqing VIP (VIP) and WanFang Data, were searched. Published randomized controlled trials (RCTs) documents obtained from these databases were included if they were associated with the research objective. The search timeframe was from the beginning of the establishment of each database to May 2018. Document selection, data abstraction and document quality evaluation were independently performed by 2 investigators. A combined analysis of the data was performed for those documents that fulfilled the study requirements; Rev Man 5.3 and Stata 12.0 software were used to compare and analyze the 2 drugs in terms of the total effective rate (TER), rate of adverse events, time required to relieve uterine contractions, onset time, time of complete relief of uterine contraction symptoms, medication duration and length of hospital stay. Results: A total of 21 RCT trials were included in the present research, according to the inclusion criteria. However, the quality of the included studies was low. The meta-analysis suggested that the TER and drug onset time of PHL were higher than those for MS, while the rate of adverse events, the time required to relieve uterine contractions, time to complete relief of uterine contraction symptoms, drug continuous treatment time and length of hospital stay were shorter than those for MS. Conclusion: The clinical efficacy of PHL is better than that of MS, and PHL obviously results in fewer adverse reactions than MS. However, due to poor quality of evidence, high quality, multi-center RCTs with large samples are required for further verification.

Interferons (IFNs) play an important role in immunomodulatory and antiviral functions. IFN-induced necroptosis has been reported in cells deficient in receptor-interacting protein kinase 1 (RIPK1), Fas-associated protein with death domain (FADD), or caspase-8, but the mechanism is largely unknown. Here, we report that the DNA-dependent activator of IFN regulatory factors (ZBP1, also known as DAI) is required for both type I (β) and type II (γ) IFN-induced necroptosis. We show that L929 fibroblast cells became susceptible to IFN-induced necroptosis when RIPK1, FADD, or Caspase-8 was genetically deleted, confirming the antinecroptotic role of these proteins in IFN signaling. We found that the pronecroptotic signal from IFN stimulation depends on new protein synthesis and identified ZBP1, an IFN-stimulated gene (ISG) product, as the de novo synthesized protein that triggers necroptosis in IFN-stimulated cells. The N-terminal domain (ND) of ZBP1 is important for ZBP1–ZBP1 homointeraction, and its RHIM domain in the C-terminal region interacts with RIPK3 to initiate RIPK3-dependent necroptosis. The antinecroptotic function of RIPK1, FADD, and caspase-8 in IFN-treated cells is most likely executed by caspase-8-mediated cleavage of RIPK3, since the inhibitory effect on necroptosis was eliminated when the caspase-8 cleavage site in RIPK3 was mutated. ZBP1-mediated necroptosis in IFN-treated cells is likely physiologically relevant, as ZBP1 KO mice were significantly protected against acute systemic inflammatory response syndrome (SIRS) induced by TNF + IFN-γ.

The selection of therapy for benign esophageal lesions depends in part on whether the lesion extends to or through the esophageal muscle wall. The advent of endoscopic dissection of deep lesions has made this distinction important in the choice between different forms of advanced endoscopic therapy. The goal of this study was to evaluate esophageal insufflation computed tomography (EICT) for the diagnosis and management of esophageal submucosal tumors (SMTs). Between April 2011 and May 2013 at the Second Affiliated Hospital of Harbin Medical University, 27 patients with esophageal SMTs diagnosed by gastroscopy were studied observationally. Entry criteria included tumors larger than 0.5 cm. We compared endoscopic ultrasound (EUS) and EICT to assess lesion depth and the relationship between the submucosal lesion and the esophageal wall using the resected lesion as the gold standard. Twenty-seven esophageal SMTs were evaluated. EUS and EICT accurately identified nine as superficial to the muscularis propria. EICT correctly identified the relation of the tumor extension and the outer esophageal wall in all 18 lesions that originated from the muscularis propria; only nine were correctly assessed by EUS (P

We report the design and characterization of UNC3866, a potent antagonist of the methyllysine (Kme) reading function of the Polycomb CBX and CDY families of chromodomains. Polycomb CBX proteins regulate gene expression by targeting Polycomb repressive complex 1 (PRC1) to sites of H3K27me3 via their chromodomains. UNC3866 binds the chromodomains of CBX4 and CBX7 most potently, with a K d of â ∼1/4100 nM for each, and is 6-to 18-fold selective as compared to seven other CBX and CDY chromodomains while being highly selective over >250 other protein targets. X-ray crystallography revealed that UNC3866's interactions with the CBX chromodomains closely mimic those of the methylated H3 tail. UNC4195, a biotinylated derivative of UNC3866, was used to demonstrate that UNC3866 engages intact PRC1 and that EED incorporation into PRC1 is isoform dependent in PC3 prostate cancer cells. Finally, UNC3866 inhibits PC3 cell proliferation, consistent with the known ability of CBX7 overexpression to confer a growth advantage, whereas UNC4219, a methylated negative control compound, has negligible effects.

TXNIP (thioredoxin-interacting protein) negatively regulates the antioxidative activity of thioredoxin and participates in pleiotropic cellular processes. Its deregulation is linked to various human diseases, including diabetes, acute myeloid leukaemia and cardiovascular diseases. The E3 ubiquitin ligase Itch (Itchy homologue) polyubiquitinates TXNIP to promote its degradation via the ubiquitin–proteasome pathway, and this Itch-mediated polyubiquitination of TXNIP is dependent on the interaction of the four WW domains of Itch with the two PPxY motifs of TXNIP. However, the molecular mechanism of this interaction of TXNIP with Itch remains elusive. In the present study, we found that each of the four WW domains of Itch exhibited different binding affinities for TXNIP, whereas multivalent engagement between the four WW domains of Itch and the two PPxY motifs of TXNIP resulted in their strong binding avidity. Our structural analyses demonstrated that the third and fourth WW domains of Itch were able to recognize both PPxY motifs of TXNIP simultaneously, supporting a multivalent binding mode between Itch and TXNIP. Interestingly, the phosphorylation status on the tyrosine residue of the PPxY motifs of TXNIP serves as a molecular switch in its choice of binding partners and thereby downstream biological signalling outcomes. Phosphorylation of this tyrosine residue of TXNIP diminished the binding capability of PPxY motifs of TXNIP to Itch, whereas this phosphorylation is a prerequisite to the binding activity of TXNIP to SHP2 [SH2 (Src homology 2) domain-containing protein tyrosine phosphatase 2] and their roles in stabilizing the phosphorylation and activation of CSK (c-Src tyrosine kinase).

TM5441, a furan-containing drug, is an inhibitor of plasminogen activator inhibitor-1 (PAI-1), which can induce intrinsic apoptosis of human cancer cell lines. The aim of this study was to identify the reactive metabolites of TM5441 and to reveal the bioactivation pathways that are associated with its hepatotoxicity. The reactive metabolites were trapped by using glutathione (GSH) or N-acetyl-lysine (NAL) in rat, dog, and human liver microsomal incubation system after exposure to TM5441. Two metabolic activation pathways were disclosed. The first bioactivation pathway was dominated by Cytochrome P450 enzymes (CYP450s); TM5441 was metabolized into cis-2-butene-1,4-dial derivative dependent on NADPH, which can be trapped in the liver microsomal incubations fortified with GSH or NAL as trapping agents. Five metabolites (M1, M2, M9, M12 and M13) associated with GSH and three metabolites (M4, M7 and M14) associated with NAL were identified by liquid chromatography-high resolution mass spectrometry. The second bioactivation pathway was catalyzed by UDP-glucuronosyltransferases (UGTs); TM5441 was conjugated with glucuronide to form acyl-glucuronide (M10), which further reacted with GSH, resulting in the identification of a TM5441-S-acyl-GSH adduct (M11) in liver microsomal incubations fortified with uridine-5'-diphosphoglucuronidc acid (UDPGA) and GSH. M9, M10, M11, M12 and M13 were also detected in bile samples of rats given TM5441. Compared with rat, dog would display closer bioactivation profiles to human. The CYP450 enzyme responsible for the bioactivation of TM5441 was mainly identified as CYP3A4, using human recombinant CYP450 enzymes and specific inhibitory studies. The UGT enzymes responsible for the bioactivation of TM5441 mainly involved UGT2B7, 1A1 and 1A4. These results facilitate the understanding of the bioactivation of TM5441 and potential toxicological implications.

The NKX3.1 homeobox gene is closely associated with the development and progression of prostate cancer. This study was to explore NKX3.1-related down-stream node genes and their possible regulating mechanisms in prostate cancer.By multi-omics analysis of the TCGA data on prostate cancer,we screened 5 node genes in the down-stream signaling pathways that were possibly related to NKX3.1.We achieved the overexpression of NKX3.1 in prostate cancer by transfecting the prostate cancer PC-3 cell lines with the NKX3.1 expression vector and determined the expression levels of the node genes by real-time PCR.Based on the results of multi-omics analysis,MAZ,LPAR3,TUBB2A,CAMKK2 and CPT1B were identified as the node genes involved in the NKX3.1-related signaling pathways in prostate cancer. The NKX3.1 overexpression experiments showed that the CAMKK2 and CPT1B genes were up-regulated 3. 439 and 4. 641 times respectively and the MAZ gene down-regulated 5.236 times in the prostate cancer PC-3 cells with the overexpression of NKX3.1.NKX3.1 may suppress the development and progression of prostate cancer by down-regulating the expression of MAZ and up-regulating those of CAMKK2 and CPT1B,and it may also be involved in the regulation of the metabolic process of prostate cancer through the CAMKK2 down-stream signaling pathway and CPT1B.

Objectives To determine the contrast-enhanced sonographic features of hepatic artery collateral transformation in patients with hepatic artery complications after liver transplantation. Methods Ninety-nine liver transplant recipients who underwent contrast-enhanced sonography were recruited from April 2004 to May 2014. The reference standards were conventional angiography and computed tomographic angiography. The contrast-enhanced sonographic features of the hepatic artery in patients with and without collateral arteries were retrospectively analyzed. Results All 15 patients with hepatic artery collateral transformation had hepatic artery thrombosis (10 of 15) or hepatic artery stenosis (5 of 15). The collateral artery detection rate on contrast-enhanced sonography was 100%. The peripheral hepatic artery could not be visualized by contrast-enhanced sonography in most of the patients with hepatic artery collateral transformation (14 of 15). Additionally, many small tortuous collateral arteries in the porta hepatis region were visualized during the arterial and early portal phases, showing reticulated/patchy (15 of 15) and striped (3 of 15) enhancement patterns on contrast-enhanced sonography. Conclusions Collateral transformation of the hepatic artery in patients with hepatic artery complications after liver transplantation appears to have characteristic features on contrast-enhanced sonography, especially a reticulated or patchy enhancement pattern in the porta hepatis region during the arterial and early portal phases combined with the absence of the peripheral hepatic artery. Contrast-enhanced sonography may be a novel method for diagnosing hepatic artery collateral transformation, which may be a highly specific sign of hepatic artery thrombosis or stenosis.

BH2, a monoclonal antibody prepared against the denatured human leukocytic antigen-B27 heavy chain (HLA-B27 HC), can immunoprecipitate the misfolded HLA-B27 HC complexed with Bip in the endoplasmic reticulum and recognize the homodimerized HLA-B27 HC that is often observed on the cell membrane of patients suffered from ankylosing spondylitis (AS). However, the recognition specificity of BH2 toward the other molecules of HLA-B type and toward the different types of HLA molecules remained uncharacterized. In this study, we carried out the HLA-typing by using the Luminex Technology to characterize the recognition specificity of BH2 and analyzed the binding domain of HLA-B27 HC by BH2. Our results indicated that BH2 preferably binds to molecules of HLA-B and -C rather than HLA-A and the binding site is located within the α2 domain of HLA-B27 HC.

Both viral infection and DNA transfection expose single-stranded or double-stranded DNA to the cytoplasm of mammalian cells. Recognition of cytosolic DNA activates a series of cellular responses, including induction of pro-inflammatory genes such as type I interferon through the well-known cGAS-STING pathway. Here we show for the first time that intracellular administration of either single or double stranded interferon stimulating DNA (ISD), but not poly(dA) suppresses cell growth in many different cell types. Suppression of cell growth by cytosolic DNA is cGAS/STING independent and associated with inhibition of glucose metabolism, ATP depletion and subsequent cellular energy stress responses including activation of AMPK and inactivation of mTORC1. Our results suggest that in concert with but independent of innate immune response, recognition of cytosolic DNA induced cellular energy stress potentially functions as a metabolic barrier to viral replication.

// Zun-yi Zhang 1 , Sheng-ling Fu 1 , Su-qin Xu 2 , Xiao Zhou 2 , Xian-shen Liu 2 , Yong-jian Xu 2 , Jian-ping Zhao 2 , Shuang Wei 2 1 Department of Surgery, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan 430030, China 2 Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan 430030, China Correspondence to: Shuang Wei, e-mail: wsdavid2001@163.com Keywords: hsa-miR-526b, Ku80, microRNA, NSCLC, p53 Received: August 24, 2014 Accepted: November 24, 2014 Published: December 22, 2014 ABSTRACT Ku80 is involved in DNA double-strand breaks (DSBs) repair. Ku80 is overexpressed in lung cancer tissues, yet, molecular mechanisms have not been examined. We identified that miRNA, hsa-miR-526b, is bound to the 3’-UTR of Ku80 mRNA, thus decreasing Ku80 expression in NSCLC cells. Hsa-miR-526b was downregulated in NSCLC tissues compared with corresponding non-tumorous tissues, and its expression was inversely correlated with Ku80 upregulation. Overexpression of Ku80 and downregulation of hsa-miR-526b were associated with poor clinical outcomes of NSCLC patients. Hsa-miR-526b suppressed NSCLC cell proliferation, clonogenicity, and induced cell cycle arrest and apoptosis. Hsa-miR-526b inhibited xenografts and orthotopic lung tumor growth. Further, Ku80 knockdown in NSCLC cells suppressed tumor properties in vitro and in vivo similar to hsa-miR-526b overexpression. In agreement, Ku80 restoration partially reversed cell cycle arrest and apoptosis induced by hsa-miR-526b in NSCLC cells in vitro and in vivo . In addition, hsa-miR-526b overexpression or Ku80 knockdown increased p53 and p21 CIP1/WAF1 expression. These findings reveal that hsa-miR-526b is a potential target in cancer therapy.

Objective To investigate electrocardiographic (ECG) characteristics and radiofrequency catheter ablation (RFCA) efficacy for premature ventricular complexes (PVCs) and idiopathic ventricular tachycardias (IVTs) originating from ventricular septum areas adjacent to atrioventricular annulus (VS-AVA). Methods Among 1,505 consecutive PVCs/IVTs cases, 106 (7.04%) were confirmed as origin of VS-AVA guided by both fluoroscopy and three-dimensional mapping system during RFCA. Characteristics of surface 12-lead ECG were analyzed. Results The overall success rate for RFCA of PVCs/IVTs originating from VS-AVA was 82.08% (87/106), common ECG characteristics were: mainly positive R wave on lead I; dominant-positive R on aVL (91/106, 85.85%) for most, r (1/106, 0.94%) or qr (14/106, 13.21%) in few; QS or qs on aVR; and decreasing R wave amplitude and increasing S wave depth on II, III, and aVF from superior to inferior septum; and S wave on at least one inferior lead (generally III). Distinctive ECG features were: precordial transition zone before or after V2 for septum adjacent to mitral (MA, 19/19, 100.0%) or tricuspid (TA, 74/87,85.05%) annulus origin; initial r wave and rS on V1 for superior septum near TA (above His bundle) origin (9/10, 90.0%) with no initial r wave for most other origins; and QS on V1 for mid-inferior septum near TA origin (73/77, 94.81%) and QR (Qr, qR or qr) on V1 for septum near MA origin (17/19, 89.47%). Conclusion Distinctive ECG characteristics of PVCs/IVTs originating from VS-AVA aid in origin localization guiding effective RFCA.

The present study aimed to investigate the characteristics of macular telangiectasia type 1 (Mac tel type 1) using spectral-domain optical coherence tomography angiography (OCTA) and compare them with the characteristics of mild diabetic macular edema (DME), to provide a new objective method for quick clinical diagnosis and treatment.A retrospective comparative analysis of 9 Mac tel type 1, 15 DME, and 15 normal eyes was performed using fluorescein angiography, spectral-domain optical coherence tomography, and OCTA. The morphological changes, retinal vessel density, and nonperfused areas were evaluated using split-spectrum amplitude-decorrelation angiography algorithm.OCTA revealed obvious saccular capillary telangiectasia and loss of parafoveal vascular density of Mac tel type 1. However, a number of line segment hyperreflective signals around the macula and more distinct nonperfusion in DME were observed. The quantitative foveal avascular zone mean area in Mac tel type 1 was larger than that in the normal eyes (0.40 ± 0.06 mmMorphological differences between Mac tel 1 and DME can be observed on OCTA. Superficial vascular density and non-perfusion area may serve as a quantitative method to identify them. Lasers Surg. Med. 49:225-232, 2017. © 2017 Wiley Periodicals, Inc.

Ankylosing spondylitis (AS) is highly associated with the expression of human leukocyte antigen-B27 (HLA-B∗27). HLA-B∗27 heavy chain (B27-HC) has an intrinsic propensity to fold slowly, leading to the accumulation of the misfolded B27-HC in the endoplasmic reticulum (ER) and formation of the HLA-B∗27 HC homodimer, (B27-HC)2, by a disulfide linkage at Cys-67. (B27-HC)2 displayed on the cell surface can act as a ligand of the killer-cell Ig-like receptor (KIR3DL2). (B27-HC)2 binds to KIR3DL2 of NK and Th17 cells and activates both cells, resulting in the activation of the IL-23/IL-17 axis to launch the inflammatory reaction in AS patients. However, activation of the IL-23/IL-17 axis originally derived from the HLA-B∗27 misfolding in the ER needs to be characterized. In this study, we delivered two HLA-B∗27-binding peptides, KRGILTLKY and SRYWAIRTR, into the ER by using a tat-derived peptide (GRKKRRQRRR)-His6-ubiquitin (THU) vehicle. Both peptides are derived from the human actin and nucleoprotein of influenza virus, respectively. Our results demonstrated that targeted delivery of both HLA-B∗27-binding peptides into the ER can promote the HLA-B∗27 folding, decrease the levels of (B27-HC)2, and suppress the activation of the IL-23/IL-17 axis in response to lipopolysaccharide. Our findings can provide a new therapeutic strategy in AS.

In this study, we aim to determine the relationship between methylation level of an inflammatory-related gene, SOCS-1 in serum samples of patients with ankylosing spondylitis (AS) and their degree of inflammation as well as serum cytokine level. Quantitative real time methylation specific PCR was performed to examine the promoter methylation of SOCS-1 in serum samples of 43 HLA-B27+ AS patients and 6 B27+ healthy controls. Degree of inflammation was accessed by spondylopathy, sacroiliitis as well as acute phase reactant, erythrocyte sedimentation rate and C-reactive protein (CRP). Serum IL-6 and TNF-α level was determined by ELISA assay. SOCS-1 methylation can only be found in serums samples from patients but not normal control. Methylation of SOCS-1 significantly associated with severity of patient's spondylopathy (P < 0.005), sacroiliitis (P < 0.005) and acute phase reactant CRP (P = 0.0278). AS patients also exhibited higher serum IL-6 (P < 0.001) and TNF-α level (P < 0.001). Importantly, patients with high serum IL-6 or TNF-α level demonstrated a significantly higher SOCS-1 methylation (P < 0.001). In conclusion, this proof-of-principle study suggested that methylation of SOCS-1 can be detected in serum of HLA-B27+ AS patients but not in B27+ controls. The pathogenic potential of SOCS-1 methylation in AS deserves further investigation.

To investigate Chinese medicine (CM) patterns and epidemiological characters of patients with influenza-like illness (ILI) syndromes in clinics in China.A prospective multi-center observational epidemiology survey on the clinical CM patterns of ILI and its prevalence was conducted from September 2009 to April 2010. A unified survey questionnaire was developed for data collection of ILI symptoms and CM patterns. Totally 45 hospitals from 22 provinces, municipality cities and autonomous regions of China participated this study. The collected data were input by EPI-data v3.1 and analyzed by SPSS 18.0, which included descriptive analysis and Chi-square test for group comparison.A total of 5,967 ILI patients were included in the study. The proportion of the 18-34 aged group (56.2%) was the largest; students (41.0%) were more than other occupations. Majority of the patients had the wind-heat invading Lung (Fei) syndrome (76%), while in Southwest China mainly wind-heat invading Lung syndrome and wind-cold tightening the exterior syndrome occurred. The typical symptoms of ILI were ranked as fatigue (80.9%), cough (72.2%), sore throat (67.2%), muscular soreness (67.1%), headache (65.4%), aversion to cold (60.1%), thirst (55.1%) and nasal obstruction (48.1%).The ILI patients in clinics were mainly teenagers and young adults. In regard to CM syndrome, wind-heat invading Lung syndrome prevailed in all regions except the Southwest China. The characteristics of CM syndrome of ILI patients may be relevant to age and region distribution.

Activated protein C (APC) is related to regulating the inflammatory response and hemodynamic stability upon reperfusion in cardiac operations and orthotopic liver transplantation (OLT). Epsilon-aminocaproic acid (EACA) is frequently used to treat fibrinolysis during OLT. It also has inhibitory effects related to the inflammatory response. However, it remains to be determined whether EACA can attenuate intraliver APC consumption and improve hemodynamic stability after reperfusion during OLT. Fifty-nine recipients were randomized to receive either EACA (150 mg kg−1 given intravenously prior to incision, followed by 15 mg kg−1 h−1 infusion until 2 h after the graft reperfusion) or the same volume of saline. Blood samples to assess plasma APC and protein C were obtained immediately before and after reperfusion from the inferior caval effluent or the portal veins for calculation of transliver differences (Δ). Hemodynamics and vasoactive medication use during the reperfusion period were observed in both groups. No transhepatic changes in protein C were found in either group. Immediately after reperfusion, a marked intraliver consumption of APC was noted in all recipients (P

Heterochromatin protein 1 (HP1), a highly conserved non-histone chromosomal protein in eukaryotes, plays important roles in the regulation of gene transcription. Each of the three human homologs of HP1 includes a chromoshadow domain (CSD). The CSD interacts with various proteins bearing the PXVXL motif but also with a region of histone H3 that bears the similar PXXVXL motif. The latter interaction has not yet been resolved in atomic detail. Here we demonstrate that the CSDs of all three human HP1 homologs have comparable affinities to the PXXVXL motif of histone H3. The HP1 C-terminal extension enhances the affinity, as does the increasing length of the H3 peptide. The crystal structure of the human HP1γ CSD (CSDγ) in complex with an H3 peptide suggests that recognition of H3 by CSDγ to some extent resembles CSD-PXVXL interaction. Nevertheless, the prolyl residue of the PXXVXL motif appears to play a role distinct from that of Pro in the known HP1β CSD-PXVXL complexes. We consequently generalize the historical CSD-PXVXL interaction model and expand the search scope for additional CSD binding partners.

IR spectra of heme and different O

Background Cervical cancer is a significant public health issue in Xinjiang China. In order to provide scientific basis for cervical cancer intervention in Xinjiang, women’s knowledge of cervical cancer was investigated in this study. Besides, relations between Uyghur women’s awareness and their age, educational background, yearly household were evaluated. Methods Questionnaire survey was conducted to 7100 Uyghur women from Karkax Hotan and Payzivat Kashgar during 2008 and 2009. Women aged 21 to 70 years, had sexual activity, no history of cervical lesion or cervical cancer were considered to be eligible to the study. Information include participants’ socio-demographic background, personal data, awareness about Pap smear, about cervical cancer and HPV, sources of information acquisition was investigated. Results 65.1% of the 7100 respondents with primary education level, and 95.0% participants were farmers. Only 7.4% had undertaken Pap smears before, not aware of the importance of the test (97.4% of 7100) was the main reason for not performing Pap smears. 29.3% of total participants had heard about cervical cancer, and only 0.14% (10 out of 7100) had heard about HPV. Top three route of knowledge acquire were television advertises (39.1%), neighbors (21.0%) and health care providers (15.0%). Women younger than 40 years, with higher educational levels and higher income had better awareness of cervical cancer and more willing to accept regular Pap smears. Conclusions Uyghur women in Xinjiang had poor knowledge of cervical cancer and HPV infection. Low awareness of women was associated with less household income and lower educational levels. TV shows and education from health care providers may increase women’s participation in cervical cancer control and prevention. Electronic supplementary material The online version of this article (doi: 10.1186/s12905-018-0512-5) contains supplementary material, which is available to authorized users.

To investigate the effects of 2 different ways of storage bag placement on some biochemical indexes of leukodepleted red blood cells (LD-RBC) to as to ensure the efficacy and safety of clinical blood transfusion.The whole blood samples of 20 donors (400 ml/donor) were selected for preparating the LP-RBC, which were divided evenly into 10 bags. The 10 bags were randomly divided into 2 groups; the bags in 1 group were placed uprightly, while the bags in another group were placed horizontally. The bags of 2 groups were stored in the same conditions. One storage bag from each group was taken randomly on day 7, 14, 21, 28, 35 respectively, and then the biochemical indexes of samples were detected and analyzed.The values of K(+) and LAC on day 14, the value of LDH on day 28 in the uprightly placed group were higher than those in the horizontally placed group (P0.05), the value of Na(+) on day 28, and the value of Glu on day 35 in the uprightly placed group were lower than those in horizontally placed group (P0.05), but there was no significant difference in Cl(-) level between 2 groups (P0.05).The storage bags placed by different ways during the storage show different influence on some biochemical indexes of LD-RBC in the storage period.

Covalent modifications of histone N-terminal tails play a critical role in regulating chromatin structure and controlling gene expression. These modifications are controlled by histone-modifying enzymes and read out by histone-binding proteins. Numerous proteins have been identified as histone modification readers. Here we report the family-wide characterization of histone binding abilities of human CW domain-containing proteins. We demonstrate that the CW domains in ZCWPW2 and MORC3/4 selectively recognize histone H3 trimethylated at Lys-4, similar to ZCWPW1 reported previously, while the MORC1/2 and LSD2 lack histone H3 Lys-4 binding ability. Our crystal structures of the CW domains of ZCWPW2 and MORC3 in complex with the histone H3 trimethylated at Lys-4 peptide reveal the molecular basis of this interaction. In each complex, two tryptophan residues in the CW domain form the "floor" and "right wall," respectively, of the methyllysine recognition cage. Our mutation results based on ZCWPW2 reveal that the right wall tryptophan residue is essential for binding, and the floor tryptophan residue enhances binding affinity. Our structural and mutational analysis highlights the conserved roles of the cage residues of CW domain across the histone methyllysine binders but also suggests why some CW domains lack histone binding ability.

SUMMARY Chromatin interactions play important roles in transcription regulation. To better understand the underlying evolutionary and functional constraints of these interactions, we implemented a systems approach to examine RNA polymerase-II-associated chromatin interactions in human cells. We found that 40% of the total genomic elements involved in chromatin interactions converged to a giant, scale-free-like, hierarchical network organized into chromatin communities. The communities were enriched in specific functions and were syntenic through evolution. Disease-associated SNPs from genome-wide association studies were enriched among the nodes with fewer interactions, implying their selection against deleterious interactions by limiting the total number of interactions, a model that we further reconciled using somatic and germline cancer mutation data. The hubs lacked disease-associated SNPs, constituted a nonrandomly interconnected core of key cellular functions, and exhibited lethality in mouse mutants, supporting an evolutionary selection that favored the nonrandom spatial clustering of the least-evolving key genomic domains against random genetic or transcriptional errors in the genome. Altogether, our analyses reveal a systems-level evolutionary framework that shapes functionally compartmentalized and error-tolerant transcriptional regulation of human genome in three dimensions.

Long-range chromatin contacts between specific DNA regulatory elements play a pivotal role in gene expression regulation, and a global characterization of these interactions in the 3-dimensional (3D) chromatin structure is imperative in understanding signaling networks and cell states. Chromatin Interaction Analysis using Paired-End Tag sequencing (ChIA-PET) is a method which converts functional chromatin structure into millions of short tag sequences. Combining Chromatin Immunoprecipitation (ChIP), proximity ligation and high-throughput sequencing, ChIA-PET provides a global and unbiased interrogation of higher-order chromatin structures associated with specific protein factors. Here, we describe the detailed procedures of the ChIA-PET methodology, unraveling transcription-associated chromatin contacts in a model human cell line.

Purpose: The purpose of this study was to investigate the influence of chronic vi rus-related liver disease severity on propofol requirements. Materials and Methods: In this study, 48 male patients with chronic hepatitis B infection were divided into three groups according to Child-Turcotte-Pugh classification of liver function (groups A, B, and C with mild, moderate and severe liver disease, respectively). After intubation, propofol concentration was adjusted by ±0.3 µg/mL increments to maintain bispectral index in the range of 40-60. Target propofol concentrations at anesthesia initiation, pre-intubation and pre-incision were recorded. Results: The initial concentration used in group C was significantly lower than that used in group A or B (p

Plant homeodomain (PHD) finger is found to be a versatile reader that functions in recruiting transcription factors and chromatin modification complexes. Bromodomain- and PHD finger-containing (BRPF) proteins are identified as scaffold component in a couple of histone acetyltransferase (HATs) complexes but the biological function of PHD fingers, composing the motif called PZPM (PHD/Zn-knuckle/PHD Motif), in BRPF proteins is far from being well understood. Here we report the three-dimensional solution structure of the second PHD finger of PZPM in human BRPF2. According to the structure, BRPF2 PHD2 possesses a two-strand β sheet which is different from any other PHD fingers. Functionally, this PHD finger can potentially bind DNA non-specifically with an evolutionarily conserved and positively charged surface. We provide the structural and interaction information of this atypical PHD finger and categorize this BRPF2 PHD2 into a new subset of PHD finger. Moreover our work also shed light on the functional aspect of the PZPM.