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The crystal structures of SdgB and SdgA from Staphylococcus aureus provide functional and structural insights into the glycosylation mechanism in staphylococcal adhesion., The initiation of infection of host tissues by Staphylococcus aureus requires a family of staphylococcal adhesive proteins containing serine–aspartate repeat (SDR) domains, such as ClfA. The O-linked glycosylation of the long-chain SDR domain mediated by SdgB and SdgA is a key virulence factor that protects the adhesive SDR proteins against host proteolytic attack in order to promote successful tissue colonization, and has also been implicated in staphylococcal agglutination, which leads to sepsis and an immunodominant epitope for a strong antibody response. Despite the biological significance of these two glycosyltransferases involved in pathogenicity and avoidance of the host innate immune response, their structures and the molecular basis of their activity have not been investigated. This study reports the crystal structures of SdgB and SdgA from S. aureus as well as multiple structures of SdgB in complex with its substrates (for example UDP, N-acetylglucosamine or SDR peptides), products (glycosylated SDR peptides) or phosphate ions. Together with biophysical and biochemical analyses, this structural work uncovered the novel mechanism by which SdgB and SdgA carry out the glycosyl-transfer process to the long SDR region in SDR proteins. SdgB undergoes dynamic changes in its structure such as a transition from an open to a closed conformation upon ligand binding and takes diverse forms, both as a homodimer and as a heterodimer with SdgA. Overall, these findings not only elucidate the putative role of the three domains of SdgB in recognizing donor and acceptor substrates, but also provide new mechanistic insights into glycosylation of the SDR domain, which can serve as a starting point for the development of antibacterial drugs against staphylococcal infections.

Given the functional attributes of Doublecortin-like kinase 1 (DCLK1) in tumor growth, invasion, metastasis, cell motility, and tumor stemness, it is emerging as a therapeutic target in gastrointestinal cancers. Although a series of specific or nonspecific ATP-competitive inhibitors were identified against DCLK1, different types of scaffolds that can be utilized for the development of highly selective inhibitors or structural understanding of binding specificities of the compounds remain limited. Here, we present our work to repurpose a Janus kinase 1 inhibitor, ruxolitinib as a DCLK1 inhibitor, showing micromolar binding affinity and inhibitory activity. Furthermore, to gain an insight into its interaction mode with DCLK1, a crystal structure of the ruxolitinib-complexed DCLK1 has been determined and analyzed. Ruxolitinib as a nonspecific DCLK1 inhibitor characterized in this work is anticipated to provide a starting point for the structure-guided discovery of selective DCLK1 inhibitors.

Objectives: Child abuse is a global problem, and various programs are under way to prevent it. The purpose of this study was to examine the effectiveness of specific programs through a systematic review of meta-analyzes of the effects of various child abuse programs. Methods: We searched the Ovid-Medline, EMBASE, and Cochrane library and so on up to October 2017 using search terms such as (child AND (maltreatment or abuse)) AND (prevent* AND(program* and educat*)) AND (meta-analysis or systemic review) in English. Results: The Child Abuse Prevention Program reported on the reduction of child abuse, parenting knowledge and attitudes, parenting behaviors, and interactions with children. We also analyzed the effects of child sexual abuse knowledge and preventive behavior through education. All results reported low or moderate positive effects. Conclusions: The results of this study suggest that prevention of child abuse is effective for both parents and children. However, consistent and systematic child abuse prevention education will be needed to confirm this conclusion.

MINERVA (melanoma invasion by ERK), also known as FAM129B, is a member of the FAM129 protein family, which is only present in vertebrates. MINERVA is involved in key signaling pathways regulating cell survival, proliferation and apoptosis and found upregulated in many types of cancer promoting invasion. However, the exact function of the protein remains elusive. X-ray crystallographic methods were implemented to determine the crystal structure of MINERVA&Delta, C, lacking C-terminal flexible region. Trypsin digestion was required before crystallization to obtain diffraction-quality crystals. While the N-terminal pleckstrin homology (PH) domain exhibits the typical fold of PH domains, lipid binding assay indicates specific affinity towards phosphatidic acid and inositol 3-phosphate. A helix-rich domain that constitutes the rest of the molecule demonstrates a novel L-shaped fold that encompasses the PH domain. The overall structure of MINERVA&Delta, C with binding assays and cell-based experiments suggest plasma membrane association of MINERVA and its function seem to be tightly regulated by various motifs within the C-terminal flexible region. Elucidation of MINERVA&Delta, C structure presents a novel fold for an &alpha, helix bundle domain that would provide a binding platform for interacting partners.

Ovarian cancer is the gynecological malignancy with the poorest prognosis, in part due to its high incidence of recurrence. Platinum agents are widely used as a first-line treatment against ovarian cancer. Recurrent tumors, however, frequently demonstrate acquired chemo-resistance to platinum agent toxicity. To improve chemo-sensitivity, combination chemotherapy regimens have been investigated. This study examined anti-tumor effects and molecular mechanisms of cytotoxicity of Oldenlandia diffusa (OD) extracts on ovarian cancer cells, in particular, cells resistant to cisplatin. Six ovarian cancer cells including A2780 and cisplatin-resistant A2780 (A2780cis) as representative cell models were used. OD was extracted with water (WOD) or 50% methanol (MOD). MOD significantly induced cell death in both cisplatin-sensitive cells and cisplatin-resistant cells. The combination treatment of MOD with cisplatin reduced viability in A2780cis cells more effectively than treatment with cisplatin alone. MOD in A2780cis cells resulted in downregulation of the epigenetic modulator KDM1B and the DNA repair gene DCLRE1B. Transcriptional suppression of KDM1B and DCLRE1B induced cisplatin sensitivity. Knockdown of KDM1B led to downregulation of DCLRE1B expression, suggesting that DCLRE1B was a KDM1B downstream target. Taken together, OD extract effectively promoted cell death in cisplatin-resistant ovarian cancer cells under cisplatin treatment through modulating KDM1B and DCLRE1B.

While transcription as regulated by histones and their post-translational modifications has been well described, the function of histone variants in this process remains poorly characterized. Potentially important insight into this process pertain to the frequently occurring mutations of H3.3, leading to G34 substitutions in childhood glioblastoma and giant cell tumor of the bone (GCTB). In this study, we have established primary cell lines from GCTB patients and used them to uncover the influence of H3.3 G34W substitutions on cellular growth behavior, gene expression, and chromatin compaction. Primary cell lines with H3.3 G34W showed increased colony formation, infiltration and proliferation, known hallmarks of tumor development. Isogenic cell lines with H3.3 G34W recapitulated the increased proliferation observed in primary cells. Transcriptomic analysis of primary cells and tumor biopsies revealed slightly more downregulated gene expression, perhaps by increased chromatin compaction. We identified components related to splicing, most prominently hnRNPs, by immunoprecipitation and mass spectrometry that specifically interact with H3.3 G34W in the isogenic cell lines. RNA-sequencing analysis and hybridization-based validations further enforced splicing aberrations. Our data uncover a role for H3.3 in RNA processing and chromatin modulation that is blocked by the G34W substitution, potentially driving the tumorigenic process in GCTB.

Background Ovarian cancer is one of the major causes of death among females in worldwide. Cisplatin is a primary anti-cancer drug against ovarian cancer, but the recurrent tumors after treatment frequently show acquired chemoresistance. Extract of Scutellaria baicalensis (SbE) has been reported to have functional compounds including baicalin, which has anti-cancer effects. However, the anti-cancer effects of SbE in ovarian cancer and its underlying mechanisms are elusive. Methods We investigated that the effects of SbE and/or cisplatin on cell death in the cisplatin sensitive ovarian cancer cell line A2780 (CSC) and the counterpart cell line that has cisplatin resistance (CRC). Molecular mechanisms of the effects, focusing on apoptosis and autophagy, were examined. Results Treatment of cisplatin or SbE reduced cell viability significantly in CSC and too much lesser extent in CRC. Cisplatin-induced cell death in CSC was mediated by p53-induced apoptosis acompanied by expresson of damage-regulated autophagy modulator (DRAM). In CRC, decreased DRAM expression (p

The efficiency of biochars (BCs) derived from paper mill sludge (PM-BC), distillery sludge (DS-BC), and pruned branches from roadside trees (PB-BC) for immobilization of selected heavy metals (Cd and Zn) in agricultural soils was examined in the current study. This examination was conducted in order to elucidate whether the recycling of organic wastes could be used as a management option for metal-contaminated agricultural soils. Biochars were applied to contaminated upland soil exceeding the guideline values for Cd (4 mg kg−1) and Zn (300 mg kg−1) in Korea. Both the incubation study and the pot trial with lettuce cultivation were carried out using soil-BCs mixtures at 0, 1, 2, and 5 % (w/w). From the incubation study, it appears that BCs incorporated into the soil induces an increasing soil pH and a significant decline (Cd 36 ~ 100 %; Zn 54 ~ 100 %) in the phytoavailable metal pool examined by 1 M NH4NO3 extraction. The PM-BC was most effective in the reduction of Cd and Zn phytoavailability, due to a significantly higher pH and surface area than the DS-BC and PB-BC. Similar results were observed in the pot trial, where the uptake of heavy metals by lettuce greatly declined with PM-BC incorporation (Cd 26 ~ 71 %; Zn 28 ~ 45 %). PM-BC enhanced the lettuce growth performance evidenced by the highest yield of lettuce being observed with PM-BC-treated soils at 5 %. This was attributed to retardation of the metal toxic effect induced by a decrease in Cd accumulation, while the increased nutrient elements originated from PM-BC. This present study indicates that paper mill sludge is a great candidate for biochar production that can be utilized as a soil amendment for metal-contaminated agricultural soils.