Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

SUMO Interacting Motifs: Structure and Function

Small ubiquitin-related modifier (SUMO) is a member of the ubiquitin-related protein family. SUMO modulates protein function through covalent conjugation to lysine residues in a large number of proteins. Once covalently conjugated to a protein, SUMO often regulates that protein’s function by recruiting other cellular proteins. Recruitment frequently involves a non-covalent interaction between SUMO and a SUMO-interacting motif (SIM) in the interacting protein. SIMs generally consist of a four-residue-long hydrophobic stretch of amino acids with aliphatic non-polar side chains flanked on one side by negatively charged amino acid residues. The SIM assumes an extended β-strand-like conformation and binds to a conserved hydrophobic groove in SUMO. In addition to hydrophobic interactions between the SIM non-polar core and hydrophobic residues in the groove, the negatively charged residues in the SIM make favorable electrostatic contacts with positively charged residues in and around the groove. The SIM/SUMO interaction can be regulated by the phosphorylation of residues adjacent to the SIM hydrophobic core, which provide additional negative charges for favorable electrostatic interaction with SUMO. The SUMO interactome consists of hundreds or perhaps thousands of SIM-containing proteins, but we do not fully understand how each SUMOylated protein selects the set of SIM-containing proteins appropriate to its function. SIM/SUMO interactions have critical functions in a large number of essential cellular processes including the formation of membraneless organelles by liquid–liquid phase separation, epigenetic regulation of transcription through histone modification, DNA repair, and a variety of host–pathogen interactions

Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation

Abstract Androgen deprivation therapy (ADT) targeting androgen/androgen receptor (AR)- signaling pathways is the main therapy for advanced prostate cancer (PCa). However, ADT eventually fails in most patients who consequently develop castration-resistant prostate cancer (CRPC). While more potent AR antagonists and blockers for androgen synthesis were developed to improve clinical outcomes, they also show to induce more diverse CRPC phenotypes. Specifically, the AR- and neuroendocrine-null PCa, DNPC, occurs in abiraterone and enzalutamide-treated patients. Here, we uncover that current ADT induces aberrant HGF/MET signaling activation that further elevates Wnt/β-catenin signaling in human DNPC samples. Co-activation of HGF/MET and Wnt/β-catenin axes in mouse prostates induces DNPC-like lesions. Single-cell RNA sequencing analyses identify increased expression and activity of XPO1 and ribosomal proteins in mouse DNPC-like cells. Elevated expression of XPO1 and ribosomal proteins is also identified in clinical DNPC specimens. Inhibition of XPO1 and ribosomal pathways represses DNPC growth in both in vivo and ex vivo conditions, evidencing future therapeutic targets

Health-related quality of life among patients with moderate-to-severe plaque psoriasis in Taiwan

Background/Objectives: Plaque psoriasis is a debilitating condition that significantly affects patient well-being. Limited data are available regarding the effect of psoriasis and treatment on health-related quality of life (HRQoL) and work ability among Taiwanese patients.To document and compare HRQoL, treatment satisfaction, and work disability among Taiwanese patients with current and past moderate-to-severe plaque psoriasis. Methods: This was a multicenter, non-interventional, cross-sectional study of adult patients with moderate-to-severe plaque psoriasis. During a single clinic visit, each patient was assessed for body surface area (BSA) involvement, Psoriasis Area Severity Index (PASI), Dermatology Life Quality Index (DLQI), Euro Quality of Life-5 Dimensions (EQ-5D), 10-level satisfaction scale for psoriasis treatment, and Working Productivity and Activity Impairment (WPAI). Multivariate regression was used to identify factors associated with HRQoL and work disability. Results: A total of 305 patients were included within the analysis. The mean PASI score was 11.83, and the mean BSA involvement was 20.90%. The mean EQ-5D score was 65.68 and the mean DLQI score was 12.55. Fewer than half of patients (45.68%) indicated they were satisfied with the standard therapy they were currently receiving. Among employed patients, the mean reduction in on-the-job effectiveness was 32.09% and the mean reduction in overall productivity was 33.48%. The regression analysis indicated that patients with more severe psoriasis defined by PASI scores show a greater impact in quality of life and impairment in work disability; and that patients who were satisfied with current standard treatment had a better quality of life. Conclusion: The effect of psoriasis on HRQoL among patients with psoriasis in Taiwan is substantial, with fewer than half of patients reporting satisfaction with therapeutic options. Keywords: DLQI, EQ-5D, Health-related quality of life, Psoriasis, WPA

Over-Expression of miR-106b Promotes Cell Migration and Metastasis in Hepatocellular Carcinoma by Activating Epithelial-Mesenchymal Transition Process

<div><p>Hepatocellular carcinoma (HCC) is one the the most fatal cancers worldwide. The poor prognosis of HCC is mainly due to the developement of distance metastasis. To investigate the mechanism of metastasis in HCC, an orthotopic HCC metastasis animal model was established. Two sets of primary liver tumor cell lines and corresponding lung metastasis cell lines were generated. <i>In vitro</i> functional analysis demonstrated that the metastatic cell line had higher invasion and migration ability when compared with the primary liver tumor cell line. These cell lines were subjected to microRNA (miRNAs) microarray analysis to identify differentially expressed miRNAs which were associated with the developement of metastasis <i>in vivo</i>. Fifteen human miRNAs, including miR-106b, were differentially expressed in 2 metastatic cell lines compared with the primary tumor cell lines. The clinical significance of miR-106b in 99 HCC clinical samples was studied. The results demonstrated that miR-106b was over-expressed in HCC tumor tissue compared with adjacent non-tumor tissue (p = 0.0005), and overexpression of miR-106b was signficantly correlated with higher tumor grade (p = 0.018). Further functional studies demonstrated that miR-106b could promote cell migration and stress fiber formation by over-expressing RhoGTPases, RhoA and RhoC. <i>In vivo</i> functional studies also showed that over-expression of miR-106b promoted HCC metastasis. These effects were related to the activation of the epithelial-mesenchymal transition (EMT) process. Our results suggested that miR-106b expression contributed to HCC metastasis by activating the EMT process promoting cell migration <i>in vitro</i> and metastasis <i>in vivo</i>.</p> </div

Orthotopic HCC metastasis animal model.

<p>(A) Primary liver tumor was detected after 1-week orthotopic implantation using luciferase labeled HCC cell line, PLC8024. (B) Metastatic nodules were formed in the lung of the SCID mice at week 10. (C) H&E staining for the lung of the SCID mice show that luciferin signal from the lung nodules are orginated from the tumor cells.</p

<i>In vitro</i> functional studies for PLC-PT and PLC-LM cell lines.

<p>(A) Cell migration ability were compared by wound healing assay. Wound closure was observed in the PLC-LM but not in the PLC-PT at 24 and 48 hours. (B) Trans-well invasion assay for PLC-PT and PLC-LM. The number of invading cells in PLC-LM are significantly higher than the PLC-PT (p = 0.01). (C) Phalloidin staining for PLC-PT and PLC-LM. Stress fiber (white arrow) was observed in PLC-LM but absent in PLC-PT.</p

<i>In vitro</i> functional studies for miR-106b in Huh7 and Hep3B cell lines.

<p>Cell migration ability was compared in Huh7 (A) and Hep3B (B) cell lines with or without over-expression of miR-106b. miR-106b over-expressing cells, Huh7/106b+ and Hep3B/106b+, show enhanced cell migration ability when compare to its corresponding vector control, Huh7/V.C. and Hep3B/V.C., at 24 and 48 hours interval. Stress fiber formation was visualized by phalloidin staining (C & D). More stress fiber (white arrow) was observed in miR-106b over-expression cells in Huh7/106b+ (C) and Hep3B/106b+ (D) cell lines compare to the vector control cell lines, Huh7/V.C. and Hep3B/V.C.</p

Candidate miRNAs identified from miRNA microarray analysis.

<p>Candidate miRNAs identified from miRNA microarray analysis.</p