Annexin A2 phosphorylation mediates cell scattering and branching morphogenesis via cofilin Activation

Dynamic remodeling of the actin cytoskeleton is required for cell spreading, motility, and migration and can be regulated by tyrosine kinase activity. Phosphotyrosine proteomic screening revealed phosphorylation of the lipid-, calcium-, and actin-binding protein annexin A2 (AnxA2) at Tyr23 as a major event preceding ts-v-Src kinase-induced cell scattering. Expression of the phospho-mimicking mutant Y23E-AnxA2 itself was sufficient to induce actin reorganization and cell scattering in MDCK cells. While Y23E-AnxA2, but not Y23A-AnxA2, enhanced Src- or hepatocyte growth factor (HGF)-induced cell scattering, short hairpin RNA-mediated knockdown of AnxA2 inhibited both v-Src- and HGF-induced cell scattering. Three-dimensional branching morphogenesis was induced in wild-type-AnxA2-expressing cells only in the presence of HGF, while Y23E-AnxA2 induced HGF-independent branching morphogenesis. Knockdown of AnxA2 prevented lumen formation during cystogenesis. The Y23E-AnxA2-induced scattering was associated with dephosphorylation/activation of the actin-severing protein cofilin. Likewise, inactive S3E-cofilin and constitutively active LIM kinase, a direct upstream kinase of cofilin, inhibited Y23E-AnxA2-induced scattering. Together, our studies indicate an essential role for AnxA2 phosphorylation in regulating cofilin-dependent actin cytoskeletal dynamics in the context of cell scattering and branching morphogenesis

Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis.

BACKGROUND: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. METHODS: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium. RESULTS: All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p  =  5.09  ×  10-4], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p  =  4.02  ×  10-4), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p  =  5.05  ×  10-19) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p  =  9.22  ×  10-6). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2-h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. CONCLUSIONS: We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer

Chemical fingerprints of emotional body odor

Contains fulltext : 221516.pdf (publisher's version ) (Open Access)Chemical communication is common among animals. In humans, the chemical basis of social communication has remained a black box, despite psychological and neural research showing distinctive physiological, behavioral, and neural consequences of body odors emitted during emotional states like fear and happiness. We used a multidisciplinary approach to examine whether molecular cues could be associated with an emotional state in the emitter. Our research revealed that the volatile molecules transmitting different emotions to perceivers also have objectively different chemical properties. Chemical analysis of underarm sweat collected from the same donors in fearful, happy, and emotionally neutral states was conducted using untargeted two-dimensional (GC×GC) coupled with time of flight (ToF) MS-based profiling. Based on the multivariate statistical analyses, we find that the pattern of chemical volatiles (N = 1655 peaks) associated with fearful state is clearly different from that associated with (pleasant) neutral state. Happy sweat is also significantly different from the other states, chemically, but shows a bipolar pattern of overlap with fearful as well as neutral state. Candidate chemical classes associated with emotional and neutral sweat have been identified, specifically, linear aldehydes, ketones, esters, and cyclic molecules (5 rings). This research constitutes a first step toward identifying the chemical fingerprints of emotion.25 p

Adenoviral delivery of IL-18 binding protein C ameliorates collagen-induced arthritis in mice.

Item does not contain fulltextElevated concentrations of interleukin-18 (IL-18) are found in both serum and synovial fluid of patients suffering from rheumatoid arthritis (RA) and this cytokine has recently been implicated in the development of experimental arthritis. In this present study, we developed an IL-18 neutralizing intervention and examined its efficacy for local intra-articular treatment of experimental arthritis. To this end we constructed an adenoviral vector containing the murine IL-18 binding protein isoform c gene (AdCMVIL-18BPc). The constructed adenoviral vector was validated on replication deficiency, transfection efficacy and ability to express biological functional IL-18BPc. Intra-articular overexpression of IL-18BPc significantly reduced incidence of collagen-induced arthritis (CIA) in treated kneejoints. Affected kneejoints of IL-18BPc-treated mice showed less severe arthritis, characterized by reduction of inflammation and destruction of bone and cartilage. Local intra-articular IL-1BPc treatment in both knees provided additional protection against CIA incidence and severity in distal paws. Measurement of serum levels of specific collagen type (CII) Abs revealed a moderate reduction of circulating IgG2a anti-CII Abs, while IgG1 anti-CII Abs remained at similar level. The present study underlines the involvement of IL-18 as an important proinflammatory cytokine in onset of experimental arthritis. Furthermore, it shows that endogenous IL-18 can be blocked efficiently through local adenoviral overexpression of IL-18BPc, indicating that treatment with IL-18BPc might contribute to joint protection in RA

The natural soluble form of IL-18 receptor beta exacerbates collagen-induced arthritis via modulation of T-cell immune responses.

Contains fulltext : 87769.pdf (publisher's version ) (Closed access)OBJECTIVE: IL-18 is a pluripotent cytokine that has been implicated in the development of rheumatoid arthritis. A soluble form of the IL-18 receptor accessory protein (sIL-18Rbeta) with unknown function has recently been identified. This study examined the ability of sIL-18Rbeta to inhibit IL-18 biological activities and to modulate immune responses during collagen-induced arthritis (CIA). METHODS: Adenoviruses encoding sIL-18Rbeta were administered intravenously in type II collagen-immunised DBA/1 mice. Humoral responses were analysed by determining anti-bovine collagen type II (BCII) antibody levels by ELISA. Cytokine production by splenic T cells and cytokine levels in serum were measured by Luminex multi-analyte technology. CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) were measured by flow cytometry. RESULTS: Intravenous delivery of Ad5.sIL-18Rbeta in collagen-immunised mice led to enhanced transgene expression in splenic antigen-presenting cells (APC). A co-culture of these sIL-18Rbeta-transduced APC with purified splenic CD3(+) T cells led to a marked inhibition of IL-18-induced IFNgamma, IL-4 and IL-17 production by CD3(+) T cells. Remarkably, systemic treatment with Ad5.sIL-18Rbeta caused an exacerbation of arthritis, and histological evaluation of knee joints showed increased cartilage and bone erosion. No significant differences were observed in anti-BCII antibodies, but the aggravation was accompanied by decreased IFNgamma (-30%) and IL-4 (-44%) and increased IL-17 (+84%) production by splenic CD3(+) T cells. In addition, reduced circulating levels of CD4(+)CD25(+)Foxp3(+) Treg and anti-inflammatory IL-10 were shown. CONCLUSION: This study identifies sIL-18Rbeta as a novel IL-18 inhibitor, which promotes CIA after intravenous overexpression by affecting Treg levels and supporting a T helper type 17 response.1 januari 201

Modulation of arthritis through overexpression of sIL-1RacP: a novel inhibitor of IL-1, distinct from IL-1Ra.

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