Confinement induces actin flow in a meiotic cytoplasm

In vivo, F-actin flows are observed at different cell life stages and participate in various developmental processes during asymmetric divisions in vertebrate oocytes, cell migration, or wound healing. Here, we show that confinement has a dramatic effect on F-actin spatiotemporal organization. We reconstitute in vitro the spontaneous generation of F-actin flow using Xenopus meiotic extracts artificially confined within a geometry mimicking the cell boundary. Perturbations of actin polymerization kinetics or F-actin nucleation sites strongly modify the network flow dynamics. A combination of quantitative image analysis and biochemical perturbations shows that both spatial localization of F-actin nucleators and actin turnover play a decisive role in generating flow. Interestingly, our in vitro assay recapitulates several symmetry-breaking processes observed in oocytes and early embryonic cells.     

p75 neurotrophin receptor regulates glucose homeostasis and insulin sensitivity

Insulin resistance is a key factor in the etiology of type 2 diabetes. Insulin-stimulated glucose uptake is mediated by the glucose transporter 4 (GLUT4), which is expressed mainly in skeletal muscle and adipose tissue. Insulin-stimulated translocation of GLUT4 from its intracellular compartment to the plasma membrane is regulated by small guanosine triphosphate hydrolases (GTPases) and is essential for the maintenance of normal glucose homeostasis. Here we show that the p75 neurotrophin receptor (p75(NTR)) is a regulator of glucose uptake and insulin resistance. p75(NTR) knockout mice show increased insulin sensitivity on normal chow diet, independent of changes in body weight. Euglycemic-hyperinsulinemic clamp studies demonstrate that deletion of the p75(NTR) gene increases the insulin-stimulated glucose disposal rate and suppression of hepatic glucose production. Genetic depletion or shRNA knockdown of p75(NTR) in adipocytes or myoblasts increases insulin-stimulated glucose uptake and GLUT4 translocation. Conversely, overexpression of p75(NTR) in adipocytes decreases insulin-stimulated glucose transport. In adipocytes, p75(NTR) forms a complex with the Rab5 family GTPases Rab5 and Rab31 that regulate GLUT4 trafficking. Rab5 and Rab31 directly interact with p75(NTR) primarily via helix 4 of the p75(NTR) death domain. Adipocytes from p75(NTR) knockout mice show increased Rab5 and decreased Rab31 activities, and dominant negative Rab5 rescues the increase in glucose uptake seen in p75(NTR) knockout adipocytes. Our results identify p75(NTR) as a unique player in glucose metabolism and suggest that signaling from p75(NTR) to Rab5 family GTPases may represent a unique therapeutic target for insulin resistance and diabetes.     

Implanted adipose progenitor cells as physicochemical regulators of breast cancer

Multipotent adipose-derived stem cells (ASCs) are increasingly used for regenerative purposes such as soft tissue reconstruction following mastectomy; however, the ability of tumors to commandeer ASC functions to advance tumor progression is not well understood. Through the integration of physical sciences and oncology approaches we investigated the capability of tumor-derived chemical and mechanical cues to enhance ASC-mediated contributions to tumor stroma formation. Our results indicate that soluble factors from breast cancer cells inhibit adipogenic differentiation while increasing proliferation, proangiogenic factor secretion, and myofibroblastic differentiation of ASCs. This altered ASC phenotype led to varied extracellular matrix (ECM) deposition and contraction thereby enhancing tissue stiffness, a characteristic feature of breast tumors. Increased stiffness, in turn, facilitated changes in ASC behavior similar to those observed with tumor-derived chemical cues. Orthotopic mouse studies further confirmed the pathological relevance of ASCs in tumor progression and stiffness in vivo. In summary, altered ASC behavior can promote tumorigenesis and, thus, their implementation for regenerative therapy should be carefully considered in patients previously treated for cancer.     

Urgent endoscopy in severe non-variceal upper gastrointestinal hemorrhage: does the Glasgow-Blatchford score help endoscopists?

Abstract Objective. The Glasgow-Blatchford score (GBS) has been validated to select severe patients with non-variceal upper gastrointestinal hemorrhage (UGIH). The aim was to compare the yield of the triage based on the GBS with an endoscopist' decision to perform an urgent upper gastrointestinal endoscopy (UGIE) in newly admitted patients and inpatients with UGIH in the setting of an endoscopy on-duty service in 13 tertiary care centers. Material and methods. During a 6-month period, GBS and patient data were collected for all patients with non-variceal UGIH for whom an UGIE was requested in emergency. If patients experienced severe endoscopic lesion, surgery or death, they were categorized as patients who had been at need for urgent UGIE. Results. The 102 UGIH patients included (mean age 62, men 73%) had a median GBS of 12 (range 0-21), significantly lower for new patients compared with inpatients (11, range 0-21 vs. 14, range 2-21, respectively, p = 0.001). If triage for urgent UGIE had followed the GBS, no more patients would have had an urgent UGIE compared with what endoscopists performed (99/102 (97%) vs. 92/102 (90%), respectively, p = 0.09). Sensitivity for the detection of patients who needed an UGIE was no different with the GBS than endoscopists (98% vs. 98%, respectively, p = 0.10) and both showed insufficient specificity (4% and 19%, respectively). Conclusions. The GBS does not detect more patients at need for urgent UGIE than on-duty endoscopists. Both methods lead to numerous unjustified UGIEs. A score that would equally help endoscopists in their decision to intervene urgently is still warranted.     

Effects of temperature on emergence and seasonality of West Nile virus in California

Temperature has played a critical role in the spatiotemporal dynamics of West Nile virus transmission throughout California from its introduction in 2003 through establishment by 2009. We compared two novel mechanistic measures of transmission risk, the temperature-dependent ratio of virus extrinsic incubation period to the mosquito gonotrophic period (BT), and the fundamental reproductive ratio (R(0)) based on a mathematical model, to analyze spatiotemporal patterns of receptivity to viral amplification. Maps of BT and R(0) were created at 20-km scale and compared throughout California to seroconversions in sentinel chicken flocks at half-month intervals. Overall, estimates of BT and R(0) agreed with intensity of transmission measured by the frequency of sentinel chicken seroconversions. Mechanistic measures such as these are important for understanding how temperature affects the spatiotemporal dynamics of West Nile virus transmission and for delineating risk estimates useful to inform vector control agency intervention decisions and communicate outbreak potential.     

Recommendations in the event of a suspected transfusion-related acute lung injury (TRALI)

The following recommendations, which aim at improving the clinical diagnosis ofTRALI and the laboratory investigations that can support it, were drawn up by a working group of the Superior Health Council. TRALI is a complication of blood transfusion that is both serious and underreported. Systematic reporting may help to develop preventive actions. Therefore, the Superior Health Council recommends that there should be a more stringent surveillance of patients who receive a blood component transfusion. The clinician should pay very close attention to any change in the patient's respiratory status (cf. dyspnoea and arterial desaturation), which should be notified systematically to the haemovigilance contact person in the hospital.