Diagnosis of Pancreatic Ductal Adenocarcinoma and Chronic Pancreatitis by Measurement of microRNA Abundance in Blood and Tissue

A solid process for diagnosis could have a substantial impact on the successful treatment of pancreatic cancer, for which currently mortality is nearly identical to incidence. Variations in the abundance of all microRNA molecules from peripheral blood cells and pancreas tissues were analyzed on microarrays and in part validated by real-time PCR assays. In total, 245 samples from two clinical centers were studied that were obtained from patients with pancreatic ductal adenocarcinoma or chronic pancreatitis and from healthy donors. Utilizing the minimally invasive blood test, receiver operating characteristic (ROC) curves and the corresponding area under the curve (AUC) analysis demonstrated very high sensitivity and specificity of a distinction between healthy people and patients with either cancer or chronic pancreatitis; respective AUC values of 0.973 and 0.950 were obtained. Confirmative and partly even more discriminative diagnosis could be performed on tissue samples with AUC values of 1.0 and 0.937, respectively. In addition, discrimination between cancer and chronic pancreatitis was achieved (AUC = 0.875). Also, several miRNAs were identified that exhibited abundance variations in both tissue and blood samples. The results could have an immediate diagnostic value for the evaluation of tumor reoccurrence in patients, who have undergone curative surgical resection, and for people with a familial risk of pancreatic cancer

Nonadditivity of critical Casimir forces

In soft condensed matter physics, effective interactions often emerge due to the spatial confinement of fluctuating fields. For instance, microscopic particles dissolved in a binary liquid mixture are subject to critical Casimir forces whenever their surfaces confine the thermal fluctuations of the order parameter of the solvent close to its critical demixing point. These forces are theoretically predicted to be nonadditive on the scale set by the bulk correlation length of the fluctuations. Here we provide direct experimental evidence of this fact by reporting the measurement of the associated many-body forces. We consider three colloidal particles in optical traps and observe that the critical Casimir force exerted on one of them by the other two differs from the sum of the forces they exert separately. This three-body effect depends sensitively on the distance from the critical point and on the chemical functionalisation of the colloid surfaces

Binding between Crossveinless-2 and Chordin Von Willebrand Factor Type C Domains Promotes BMP Signaling by Blocking Chordin Activity

BACKGROUND: Crossveinless-2 (CV2) is an extracellular BMP modulator protein of the Chordin family, which can either enhance or inhibit BMP activity. CV2 binds to BMP2 via subdomain 1 of the first of its five N-terminal von Willebrand factor type C domains (VWC1). Previous studies showed that this BMP binding is required for the anti-, but not for the pro-BMP effect of CV2. More recently, it was shown that CV2 can also bind to the BMP inhibitor Chordin. However, it remained unclear which domains mediate this binding, and whether it accounts for an anti- or pro-BMP effect. PRINCIPAL FINDINGS: Here we report that a composite interface of CV2 consisting of subdomain 2 of VWC1 and of VWC2-4, which are dispensable for BMP binding, binds to the VWC2 domain of Chordin. Functional data obtained in zebrafish embryos indicate that this binding of Chordin is required for CV2's pro-BMP effect, which actually is an anti-Chordin effect and, at least to a large extent, independent of Tolloid-mediated Chordin degradation. We further demonstrate that CV2 mutant versions that per se are incapable of BMP binding can attenuate the Chordin/BMP interaction. CONCLUSIONS: We have physically dissected the anti- and pro-BMP effects of CV2. Its anti-BMP effect is obtained by binding to BMP via subdomain1 of the VWC1 domain, a binding that occurs in competition with Chordin. In contrast, its pro-BMP effect is achieved by direct binding to Chordin via subdomain 2 of VWC1 and VWC2-4. This binding seems to induce conformational changes within the Chordin protein that weaken Chordin's affinity to BMP. We propose that in ternary Chordin-CV2-BMP complexes, both BMP and Chordin are directly associated with CV2, whereas Chordin is pushed away from BMP, ensuring that BMPs can be more easily delivered to their receptors

Genetic Modifier Screens Reveal New Components that Interact with the Drosophila Dystroglycan-Dystrophin Complex

The Dystroglycan-Dystrophin (Dg-Dys) complex has a capacity to transmit information from the extracellular matrix to the cytoskeleton inside the cell. It is proposed that this interaction is under tight regulation; however the signaling/regulatory components of Dg-Dys complex remain elusive. Understanding the regulation of the complex is critical since defects in this complex cause muscular dystrophy in humans. To reveal new regulators of the Dg-Dys complex, we used a model organism Drosophila melanogaster and performed genetic interaction screens to identify modifiers of Dg and Dys mutants in Drosophila wing veins. These mutant screens revealed that the Dg-Dys complex interacts with genes involved in muscle function and components of Notch, TGF-β and EGFR signaling pathways. In addition, components of pathways that are required for cellular and/or axonal migration through cytoskeletal regulation, such as Semaphorin-Plexin, Frazzled-Netrin and Slit-Robo pathways show interactions with Dys and/or Dg. These data suggest that the Dg-Dys complex and the other pathways regulating extracellular information transfer to the cytoskeletal dynamics are more intercalated than previously thought

Down-Regulation of Honey Bee IRS Gene Biases Behavior toward Food Rich in Protein

Food choice and eating behavior affect health and longevity. Large-scale research efforts aim to understand the molecular and social/behavioral mechanisms of energy homeostasis, body weight, and food intake. Honey bees (Apis mellifera) could provide a model for these studies since individuals vary in food-related behavior and social factors can be controlled. Here, we examine a potential role of peripheral insulin receptor substrate (IRS) expression in honey bee foraging behavior. IRS is central to cellular nutrient sensing through transduction of insulin/insulin-like signals (IIS). By reducing peripheral IRS gene expression and IRS protein amount with the use of RNA interference (RNAi), we demonstrate that IRS influences foraging choice in two standard strains selected for different food-hoarding behavior. Compared with controls, IRS knockdowns bias their foraging effort toward protein (pollen) rather than toward carbohydrate (nectar) sources. Through control experiments, we establish that IRS does not influence the bees' sucrose sensory response, a modality that is generally associated with food-related behavior and specifically correlated with the foraging preference of honey bees. These results reveal a new affector pathway of honey bee social foraging, and suggest that IRS expressed in peripheral tissue can modulate an insect's foraging choice between protein and carbohydrate sources

Ecology and distribution of Leptospira spp., reservoir hosts and environmental interaction in Sri Lanka, with identification of a new strain

Leptospirosis is a neglected zoonotic disease and one of the leading causes of zoonotic morbidity and mortality, particularly in resource-poor settings. Sri Lanka has one of the highest disease burdens worldwide, with occasional endemic leptospirosis outbreaks (2008, 2011). Rodents are considered the main wildlife reservoir, but due to a scarcity of studies it is unclear which particular species contributes to bacterial transmission and reservoir maintenance in this multi-host multi-parasite system. Several rodent species act as agricultural pests both in rice fields and in food storage facilities. To unravel the interactions among the small mammal communities, pathogenic Leptospira spp. and human transmission pathways, we collected animals from smallholder food storage facilities, where contact between humans and small mammals is most likely, and screened kidney tissue samples for Leptospira spp. using PCR. Samples were collected in three climatic zones along a rainfall gradient. Pathogenic Leptospira spp. were detected in small mammal communities in 37 (74%) out of 50 sampled farms and 61 (12%) out of 500 collected individuals were infected. The small mammal community was comprised of Rattus rattus (87.6%), Suncus shrews (8.8%), Bandicota spp. (2.8%) and Mus booduga (0.8%). Three pathogenic Leptospira spp. were identified, L. borgpetersenii (n = 34), L. interrogans (n = 15), and L. kirschneri (n = 1). Suncus shrews were commonly infected (32%), followed by B. indica (23%) and R. rattus (10%). L. borgpetersenii strains similar to strains previously extracted from human clinal samples in Sri Lanka were detected in R. rattus and Suncus shrews. L. interrogans was observed in R. rattus only. A single L. kirschneri infection was found in M. booduga. The presence of human pathogenic Leptospira species in an agricultural pest rodent (R. rattus) and in commensal shrews (Suncus) calls for management of these species in commensal settings. Further investigation of the interplay between pathogen and reservoir population dynamics, overlap in geographic range and the extent of spill-over to humans in and around rural settlements is required to identify optimal management approaches