A short term −12° head down tilt does not mimic microgravity in terms of human gonadal function

A significant reversible decrease in testosterone (T) has been associated with microgravity in male rodents and humans. Urinary T excretion increases in primates under hypergravity. Hypogonadism is somehow related to abnormally high levels of leptin (L), a hormone produced by the adipose tissue which has been found to increase under microgravity simulation conditions like head down bed rest (HDBR). The aim of this study was to assess hemodynamic and pituitary-adrenal and -gonadal adaptation to an acute HDBR test to be eventually used on a routine basis to get better prepared to next space flights. The Authors performed a 1 hour ?12° HDBR in 6 male and 6 female volunteers who underwent heart rate and blood pressure measurement together with a blood draw three times at 30 min intervals from the start to the end of the test for L, T, estradiol (E₂), LH, androstenedione (A), cortisol (F), ACTH. 12 age- and sexmatched control subjects followed the same protocol except for keeping the sitting position all the time. According to the ANOVA for repeated measures, no changes occurred in L, T, E₂ or LH whereas A, F and ACTH significantly decreased independently of gender. During HDBR systolic blood pressure decreased in both genders, diastolic blood pressure decreased significantly only in men and HR showed a more clear-cut decrease in women than in men. As a conclusion, such an acute steep-slope HDBR protocol may be efficiently used to testing immediate individual haemodynamic or adrenal response to microgravity but is not suitable for studies concerning gonadal adaptation.     

Diagnosing attention disorders in a virtual classroom

The virtual classroom provides an efficient and scalable tool for conducting attention testing. The University of Southern California integrated media systems center and digital media works have partnered to develop virtual reality technology applications for the study, assessment, and rehabilitation of cognitive and functional processes. This work primarily focuses on the development of systems that address the special needs of clinical populations with central nervous system dysfunctions such as brain injury, learning disabilities, or neurological disorders.     

Discovery of an Allosteric Ligand Binding Site in SMYD3 Lysine Methyltransferase

SMYD3 is a multifunctional epigenetic enzyme with lysine methyltransferase activity and various interaction partners. It is implicated in the pathophysiology of cancers but with an unclear mechanism. To discover tool compounds for clarifying its biochemistry and potential as a therapeutic target, a set of drug-like compounds was screened in a biosensor-based competition assay. Diperodon was identified as an allosteric ligand; its R and S enantiomers were isolated, and their affinities to SMYD3 were determined (K_D=42 and 84 μM, respectively). Co-crystallization revealed that both enantiomers bind to a previously unidentified allosteric site in the C-terminal protein binding domain, consistent with its weak inhibitory effect. No competition between diperodon and HSP90 (a known SMYD3 interaction partner) was observed although SMYD3–HSP90 binding was confirmed (K_D=13 μM). Diperodon clearly represents a novel starting point for the design of tool compounds interacting with a druggable allosteric site, suitable for the exploration of noncatalytic SMYD3 functions and therapeutics with new mechanisms of action.     

Description and composition of bio-inspired design patterns: a complete overview

In the last decade, bio-inspired self-organising mechanisms have been applied to different domains, achieving results beyond traditional approaches. However, researchers usually use these mechanisms in an ad-hoc manner. In this way, their interpretation, definition, boundary (i.e. when one mechanism stops, and when another starts), and implementation typically vary in the existing literature, thus preventing these mechanisms from being applied clearly and systematically to solve recurrent problems. To ease engineering of artificial bio-inspired systems, this paper describes a catalogue of bio-inspired mechanisms in terms of modular and reusable design patterns organised into different layers. This catalogue uniformly frames and classifies a variety of different patterns. Additionally, this paper places the design patterns inside existing self-organising methodologies and hints for selecting and using a design pattern.     

Hydromorphology Meets Mammal Ecology: River Morphological Quality,Recent Channel Adjustments and Otter Resilience

The need for a multidisciplinary approach for characterizing water bodies in terms of morphological, chemical and ecological quality has hastened the growth of hydromorphology as a cross‐disciplinary topic at the interface of hydrology, geomorphology and ecology. Many authors have analysed how hydroecology may affect freshwater biodiversity, although little is known about how this biodiversity might be affected by river morphological quality. We examined how well the presence of the semi‐aquatic Eurasian otter can be predicted by the rivers' morphological quality and its adjustments over the last decades. We tested the morphological quality index (MQI) methodology in 38 reaches of five rivers in southern Italy, 23 of which were positive to otter presence. In each reach, we examined 28 indicators contributing to the MQI and its 11 sub‐indices. The results showed a significant relationship between the probability of the presence of otters, MQI, and some sub‐indices. The best performing sub‐indices were related to channel adjustments and the continuity of river processes. A more detailed analysis of channel adjustments showed a detrimental effect of channel incision (>3 m) and a positive effect of narrowing, particularly where it occurred simultaneously with the development of forest in the new floodplain. The continuity of river processes has driven the migration of river banks and the development of ponds and secondary channels, likely increasing the availability of dens and resting sites and the hunting capabilities of otters. Our results stressed the importance of fluvial dynamics and sustainable adaptive river management for the habitat quality of semi‐aquatic species. Copyright © 2014 John Wiley & Sons, Ltd.     

Hereditary Prostate Cancer: Genes Related,Target Therapy and Prevention

Prostate cancer (PCa) is globally the second most diagnosed cancer type and the most common cause of cancer-related deaths in men. Family history of PCa, hereditary breast and ovarian cancer (HBOC) and Lynch syndromes (LS), are among the most important risk factors compared to age, race, ethnicity and environmental factors for PCa development. Hereditary prostate cancer (HPCa) has the highest heritability of any major cancer in men. The proportion of PCa attributable to hereditary factors has been estimated in the range of 5–15%. To date, the genes more consistently associated to HPCa susceptibility include mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and homologous recombination genes (BRCA1/2, ATM, PALB2, CHEK2). Additional genes are also recommended to be integrated into specific research, including HOXB13, BRP1 and NSB1. Importantly, BRCA1/BRCA2 and ATM mutated patients potentially benefit from Poly (ADP-ribose) polymerase PARP inhibitors, through a mechanism of synthetic lethality, causing selective tumor cell cytotoxicity in cell lines. Moreover, the detection of germline alterations in MMR genes has therapeutic implications, as it may help to predict immunotherapy benefits. Here, we discuss the current knowledge of the genetic basis for inherited predisposition to PCa, the potential target therapy, and the role of active surveillance as a management strategy for patients with low-risk PCa. Finally, the current PCa guideline recommendations are reviewed.     

The influence of lateral forces on the cell stiffness measurement by optical tweezers vertical indentation

We studied the lateral forces arising during the vertical indentation of the cell membrane by an optically trapped microbead, using back focal plane interferometry to determine force components in all directions. We analyzed the cell-microbead interaction and showed that indeed the force had also lateral components. Using the Hertz model, we calculated and compared the elastic moduli resulting from the total and vertical forces, showing that the differences are important and the total force should be considered. To confirm our results we analyzed cells from two breast cancer cell lines: MDA-MB-231 and HBL-100, known to have different cancer aggressiveness and hence stiffness.     

Diet supplementation with donkey milk upregulates liver mitochondrial uncoupling,reduces energy efficiency and improves antioxidant and antiinflammatory defences in rats

Dietary PUFA, mainly those of the n‐3 family, are known to play essential roles in the maintenance of energy balance and in the reduction of body fat deposition through the upregulation of mitochondrial uncoupling that is the main source of reactive oxygen species. We hypothesized that rat supplementation with raw donkey's milk (DM), characterized by low‐fat content and higher n3:n6 ratio, may affect energy balance, lipid metabolism, and prooxidant status as compared to animals treated with cow's milk. In the present study, the effects of drinking raw DM (for 4 weeks) on energy balance, lipid metabolism, antiinflammatory, and antioxidant/detoxifying defences was compared to that produced by rat intake of an iso‐energetic amount of raw cow's milk. The hypolipidemic effect produced by DM paralleled with the enhanced mitochondrial activity/proton leakage and with the increased activity or expression of mitochondrial markers namely, carnitine palmitoyl transferase and uncoupling protein 2. The association of decreased energy efficiency with reduced proinflammatory signs (TNF‐α and LPS levels) with the significant increase antioxidant (total thiols) and detoxifying enzyme activities (glutathione‐S‐transferase NADH quinone oxidoreductase) in DM‐treated animals, indicated that beneficial effects were attributable, at least in part, to the activation of nuclear factor 2 erythroid‐related factor 2 pathway.