Disruption of Kcc2-dependent inhibition of olfactory bulb output neurons suggests its importance in odour discrimination

Synaptic inhibition in the olfactory bulb (OB), the first relay station of olfactory information, is believed to be important for odour discrimination. We interfered with GABAergic inhibition of mitral and tufted cells (M/T cells), the principal neurons of the OB, by disrupting their potassium- chloride cotransporter 2 (Kcc2). Roughly, 70% of mice died around 3 weeks, but surviving mice appeared normal. In these mice, the resulting increase in the intracellular Cl− concentration nearly abolished GABA-induced hyperpolarization of mitral cells (MCs) and unexpectedly increased the number of perisomatic synapses on MCs. In vivo analysis of odorant-induced OB electrical activity revealed increased M/T cell firing rate, altered phasing of action potentials in the breath cycle and disrupted separation of odour- induced M/T cell activity patterns. Mice also demonstrated a severely impaired ability to discriminate chemically similar odorants or odorant mixtures. Our work suggests that precisely tuned GABAergic inhibition onto M/T cells is crucial for M/T cell spike pattern separation needed to distinguish closely similar odours

Vascular network remodeling via vessel cooption, regression and growth in tumors

The transformation of the regular vasculature in normal tissue into a highly inhomogeneous tumor specific capillary network is described by a theoretical model incorporating tumor growth, vessel cooption, neo-vascularization, vessel collapse and cell death. Compartmentalization of the tumor into several regions differing in vessel density, diameter and in necrosis is observed for a wide range of parameters in agreement with the vessel morphology found in human melanoma. In accord with data for human melanoma the model predicts, that microvascular density (MVD, regarded as an important diagnostic tool in cancer treatment, does not necessarily determine the tempo of tumor progression. Instead it is suggested, that the MVD of the original tissue as well as the metabolic demand of the individual tumor cell plays the major role in the initial stages of tumor growth.Comment: 30 pages, 11 figures (higher resolution at http://www.uni-saarland.de/fak7/rieger/HOMEPAGE/BJ0.pdf

Cardiovascular and metabolic determinants of quality of life in patients with cancer

AIMS: Maintaining quality of life (QoL) in patients with cancer has gathered significant interest, but little is known about its major determinants. We sought to identify determinants of QoL in patients undergoing cancer treatment as well as in treatment-naïve patients about to commence such therapy. METHODS AND RESULTS: QoL was assessed in 283 patients with cancer using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 questionnaire. All patients underwent a battery of tests including physical examination, resting electrocardiogram, hand grip strength, and biochemistry assessment. Using multivariable logistic regression, we found that age [odds ratio (OR) 0.954, 95% confidence interval (CI) 0.916-0.994], resting heart rate (OR 1.036, 95% CI 1.004-1.068), hand grip strength (OR 0.932, 95% CI 0.878-0.990), and the presence of cachexia (OR 4.334, 95% CI 1.767-10.631) and dyspnoea (OR 3.725, 95% CI 1.540-9.010; all P < 0.05) remained independently predictive of reduced QoL. CONCLUSIONS: Therefore, it may be reasonable to address circumstances that are affecting muscle mass, body weight, and heart rate to maintaining QoL; however, prospective studies to test these endpoints are required

Platinum-group elements, S, Se and Cu in highly depleted abyssal peridotites from the Mid-Atlantic Ocean Ridge (ODP Hole 1274A): Influence of hydrothermal and magmatic processes

Highly depleted harzburgites and dunites were recovered from ODP Hole 1274A, near the intersection between the Mid-Atlantic Ocean Ridge and the 15°20′N Fracture Zone. In addition to high degrees of partial melting, these peridotites underwent multiple episodes of melt-rock reaction and intense serpentinization and seawater alteration close to the seafloor. Low concentrations of Se, Cu and platinum-group elements (PGE) in harzburgites drilled at around 35-85 m below seafloor are consistent with the consumption of mantle sulfides after high degrees (>15-20 %) of partial melting and redistribution of chalcophile and siderophile elements into PGE-rich residual microphases. Higher concentrations of Cu, Se, Ru, Rh and Pd in harzburgites from the uppermost and lowest cores testify to late reaction with a sulfide melt. Dunites were formed by percolation of silica- and sulfur-undersaturated melts into low-Se harzburgites. Platinum-group and chalcophile elements were not mobilized during dunite formation and mostly preserve the signature of precursor harzburgites, except for higher Ru and lower Pt contents caused by precipitation and removal of platinum-group minerals. During serpentinization at low temperature (<250 °C) and reducing conditions, mantle sulfides experienced desulfurization to S-poor sulfides (mainly heazlewoodite) and awaruite. Contrary to Se and Cu, sulfur does not record the magmatic evolution of peridotites but was mostly added in hydrothermal sulfides and sulfate from seawater. Platinum-group elements were unaffected by post-magmatic low-temperature processes, except Pt and Pd that may have been slightly remobilized during oxidative seawater alteration

Lunar samples record an impact 4.2 billion years ago that may have formed the Serenitatis Basin

Impact cratering on the Moon and the derived size-frequency distribution functions of lunar impact craters are used to determine the ages of unsampled planetary surfaces across the Solar System. Radiometric dating of lunar samples provides an absolute age baseline, however, crater-chronology functions for the Moon remain poorly constrained for ages beyond 3.9 billion years. Here we present U–Pb geochronology of phosphate minerals within shocked lunar norites of a boulder from the Apollo 17 Station 8. These minerals record an older impact event around 4.2 billion years ago, and a younger disturbance at around 0.5 billion years ago. Based on nanoscale observations using atom probe tomography, lunar cratering records, and impact simulations, we ascribe the older event to the formation of the large Serenitatis Basin and the younger possibly to that of the Dawes crater. This suggests the Serenitatis Basin formed unrelated to or in the early stages of a protracted Late Heavy Bombardment

Dissecting the role of polarity regulators in cancer through the use of mouse models

Loss of cell polarity and tissue architecture is a hallmark of aggressive epithelial cancers. In addition to serving as an initial barrier to tumorigenesis, evidence in the literature has pointed towards a highly conserved role for many polarity regulators during tumor formation and progression. Here, we review recent developments in the field that have been driven by genetically engineered mouse models that establish the tumor suppressive and context dependent oncogenic function of cell polarity regulators in vivo. These studies emphasize the complexity of the polarity network during cancer formation and progression, and reveal the need to interpret polarity protein function in a cell-type and tissue specific manner. They also highlight how aberrant polarity signaling could provide a novel route for therapeutic intervention to improve our management of malignancies in the clinic