Mineralhaushalt und hormonale Aktivität im Winterschlaf

Summary A review is presented on the metabolism of sodium, potassium, calcium and magnesium during natural hibernation in mammals, and its relation to endocrine activity. With the entrance into hibernation, a change of homeostasis and an initial vagoinsular stage occur, resulting for instance in a hyperpotassemia. When the body temperature falls further, a sympathicoadrenal stage is observed whilst the serum potassium attains its normal level, probably favoured by simultaneous activation of the zona glomerulosa. Most animals show an increase of serum calcium and magnesium in hibernation in consequence of anhydremia, as well as of probably parathyreoid activity. It is suggested that an aldosterone and/or ADH secretion is provoked by diminishing of the intravasal space in deep hibernation. The mineral metabolism of bats differs in several points from that of other hibernators.     

A central nervous system effect of a non-hallucinatory lysergic acid derivative

Zusammenfassung Ähnlich wie Serotonin und LSD-25 vermindert BOL-148, ein Lysergsäurederivat, das keine Halluzinationen erzeugt, die durch den Balken fortgeleiteten, postsynaptischen Potentiale. Vorbehandlung mit BOL-148 macht das Versuchstier für ungefähr eine Stunde unempfindlich gegen Serotonin. BOL-148 blockiert anscheinend im Zentralnervensystem wie auch in der Peripherie den Serotonineffekt. Es wird versucht, zu erklären, weshalb diese Droge keine Halluzinationen bewirkt.     

De novo mutations revealed by whole-exome sequencing are strongly associated with autism

Multiple studies have confirmed the contribution of rare de novo copy number variations to the risk for autism spectrum disorders. But whereas de novo single nucleotide variants have been identified in affected individuals, their contribution to risk has yet to be clarified. Specifically, the frequency and distribution of these mutations have not been well characterized in matched unaffected controls, and such data are vital to the interpretation of de novo coding mutations observed in probands. Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent de novo single nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, α subunit), a result that is highly unlikely by chance.     

Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion

Drug resistance presents a challenge to the treatment of cancer patients. Many studies have focused on cell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour micro-environment confers innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. We found that stroma-mediated resistance is common, particularly to targeted agents. We characterized further the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibitors because most patients with this type of cancer show some degree of innate resistance. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)-AKT signalling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, this study indicates that the systematic dissection of interactions between tumours and their micro-environment can uncover important mechanisms underlying drug resistance.     

The diet of Australopithecus sediba

Specimens of Australopithecus sediba from the site of Malapa, South Africa (dating from approximately 2 million years (Myr) ago) present a mix of primitive and derived traits that align the taxon with other Australopithecus species and with early Homo. Although much of the available cranial and postcranial material of Au. sediba has been described, its feeding ecology has not been investigated. Here we present results from the first extraction of plant phytoliths from dental calculus of an early hominin. We also consider stable carbon isotope and dental microwear texture data for Au. sediba in light of new palaeoenvironmental evidence. The two individuals examined consumed an almost exclusive C(3) diet that probably included harder foods, and both dicotyledons (for example, tree leaves, fruits, wood and bark) and monocotyledons (for example, grasses and sedges). Like Ardipithecus ramidus (approximately 4.4 Myr ago) and modern savanna chimpanzees, Au. sediba consumed C(3) foods in preference to widely available C(4) resources. The inferred consumption of C(3) monocotyledons, and wood or bark, increases the known variety of early hominin foods. The overall dietary pattern of these two individuals contrasts with available data for other hominins in the region and elsewhere.     

Clonal selection drives genetic divergence of metastatic medulloblastoma

Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord. Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour. Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies.     

Deglacial rapid sea level rises caused by ice-sheet saddle collapses

The last deglaciation (21 to 7 thousand years ago) was punctuated by several abrupt meltwater pulses, which sometimes caused noticeable climate change. Around 14 thousand years ago, meltwater pulse 1A (MWP-1A), the largest of these events, produced a sea level rise of 14-18?metres over 350?years. Although this enormous surge of water certainly originated from retreating ice sheets, there is no consensus on the geographical source or underlying physical mechanisms governing the rapid sea level rise. Here we present an ice-sheet modelling simulation in which the separation of the Laurentide and Cordilleran ice sheets in North America produces a meltwater pulse corresponding to MWP-1A. Another meltwater pulse is produced when the Labrador and Baffin ice domes around Hudson Bay separate, which could be associated with the '8,200-year' event, the most pronounced abrupt climate event of the past nine thousand years. For both modelled pulses, the saddle between the two ice domes becomes subject to surface melting because of a general surface lowering caused by climate warming. The melting then rapidly accelerates as the saddle between the two domes gets lower, producing nine metres of sea level rise over 500 years. This mechanism of an ice 'saddle collapse' probably explains MWP-1A and the 8,200-year event and sheds light on the consequences of these events on climate.