Intramontane lacustrine basins in the Siberian Altai: recorders of Cenozoic intracontinental tectonic and climatic events

The Altai Mountains are part of the vast intracontinental Central Asian orogenic system that formed during the Cenozoic as a distal effect of continued indentation of the Indian plate into the Eurasian continent. In the Siberian part of the Altai Mountains there is ample evidence to suggest that the pre-Cenozoic structural fabric of its basement is a controlling factor in the Cenozoic deformation and development of this intracontinental orogen. We give evidence that important Paleozoic fault zones were reactivated during the Cenozoic, particularly the Late Cenozoic and play a key role in the formation, evolution and current morphology of the Siberian Altai Mountains. Some of these faults are still active and recent and historic movements along them have triggered large seismic events. Late Cenozoic reactivation was expressed as pure thrust, oblique thrust to pure strike-slip faulting, resulting in an overall transpressive tectonic regime. In some cases, as for the graben basin of Lake Teletskoye, local, pure extensional stresses are responsible for its formation as we show in this contribution. Various other intramontane, tectonic basins developed. Some of these are very recent structures (the Teletskoye Basin) and are Pleistocene in age or younger, others have a prolonged history and contain a relatively complete Cenozoic sedimentary section, with evidence of Late Mesozoic precursor basins (Chuya Basin, Dzhulukul Basin). Some of these exhibit indications of marine incursions, but the basins are predominantly continental. The development of these basins is clearly associated with the location and Cenozoic reactivation of aforementioned long-lived fault zones in the Altai tectonic assemblage. Many of these basins accommodated fresh water lakes during their evolution and some are still the site of contemporary mountain lakes. Their stratigraphy, as well as the sedimentary architecture and basin morphology is manifestly influenced by and progresses with the stages of (Late) Cenozoic intracontinental mountain building and erosive denudation of the growing mountain ranges. Together with the clastic sedimentary input and the provenance characteristics, the intramontane Altai basin deposits are affected by evolving climatic conditions. These conditions dictate the main mode of erosion and transport, influence the sedimentary facies and supply rate and create the framework for a specific biocoenosis signature found in the fossil record. Our contribution reviews the data obtained over the last years from a selection of intramontane lacustrine basins in the Siberian Altai Mountains. We direct our attention in particular to the Teletskoye basin, the Chuya-Kurai Basin and the Dzhulukul Basin. We combine sedimentologic-stratigraphic data with basin architecture and morphology, and with basement geochronologic-thermochronologic constraints (apatite fission-track, U/Pb and Ar-dating) in order to show the potential of these basins as recorders of Cenozoic tectonic and climatic events in relation with basement features. While for example the data obtained from the Chuya Basin yields a continuous Cenozoic picture of deformation and climatic evolution of the Altai area, data from the Teletskoye Basin zooms in with higher resolution on the Pleistocene to Recent history. In general, all data point towards intensifying tectonic reactivation and mountain building of the Siberian Altai Mountains since the Middle Cenozoic, with clear peak activity in the Pliocene to Recent. This is demonstrated by the molassetype deposits in these basins, and by thermochronologic constraints. This activity is ongoing and structural, (paleo)seismic, geomorphologic and sedimentologic data corroborates this. The lacustrine Altai basins provide a record for a more or less continuous progressive cooling and aridification of the Altai area during the Cenozoic as manifested in the pollen fossil assemblages found in the Altai sediments

Long-term effect of chemogenetic suppression of excitatory hippocampal neurons on spontaneous seizures in a rat model for temporal lobe epilepsy

Objective. One third of epilepsy patients cannot be helped using conventional medication. Selective hippocampal suppression using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) have potential to address this unmet need. We evaluated whether DREADD-mediated seizure suppression could be obtained in the intraperitoneal kainic acid (IPKA) rat model for temporal lobe epilepsy. Methods. The inhibitory DREADD hM4Di was selectively expressed in excitatory neurons in one hippocampus of IPKA rats. Naïve IPKA rats were included as control group. The effect of clozapine-mediated DREADD activation on dentate gyrus evoked potentials (DGEPs) was evaluated. Next, the effect of DREADD activation on spontaneous seizures was examined using continuous video-electroencephalography. Animals were systemically treated with single (0.1 mg/kg/24h) and repeated (0.1 mg/kg/6h) clozapine injections. Finally, long-term continuous release of clozapine and olanzapine (both 2.8 mg/kg/7d) using implantable osmotic minipumps was evaluated. Results. In the DREADD group, inhibition of DGEPs was observed after clozapine treatment, whereas no effect was observed in control animals. Only in DREADD-expressing animals, a single dose of clozapine reduced seizure frequency during the first six hours post injection. When clozapine was administered every six hours, seizures were suppressed the entire day. Long term treatment resulted in a significant seizure-suppressing effect during the first four days, after which tolerance developed. Significance. This study shows that unilateral inhibition of hippocampus using chemogenetics results in potent seizure suppressing effects in the IPKA rat model, even months after vector injection. It indicates that chemogenetic neuromodulation could contribute to a more optimal treatment for temporal lobe epilepsy

Depletion of RIPK3 or MLKL blocks TNF-driven necroptosis and switches towards a delayed RIPK1 kinase-dependent apoptosis

In human cells, the RIPK1-RIPK3-MLKL-PGAM5-Drp1 axis drives tumor necrosis factor (TNF)-induced necroptosis through mitochondrial fission, but whether this pathway is conserved among mammals is not known. To answer this question, we analyzed the presence and functionality of the reported necroptotic axis in mice. As in humans, knockdown of receptorinteracting kinase-3 (RIPK3) or mixed lineage kinase domain like (MLKL) blocks TNF-induced necroptosis in L929 fibrosarcoma cells. However, repression of either of these proteins did not protect the cells from death, but instead induced a switch from TNF-induced necroptosis to receptor-interacting kinase-1 (RIPK1) kinase-dependent apoptosis. In addition, although mitochondrial fission also occurs during TNF-induced necroptosis in L929 cells, we found that knockdown of phosphoglycerate mutase 5 (PGAM5) and dynamin 1 like protein (Drp1) did not markedly protect the cells from TNF-induced necroptosis. Depletion of Pink1, a reported interactor of both PGAM5 and Drp1, did not affect TNF-induced necroptosis. These results indicate that in these murine cells mitochondrial fission and Pink1 dependent processes, including Pink-Parkin dependent mitophagy, apparently do not promote necroptosis. Our data demonstrate that the core components of the necrosome (RIPK1, RIPK3 and MLKL) are crucial to induce TNF-dependent necroptosis both in human and in mouse cells, but the associated mechanisms may differ between the two species or cell types

ATP13A2 deficiency disrupts lysosomal polyamine export

ATP13A2 (PARK9) is a late endolysosomal transporter that is genetically implicated in a spectrum of neurodegenerative disorders, including Kufor-Rakeb syndrome—a parkinsonism with dementia1—and early-onset Parkinson’s disease2. ATP13A2 offers protection against genetic and environmental risk factors of Parkinson’s disease, whereas loss of ATP13A2 compromises lysosomes3. However, the transport function of ATP13A2 in lysosomes remains unclear. Here we establish ATP13A2 as a lysosomal polyamine exporter that shows the highest affinity for spermine among the polyamines examined. Polyamines stimulate the activity of purified ATP13A2, whereas ATP13A2 mutants that are implicated in disease are functionally impaired to a degree that correlates with the disease phenotype. ATP13A2 promotes the cellular uptake of polyamines by endocytosis and transports them into the cytosol, highlighting a role for endolysosomes in the uptake of polyamines into cells. At high concentrations polyamines induce cell toxicity, which is exacerbated by ATP13A2 loss due to lysosomal dysfunction, lysosomal rupture and cathepsin B activation. This phenotype is recapitulated in neurons and nematodes with impaired expression of ATP13A2 or its orthologues. We present defective lysosomal polyamine export as a mechanism for lysosome-dependent cell death that may be implicated in neurodegeneration, and shed light on the molecular identity of the mammalian polyamine transport system

ATP13A3 is a major component of the enigmatic mammalian polyamine transport system

Polyamines, such as putrescine, spermidine, and spermine, are physiologically important polycations, but the transporters responsible for their uptake in mammalian cells remain poorly characterized. Here, we reveal a new component of the mammalian polyamine transport system using CHO-MG cells, a widely used model to study alternative polyamine uptake routes and characterize polyamine transport inhibitors for therapy. CHO-MG cells present polyamine uptake deficiency and resistance to a toxic polyamine biosynthesis inhibitor methylglyoxal bis-(guanylhydrazone) (MGBG), but the molecular defects responsible for these cellular characteristics remain unknown. By genome sequencing of CHO-MG cells, we identified mutations in an unexplored gene, ATP13A3, and found disturbed mRNA and protein expression. ATP13A3 encodes for an orphan P5B-ATPase (ATP13A3), a P-type transport ATPase that represents a candidate polyamine transporter. Interestingly, ATP13A3 complemented the putrescine transport deficiency and MGBG resistance of CHO-MG cells, whereas its knockdown in WT cells induced a CHO-MG phenotype demonstrated as a decrease in putrescine uptake and MGBG sensitivity. Taken together, our findings identify ATP13A3, which has been previously genetically linked with pulmonary arterial hypertension, as a major component of the mammalian polyamine transport system that confers sensitivity to MGBG

Tomato: a crop species amenable to improvement by cellular and molecular methods

Tomato is a crop plant with a relatively small DNA content per haploid genome and a well developed genetics. Plant regeneration from explants and protoplasts is feasable which led to the development of efficient transformation procedures. In view of the current data, the isolation of useful mutants at the cellular level probably will be of limited value in the genetic improvement of tomato. Protoplast fusion may lead to novel combinations of organelle and nuclear DNA (cybrids), whereas this technique also provides a means of introducing genetic information from alien species into tomato. Important developments have come from molecular approaches. Following the construction of an RFLP map, these RFLP markers can be used in tomato to tag quantitative traits bred in from related species. Both RFLP's and transposons are in the process of being used to clone desired genes for which no gene products are known. Cloned genes can be introduced and potentially improve specific properties of tomato especially those controlled by single genes. Recent results suggest that, in principle, phenotypic mutants can be created for cloned and characterized genes and will prove their value in further improving the cultivated tomato.

Developing core elements and checklist items for global hospital antimicrobial stewardship programmes:a consensus approach

International audienc

Current issues in medically assisted reproduction and genetics in Europe: research, clinical practice, ethics, legal issues and policy. European Society of Human Genetics and European Society of Human Reproduction and Embryology.

In March 2005, a group of experts from the European Society of Human Genetics and European Society of Human Reproduction and Embryology met to discuss the interface between genetics and assisted reproductive technology (ART), and published an extended background paper, recommendations and two Editorials. Seven years later, in March 2012, a follow-up interdisciplinary workshop was held, involving representatives of both professional societies, including experts from the European Union Eurogentest2 Coordination Action Project. The main goal of this meeting was to discuss developments at the interface between clinical genetics and ARTs. As more genetic causes of reproductive failure are now recognised and an increasing number of patients undergo testing of their genome before conception, either in regular health care or in the context of direct-to-consumer testing, the need for genetic counselling and preimplantation genetic diagnosis (PGD) may increase. Preimplantation genetic screening (PGS) thus far does not have evidence from randomised clinical trials to substantiate that the technique is both effective and efficient. Whole-genome sequencing may create greater challenges both in the technological and interpretational domains, and requires further reflection about the ethics of genetic testing in ART and PGD/PGS. Diagnostic laboratories should be reporting their results according to internationally accepted accreditation standards (International Standards Organisation - ISO 15189). Further studies are needed in order to address issues related to the impact of ART on epigenetic reprogramming of the early embryo. The legal landscape regarding assisted reproduction is evolving but still remains very heterogeneous and often contradictory. The lack of legal harmonisation and uneven access to infertility treatment and PGD/PGS fosters considerable cross-border reproductive care in Europe and beyond. The aim of this paper is to complement previous publications and provide an update of selected topics that have evolved since 2005