Tetraspanin (TSP-17) Protects Dopaminergic Neurons against 6-OHDA-Induced Neurodegeneration in <i>C. elegans</i>

Parkinson's disease (PD), the second most prevalent neurodegenerative disease after Alzheimer's disease, is linked to the gradual loss of dopaminergic neurons in the substantia nigra. Disease loci causing hereditary forms of PD are known, but most cases are attributable to a combination of genetic and environmental risk factors. Increased incidence of PD is associated with rural living and pesticide exposure, and dopaminergic neurodegeneration can be triggered by neurotoxins such as 6-hydroxydopamine (6-OHDA). In C. elegans, this drug is taken up by the presynaptic dopamine reuptake transporter (DAT-1) and causes selective death of the eight dopaminergic neurons of the adult hermaphrodite. Using a forward genetic approach to find genes that protect against 6-OHDA-mediated neurodegeneration, we identified tsp-17, which encodes a member of the tetraspanin family of membrane proteins. We show that TSP-17 is expressed in dopaminergic neurons and provide genetic, pharmacological and biochemical evidence that it inhibits DAT-1, thus leading to increased 6-OHDA uptake in tsp-17 loss-of-function mutants. TSP-17 also protects against toxicity conferred by excessive intracellular dopamine. We provide genetic and biochemical evidence that TSP-17 acts partly via the DOP-2 dopamine receptor to negatively regulate DAT-1. tsp-17 mutants also have subtle behavioral phenotypes, some of which are conferred by aberrant dopamine signaling. Incubating mutant worms in liquid medium leads to swimming-induced paralysis. In the L1 larval stage, this phenotype is linked to lethality and cannot be rescued by a dop-3 null mutant. In contrast, mild paralysis occurring in the L4 larval stage is suppressed by dop-3, suggesting defects in dopaminergic signaling. In summary, we show that TSP-17 protects against neurodegeneration and has a role in modulating behaviors linked to dopamine signaling

Consistent phenological shifts in the making of a biodiversity hotspot: the Cape flora

Background The best documented survival responses of organisms to past climate change on short (glacial-interglacial) timescales are distributional shifts. Despite ample evidence on such timescales for local adaptations of populations at specific sites, the long-term impacts of such changes on evolutionary significant units in response to past climatic change have been little documented. Here we use phylogenies to reconstruct changes in distribution and flowering ecology of the Cape flora - South Africa's biodiversity hotspot - through a period of past (Neogene and Quaternary) changes in the seasonality of rainfall over a timescale of several million years. Results Forty-three distributional and phenological shifts consistent with past climatic change occur across the flora, and a comparable number of clades underwent adaptive changes in their flowering phenology (9 clades; half of the clades investigated) as underwent distributional shifts (12 clades; two thirds of the clades investigated). Of extant Cape angiosperm species, 14-41% have been contributed by lineages that show distributional shifts consistent with past climate change, yet a similar proportion (14-55%) arose from lineages that shifted flowering phenology. Conclusions Adaptive changes in ecology at the scale we uncover in the Cape and consistent with past climatic change have not been documented for other floras. Shifts in climate tolerance appear to have been more important in this flora than is currently appreciated, and lineages that underwent such shifts went on to contribute a high proportion of the flora's extant species diversity. That shifts in phenology, on an evolutionary timescale and on such a scale, have not yet been detected for other floras is likely a result of the method used; shifts in flowering phenology cannot be detected in the fossil record

The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Early chronic kidney disease: diagnosis, management and models of care

Chronic kidney disease (CKD) is prevalent in many countries, and the costs associated with the care of patients with end-stage renal disease (ESRD) are estimated to exceed US$1 trillion globally. The clinical and economic rationale for the design of timely and appropriate health system responses to limit the progression of CKD to ESRD is clear. Clinical care might improve if early-stage CKD with risk of progression to ESRD is differentiated from early-stage CKD that is unlikely to advance. The diagnostic tests that are currently used for CKD exhibit key limitations; therefore, additional research is required to increase awareness of the risk factors for CKD progression. Systems modelling can be used to evaluate the impact of different care models on CKD outcomes and costs. The US Indian Health Service has demonstrated that an integrated, system-wide approach can produce notable benefits on cardiovascular and renal health outcomes. Economic and clinical improvements might, therefore, be possible if CKD is reconceptualized as a part of primary care. This Review discusses which early CKD interventions are appropriate, the optimum time to provide clinical care, and the most suitable model of care to adopt

Contrasting Biogeographic and Diversification Patterns in Two Mediterranean-Type Ecosystems

The five Mediterranean regions of the world comprise almost 50,000 plant species (ca 20% of the known vascular plants) despite accounting for less than 5% of the world’s land surface. The ecology and evolutionary history of two of these regions, the Cape Floristic Region and the Mediterranean Basin, have been extensively investigated, but there have been few studies aimed at understanding the historical relationships between them. Here, we examine the biogeographic and diversification processes that shaped the evolution of plant diversity in the Cape and the Mediterranean Basin using a large plastid data set for the geophyte family Hyacinthaceae (comprising ca. 25% of the total diversity of the group), a group found mainly throughout Africa and Eurasia. Hyacinthaceae is a predominant group in the Cape and the Mediterranean Basin both in terms of number of species and their morphological and ecological variability. Using state-of-the-art methods in biogeography and diversification, we found that the Old World members of the family originated in sub-Saharan Africa at the Paleocene–Eocene boundary and that the two Mediterranean regions both have high diversification rates, but contrasting biogeographic histories. While the Cape diversity has been greatly influenced by its relationship with sub-Saharan Africa throughout the history of the family, the Mediterranean Basin had no connection with the latter after the onset of the Mediterranean climate in the region and the aridification of the Sahara. The Mediterranean Basin subsequently contributed significantly to the diversity of neighbouring areas, especially Northern Europe and the Middle East, whereas the Cape can be seen as a biogeographical cul-de-sac, with only a few dispersals toward sub-Saharan Africa. The understanding of the evolutionary history of these two important repositories of biodiversity would benefit from the application of the framework developed here to other groups of plants present in the two regions

Effects of maternal proteic undernutrition on the neurons of the myenteric plexus of the duodenum of rats

The purpose of this study was to verify the effects of proteic undernutrition on the neurons of the myenteric plexus from the duodenum of Wistar rats. Twenty-four animals at the age of 60 days were divided in four groups, which were named according to the period their mothers received hypoproteic ration (8%). Some segments of duodenum were subjected to histological treatment and stained with hematoxilin-eosin and some were used for whoie mount preparations stained with Giemsa. We observed small, medium-sized and large neurons grouped in ganglia of various shapes. It was concluded that the maternal proteic undernutrition does not affect the organization of the myenteric plexus and that animals submitted to undernutrition during gestation and lactation, when normally fed, show neurons with strongly basophilic cytoplasm and larger cellular bodies than those from control animals.O propósito deste estudo foi investigar os efeitos da desnutrição proteica sobre os neurônios do plexo mientérico do duodeno de ratos Wistar. Vinte e quatro animais com 60 dias de idade foram divididos em 4 grupos e denominados de acordo com o período em que suas mães receberam ração hipoproteica (8%). Alguns segmentos de duodeno foram submetidos a tratamento histológico e corados com hematoxilina-eosinae alguns foram utilizados na elaboração dos preparados de membrana corados com Giemsa. Observamos neurônios pequenos, médios e grandes formando gânglios de formatos diversos. Concluiu-se que a desnutrição proteica materna não afeta a organização do plexo mientérico e que animais desnutridos na gestação e lactação quando voltam a receber dieta com teor proteico normal apresentam neurônios com citoplasma fortemente basofílico e geralmente maiores que o de animais normo-alimentados