Single-molecule measurements reveal that PARP1 condenses DNA by loop stabilization

Poly(ADP-ribose) polymerase 1 (PARP1) is an abundant nuclear enzyme that plays important roles in DNA repair, chromatin organization and transcription regulation. Although binding and activation of PARP1 by DNA damage sites has been extensively studied, little is known about how PARP1 binds to long stretches of undamaged DNA and how it could shape chromatin architecture. Here, using single-molecule techniques, we show that PARP1 binds and condenses undamaged, kilobase-length DNA subject to sub-piconewton mechanical forces. Stepwise decondensation at high force and DNA braiding experiments show that the condensation activity is due to the stabilization of DNA loops by PARP1. PARP inhibitors do not affect the level of condensation of undamaged DNA but act to block condensation reversal for damaged DNA in the presence of NAD+. Our findings suggest a mechanism for PARP1 in the organization of chromatin structure

Impairment of Adenosinergic System in Rett syndrome: Novel Therapeutic Target to Boost BDNF Signalling

Rett syndrome (RTT; OMIM#312750) is mainly caused by mutations in the X-linked MECP2 gene (methyl-CpG-binding protein 2 gene; OMIM*300005), which leads to impairments in the brain-derived neurotrophic factor (BDNF) signalling. The boost of BDNF mediated effects would be a significant breakthrough but it has been hampered by the difficulty to administer BDNF to the central nervous system. Adenosine, an endogenous neuromodulator, may accomplish that role since through A2AR it potentiates BDNF synaptic actions in healthy animals. We thus characterized several hallmarks of the adenosinergic and BDNF signalling in RTT and explored whether A2AR activation could boost BDNF actions. For this study, the RTT animal model, the Mecp2 knockout (Mecp2-/y) (B6.129P2 (C)-Mecp2tm1.1Bird/J) mouse was used. Whenever possible, parallel data was also obtained from post-mortem brain samples from one RTT patient. Ex vivo extracellular recordings of field excitatory post-synaptic potentials in CA1 hippocampal area were performed to evaluate synaptic transmission and long-term potentiation (LTP). RT-PCR was used to assess mRNA levels and Western Blot or radioligand binding assays were performed to evaluate protein levels. Changes in cortical and hippocampal adenosine content were assessed by liquid chromatography with diode array detection (LC/DAD). Hippocampal ex vivo experiments revealed that the facilitatory actions of BDNF upon LTP is absent in Mecp2-/y mice and that TrkB full-length (TrkB-FL) receptor levels are significantly decreased. Extracts of the hippocampus and cortex of Mecp2-/y mice revealed less adenosine amount as well as less A2AR protein levels when compared to WT littermates, which may partially explain the deficits in adenosinergic tonus in these animals. Remarkably, the lack of BDNF effect on hippocampal LTP in Mecp2-/y mice was overcome by selective activation of A2AR with CGS21680. Overall, in Mecp2-/y mice there is an impairment on adenosinergic system and BDNF signalling. These findings set the stage for adenosine-based pharmacological therapeutic strategies for RTT, highlighting A2AR as a therapeutic target in this devastating pathology.info:eu-repo/semantics/publishedVersio

Decline in Diarrhea Mortality and Admissions after Routine Childhood Rotavirus Immunization in Brazil: A Time-Series Analysis

A time series analysis by Manish Patel and colleagues shows that the introduction of rotavirus vaccination in Brazil is associated with reduced diarrhea-related deaths and hospital admissions in children under 5 years of age

Anthropogenic disturbance in tropical forests can double biodiversity loss from deforestation

Concerted political attention has focused on reducing deforestation1,2,3, and this remains the cornerstone of most biodiversity conservation strategies4,5,6. However, maintaining forest cover may not reduce anthropogenic forest disturbances, which are rarely considered in conservation programmes6. These disturbances occur both within forests, including selective logging and wildfires7,8, and at the landscape level, through edge, area and isolation effects9. Until now, the combined effect of anthropogenic disturbance on the conservation value of remnant primary forests has remained unknown, making it impossible to assess the relative importance of forest disturbance and forest loss. Here we address these knowledge gaps using a large data set of plants, birds and dung beetles (1,538, 460 and 156 species, respectively) sampled in 36 catchments in the Brazilian state of Pará. Catchments retaining more than 69–80% forest cover lost more conservation value from disturbance than from forest loss. For example, a 20% loss of primary forest, the maximum level of deforestation allowed on Amazonian properties under Brazil’s Forest Code5, resulted in a 39–54% loss of conservation value: 96–171% more than expected without considering disturbance effects. We extrapolated the disturbance-mediated loss of conservation value throughout Pará, which covers 25% of the Brazilian Amazon. Although disturbed forests retained considerable conservation value compared with deforested areas, the toll of disturbance outside Pará’s strictly protected areas is equivalent to the loss of 92,000–139,000 km2 of primary forest. Even this lowest estimate is greater than the area deforested across the entire Brazilian Amazon between 2006 and 2015 (ref. 10). Species distribution models showed that both landscape and within-forest disturbances contributed to biodiversity loss, with the greatest negative effects on species of high conservation and functional value. These results demonstrate an urgent need for policy interventions that go beyond the maintenance of forest cover to safeguard the hyper-diversity of tropical forest ecosystems