Local IGF-1 isoform protects cardiomyocytes from hypertrophic and oxidative stresses via SirT1 activity

Oxidative and hypertrophic stresses contribute to the pathogenesis of heart failure. Insulin-like growth factor-1 (IGF-1) is a peptide hormone with a complex post-transcriptional regulation, generating distinct isoforms. Locally acting IGF-1 isoform (mIGF-1) helps the heart to recover from toxic injury and from infarct. In the murine heart, moderate overexpression of the NAD+-dependent deacetylase SirT1 was reported to mitigate oxidative stress. SirT1 is known to promote lifespan extension and to protect from metabolic challenges. Circulating IGF-1 and SirT1 play antagonizing biological roles and share molecular targets in the heart, in turn affecting cardiomyocyte physiology. However, how different IGF-1 isoforms may impact SirT1 and affect cardiomyocyte function is unknown. Here we show that locally acting mIGF-1 increases SirT1 expression/activity, whereas circulating IGF-1 isoform does not affect it, in cultured HL-1 and neonatal cardiomyocytes. mIGF-1-induced SirT1 activity exerts protection against angiotensin II (Ang II)-triggered hypertrophy and against paraquat (PQ) and Ang II-induced oxidative stress. Conversely, circulating IGF-1 triggered itself oxidative stress and cardiomyocyte hypertrophy. Interestingly, potent cardio-protective genes (adiponectin, UCP-1 and MT-2) were increased specifically in mIGF-1-overexpressing cardiomyocytes, in a SirT1-dependent fashion. Thus, mIGF-1 protects cardiomyocytes from oxidative and hypertrophic stresses via SirT1 activity, and may represent a promising cardiac therapeutic

Projected increases in the annual flood pulse of the Western Amazon

The impact of a changing climate on the Amazon basin is a subject of intensive research because of its rich biodiversity and the significant role of rainforests in carbon cycling. Climate change has also a direct hydrological impact, and increasing efforts have focused on understanding the hydrological dynamics at continental and subregional scales, such as the Western Amazon. New projections from the Coupled Model Inter-comparison Project Phase 5 ensemble indicate consistent climatic warming and increasing seasonality of precipitation in the Peruvian Amazon basin. Here we use a distributed land surface model to quantify the potential impact of this change in the climate on the hydrological regime of the upper Amazon river. Using extreme value analysis, historical and future projections of the annual minimum, mean, and maximum river flows are produced for a range of return periods between 1 and 100 yr. We show that the RCP 4.5 and 8.5 scenarios of climate change project an increased severity of the wet season flood pulse (7.5% and 12% increases respectively for the 100 yr return floods). These findings agree with previously projected increases in high extremes under the Special Report on Emissions Scenarios climate projections, and are important to highlight due to the potential consequences on reproductive processes of in-stream species, swamp forest ecology, and socio-economy in the floodplain, amidst a growing literature that more strongly emphasises future droughts and their impact on the viability of the rainforest system over greater Amazonia

Adjustment of global precipitation data for enhanced hydrologic modeling of tropical Andean watersheds

Global gridded precipitation is an essential driving input for hydrologic models to simulate runoff dynamics in large river basins. However, the data often fail to adequately represent precipitation variability in mountainous regions due to orographic effects and sparse and highly uncertain gauge data. Water balance simulations in tropical montane regions covered by cloud forests are especially challenging because of the additional water input from cloud water interception. The ISI-MIP2 hydrologic model ensemble encountered these problems for Andean sub-basins of the Upper Amazon Basin, where all models significantly underestimated observed runoff. In this paper, we propose simple yet plausible ways to adjust global precipitation data provided by WFDEI, the WATCH Forcing Data methodology applied to ERA-Interim reanalysis, for tropical montane watersheds. The modifications were based on plausible reasoning and freely available tropics-wide data: (i) a high-resolution climatology of the Tropical Rainfall Measuring Mission (TRMM) and (ii) the percentage of tropical montane cloud forest cover. Using the modified precipitation data, runoff predictions significantly improved for all hydrologic models considered. The precipitation adjustment methods presented here have the potential to enhance other global precipitation products for hydrologic model applications in the Upper Amazon Basin as well as in other tropical montane watersheds

Deciphering Lyman-α\alpha Emission Deep into the Epoch of Reionisation

A major event in cosmic history is the genesis of the first starlight in our Universe, ending the ''Dark Ages''. During this epoch, the earliest luminous sources were enshrouded in neutral and pristine gas, which was gradually ionised in a process called ''reionisation''. Hence, one of the brightest emission lines in star-forming galaxies, Lyman-$\alpha$ (Ly-$\alpha$), was predicted to emerge only towards the end of the epoch of reionisation, about one billion years after the Big Bang. However, this picture has been challenged over the past decade by the surprising detection of Ly-$\alpha$ in galaxies less than 500 million years old. Here we show, by taking advantage of both high-resolution and high-sensitivity images from the James Webb Space Telescope programs PRIMER, CEERS and FRESCO, that all galaxies in our sample of Ly-$\alpha$ emitters deep in the epoch of reionisation have close companions. To understand the physical processes that lead to the observed Ly-$\alpha$ emission in our sample, we take advantage of novel on-the-fly radiative transfer magnetohydrodynamical simulations with cosmic ray feedback. We find that in the early Universe, the rapid build up of mass through frequent galactic mergers leads to very bursty star formation which in turn drives episodes of high intrinsic Ly-$\alpha$ emission and facilitates the escape of Ly-$\alpha$ photons along channels cleared of neutral gas. These merging galaxies reside in clustered environments thus creating sufficiently large ionised bubbles. This presents a solution to the long-standing puzzle of the detection of Ly-$\alpha$ emission deep into the epoch of reionisation.Comment: Submitted to Nature. 38 pages, 9 figures, 2 table

A comparative study of different slot configurations for PM brushless machines used for vehicle traction.

This work describes the design and optimization\ud process of a direct-drive permanent magnet synchronous\ud machine that is suitable for electric motorcycles. The machine is\ud designed to develop approximately the same power than a\ud conventional 250cc motorcycle internal combustion engine. The\ud main goal of this work is to design an outer-rotor machine that is\ud coupled directly to the wheel (direct-drive or in-wheel motor), so\ud it is necessary to know the dimensions and arrangements of the\ud wheels. The direct-drive systems do not need any gearbox to\ud drive the vehicle, so that the global efficiency is higher than\ud conventional systems employing a gearbox. The design and\ud performance of the machine are assessed by means of simulations\ud using the finite element method. The finite element method is the\ud main tool to optimize the machine’s design.FAPESPCAPE

Methionine 129 variant of human prion protein oligomerizes more rapidly than the valine 129 variant

The human PrP gene (PRNP) has two common alleles that encode either methionine or valine at codon 129. This polymorphism modulates disease susceptibility and phenotype of human transmissible spongiform encyphalopathies, but the molecular mechanism by which these effects are mediated remains unclear. Here, we compared the misfolding pathway that leads to the formation of beta-sheet-rich oligomeric isoforms of the methionine 129 variant of PrP to that of the valine 129 variant. We provide evidence for differences in the folding behavior between the two variants at the early stages of oligomer formation. We show that Met(129) has a higher propensity to form beta-sheet-rich oligomers, whereas Val(129) has a higher tendency to fold into alpha-helical-rich monomers. An equimolar mixture of both variants displayed an intermidate folding behavior. We show that the oligomers of both variants are initially a mixture of alpha- and beta-rich conformers that evolve with time to an increasingly homogeneous beta-rich form. This maturation process, which involves no further change in proteinase K resistance, occurs more rapidly in the Met(129) form than the Val(129) form. Although the involvement of such beta-rich oligomers in prion pathogenesis is speculative, the misfolding behavior could, in part, explain the higher susceptibility of individuals that are methionine homozygote to both sporadic and variant Creutzfeldt-Jakob disease

Novel Marine Phenazines as Potential Cancer Chemopreventive and Anti-Inflammatory Agents

Two new (1 and 2) and one known phenazine derivative (lavanducyanin, 3) were isolated and identified from the fermentation broth of a marine-derived Streptomyces sp. (strain CNS284). In mammalian cell culture studies, compounds 1, 2 and 3 inhibited TNF-α-induced NFκB activity (IC50 values of 4.1, 24.2, and 16.3 μM, respectively) and LPS-induced nitric oxide production (IC50 values of >48.6, 15.1, and 8.0 μM, respectively). PGE2 production was blocked with greater efficacy (IC50 values of 7.5, 0.89, and 0.63 μM, respectively), possibly due to inhibition of cyclooxygenases in addition to the expression of COX-2. Treatment of cultured HL-60 cells led to dose-dependent accumulation in the subG1 compartment of the cell cycle, as a result of apoptosis. These data provide greater insight on the biological potential of phenazine derivatives, and some guidance on how various substituents may alter potential anti-inflammatory and anti-cancer effects

Feedback Inhibition in the PhoQ/PhoP Signaling System by a Membrane Peptide

The PhoQ/PhoP signaling system responds to low magnesium and the presence of certain cationic antimicrobial peptides. It regulates genes important for growth under these conditions, as well as additional genes important for virulence in many gram-negative pathogens. PhoQ is a sensor kinase that phosphorylates and activates the transcription factor PhoP. Since feedback inhibition is a common theme in stress-response circuits, we hypothesized that some members of the PhoP regulon may play such a role in the PhoQ/PhoP pathway. We therefore screened for PhoP-regulated genes that mediate feedback in this system. We found that deletion of mgrB (yobG), which encodes a 47 amino acid peptide, results in a potent increase in PhoP-regulated transcription. In addition, over-expression of mgrB decreased transcription at both high and low concentrations of magnesium. Localization and bacterial two-hybrid studies suggest that MgrB resides in the inner-membrane and interacts directly with PhoQ. We further show that MgrB homologs from Salmonella typhimurium and Yersinia pestis also repress PhoP-regulated transcription in these organisms. In cell regulatory circuits, feedback has been associated with modulating the induction kinetics and/or the cell-to-cell variability in response to stimulus. Interestingly, we found that elimination of MgrB-mediated feedback did not have a significant effect on the kinetics of reporter protein production and did not decrease the variability in expression among cells. Our results indicate MgrB is a broadly conserved membrane peptide that is a critical mediator of negative feedback in the PhoQ/PhoP circuit. This new regulator may function as a point of control that integrates additional input signals to modulate the activity of this important signaling system