Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.

The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation

Accreting Black Holes

This chapter provides a general overview of the theory and observations of black holes in the Universe and on their interpretation. We briefly review the black hole classes, accretion disk models, spectral state classification, the AGN classification, and the leading techniques for measuring black hole spins. We also introduce quasi-periodic oscillations, the shadow of black holes, and the observations and the theoretical models of jets.Comment: 41 pages, 18 figures. To appear in "Tutorial Guide to X-ray and Gamma-ray Astronomy: Data Reduction and Analysis" (Ed. C. Bambi, Springer Singapore, 2020). v3: fixed some typos and updated some parts. arXiv admin note: substantial text overlap with arXiv:1711.1025

Rapid interhemispheric climate links via the Australasian monsoon during the last deglaciation

Recent studies have proposed that millennial-scale reorganization of the ocean-atmosphere circulation drives increased upwelling in the Southern Ocean, leading to rising atmospheric carbon dioxide levels and ice age terminations. Southward migration of the global monsoon is thought to link the hemispheres during deglaciation, but vital evidence from the southern sector of the vast Australasian monsoon system is yet to emerge. Here we present a 230thorium-dated stalagmite oxygen isotope record of millennial-scale changes in Australian–Indonesian monsoon rainfall over the last 31,000 years. The record shows that abrupt southward shifts of the Australian–Indonesian monsoon were synchronous with North Atlantic cold intervals 17,600–11,500 years ago. The most prominent southward shift occurred in lock-step with Heinrich Stadial 1 (17,600–14,600 years ago), and rising atmospheric carbon dioxide. Our findings show that millennial-scale climate change was transmitted rapidly across Australasia and lend support to the idea that the 3,000-year-long Heinrich 1 interval could have been critical in driving the last deglaciation

A change in the optical polarization associated with a gamma-ray flare in the blazar 3C 279

It is widely accepted that strong and variable radiation detected over all accessible energy bands in a number of active galaxies arises from a relativistic, Doppler-boosted jet pointing close to our line of sight. The size of the emitting zone and the location of this region relative to the central supermassive black hole are, however, poorly known, with estimates ranging from light-hours to a light-year or more. Here we report the coincidence of a gamma-ray flare with a dramatic change of optical polarization angle. This provides evidence for co-spatiality of optical and gamma-ray emission regions and indicates a highly ordered jet magnetic field. The results also require a non-axisymmetric structure of the emission zone, implying a curved trajectory for the emitting material within the jet, with the dissipation region located at a considerable distance from the black hole, at about 10^5 gravitational radii.Comment: Published in Nature issued on 18 February 2010. Corresponding authors: Masaaki Hayashida and Greg Madejsk

Extratropical forcing and tropical rainfall distribution: energetics framework and ocean Ekman advection

Intense tropical rainfall occurs in a narrow belt near the equator, called the inter-tropical convergence zone (ITCZ). In the past decade, the atmospheric energy budget has been used to explain changes in the zonal-mean ITCZ position. The energetics framework provides a mechanism for extratropics-to-tropics teleconnections, which have been postulated from paleoclimate records. In atmosphere models coupled with a motionless slab ocean, the ITCZ shifts toward the warmed hemisphere in order for the Hadley circulation to transport energy toward the colder hemisphere. However, recent studies using fully coupled models show that tropical rainfall can be rather insensitive to extratropical forcing when ocean dynamics is included. Here, we explore the effect of meridional Ekman heat advection while neglecting the upwelling effect on the ITCZ response to prescribed extratropical thermal forcing. The tropical component of Ekman advection is a negative feedback that partially compensates the prescribed forcing, whereas the extratropical component is a positive feedback that amplifies the prescribed forcing. Overall, the tropical negative feedback dominates over the extratropical positive feedback. Thus, including Ekman advection reduces the need for atmospheric energy transport, dampening the ITCZ response. We propose to build a hierarchy of ocean models to systematically explore the full dynamical response of the coupled climate system

The impact of positive psychological interventions on well-being in healthy elderly people

This systematic review aims to evaluate the impact of Positive Psychological Interventions (PPIs) on well-being in healthy older adults. Systematic review of PPIs obtained from three electronic databases (PsycINFO, Scopus, and Web of Science) was undertaken. Inclusion criteria were: that they were positive psychology intervention, included measurement of well-being, participants were aged over 60 years, and the studies were in English. The Cochrane Collaboration Guidelines dimensions of quality control, randomization, comparability, follow-up rate, dropout, blinding assessors are used to rate the quality of studies by two reviewers independently. The RE-AIM (Reach, Efficacy, Adoption, Implementation, and Maintenance) for evaluation of PPIs effectiveness was also applied. The final review included eight articles, each describing a positive psychological intervention study. The reminiscence interventions were the most prevalent type of PPIs to promote and maintain well-being in later life. Only two studies were rated as high quality, four were of moderate-quality and two were of low-quality. Overall results indicated that efficacy criteria (89%), reach criteria (85%), adoption criteria (73%), implementation criteria (67%), and maintenance criteria (4%) across a variety of RE-AIM dimensions. Directions for future positive psychological research related to RE-AIM, and implications for decision-making, are described

Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing

Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we characterized the ability of romidepsin (RMD), a histone deacetylase inhibitor approved for the treatment of T-cell lymphomas, to activate the expression of latent HIV. In an in vitro T-cell model of HIV latency, RMD was the most potent inducer of HIV (EC50 = 4.5 nM) compared with vorinostat (VOR; EC50 = 3,950 nM) and other histone deacetylase (HDAC) inhibitors in clinical development including panobinostat (PNB; EC50 = 10 nM). The HIV induction potencies of RMD, VOR, and PNB paralleled their inhibitory activities against multiple human HDAC isoenzymes. In both resting and memory CD4 T cells isolated from HIV-infected patients on suppressive combination antiretroviral therapy (cART), a 4-hour exposure to 40 nM RMD induced a mean 6-fold increase in intracellular HIV RNA levels, whereas a 24-hour treatment with 1 μM VOR resulted in 2- to 3-fold increases. RMD-induced intracellular HIV RNA expression persisted for 48 hours and correlated with sustained inhibition of cell-associated HDAC activity. By comparison, the induction of HIV RNA by VOR and PNB was transient and diminished after 24 hours. RMD also increased levels of extracellular HIV RNA and virions from both memory and resting CD4 T-cell cultures. The activation of HIV expression was observed at RMD concentrations below the drug plasma levels achieved by doses used in patients treated for T-cell lymphomas. In conclusion, RMD induces HIV expression ex vivo at concentrations that can be achieved clinically, indicating that the drug may reactivate latent HIV in patients on suppressive cART

Biology of human hair: Know your hair to control it

Hair can be engineered at different levels—its structure and surface—through modification of its constituent molecules, in particular proteins, but also the hair follicle (HF) can be genetically altered, in particular with the advent of siRNA-based applications. General aspects of hair biology are reviewed, as well as the most recent contributions to understanding hair pigmentation and the regulation of hair development. Focus will also be placed on the techniques developed specifically for delivering compounds of varying chemical nature to the HF, indicating methods for genetic/biochemical modulation of HF components for the treatment of hair diseases. Finally, hair fiber structure and chemical characteristics will be discussed as targets for keratin surface functionalization

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

This is the final version of the article. Available from the publisher via the DOI in this record.Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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