HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS

A prominent feature of late-onset neurodegenerative diseases is accumulation of misfolded protein in vulnerable neurons. When levels of misfolded protein overwhelm degradative pathways, the result is cellular toxicity and neurodegeneration. Cellular mechanisms for degrading misfolded protein include the ubiquitin-proteasome system (UPS), the main non-lysosomal degradative pathway for ubiquitinated proteins, and autophagy, a lysosome-mediated degradative pathway. The UPS and autophagy have long been viewed as complementary degradation systems with no point of intersection. This view has been challenged by two observations suggesting an apparent interaction: impairment of the UPS induces autophagy in vitro, and conditional knockout of autophagy in the mouse brain leads to neurodegeneration with ubiquitin-positive pathology. It is not known whether autophagy is strictly a parallel degradation system, or whether it is a compensatory degradation system when the UPS is impaired; furthermore, if there is a compensatory interaction between these systems, the molecular link is not known. Here we show that autophagy acts as a compensatory degradation system when the UPS is impaired in Drosophila melanogaster, and that histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase that interacts with polyubiquitinated proteins, is an essential mechanistic link in this compensatory interaction. We found that compensatory autophagy was induced in response to mutations affecting the proteasome and in response to UPS impairment in a fly model of the neurodegenerative disease spinobulbar muscular atrophy. Autophagy compensated for impaired UPS function in an HDAC6-dependent manner. Furthermore, expression of HDAC6 was sufficient to rescue degeneration associated with UPS dysfunction in vivo in an autophagy-dependent manner. This study suggests that impairment of autophagy (for example, associated with ageing or genetic variation) might predispose to neurodegeneration. Morover, these findings suggest that it may be possible to intervene in neurodegeneration by augmenting HDAC6 to enhance autophagy.     

A reversible wet/dry adhesive inspired by mussels and geckos

The adhesive strategy of the gecko relies on foot pads composed of specialized keratinous foot-hairs called setae, which are subdivided into terminal spatulae of approximately 200 nm (ref. 1). Contact between the gecko foot and an opposing surface generates adhesive forces that are sufficient to allow the gecko to cling onto vertical and even inverted surfaces. Although strong, the adhesion is temporary, permitting rapid detachment and reattachment of the gecko foot during locomotion. Researchers have attempted to capture these properties of gecko adhesive in synthetic mimics with nanoscale surface features reminiscent of setae; however, maintenance of adhesive performance over many cycles has been elusive, and gecko adhesion is greatly diminished upon full immersion in water. Here we report a hybrid biologically inspired adhesive consisting of an array of nanofabricated polymer pillars coated with a thin layer of a synthetic polymer that mimics the wet adhesive proteins found in mussel holdfasts. Wet adhesion of the nanostructured polymer pillar arrays increased nearly 15-fold when coated with mussel-mimetic polymer. The system maintains its adhesive performance for over a thousand contact cycles in both dry and wet environments. This hybrid adhesive, which combines the salient design elements of both gecko and mussel adhesives, should be useful for reversible attachment to a variety of surfaces in any environment.     

The development of a protoplanetary disk from its natal envelope

Class 0 protostars, the youngest type of young stellar objects, show many signs of rapid development from their initial, spheroidal configurations, and therefore are studied intensively for details of the formation of protoplanetary disks within protostellar envelopes. At millimetre wavelengths, kinematic signatures of collapse have been observed in several such protostars, through observations of molecular lines that probe their outer envelopes. It has been suggested that one or more components of the proto-multiple system NGC 1333-IRAS 4 (refs 1, 2) may display signs of an embedded region that is warmer and denser than the bulk of the envelope. Here we report observations that reveal details of the core on Solar System dimensions. We detect in NGC 1333-IRAS 4B a rich emission spectrum of H2O, at wavelengths 20-37 microm, which indicates an origin in extremely dense, warm gas. We can model the emission as infall from a protostellar envelope onto the surface of a deeply embedded, dense disk, and therefore see the development of a protoplanetary disk. This is the only example of mid-infrared water emission from a sample of 30 class 0 objects, perhaps arising from a favourable orientation; alternatively, this may be an early and short-lived stage in the evolution of a protoplanetary disk.     

Classification and Categorical Inputs with Treed Gaussian Process Models

Recognizing the successes of treed Gaussian process (TGP) models as an interpretable and thrifty model for nonparametric regression, we seek to extend the model to classification. Both treed models and Gaussian processes (GPs) have, separately, enjoyed great success in application to classification problems. An example of the former is Bayesian CART. In the latter, real-valued GP output may be utilized for classification via latent variables, which provide classification rules by means of a softmax function. We formulate a Bayesian model averaging scheme to combine these two models and describe a Monte Carlo method for sampling from the full posterior distribution with joint proposals for the tree topology and the GP parameters corresponding to latent variables at the leaves. We concentrate on efficient sampling of the latent variables, which is important to obtain good mixing in the expanded parameter space. The tree structure is particularly helpful for this task and also for developing an efficient scheme for handling categorical predictors, which commonly arise in classification problems. Our proposed classification TGP (CTGP) methodology is illustrated on a collection of synthetic and real data sets. We assess performance relative to existing methods and thereby show how CTGP is highly flexible, offers tractable inference, produces rules that are easy to interpret, and performs well out of sample.     

Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy

Latency and ongoing replication have both been proposed to explain the drug-insensitive human immunodeficiency virus (HIV) reservoir maintained during antiretroviral therapy. Here we explore a novel mechanism for ongoing HIV replication in the face of antiretroviral drugs. We propose a model whereby multiple infections per cell lead to reduced sensitivity to drugs without requiring drug-resistant mutations, and experimentally validate the model using multiple infections per cell by cell-free HIV in the presence of the drug tenofovir. We then examine the drug sensitivity of cell-to-cell spread of HIV, a mode of HIV transmission that can lead to multiple infection events per target cell. Infections originating from cell-free virus decrease strongly in the presence of antiretrovirals tenofovir and efavirenz whereas infections involving cell-to-cell spread are markedly less sensitive to the drugs. The reduction in sensitivity is sufficient to keep multiple rounds of infection from terminating in the presence of drugs. We examine replication from cell-to-cell spread in the presence of clinical drug concentrations using a stochastic infection model and find that replication is intermittent, without substantial accumulation of mutations. If cell-to-cell spread has the same properties in vivo, it may have adverse consequences for the immune system, lead to therapy failure in individuals with risk factors, and potentially contribute to viral persistence and hence be a barrier to curing HIV infection.     

Genome sequence and analysis of the tuber crop potato

Potato (Solanum tuberosum L.) is the world's most important non-grain food crop and is central to global food security. It is clonally propagated, highly heterozygous, autotetraploid, and suffers acute inbreeding depression. Here we use a homozygous doubled-monoploid potato clone to sequence and assemble 86% of the 844-megabase genome. We predict 39,031 protein-coding genes and present evidence for at least two genome duplication events indicative of a palaeopolyploid origin. As the first genome sequence of an asterid, the potato genome reveals 2,642 genes specific to this large angiosperm clade. We also sequenced a heterozygous diploid clone and show that gene presence/absence variants and other potentially deleterious mutations occur frequently and are a likely cause of inbreeding depression. Gene family expansion, tissue-specific expression and recruitment of genes to new pathways contributed to the evolution of tuber development. The potato genome sequence provides a platform for genetic improvement of this vital crop.     

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140?mm?Hg systolic blood pressure or ≥90?mm?Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.     

Evidence for a spin-aligned neutron-proton paired phase from the level structure of (92)Pd

Shell structure and magic numbers in atomic nuclei were generally explained by pioneering work that introduced a strong spin-orbit interaction to the nuclear shell model potential. However, knowledge of nuclear forces and the mechanisms governing the structure of nuclei, in particular far from stability, is still incomplete. In nuclei with equal neutron and proton numbers (N = Z), enhanced correlations arise between neutrons and protons (two distinct types of fermions) that occupy orbitals with the same quantum numbers. Such correlations have been predicted to favour an unusual type of nuclear superfluidity, termed isoscalar neutron-proton pairing, in addition to normal isovector pairing. Despite many experimental efforts, these predictions have not been confirmed. Here we report the experimental observation of excited states in the N = Z = 46 nucleus (92)Pd. Gamma rays emitted following the (58)Ni((36)Ar,2n)(92)Pd fusion-evaporation reaction were identified using a combination of state-of-the-art high-resolution γ-ray, charged-particle and neutron detector systems. Our results reveal evidence for a spin-aligned, isoscalar neutron-proton coupling scheme, different from the previous prediction. We suggest that this coupling scheme replaces normal superfluidity (characterized by seniority coupling) in the ground and low-lying excited states of the heaviest N = Z nuclei. Such strong, isoscalar neutron-proton correlations would have a considerable impact on the nuclear level structure and possibly influence the dynamics of rapid proton capture in stellar nucleosynthesis.     

Comprehensive analysis of the chromatin landscape in Drosophila melanogaster

Chromatin is composed of DNA and a variety of modified histones and non-histone proteins, which have an impact on cell differentiation, gene regulation and other key cellular processes. Here we present a genome-wide chromatin landscape for Drosophila melanogaster based on eighteen histone modifications, summarized by nine prevalent combinatorial patterns. Integrative analysis with other data (non-histone chromatin proteins, DNase I hypersensitivity, GRO-Seq reads produced by engaged polymerase, short/long RNA products) reveals discrete characteristics of chromosomes, genes, regulatory elements and other functional domains. We find that active genes display distinct chromatin signatures that are correlated with disparate gene lengths, exon patterns, regulatory functions and genomic contexts. We also demonstrate a diversity of signatures among Polycomb targets that include a subset with paused polymerase. This systematic profiling and integrative analysis of chromatin signatures provides insights into how genomic elements are regulated, and will serve as a resource for future experimental investigations of genome structure and function.