The local partial autocorrelation function and some applications

The classical regular and partial autocorrelation functions are powerful tools for stationary time series modelling and analysis. However, it is increasingly recognized that many time series are not stationary and the use of classical global autocorrelations can give misleading answers. This article introduces two estimators of the local partial autocorrelation function and establishes their asymptotic properties. The article then illustrates the use of these new estimators on both simulated and real time series. The examples clearly demonstrate the strong practical benefits of local estimators for time series that exhibit nonstationarities

HUWE1 E3 ligase promotes PINK1/PARKINindependent mitophagy by regulating AMBRA1 activation via IKKa

The selective removal of undesired or damaged mitochondria by autophagy, known as mitophagy, is crucial for cellular homoeostasis, and prevents tumour diffusion, neurodegeneration and ageing. The pro-autophagic molecule AMBRA1 (autophagy/beclin-1 regulator-1) has been defined as a novel regulator of mitophagy in both PINK1/PARKIN-dependent and -independent systems. Here, we identified the E3 ubiquitin ligase HUWE1 as a key inducing factor in AMBRA1-mediated mitophagy, a process that takes place independently of the main mitophagy receptors. Furthermore, we show that mitophagy function of AMBRA1 is post-translationally controlled, upon HUWE1 activity, by a positive phosphorylation on its serine 1014. This modification is mediated by the IKKα kinase and induces structural changes in AMBRA1, thus promoting its interaction with LC3/GABARAP (mATG8) proteins and its mitophagic activity. Altogether, these results demonstrate that AMBRA1 regulates mitophagy through a novel pathway, in which HUWE1 and IKKα are key factors, shedding new lights on the regulation of mitochondrial quality control and homoeostasis in mammalian cells

Prevalence of Disorders Recorded in Dogs Attending Primary-Care Veterinary Practices in England

Purebred dog health is thought to be compromised by an increasing occurence of inherited diseases but inadequate prevalence data on common disorders have hampered efforts to prioritise health reforms. Analysis of primary veterinary practice clinical data has been proposed for reliable estimation of disorder prevalence in dogs. Electronic patient record (EPR) data were collected on 148,741 dogs attending 93 clinics across central and south-eastern England. Analysis in detail of a random sample of EPRs relating to 3,884 dogs from 89 clinics identified the most frequently recorded disorders as otitis externa (prevalence 10.2%, 95% CI: 9.1-11.3), periodontal disease (9.3%, 95% CI: 8.3-10.3) and anal sac impaction (7.1%, 95% CI: 6.1-8.1). Using syndromic classification, the most prevalent body location affected was the head-and-neck (32.8%, 95% CI: 30.7-34.9), the most prevalent organ system affected was the integument (36.3%, 95% CI: 33.9-38.6) and the most prevalent pathophysiologic process diagnosed was inflammation (32.1%, 95% CI: 29.8-34.3). Among the twenty most-frequently recorded disorders, purebred dogs had a significantly higher prevalence compared with crossbreds for three: otitis externa (P = 0.001), obesity (P = 0.006) and skin mass lesion (P = 0.033), and popular breeds differed significantly from each other in their prevalence for five: periodontal disease (P = 0.002), overgrown nails (P = 0.004), degenerative joint disease (P = 0.005), obesity (P = 0.001) and lipoma (P = 0.003). These results fill a crucial data gap in disorder prevalence information and assist with disorder prioritisation. The results suggest that, for maximal impact, breeding reforms should target commonly-diagnosed complex disorders that are amenable to genetic improvement and should place special focus on at-risk breeds. Future studies evaluating disorder severity and duration will augment the usefulness of the disorder prevalence information reported herein

The localization of myosin VI at the golgi complex and leading edge of fibroblasts and its phosphorylation and recruitment into membrane ruffles of A431 cells after growth factor stimulation.

Myosin VI is an unconventional myosin that may play a role in vesicular membrane traffic through actin rich regions of the cytoplasm in eukaryotic cells. In this study we have cloned and sequenced a cDNA encoding a chicken intestinal brush border myosin VI. Polyclonal antisera were raised to bacterially expressed fragments of this myosin VI. The affinity purified antibodies were highly specific for myosin VI by immunoblotting and immunoprecipitation and were used to study the localization of the protein by immunofluorescence and immunoelectron microscopy. It was found that in NRK and A431 cells, myosin VI was associated with both the Golgi complex and the leading, ruffling edge of the cell as well as being present in a cytosolic pool. In A431 cells in which cell surface ruffling was stimulated by EGF, myosin VI was phosphorylated and recruited into the newly formed ruffles along with ezrin and myosin V. In vitro experiments suggested that a p21-activated kinase (PAK) might be the kinase responsible for phosphorylation in the motor domain. These results strongly support a role for myosin VI in membrane traffic on secretory and endocytic pathways

Decadal predictions of the cooling and freshening of the North Atlantic in the 1960s and the role of ocean circulation

In the 1960s North Atlantic sea surface temperatures (SST) cooled rapidly. The magnitude of the cooling was largest in the North Atlantic subpolar gyre (SPG), and was coincident with a rapid freshening of the SPG. Here we analyze hindcasts of the 1960s North Atlantic cooling made with the UK Met Office’s decadal prediction system (DePreSys), which is initialised using observations. It is shown that DePreSys captures—with a lead time of several years—the observed cooling and freshening of the North Atlantic SPG. DePreSys also captures changes in SST over the wider North Atlantic and surface climate impacts over the wider region, such as changes in atmospheric circulation in winter and sea ice extent. We show that initialisation of an anomalously weak Atlantic Meridional Overturning Circulation (AMOC), and hence weak northward heat transport, is crucial for DePreSys to predict the magnitude of the observed cooling. Such an anomalously weak AMOC is not captured when ocean observations are not assimilated (i.e. it is not a forced response in this model). The freshening of the SPG is also dominated by ocean salt transport changes in DePreSys; in particular, the simulation of advective freshwater anomalies analogous to the Great Salinity Anomaly were key. Therefore, DePreSys suggests that ocean dynamics played an important role in the cooling of the North Atlantic in the 1960s, and that this event was predictable

Molecular Evolution of Aminoacyl tRNA Synthetase Proteins in the Early History of Life

Aminoacyl-tRNA synthetases (aaRS) consist of several families of functionally conserved proteins essential for translation and protein synthesis. Like nearly all components of the translation machinery, most aaRS families are universally distributed across cellular life, being inherited from the time of the Last Universal Common Ancestor (LUCA). However, unlike the rest of the translation machinery, aaRS have undergone numerous ancient horizontal gene transfers, with several independent events detected between domains, and some possibly involving lineages diverging before the time of LUCA. These transfers reveal the complexity of molecular evolution at this early time, and the chimeric nature of genomes within cells that gave rise to the major domains. Additionally, given the role of these protein families in defining the amino acids used for protein synthesis, sequence reconstruction of their pre-LUCA ancestors can reveal the evolutionary processes at work in the origin of the genetic code. In particular, sequence reconstructions of the paralog ancestors of isoleucyl- and valyl- RS provide strong empirical evidence that at least for this divergence, the genetic code did not co-evolve with the aaRSs; rather, both amino acids were already part of the genetic code before their cognate aaRSs diverged from their common ancestor. The implications of this observation for the early evolution of RNA-directed protein biosynthesis are discussed.National Science Foundation (U.S.) (Grant DEB 0830024)National Science Foundation (U.S.) (Grant DEB 0936234)United States. National Aeronautics and Space Administration (NASA Postdoctoral Fellowship

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Unequal household carbon footprints in China

Households’ carbon footprints are unequally distributed among the rich and poor due to differences in the scale and patterns of consumption. We present distributional focused carbon footprints for Chinese households and use a carbon-footprint-Gini coefficient to quantify inequalities. We find that in 2012 the urban very rich, comprising 5% of population, induced 19% of the total carbon footprint from household consumption in China, with 6.4 tCO2/cap. The average Chinese household footprint remains comparatively low (1.7 tCO2/cap), while those of the rural population and urban poor, comprising 58% of population, are 0.5–1.6 tCO2/cap. Between 2007 and 2012 the total footprint from households increased by 19%, with 75% of the increase due to growing consumption of the urban middle class and the rich. This suggests that a transformation of Chinese lifestyles away from the current trajectory of carbon-intensive consumption patterns requires policy interventions to improve living standards and encourage sustainable consumption

Generation of an ultrabroadband supercontinuum in the mid-infrared region using dispersion-engineered GeAsSe photonic crystal fiber

An ultrabroadband mid-infrared (MIR) region supercontinuum (SC) is demonstrated numerically through dispersion-engineered traditional chalcogenide (ChG) photonic crystal fiber (PCF). By varying structural parameters pitch (hole to hole spacing) and air-hole diameter to pitch ratio, a number of 10-mm-long hexagonal PCFs made employing GeAsSe ChG glass as a core and air-holes of hexagonal lattice running through their lengths as a cladding are optimized to predict an efficient mid-infrared region SC spectral emission by pumping them using a tunable pump source between 2.9 and 3.3 µm. Simulations are carried out using an ultrashort pump pulse of 100-fs duration with a low pulse peak powers of between 3 and 4 kW into the optimized designs. It is found through numerical analysis that efficient SC spectral broadening with flattened output can be obtained by increasing the PCF pitch rather than increasing the PCF cladding containing air-hole diameter although a larger nonlinear coefficient could be obtained through increasing air-hole diameter of an optimized design. Simulation results show that the SC spectra can be broadened up to 12.2 µm for a certain design with a peak power of 3 kW. Using a peak power of 4 kW, it is possible to obtain SC spectral broadening beyond 14 µm with an optimized design spanning the wavelength range from 1.8 to 14 µm which covers the electromagnetic spectrum required for MIR molecular fingerprint region applications such as sensing and biological imaging

Spatial navigation deficits — overlooked cognitive marker for preclinical Alzheimer disease?

Detection of incipient Alzheimer disease (AD) pathophysiology is critical to identify preclinical individuals and target potentially disease-modifying therapies towards them. Current neuroimaging and biomarker research is strongly focused in this direction, with the aim of establishing AD fingerprints to identify individuals at high risk of developing this disease. By contrast, cognitive fingerprints for incipient AD are virtually non-existent as diagnostics and outcomes measures are still focused on episodic memory deficits as the gold standard for AD, despite their low sensitivity and specificity for identifying at-risk individuals. This Review highlights a novel feature of cognitive evaluation for incipient AD by focusing on spatial navigation and orientation deficits, which are increasingly shown to be present in at-risk individuals. Importantly, the navigation system in the brain overlaps substantially with the regions affected by AD in both animal models and humans. Notably, spatial navigation has fewer verbal, cultural and educational biases than current cognitive tests and could enable a more uniform, global approach towards cognitive fingerprints of AD and better cognitive treatment outcome measures in future multicentre trials. The current Review appraises the available evidence for spatial navigation and/or orientation deficits in preclinical, prodromal and confirmed AD and identifies research gaps and future research priorities