Senescence under appraisal: hopes and challenges revisited.

In recent years, cellular senescence has become the focus of attention in multiple areas of biomedical research. Typically defined as an irreversible cell cycle arrest accompanied by increased cellular growth, metabolic activity and by a characteristic messaging secretome, cellular senescence can impact on multiple physiological and pathological processes such as wound healing, fibrosis, cancer and ageing. These unjustly called 'zombie cells' are indeed a rich source of opportunities for innovative therapeutic development. In this review, we collate the current understanding of the process of cellular senescence and its two-faced nature, i.e. beneficial/detrimental, and reason this duality is linked to contextual aspects. We propose the senescence programme as an endogenous pro-resolving mechanism that may lead to sustained inflammation and damage when dysregulated or when senescent cells are not cleared efficiently. This pro-resolving model reconciles the paradoxical two faces of senescence by emphasising that it is the unsuccessful completion of the programme, and not senescence itself, what leads to pathology. Thus, pro-senescence therapies under the right context, may favour inflammation resolution. We also review the evidence for the multiple therapeutic approaches under development based on senescence, including its induction, prevention, clearance and the use of senolytic and senomorphic drugs. In particular, we highlight the importance of the immune system in the favourable outcome of senescence and the implications of an inefficient immune surveillance in completion of the senescent cycle. Finally, we identify and discuss a number of challenges and existing gaps to encourage and stimulate further research in this exciting and unravelled field, with the hope of promoting and accelerating the clinical success of senescence-based therapies

The potential to reduce the risks posed by tailings dams using satellite-based information

The failures of tailings dams, used to store waste from mining operations, pose a significant risk to the health of people and the environment, especially in many low income countries where the extractive industry makes a significant contribution to the nation's wealth. Recently the rate of failure of tailings dams has increased. The demand for raw materials and increases in intense rainfall as a result of climate change will exacerbate this issue in the future. The monitoring of tailings dams is essential to reduce their probability of failure. Virtually all the recent tailings dams failures were preventable. However, there is generally a lack of transparency and accountability for these structures by mining companies. In the past 10 years an increase in the global coverage and accuracy of Earth Observation (EO) based information has made it technically possible to use EO-based data to remotely monitor critical aspects of tailings dams, such as their deformation and the leakage of pollutants. This paper describes the development of an EO-based service, being piloted in Peru, which would allow tailings dams to be monitored cost effectively, and also help to forecast any potentially risk inducing behaviour from tailings dams several weeks in advance. Many regulatory bodies in low income countries do not have the resources to adequately monitor mining operations. A low cost EO-based system could improve the transparency and safety of tailings dams, allowing timely preventative interventions to be made where the probability of failure is found to be high

DAMSAT: An Eye in the Sky for Monitoring Tailings Dams

During the past decade, there have been a number of catastrophic tailings dam failures. Affordable monitoring systems, as well as methods to assess the risk posed to communities living downstream of these structures, are needed. In recent years the availability and accuracy of remote sensing information has increased, whilst its cost has decreased. This paper provides an overview of DAMSAT, a web-based system that brings together Earth observation and other data to help governments and mining companies monitor tailing dams, and estimate the downstream risks they pose. The methods developed are being piloted in Peru at a number of tailings dams, with the overall goal of improving the decision making process and sharing of information with respect to managing these structures. Engagement with Peruvian stakeholders has shown that DAMSAT provides tools that can help government authorities both reduce the risks and increase the sustainability of mining

DER PARTISANENSPUR DURCH VORGEBIRGE NACHGEHEND

Autor opisuje razvoj partizanskog pokreta (od kraja 1941. i početka 1942. do siječnja 1945.) i borbene akcije partizanskih jedinica koje su poduzele tijekom Drugoga svjetskog rata u Podgorju.Ende 1941 und Anfang 1942 viele fortschrittliche Bewohner des Senjer Gebirges — von Jurjevo bis Karlobag — wurden die Mitarbeiter der Volksbefreiungsbewegung. Ende 1942 und Anfang 1943 wurde die Partisanenabteilung errichtet. Sie gab einen grossen Beitrag zum Aufstand und zum Volksbefreiuneskrieg auf dem Gebiet des Kroatischen Kustenlandes. Eine Reihe von Kampfleistungen wurde von den Kämpfern aus dieser Abteilung ausgefuhrt, die Mitarbeit des Volkes wurde ausgebreitet und die italienische Kapitulation wurde bereit erwartet. Diese Abteilung gewann grosse Verdienste bei der italienischen Kapitulation auf den Inseln Rab und Pag. Dort half sie den geformten Kampfgruppen in der Abrüstung des Feindes. Auf diesem ganze befreiten Gebiet wurde die Volksbehörde herrgestellt, aber Anfang 1944 drangen in Senj und in das Vorgebirge starke deutsche Kräfte ein, und Senj wurde wieder okkupiert. Das erneuerte Terror verursachte eine Unsicherheit bei dem Volk. Die einheimischen Aktivisten stellten mit Hilfe des See- und Küstensektors (POS) eine andere Militäreinheit — eine neue Abteilung her. Sie stellte sich dem Feinde gegeniiber und gewann — dank dem Waffenkampf — das Zutrauen des Volkes

LSD1-mediated enhancer silencing attenuates retinoic acid signalling during pancreatic endocrine cell development

Developmental progression depends on temporally defined changes in gene expression mediated by transient exposure of lineage intermediates to signals in the progenitor niche. To determine whether cell-intrinsic epigenetic mechanisms contribute to signal-induced transcriptional responses, here we manipulate the signalling environment and activity of the histone demethylase LSD1 during differentiation of hESC-gut tube intermediates into pancreatic endocrine cells. We identify a transient requirement for LSD1 in endocrine cell differentiation spanning a short time-window early in pancreas development, a phenotype we reproduced in mice. Examination of enhancer and transcriptome landscapes revealed that LSD1 silences transiently active retinoic acid (RA)-induced enhancers and their target genes. Furthermore, prolonged RA exposure phenocopies LSD1 inhibition, suggesting that LSD1 regulates endocrine cell differentiation by limiting the duration of RA signalling. Our findings identify LSD1-mediated enhancer silencing as a cell-intrinsic epigenetic feedback mechanism by which the duration of the transcriptional response to a developmental signal is limited

Pancreatic progenitor epigenome maps prioritize type 2 diabetes risk genes with roles in development

Genetic variants associated with type 2 diabetes (T2D) risk affect gene regulation in metabolically relevant tissues, such as pancreatic islets. Here, we investigated contributions of regulatory programs active during pancreatic development to T2D risk. Generation of chromatin maps from developmental precursors throughout pancreatic differentiation of human embryonic stem cells (hESCs) identifies enrichment of T2D variants in pancreatic progenitor-specific stretch enhancers that are not active in islets. Genes associated with progenitor-specific stretch enhancers are predicted to regulate developmental processes, most notably tissue morphogenesis. Through gene editing in hESCs, we demonstrate that progenitor-specific enhancers harboring T2D-associated variants regulate cell polarity genes (LAMA1) and (CRB2). Knockdown of (lama1) or (crb2) in zebrafish embryos causes a defect in pancreas morphogenesis and impairs islet cell development. Together, our findings reveal that a subset of T2D risk variants specifically affects pancreatic developmental programs, suggesting that dysregulation of developmental processes can predispose to T2D

Attentional differences in a driving hazard perception task in adults with autism spectrum disorders

The current study explored attentional processing of social and non social stimuli in ASD within the context of a driving hazard perception task. Participants watched videos of road scenes and detected hazards while their eye movements were recorded. Although individuals with ASD demonstrated relatively good detection of driving hazards, they were slower to orient to hazards. Greater attentional capture in the time preceding the hazards’ onset was associated with lower verbal IQ. The findings suggest that individuals with ASD may distribute and direct their attention diferently when identifying driving hazards

The Y-Chromosome Tree Bursts into Leaf: 13,000 High-Confidence SNPs Covering the Majority of Known Clades

Many studies of human populations have used the male-specific region of the Y chromosome (MSY) as a marker, but MSY sequence variants have traditionally been subject to ascertainment bias. Also, dating of haplogroups has relied on Y-specific short tandem repeats (STRs), involving problems of mutation rate choice, and possible long-term mutation saturation. Next-generation sequencing can ascertain single nucleotide polymorphisms (SNPs) in an unbiased way, leading to phylogenies in which branch-lengths are proportional to time, and allowing the times-to-most-recent-common-ancestor (TMRCAs) of nodes to be estimated directly. Here we describe the sequencing of 3.7 Mb of MSY in each of 448 human males at a mean coverage of 51x, yielding 13,261 high-confidence SNPs, 65.9% of which are previously unreported. The resulting phylogeny covers the majority of the known clades, provides date estimates of nodes, and constitutes a robust evolutionary framework for analyzing the history of other classes of mutation. Different clades within the tree show subtle but significant differences in branch lengths to the root. We also apply a set of 23 Y-STRs to the same samples, allowing SNP- and STR-based diversity and TMRCA estimates to be systematically compared. Ongoing purifying selection is suggested by our analysis of the phylogenetic distribution of nonsynonymous variants in 15 MSY single-copy genes

Genetic variation among species, races, forms and inbred lines of lac insects belonging to the genus Kerria (Homoptera, Tachardiidae)

The lac insects (Homoptera: Tachardiidae), belonging to the genus Kerria, are commercially exploited for the production of lac. Kerria lacca is the most commonly used species in India. RAPD markers were used for assessing genetic variation in forty-eight lines of Kerria, especially among geographic races, infrasubspecific forms, cultivated lines, inbred lines, etc., of K. lacca. In the 48 lines studied, the 26 RAPD primers generated 173 loci, showing 97.7% polymorphism. By using neighbor-joining, the dendrogram generated from the similarity matrix resolved the lines into basically two clusters and outgroups. The major cluster, comprising 32 lines, included mainly cultivated lines of the rangeeni form, geographic races and inbred lines of K. lacca. The second cluster consisted of eight lines of K. lacca, seven of the kusmi form and one of the rangeeni from the southern state of Karnataka. The remaining eight lines formed a series of outgroups, this including a group of three yellow mutant lines of K. lacca and other species of the Kerria studied, among others. Color mutants always showed distinctive banding patterns compared to their wild-type counterparts from the same population. This study also adds support to the current status of kusmi and rangeeni, as infraspecific forms of K. lacca

In the blood: the myth and reality of genetic markers of identity

The differences between copies of the human genome are very small, but tend to cluster in different populations. So, despite the fact that low inter-population differentiation does not support a biological definition of races statistical methods are nonetheless claimed to be able to predict successfully the population of origin of a DNA sample. Such methods are employed in commercial genetic ancestry tests, and particular genetic signatures, often in the male-specific Y-chromosome or maternally-inherited mitochondrial DNA, have become widely identified with particular ancestral or existing groups, such as Vikings, Jews, or Zulus. Here, we provide a primer on genetics, and describe how genetic markers have become associated with particular groups. We describe the conflict between population genetics and individual-based genetics and the pitfalls of over-simplistic genetic interpretations, arguing that although the tests themselves are reliable, the interpretations are unreliable and strongly influenced by cultural and other social forces.</p