Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus

Autosomal dominant North Carolina macular dystrophy (NCMD) is believed to represent a failure of macular development. The disorder has been linked to two loci, MCDR1 (chromosome 6q16) and MCDR3 (chromosome 5p15-p13). Recently, non-coding variants upstream of PRDM13 (MCDR1) and a duplication including IRX1 (MCDR3) have been identified. However, the underlying disease-causing mechanism remains uncertain. Through a combination of sequencing studies on eighteen NCMD families, we report two novel overlapping duplications at the MCDR3 locus, in a gene desert downstream of IRX1 and upstream of ADAMTS16. One duplication of 43 kb was identified in nine families (with evidence for a shared ancestral haplotype), and another one of 45 kb was found in a single family. Three families carry the previously reported V2 variant (MCDR1), while five remain unsolved. The MCDR3 locus is thus refined to a shared region of 39 kb that contains DNAse hypersensitive sites active at a restricted time window during retinal development. Publicly available data confirmed expression of IRX1 and ADAMTS16 in human fetal retina, with IRX1 preferentially expressed in fetal macula. These findings represent a major advance in our understanding of the molecular genetics of NCMD and provide insights into the genetic pathways involved in human macular development

Defining the key wintering habitats in the Sahel for declining African-Eurasian migrants using expert assessment

SummaryThe Sahel in West Africa is a major wintering area for many western Palearctic migrants. The breeding populations of many of these have declined over the past 50 years. However, there have been few intensive field studies on migrant ecology in the Sahel and these were generally within a very restricted area. Consequently our knowledge of the distribution of species within this extensive area and the habitat associations of these species is limited. Understanding these habitat associations is essential for the effective conservation management of populations. We brought together a group of experts and consulted a wider group by email to assess the main Sahelian habitat types used by 68 African-Eurasian migrant bird species. Those species that showed strongest declines during 1970–1990 were associated with more open habitats than those newly declining during 1990–2000, when declining species were associated with habitats with more shrubs and trees. Populations of species that winter in the Sahel are generally stable or increasing now as rainfall has increased and is now near the long-term average for the Sahel. Those which use the Sahel only as a staging area are, in many cases, in rapid decline at present.We would like to thank Andy Clements, Paul Donald, Lincoln Fishpool and Mike Mortimore for contributing to the workshop and Peter Jones, Ian Newton, Volker Salewski, Tim Wacher, Eddy Wymenga and Leo Zwarts for useful comments by email on draft habitat importance scores. This study was funded by the Newton Trust and the Cambridge Conservation Initiative Collaborative Fund, supported by Arcadia. WJS is funded by Arcadia.This is the accepted manuscript of a paper published in Bird Conservation International, Volume 24, Issue 04, December 2014, pp 477-491, DOI: http://dx.doi.org/10.1017/S0959270913000531, Published online: 24 February 201

Presymptomatic risk assessment for chronic non-communicable diseases

The prevalence of common chronic non-communicable diseases (CNCDs) far overshadows the prevalence of both monogenic and infectious diseases combined. All CNCDs, also called complex genetic diseases, have a heritable genetic component that can be used for pre-symptomatic risk assessment. Common single nucleotide polymorphisms (SNPs) that tag risk haplotypes across the genome currently account for a non-trivial portion of the germ-line genetic risk and we will likely continue to identify the remaining missing heritability in the form of rare variants, copy number variants and epigenetic modifications. Here, we describe a novel measure for calculating the lifetime risk of a disease, called the genetic composite index (GCI), and demonstrate its predictive value as a clinical classifier. The GCI only considers summary statistics of the effects of genetic variation and hence does not require the results of large-scale studies simultaneously assessing multiple risk factors. Combining GCI scores with environmental risk information provides an additional tool for clinical decision-making. The GCI can be populated with heritable risk information of any type, and thus represents a framework for CNCD pre-symptomatic risk assessment that can be populated as additional risk information is identified through next-generation technologies.Comment: Plos ONE paper. Previous version was withdrawn to be updated by the journal's pdf versio

Arp2/3 complex interactions and actin network turnover in lamellipodia

Cell migration is initiated by lamellipodia—membrane-enclosed sheets of cytoplasm containing densely packed actin filament networks. Although the molecular details of network turnover remain obscure, recent work points towards key roles in filament nucleation for Arp2/3 complex and its activator WAVE complex. Here, we combine fluorescence recovery after photobleaching (FRAP) of different lamellipodial components with a new method of data analysis to shed light on the dynamics of actin assembly/disassembly. We show that Arp2/3 complex is incorporated into the network exclusively at the lamellipodium tip, like actin, at sites coincident with WAVE complex accumulation. Capping protein likewise showed a turnover similar to actin and Arp2/3 complex, but was confined to the tip. In contrast, cortactin—another prominent Arp2/3 complex regulator—and ADF/cofilin—previously implicated in driving both filament nucleation and disassembly—were rapidly exchanged throughout the lamellipodium. These results suggest that Arp2/3- and WAVE complex-driven actin filament nucleation at the lamellipodium tip is uncoupled from the activities of both cortactin and cofilin. Network turnover is additionally regulated by the spatially segregated activities of capping protein at the tip and cofilin throughout the mesh

Behavioral responses to injury and death in wild Barbary macaques (Macaca sylvanus)

The wounding or death of a conspecific has been shown to elicit varied behavioral responses throughout thanatology. Recently, a number of reports have presented contentious evidence of epimeletic behavior towards the dying and dead among non-human animals, a behavioral trait previously considered uniquely human. Here, we report on the behavioral responses of Barbary macaques, a social, non-human primate, to the deaths of four group members (one high-ranking adult female, one high-ranking adult male, one juvenile male, and one female infant), all caused by road traffic accidents. Responses appeared to vary based on the nature of the death (protracted or instant) and the age class of the deceased. Responses included several behaviors with potential adaptive explanations or consequences. These included exploration, caretaking (guarding, carrying, and grooming), and proximity to wounded individuals or corpses, and immediate as well as longer-lasting distress behaviors from other group members following death, all of which have been reported in other non-human primate species. These observations add to a growing body of comparative evolutionary analysis of primate thanatology and help to highlight the multifaceted impacts of human-induced fatalities on an endangered and socially complex primate. © 2016, Japan Monkey Centre and Springer Japan

Building Babies - Chapter 16

In contrast to birds, male mammals rarely help to raise the offspring. Of all mammals, only among rodents, carnivores, and primates, males are sometimes intensively engaged in providing infant care (Kleiman and Malcolm 1981). Male caretaking of infants has long been recognized in nonhuman primates (Itani 1959). Given that infant care behavior can have a positive effect on the infant’s development, growth, well-being, or survival, why are male mammals not more frequently involved in “building babies”? We begin the chapter defining a few relevant terms and introducing the theory and hypotheses that have historically addressed the evolution of paternal care. We then review empirical findings on male care among primate taxa, before focusing, in the final section, on our own work on paternal care in South American owl monkeys (Aotus spp.). We conclude the chapter with some suggestions for future studies.Deutsche Forschungsgemeinschaft (HU 1746/2-1) Wenner-Gren Foundation, the L.S.B. Leakey Foundation, the National Geographic Society, the National Science Foundation (BCS-0621020), the University of Pennsylvania Research Foundation, the Zoological Society of San Dieg

Inhibition of macrophage migration inhibitory factor decreases proliferation and cytokine expression in bladder cancer cells

BACKGROUND: The importance of various inflammatory cytokines in maintaining tumor cell growth and viability is well established. Increased expression of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) has previously been associated with various types of adenocarcinoma. METHODS: MIF IHC was used to localize MIF in human bladder tissue. ELISA and Western blot analysis determined the synthesis and secretion of MIF by human bladder transitional cell carcinoma cells. The effects of MIF inhibitors (high molecular weight hyaluronate (HA), anti-MIF antibody or MIF anti-sense) on cell growth and cytokine expression were analyzed. RESULTS: Human bladder cancer cells (HT-1376) secrete detectable amounts of MIF protein. Treatment with HA, anti-MIF antibody and MIF anti-sense reduced HT-1376 cell proliferation, MIF protein secretion, MIF gene expression and secreted inflammatory cytokines. Our evidence suggests MIF interacts with the invariant chain, CD74 and the major cell surface receptor for HA, CD44. CONCLUSIONS: This study is the first to report MIF expression in the human bladder and these findings support a role for MIF in tumor cell proliferation. Since MIF participates in the inflammatory response and bladder cancer is associated with chronic inflammatory conditions, these new findings suggest that neutralizing bladder tumor MIF may serve as a novel therapeutic treatment for bladder carcinoma

Interaction between Ammonium Toxicity and Green Tide Development Over Seagrass Meadows:A Laboratory Study

Eutrophication affects seagrasses negatively by increasing light attenuation through stimulation of biomass of fast-growing, bloom-forming algae and because high concentrations of ammonium in the water can be toxic to higher plants. We hypothesized nevertheless, that moderate amounts of nitrophilic macroalgae that coexists with seagrasses under eutrophic conditions, can alleviate the harmful effects of eutrophication on seagrasses by reducing ammonium concentrations in the seawater to non-toxic levels because such algae have a very large capacity to take up inorganic nutrients. We studied therefore how combinations of different ammonium concentrations (0, 25 and 50 μM) and different standing stocks of macroalgae (i.e. 0, 1 and 6 layers of Ulva sp.) affected survival, growth and net production of the seagrass Zostera noltei. In the absence of Ulva sp., increasing ammonium concentrations had a negative influence on the performance of Z. noltei. The presence of Ulva sp. without ammonium supply had a similar, but slightly smaller, negative effect on seagrass fitness due to light attenuation. When ammonium enrichment was combined with presence of Ulva sp., Ulva sp. ameliorated some of negative effects caused by high ammonium availability although Ulva sp. lowered the availability of light. Benthic microalgae, which increased in biomass during the experiment, seemed to play a similar role as Ulva sp.--they contributed to remove ammonium from the water, and thus, aided to keep the ammonium concentrations experienced by Z. noltei at relatively non-toxic levels. Our findings show that moderate amounts of drift macroalgae, eventually combined with increasing stocks of benthic microalgae, may aid seagrasses to alleviate toxic effects of ammonium under eutrophic conditions, which highlights the importance of high functional diversity for ecosystem resistance to anthropogenic disturbance

The use of Bayesian latent class cluster models to classify patterns of cognitive performance in healthy ageing

The main focus of this study is to illustrate the applicability of latent class analysis in the assessment of cognitive performance profiles during ageing. Principal component analysis (PCA) was used to detect main cognitive dimensions (based on the neurocognitive test variables) and Bayesian latent class analysis (LCA) models (without constraints) were used to explore patterns of cognitive performance among community-dwelling older individuals. Gender, age and number of school years were explored as variables. Three cognitive dimensions were identified: general cognition (MMSE), memory (MEM) and executive (EXEC) function. Based on these, three latent classes of cognitive performance profiles (LC1 to LC3) were identified among the older adults. These classes corresponded to stronger to weaker performance patterns (LC1>LC2>LC3) across all dimensions; each latent class denoted the same hierarchy in the proportion of males, age and number of school years. Bayesian LCA provided a powerful tool to explore cognitive typologies among healthy cognitive agers.The study is integrated in the "Maintaining health in old age through homeostasis (SWITCHBOX)" collaborative project funded by the European Commission FP7 initiative (grant HEALTH-F2-2010-259772). NS and JAP are main team members of the European consortium SWITCHBOX (http://www.switchbox-online.eu/). NCS is supported by a SwitchBox post-doctoral fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript