UBE2QL1 is Disrupted by a Constitutional Translocation Associated with Renal Tumor Predisposition and is a Novel Candidate Renal Tumor Suppressor Gene

Investigation of rare familial forms of renal cell carcinoma (RCC) has led to the identification of genes such as VHL and MET that are also implicated in the pathogenesis of sporadic RCC. In order to identify a novel candidate renal tumor suppressor gene, we characterized the breakpoints of a constitutional balanced translocation, t(5;19)(p15.3;q12), associated with familial RCC and found that a previously uncharacterized gene UBE2QL1 was disrupted by the chromosome 5 breakpoint. UBE2QL1 mRNA expression was downregulated in 78.6% of sporadic RCC and, although no intragenic mutations were detected, gene deletions and promoter region hypermethylation were detected in 17.3% and 20.3%, respectively, of sporadic RCC. Reexpression of UBE2QL1 in a deficient RCC cell line suppressed anchorage-independent growth. UBE2QL1 shows homology to the E2 class of ubiquitin conjugating enzymes and we found that (1) UBE2QL1 possesses an active-site cysteine (C88) that is monoubiquitinated in vivo, and (2) UBE2QL1 interacts with FBXW7 (an F box protein providing substrate recognition to the SCF E3 ubiquitin ligase) and facilitates the degradation of the known FBXW7 targets, CCNE1 and mTOR. These findings suggest UBE2QL1 as a novel candidate renal tumor suppressor gen

Tales of Emergence - Synthetic Biology as a Scientific Community in the Making

International audienceThis article locates the beginnings of a synthetic biology network and thereby probes the formation of a potential disciplinary community. We consider the ways that ideas of community are mobilized, both by scientists and policy-makers in building an agenda for new forms of knowledge work, and by social scientists as an analytical device to understand new formations for knowledge production. As participants in, and analysts of, a network in synthetic biology, we describe our current understanding of synthetic biology by telling four tales of community making. The first tale tells of the mobilization of synthetic biology within a European context. The second tale describes the approach to synthetic biology community formation in the UK. The third narrates the creation of an institutionally based, funded 'network in synthetic biology'. The final tale de-localizes community-making efforts by focussing on 'devices' that make communities. In tying together these tales, our analysis suggests that the potential community can be understood in terms of 'movements'--the (re)orientation and enrolment of people, stories, disciplines and policies; and of 'stickiness'--the objects and glues that begin to bind together the various constitutive elements of community

Deep-water Tectono-Stratigraphy at a Plate Boundary Constrained by Large N-Detrital Zircon and Micropaleontological Approaches: Peninsular Ranges Forearc, Baja California, Mexico

The distribution of sedimentary systems on Earth’s surface is intimately linked to tectonics, therefore, at plate boundaries the stratigraphic archive can unlock the timing and style of tectonism and relative plate motions. Using large-n detrital zircon and micropaleontological analyses, tied to field mapping and data collection, we unravel the timing of strike-slip motion and its influence on the development of a Cretaceous submarine canyon on a long-lived oblique-convergent margin. Structural analysis demonstrates that the canyon bedrock, composed of fluvial rocks (La Bocana Roja Fm., of maximum depositional age (MDA): 93.6±1.1 Ma), underwent both syn- and post-depositional contractional and extensional deformation during the Cenomanian-Turonian in response to dextral strike-slip movement. Relative sea-level rise associated with basin subsidence and hinterland uplift was coincident with incision and fill of a submarine canyon system (Punta Baja Fm., MDA 87.1±1.5 Ma to 84.9±2.0 Ma), which exploited structural lineaments in the bedrock. The canyon was filled by sediment derived from an uplifted magmatic arc during the Coniacian to Santonian, most likely shed from erosional topography associated with plutonic intrusions to the NE. Structural data suggest that oblique dextral strike-slip motion on the Pacific margin controlled the development and location of submarine erosion, and had ended by the earliest Santonian, significantly earlier than previously estimated. Basinward tilting led to uplift, followed by transgression and wave ravinement of the canyon fill, which was then overlain by a shallow-marine to fluvial system. Thus, the canyon was cut, filled, buried, uplifted and rotated basinward, planed off through wave ravinement, and onlapped by shallow-marine to fluvial sediments within an 8 Myr period. Our findings, in part, reconcile contrasting basin evolution models for the Late Mesozoic Pacific margin

Predation by Bears Drives Senescence in Natural Populations of Salmon

Classic evolutionary theory predicts that populations experiencing higher rates of environmentally caused (“extrinsic”) mortality should senesce more rapidly, but this theory usually neglects plausible relationships between an individual's senescent condition and its susceptibility to extrinsic mortality. We tested for the evolutionary importance of this condition dependence by comparing senescence rates among natural populations of sockeye salmon (Oncorhynchus nerka) subject to varying degrees of predation by brown bears (Ursus arctos). We related senescence rates in six populations to (1) the overall rate of extrinsic mortality, and (2) the degree of condition dependence in this mortality. Senescence rates were determined by modeling the mortality of individually-tagged breeding salmon at each site. The overall rate of extrinsic mortality was estimated as the long-term average of the annual percentage of salmon killed by bears. The degree of condition dependence was estimated as the extent to which bears killed salmon that exhibited varying degrees of senescence. We found that the degree of condition dependence in extrinsic mortality was very important in driving senescence: populations where bears selectively killed fish showing advanced senescence were those that senesced least rapidly. The overall rate of extrinsic mortality also contributed to among-population variation in senescence-but to a lesser extent. Condition-dependent susceptibility to extrinsic mortality should be incorporated more often into theoretical models and should be explicitly tested in natural populations

Expression and DNA methylation of TNF, IFNG and FOXP3 in colorectal cancer and their prognostic significance.

BACKGROUND: Colorectal cancer (CRC) progression is associated with suppression of host cell-mediated immunity and local immune escape mechanisms. Our aim was to assess the immune function in terms of expression of TNF, IFNG and FOXP3 in CRC. METHODS: Sixty patients with CRC and 15 matched controls were recruited. TaqMan quantitative PCR and methylation-specific PCR was performed for expression and DNA methylation analysis of TNF, IFNG and FOXP3. Survival analysis was performed over a median follow-up of 48 months. RESULTS: TNF was suppressed in tumour and IFNG was suppressed in peripheral blood mononuclear cells (PBMCs) of patients with CRC. Tumours showed enhanced expression of FOXP3 and was significantly higher when tumour size was >38 mm (median tumour size; P=0.006, Mann-Whitney U-test). Peripheral blood mononuclear cell IFNG was suppressed in recurrent CRC (P=0.01). Methylated TNFpromoter (P=0.003) and TNFexon1 (P=0.001) were associated with significant suppression of TNF in tumours. Methylated FOXP3cpg was associated with significant suppression of FOXP3 in both PBMC (P=0.018) and tumours (P=0.010). Reduced PBMC FOXP3 expression was associated with significantly worse overall survival (HR=8.319, P=0.019). CONCLUSIONS: We have detected changes in the expression of immunomodulatory genes that could act as biomarkers for prognosis and future immunotherapeutic strategies

Malaria mortality in Africa and Asia: evidence from INDEPTH health and demographic surveillance system sites.

BACKGROUND: Malaria continues to be a major cause of infectious disease mortality in tropical regions. However, deaths from malaria are most often not individually documented, and as a result overall understanding of malaria epidemiology is inadequate. INDEPTH Network members maintain population surveillance in Health and Demographic Surveillance System sites across Africa and Asia, in which individual deaths are followed up with verbal autopsies. OBJECTIVE: To present patterns of malaria mortality determined by verbal autopsy from INDEPTH sites across Africa and Asia, comparing these findings with other relevant information on malaria in the same regions. DESIGN: From a database covering 111,910 deaths over 12,204,043 person-years in 22 sites, in which verbal autopsy data were handled according to the WHO 2012 standard and processed using the InterVA-4 model, over 6,000 deaths were attributed to malaria. The overall period covered was 1992-2012, but two-thirds of the observations related to 2006-2012. These deaths were analysed by site, time period, age group and sex to investigate epidemiological differences in malaria mortality. RESULTS: Rates of malaria mortality varied by 1:10,000 across the sites, with generally low rates in Asia (one site recording no malaria deaths over 0.5 million person-years) and some of the highest rates in West Africa (Nouna, Burkina Faso: 2.47 per 1,000 person-years). Childhood malaria mortality rates were strongly correlated with Malaria Atlas Project estimates of Plasmodium falciparum parasite rates for the same locations. Adult malaria mortality rates, while lower than corresponding childhood rates, were strongly correlated with childhood rates at the site level. CONCLUSIONS: The wide variations observed in malaria mortality, which were nevertheless consistent with various other estimates, suggest that population-based registration of deaths using verbal autopsy is a useful approach to understanding the details of malaria epidemiology

Direct multiplex imaging and optogenetics of Rho GTPases enabled by near-infrared FRET

Direct visualization and light control of several cellular processes is a challenge, owing to the spectral overlap of available genetically encoded probes. Here we report the most red-shifted monomeric near-infrared (NIR) fluorescent protein, miRFP720, and the fully NIR Forster resonance energy transfer (FRET) pair miRFP670-miRFP720, which together enabled design of biosensors compatible with CFP-YFP imaging and blue-green optogenetic tools. We developed a NIR biosensor for Rac1 GTPase and demonstrated its use in multiplexed imaging and light control of Rho GTPase signaling pathways. Specifically, we combined the Rac1 biosensor with CFP-YFP FRET biosensors for RhoA and for Rac1-GDI binding, and concurrently used the LOV-TRAP tool for upstream Rac1 activation. We directly observed and quantified antagonism between RhoA and Rac1 dependent on the RhoA-downstream effector ROCK; showed that Rac1 activity and GDI binding closely depend on the spatiotemporal coordination between these two molecules; and simultaneously observed Rac1 activity during optogenetic manipulation of Rac1.Peer reviewe

Climate Change and invasibility of the Antarctic benthos

Benthic communities living in shallow-shelf habitats in Antarctica (<100-m depth) are archaic in their structure and function. Modern predators, including fast-moving, durophagous (skeleton-crushing) bony fish, sharks, and crabs, are rare or absent; slow-moving invertebrates are the top predators; and epifaunal suspension feeders dominate many soft substratum communities. Cooling temperatures beginning in the late Eocene excluded durophagous predators, ultimately resulting in the endemic living fauna and its unique food-web structure. Although the Southern Ocean is oceanographically isolated, the barriers to biological invasion are primarily physiological rather than geographic. Cold temperatures impose limits to performance that exclude modern predators. Global warming is now removing those physiological barriers, and crabs are reinvading Antarctica. As sea temperatures continue to rise, the invasion of durophagous predators will modernize the shelf benthos and erode the indigenous character of marine life in Antarctica

Drones count wildlife more accurately and precisely than humans

Human activities are creating environmental conditions that pose threats and present opportunities for wildlife. In turn, this creates challenges for conservation managers. Some species have benefited from anthropogenic actions. For example, many invasive species profit from human‐assisted dispersal (Banks, Paini, Bayliss, & Hodda, 2015; Hulme, 2009), and mesopredators may thrive following human‐driven loss of top predators (Ritchie & Johnson, 2009). However, in many cases, wildlife populations are undergoing alarming declines, and extinction rates are now as high as 100‐fold greater than the background extinction rate (Ceballos et al., 2015). Ecological monitoring is essential for understanding these population dynamics, and rigorous monitoring facilitates informed management. The effectiveness of management decision‐making is often dependent on the accuracy and timeliness of the relevant ecological data upon which decisions are based, meaning that improvements to data collection methods may herald improved ecological outcomes from management actions

The fitness of African malaria vectors in the presence and limitation of host behaviour

<p>Background Host responses are important sources of selection upon the host species range of ectoparasites and phytophagous insects. However little is known about the role of host responses in defining the host species range of malaria vectors. This study aimed to estimate the relative importance of host behaviour to the feeding success and fitness of African malaria vectors, and assess its ability to predict their known host species preferences in nature.</p> <p>Methods Paired evaluations of the feeding success and fitness of African vectors Anopheles arabiensis and Anopheles gambiae s.s in the presence and limitation of host behaviour were conducted in a semi-field system (SFS) at Ifakara Health Institute, Tanzania. In one set of trials, mosquitoes were released within the SFS and allowed to forage overnight on a host that was free to exhibit natural behaviour in response to insect biting. In the other, mosquitoes were allowed to feed directly on from the skin surface of immobile hosts. The feeding success and subsequent fitness of vectors under these conditions were investigated on 6 host types (humans, calves, chickens, cows, dogs and goats) to assess whether physical movements of preferred host species (cattle for An. arabiensis, humans for An. gambiae s.s.) were less effective at preventing mosquito bites than those of common alternatives.</p> <p>Results Anopheles arabiensis generally had greater feeding success when applied directly to host skin than when foraging on unrestricted hosts (in five of six host species). However, An. gambiae s.s obtained blood meals from free and restrained hosts with similar success from most host types (four out of six). Overall, the blood meal size, oviposition rate, fecundity and post-feeding survival of mosquito vectors were significantly higher after feeding on hosts free to exhibit behaviour, than those who were immobilized during feeding trials.</p> <p>Conclusions Allowing hosts to move freely during exposure to mosquitoes was associated with moderate reductions in mosquito feeding success, but no detrimental impact to the subsequent fitness of mosquitoes that were able to feed upon them. This suggests that physical defensive behaviours exhibited by common host species including humans do not impose substantial fitness costs on African malaria vectors.</p&gt