Road traffic kills hundreds of millions of animals every year, posing a critical threat to the populations of many species. To address this problem there are more than forty types of road mitigation ...measures available that aim to reduce wildlife mortality on roads (road-kill). For road planners, deciding on what mitigation method to use has been problematic because there is little good information about the relative effectiveness of these measures in reducing road-kill, and the costs of these measures vary greatly. We conducted a meta-analysis using data from 50 studies that quantified the relationship between road-kill and a mitigation measure designed to reduce road-kill. Overall, mitigation measures reduce road-kill by 40% compared to controls. Fences, with or without crossing structures, reduce road-kill by 54%. We found no detectable effect on road-kill of crossing structures without fencing. We found that comparatively expensive mitigation measures reduce large mammal road-kill much more than inexpensive measures. For example, the combination of fencing and crossing structures led to an 83% reduction in road-kill of large mammals, compared to a 57% reduction for animal detection systems, and only a 1% for wildlife reflectors. We suggest that inexpensive measures such as reflectors should not be used until and unless their effectiveness is tested using a high-quality experimental approach. Our meta-analysis also highlights the fact that there are insufficient data to answer many of the most pressing questions that road planners ask about the effectiveness of road mitigation measures, such as whether other less common mitigation measures (e.g., measures to reduce traffic volume and/or speed) reduce road mortality, or to what extent the attributes of crossing structures and fences influence their effectiveness. To improve evaluations of mitigation effectiveness, studies should incorporate data collection before the mitigation is applied, and we recommend a minimum study duration of four years for Before-After, and a minimum of either four years or four sites for Before-After-Control-Impact designs.
We design and demonstrate broadband directional couplers that use asymmetric-waveguide based phase control sections, on the silicon-on-insulator platform. Broadband directional couplers with various ...power splitting ratios, including 10%/90%, 20%/80%, 30%/70%, 40%/60% and 50%/50%, were realized for both transverse electric (TE) and transverse magnetic (TM) modes. Some of the devices exhitbit bandwidths in excess of 100 nm, and all in excess of 75 nm. The footprints of the TE mode couplers are 32 μm ×1.3 μm, or less, and those of the TM mode couplers are 13 μm ×1.3 μm, or less.
Hepatocyte nuclear factor 4α (HNF4α) is essential for liver development and hepatocyte function. Here, we show that transient inhibition of HNF4α initiates hepatocellular transformation through a ...microRNA-inflammatory feedback loop circuit consisting of miR-124, IL6R, STAT3, miR-24, and miR-629. Moreover, we show that, once this circuit is activated, it maintains suppression of HNF4α and sustains oncogenesis. Systemic administration of miR-124, which modulates inflammatory signaling, prevents and suppresses hepatocellular carcinogenesis by inducing tumor-specific apoptosis without toxic side effects. As we also show that this HNF4α circuit is perturbed in human hepatocellular carcinomas, our data raise the possibility that manipulation of this microRNA feedback-inflammatory loop has therapeutic potential for treating liver cancer.
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► HNF4α transient inhibition induces hepatocellular transformation ► The HNF4α feedback loop circuit links inflammation to liver cancer ► MiR-124 regulates IL6-STAT3-signaling pathway ► Systemic delivery of miR-124 inhibits HCC development
Transient inhibition of a key liver transcription factor promotes cellular transformation and liver cancer by stabilizing a microRNA-mediated inflammatory circuit.
A transient inflammatory signal can initiate an epigenetic switch from nontransformed to cancer cells via a positive feedback loop involving NF-κB, Lin28, let-7, and IL-6. We identify differentially ...regulated microRNAs important for this switch and putative transcription factor binding sites in their promoters. STAT3, a transcription factor activated by IL-6, directly activates miR-21 and miR-181b-1. Remarkably, transient expression of either microRNA induces the epigenetic switch. MiR-21 and miR-181b-1, respectively, inhibit PTEN and CYLD tumor suppressors, leading to increased NF-κB activity required to maintain the transformed state. These STAT3-mediated regulatory circuits are required for the transformed state in diverse cell lines and tumor growth in xenografts, and their transcriptional signatures are observed in colon adenocarcinomas. Thus, STAT3 is not only a downstream target of IL-6 but, with miR-21, miR-181b-1, PTEN, and CYLD, is part of the positive feedback loop that underlies the epigenetic switch that links inflammation to cancer.
► Identification of differentially regulated microRNAs during transformation ► STAT3 activates miR-21 and miR-181b-1, which target PTEN and CYLD ► Transient expression of miR-21 or miR-181b-1 induces stable transformation ► STAT3-induced pathway in the epigenetic switch linking inflammation to cancer
The last 20 years have seen a dramatic increase in efforts to mitigate the negative effects of roads and traffic on wildlife, including fencing to prevent wildlife-vehicle collisions and wildlife ...crossing structures to facilitate landscape connectivity. While not necessarily explicitly articulated, the fundamental drivers behind road mitigation are human safety, animal welfare, and/or wildlife conservation. Concomitant with the increased effort to mitigate has been a focus on evaluating road mitigation. So far, research has mainly focussed on assessing the use of wildlife crossing structures, demonstrating that a broad range of species use them. However, this research has done little to address the question of the effectiveness of crossing structures, because use of a wildlife crossing structure does not necessarily equate to its effectiveness. The paucity of studies directly examining the effectiveness of crossing structures is exacerbated by the fact that such studies are often poorly designed, which limits the level of inference that can be made. Without well performed evaluations of the effectiveness of road mitigation measures, we may endanger the viability of wildlife populations and inefficiently use financial resources by installing structures that are not as effective as we think they are. In this paper we outline the essential elements of a good experimental design for such assessments and prioritize the parameters to be measured. The framework we propose will facilitate collaboration between road agencies and scientists to undertake research programs that fully evaluate effectiveness of road mitigation measures. We discuss the added value of road mitigation evaluations for policy makers and transportation agencies and provide recommendations on how to incorporate such evaluations in road planning practices.
Context
Many connectivity metrics have been used to measure the connectivity of a landscape and to evaluate the effects of land-use changes and potential mitigation measures. However, there are still ...gaps in our understanding of how to accurately quantify landscape connectivity.
Objectives
A number of metrics only measure between-patch connectivity, i.e. the connectivity between different habitat patches, which can produce misleading results. This paper demonstrates that the inclusion of within-patch connectivity is important for accurate results.
Methods
The behavior of two metrics is compared: the Connectance Index (
CONNECT
), which measures only between-patch connectivity, and the effective mesh size (
m
eff
), which includes both within-patch and between-patch connectivity. The connectivity values of both metrics were calculated on a set of simulated landscapes. Twenty cities were then added to these landscapes to calculate the resulting changes in connectivity.
Results
We found that when using
CONNECT
counter-intuitive results occurred due to not including within-patch connectivity, such as scenarios where connectivity increased with increasing habitat loss and fragmentation. These counter-intuitive results were resolved when using
m
eff
. For example, landscapes with low habitat amount may be particularly sensitive to urban development, but this is not reflected by
CONNECT
.
Conclusions
Applying misleading results from metrics like
CONNECT
can have detrimental effects on natural ecosystems, because reductions in within-patch connectivity by human activities are neglected. Therefore, this paper provides evidence for the crucial need to consider the balance between within-patch connectivity and between-patch connectivity when calculating the connectivity of landscapes.
Autophagy is an intracellular degradation pathway that functions in protein and organelle turnover in response to starvation and cellular stress. Autophagy is initiated by the formation of a complex ...containing Beclin 1 (BECN1) and its binding partner Phosphoinositide-3-kinase, class 3 (PIK3C3). Recently, BECN1 deficiency was shown to enhance the pathology of a mouse model of Alzheimer Disease (AD). However, the mechanism by which BECN1 or autophagy mediate these effects are unknown. Here, we report that the levels of Amyloid precursor protein (APP) and its metabolites can be reduced through autophagy activation, indicating that they are a substrate for autophagy. Furthermore, we find that knockdown of Becn1 in cell culture increases the levels of APP and its metabolites. Accumulation of APP and APP C-terminal fragments (APP-CTF) are accompanied by impaired autophagosomal clearance. Pharmacological inhibition of autophagosomal-lysosomal degradation causes a comparable accumulation of APP and APP-metabolites in autophagosomes. Becn1 reduction in cell culture leads to lower levels of its binding partner Pik3c3 and increased presence of Microtubule-associated protein 1, light chain 3 (LC3). Overexpression of Becn1, on the other hand, reduces cellular APP levels. In line with these observations, we detected less BECN1 and PIK3C3 but more LC3 protein in brains of AD patients. We conclude that BECN1 regulates APP processing and turnover. BECN1 is involved in autophagy initiation and autophagosome clearance. Accordingly, BECN1 deficiency disrupts cellular autophagy and autophagosomal-lysosomal degradation and alters APP metabolism. Together, our findings suggest that autophagy and the BECN1-PIK3C3 complex regulate APP processing and play an important role in AD pathology.
We demonstrate that n-doped resistive heaters in silicon waveguides show photoconductive effects with high responsivities. These photoconductive heaters, integrated into microring resonator ...(MRR)-based filters, were used to automatically tune and stabilize the filter's resonance wavelength to the input laser's wavelength. This is achieved without requiring dedicated defect implantations, additional material depositions, dedicated photodetectors, or optical power tap-outs. Automatic wavelength stabilization of first-order MRR and second-order series-coupled MRR filters is experimentally demonstrated. Open eye diagrams were obtained for data transmission at 12.5 Gb/s while the temperature was varied by 5 °C at a rate of 0.28 °C/s. We theoretically show that series-coupled MRR-based filters of any order can be automatically tuned by using photoconductive heaters to monitor the light intensity in each MRR, and sequentially aligning the resonance of each MRR to the laser's wavelength.
•The novel sprawl metric presented is Weighted Urban Proliferation (WUP).•WUP is a combination of built-up area, its dispersion, and its utilization density.•The degree of urban sprawl in Switzerland ...increased by 155% between 1935 and 2002.•Examples from parts of Switzerland demonstrate that sprawl can be reduced.•WUP is suitable for performance control of limits to urban sprawl.
Growing urban sprawl is a serious concern worldwide for a number of environmental and economic reasons and is a major challenge on the way to sustainable land use. To address this increasing problem, there is an urgent need for quantitative measurement. Every meaningful method to measure the degree of urban sprawl needs to be based on a clear definition of “urban sprawl” disentangling causes and consequences of urban sprawl from the phenomenon of urban sprawl itself, as urban sprawl has differing causes and consequences in different regions and regulatory contexts. Weighted Urban Proliferation (WUP) – the novel method presented in this paper – is based on the following definition of urban sprawl: the more area built over in a given landscape (amount of built-up area) and the more dispersed this built-up area in the landscape (spatial configuration), and the higher the uptake of built-up area per inhabitant or job (lower utilization intensity in the built-up area), the higher the degree of urban sprawl. However, there is a lack of reliable measures of urban sprawl that integrate these three dimensions in a single metric. Therefore, these three independent dimensions need to be combined according to the qualitative assessment of sprawl to create a suitable metric – which is exactly what the WUP metric does using two weighting functions.
Switzerland serves as an example of applying this method to examine the current state, for comparisons among regions, for historical analysis, and for assessing planning scenarios. The degree of urban sprawl in Switzerland increased by 155% between 1935 and 2002, and without rigorous measures, scenarios of future urban sprawl show that it is likely to further increase by more than 50% until 2050. Examples from parts of Switzerland demonstrate that sprawl can be reduced. As a consequence of intense public discussion, the Swiss Spatial Planning Act was revised in 2013 to make it tighter. We conclude that the new method is more suitable than previous methods to quantify the indicator “urban sprawl” in monitoring systems, e.g., it has now been implemented in monitoring systems in Switzerland. The new WUP method is highly suitable for performance control of limits to urban sprawl once they are implemented and for application to other countries around the globe.
HIV-infected individuals are living longer on antiretroviral therapy, but many patients display signs that in some ways resemble premature aging. To investigate and quantify the impact of chronic HIV ...infection on aging, we report a global analysis of the whole-blood DNA methylomes of 137 HIV+ individuals under sustained therapy along with 44 matched HIV− individuals. First, we develop and validate epigenetic models of aging that are independent of blood cell composition. Using these models, we find that both chronic and recent HIV infection lead to an average aging advancement of 4.9 years, increasing expected mortality risk by 19%. In addition, sustained infection results in global deregulation of the methylome across >80,000 CpGs and specific hypomethylation of the region encoding the human leukocyte antigen locus (HLA). We find that decreased HLA methylation is predictive of lower CD4 / CD8 T cell ratio, linking molecular aging, epigenetic regulation, and disease progression.
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•Methylome-wide analysis of HIV chronically infected, cART treated individuals•HIV+ individuals have an epigenetic age 4.9 years older than healthy controls•HLA locus is hypomethylated in HIV+ individuals•HIV methylation aging signature is validated in purified cells
Gross et al. investigate the impact of chronic HIV infection by profiling the DNA methylomes of HIV+ individuals and matched HIV− controls. Using epigenetic models of aging, they observe that HIV+ individuals show an age advancement of 4.9 years in whole blood and validate these results in pure cell samples.
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