Assessment of Effects of an Oil Pipeline on Caribou, Rangifer tarandus granti, Use of Riparian Habitats in Arctic Alaska, 2001-2003

Elevated oil field pipelines may alter Caribou (Rangifer tarandus granti) movements and delay or prevent access to insect relief habitat. In an attempt to determine if the 40-km elevated Badami pipeline in northern Alaska changed Caribou use of riparian habitats at the three river crossings where the pipeline is buried, we quantified Caribou habitat use at all three crossings using time-lapse video cameras and aerial distribution surveys over three summers. We compared habitat use, behavior and duration of observations among pipeline and non-pipeline sites. We used a block experimental design with cameras at four sites at the three river crossings to evaluate differences in numbers of Caribou per day at pipeline and non-pipeline sites. At each crossing, four cameras were positioned, with one pair of cameras next to the pipeline (pipeline sites) and one pair of cameras 1.8-3.2 km upstream from the pipeline (non-pipeline sites); where cameras monitored the river bank and channel (river habitat) and the tundra within about 200 m of the river (tundra habitat). Peak numbers of Caribou per day occurred during early July 2003 and mid-July 2001 and 2002. Large numbers of Caribou recorded north of the pipeline during aerial surveys did not usually correspond with increased number per day recorded by cameras suggesting Caribou probably also crossed the pipeline outside of the riparian areas. We assessed local changes in riparian habitat use by comparing the numbers of Caribou per day in river and tundra habitats at pipeline and non-pipeline sites and found no difference. We assessed regional changes in riparian habitat use by comparing numbers of Caribou per day at pipeline sites and at non-pipeline sites and found no difference. Caribou groups spent an average of 1 minute longer at tundra pipeline sites and groups spent 30 seconds longer feeding and trotting at pipeline sites, but these differences were not significant

Conservation of ciliary proteins in plants with no cilia

<p>Abstract</p> <p>Background</p> <p>Eukaryotic cilia are complex, highly conserved microtubule-based organelles with a broad phylogenetic distribution. Cilia were present in the last eukaryotic common ancestor and many proteins involved in cilia function have been conserved through eukaryotic diversification. However, cilia have also been lost multiple times in different lineages, with at least two losses occurring within the land plants. Whereas all non-seed plants produce cilia for motility of male gametes, some gymnosperms and all angiosperms lack cilia. During these evolutionary losses, proteins with ancestral ciliary functions may be lost or co-opted into different functions.</p> <p>Results</p> <p>Here we identify a core set of proteins with an inferred ciliary function that are conserved in ciliated eukaryotic species. We interrogate this genomic dataset to identify proteins with a predicted ancestral ciliary role that have been maintained in non-ciliated land plants. In support of our prediction, we demonstrate that several of these proteins have a flagellar localisation in protozoan trypanosomes. The phylogenetic distribution of these genes within the land plants indicates evolutionary scenarios of either sub- or neo-functionalisation and expression data analysis shows that these genes are highly expressed in <it>Arabidopsis thaliana </it>pollen cells.</p> <p>Conclusions</p> <p>A large number of proteins possess a phylogenetic ciliary profile indicative of ciliary function. Remarkably, many genes with an ancestral ciliary role are maintained in non-ciliated land plants. These proteins have been co-opted to perform novel functions, most likely before the loss of cilia, some of which appear related to the formation of the male gametes.</p

Improved Discretization Analysis for Underdamped Langevin Monte Carlo

Underdamped Langevin Monte Carlo (ULMC) is an algorithm used to sample from unnormalized densities by leveraging the momentum of a particle moving in a potential well. We provide a novel analysis of ULMC, motivated by two central questions: (1) Can we obtain improved sampling guarantees beyond strong log-concavity? (2) Can we achieve acceleration for sampling? For (1), prior results for ULMC only hold under a log-Sobolev inequality together with a restrictive Hessian smoothness condition. Here, we relax these assumptions by removing the Hessian smoothness condition and by considering distributions satisfying a Poincar\'e inequality. Our analysis achieves the state of art dimension dependence, and is also flexible enough to handle weakly smooth potentials. As a byproduct, we also obtain the first KL divergence guarantees for ULMC without Hessian smoothness under strong log-concavity, which is based on a new result on the log-Sobolev constant along the underdamped Langevin diffusion. For (2), the recent breakthrough of Cao, Lu, and Wang (2020) established the first accelerated result for sampling in continuous time via PDE methods. Our discretization analysis translates their result into an algorithmic guarantee, which indeed enjoys better condition number dependence than prior works on ULMC, although we leave open the question of full acceleration in discrete time. Both (1) and (2) necessitate R\'enyi discretization bounds, which are more challenging than the typically used Wasserstein coupling arguments. We address this using a flexible discretization analysis based on Girsanov's theorem that easily extends to more general settings

Citizenship Documentation Requirement for Medical Eligibility: Effects on Oregon Children

BACKGROUND AND OBJECTIVES: The Deficit Reduction Act (DRA) of 2005 mandated Medicaid beneficiaries to document citizenship. Using a prospective cohort (n=104,375), we aimed to (1) determine characteristics of affected children, (2) describe effects on health insurance coverage and access to needed health care, and (3) model the causal relationship between this new policy, known determinants of health care access, and receipt of needed health care. METHODS: We identified a stratified random sample of children shortly after the DRA was implemented and used state records and surveys to compare three groups: children denied Medicaid for inability to document citizenship, children denied for other reasons, and children accepted for coverage. To combat survey nonresponse, we used Medicaid records to identify differences between responders and nonrespondents and created survey weights to account for these differences. Weighted simple and multivariable logistic regression described the complete, originally identified population. RESULTS: Children denied Medicaid for inability to document citizenship were likely to be US citizens, were medically and socially more vulnerable than their peers, and went on to have gaps in health insurance coverage and unmet health care needs. The DRA led to persistent loss of insurance coverage, which decreased access to needed health care. Having a usual source of care was an effect modifier in this relationship. CONCLUSIONS: Our findings demonstrate the negative consequences of the DRA and support the use of automated methods of citizenship verification allowed under the Patient Protection and Affordable Care Act

Identification of KLHDC2 as an efficient proximity-induced degrader of K-RAS, STK33, β-catenin, and FoxP3

Targeted protein degradation (TPD), induced by enforcing target proximity to an E3 ubiquitin ligase using small molecules has become an important drug discovery approach for targeting previously undruggable disease-causing proteins. However, out of over 600 E3 ligases encoded by the human genome, just over 10 E3 ligases are currently utilized for TPD. Here, using the affinity-directed protein missile (AdPROM) system, in which an anti-GFP nanobody was linked to an E3 ligase, we screened over 30 E3 ligases for their ability to degrade 4 target proteins, K-RAS, STK33, β-catenin, and FoxP3, which were endogenously GFP-tagged. Several new E3 ligases, including CUL2 diGly receptor KLHDC2, emerged as effective degraders, suggesting that these E3 ligases can be taken forward for the development of small-molecule degraders, such as proteolysis targeting chimeras (PROTACs). As a proof of concept, we demonstrate that a KLHDC2-recruiting peptide-based PROTAC connected to chloroalkane is capable of degrading HALO-GFP protein in cells

Transcriptome analysis suggests a role for the differential expression of cerebral aquaporins and the MAPK signalling pathway in human temporal lobe epilepsy

Epilepsies are common disorders of the central nervous system (CNS), affecting up to 2% of the global population. Pharmaco-resistance is a major clinical challenge affecting about 30% of temporal lobe epilepsy (TLE) patients. Water homeostasis has been shown crucial for regulation of neuronal excitability. The control of water movement is achieved through a family of small integral membrane channel proteins called aquaporins (AQPs). Despite the fact that changes in water homeostasis occur in sclerotic hippocampi of people with TLE, the expression of AQPs in the epileptic brain is not fully characterised. This study uses microarray and ELISA methods to analyse the mRNA and protein expression of the human cerebral AQPs in sclerotic hippocampi (TLE-HS) and adjacent neocortex tissue (TLE-NC) of TLE patients. The expression of AQP1 and AQP4 transcripts was significantly increased, while that of the AQP9 transcript was significantly reduced in TLE-HS compared to TLE-NC. AQP4 protein expression was also increased while expression of AQP1 protein remained unchanged, and AQP9 was undetected. Microarray data analysis identified 3,333 differentially regulated genes and suggested the involvement of the MAPK signalling pathway in TLE pathogenesis. Proteome array data validated the translational profile for 26 genes and within the MAPK pathway (e.g. p38, JNK) that were identified as differentially expressed from microarray analysis. ELISA data showed that p38 and JNK inhibitors decrease AQP4 protein levels in cultured human primary cortical astrocytes. Elucidating the mechanism of selective regulation of different AQPs and associated regulatory proteins may provide a new therapeutic approach to epilepsy treatment. This article is protected by copyright. All rights reserved

A First Comparison of Kepler Planet Candidates in Single and Multiple Systems

In this letter we present an overview of the rich population of systems with multiple candidate transiting planets found in the first four months of Kepler data. The census of multiples includes 115 targets that show 2 candidate planets, 45 with 3, 8 with 4, and 1 each with 5 and 6, for a total of 170 systems with 408 candidates. When compared to the 827 systems with only one candidate, the multiples account for 17 percent of the total number of systems, and a third of all the planet candidates. We compare the characteristics of candidates found in multiples with those found in singles. False positives due to eclipsing binaries are much less common for the multiples, as expected. Singles and multiples are both dominated by planets smaller than Neptune; 69 +2/-3 percent for singles and 86 +2/-5 percent for multiples. This result, that systems with multiple transiting planets are less likely to include a transiting giant planet, suggests that close-in giant planets tend to disrupt the orbital inclinations of small planets in flat systems, or maybe even to prevent the formation of such systems in the first place.Comment: 13 pages, 13 figures, submitted to ApJ Letter

The small molecule curcumin analog FLLL32 induces apoptosis in melanoma cells via STAT3 inhibition and retains the cellular response to cytokines with anti-tumor activity

Background: We characterized the biologic effects of a novel small molecule STAT3 pathway inhibitor that is derived from the natural product curcumin. We hypothesized this lead compound would specifically inhibit the STAT3 signaling pathway to induce apoptosis in melanoma cells. Results: FLLL32 specifically reduced STAT3 phosphorylation at Tyr705 (pSTAT3) and induced apoptosis at micromolar amounts in human melanoma cell lines and primary melanoma cultures as determined by annexin V/propidium iodide staining and immunoblot analysis. FLLL32 treatment reduced expression of STAT3-target genes, induced caspase-dependent apoptosis, and reduced mitochondrial membrane potential. FLLL32 displayed specificity for STAT3 over other homologous STAT proteins. In contrast to other STAT3 pathway inhibitors (WP1066, JSI-124, Stattic), FLLL32 did not abrogate IFN-γ-induced pSTAT1 or downstream STAT1-mediated gene expression as determined by Real Time PCR. In addition, FLLL32 did not adversely affect the function or viability of immune cells from normal donors. In peripheral blood mononuclear cells (PBMCs), FLLL32 inhibited IL-6-induced pSTAT3 but did not reduce signaling in response to immunostimulatory cytokines (IFN-γ, IL 2). Treatment of PBMCs or natural killer (NK) cells with FLLL32 also did not decrease viability or granzyme b and IFN-γ production when cultured with K562 targets as compared to vehicle (DMSO). Conclusions: These data suggest that FLLL32 represents a lead compound that could serve as a platform for further optimization to develop improved STAT3 specific inhibitors for melanoma therapy

Comparative genomic analysis of the ‘pseudofungus’ Hyphochytrium catenoides

Eukaryotic microbes have three primary mechanisms for obtaining nutrients and energy: phagotrophy, photosynthesis and osmotrophy. Traits associated with the latter two functions arose independently multiple times in the eukaryotes. The Fungi successfully coupled osmotrophy with filamentous growth, and similar traits are also manifested in the Pseudofungi (oomycetes and hyphochytriomycetes). Both the Fungi and the Pseudofungi encompass a diversity of plant and animal parasites. Genome-sequencing efforts have focused on host-associated microbes (mutualistic symbionts or parasites), providing limited comparisons with free-living relatives. Here we report the first draft genome sequence of a hyphochytriomycete ‘pseudofungus’; Hyphochytrium catenoides. Using phylogenomic approaches, we identify genes of recent viral ancestry, with related viral derived genes also present on the genomes of oomycetes, suggesting a complex history of viral coevolution and integration across the Pseudofungi. H. catenoides has a complex life cycle involving diverse filamentous structures and a flagellated zoospore with a single anterior tinselate flagellum. We use genome comparisons, drug sensitivity analysis and high-throughput culture arrays to investigate the ancestry of oomycete/pseudofungal characteristics, demonstrating that many of the genetic features associated with parasitic traits evolved specifically within the oomycete radiation. Comparative genomics also identified differences in the repertoire of genes associated with filamentous growth between the Fungi and the Pseudofungi, including differences in vesicle trafficking systems, cell-wall synthesis pathways and motor protein repertoire, demonstrating that unique cellular systems underpinned the convergent evolution of filamentous osmotrophic growth in these two eukaryotic groups