Discovery of 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425), a potent and orally bioavailable tissue-nonspecific alkaline phosphatase (TNAP) inhibitor

Tissue-nonspecific alkaline phosphatase (TNAP) is an ectoenzyme crucial for bone matrix mineralization via its ability to hydrolyze extracellular inorganic pyrophosphate (ePP_i), a potent mineralization inhibitor, to phosphate (P_i). By the controlled hydrolysis of ePP_i, TNAP maintains the correct ratio of P_i to ePP_i and therefore enables normal skeletal and dental calcification. In other areas of the body low ePP_i levels lead to the development of pathological soft-tissue calcification, which can progress to a number of disorders. TNAP inhibitors have been shown to prevent these processes via an increase of ePP_i. Herein we describe the use of a whole blood assay to optimize a previously described series of TNAP inhibitors resulting in 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425), a potent, selective and oral bioavailable compound that robustly inhibits TNAP in vivo.     

Matrix‐glycoprotein interactions required for budding of a plant nucleorhabdovirus and induction of inner nuclear membrane invagination

Nucleorhabdoviruses such as Sonchus yellow net virus (SYNV) replicate in the nuclei and undergo morphogenesis at the inner nuclear membrane (IM) in plant cells. Mature particles are presumed to form by budding of the Matrix (M) protein‐nucleocapsid complexes through host IMs to acquire host phospholipids and the surface glycoproteins (G). To address mechanisms underlying nucleorhabdovirus budding, we generated recombinant SYNV G mutants containing a truncated amino‐terminal (NT) or carboxyl‐terminal (CT) domain. Electron microscopy and sucrose gradient centrifugation analyses showed that the CT domain is essential for virion morphogenesis whereas the NT domain is also required for efficient budding. SYNV infection induces IM invaginations that are thought to provide membrane sites for virus budding. We found that in the context of viral infections, interactions of the M protein with the CT domain of the membrane‐anchored G protein mediate M protein translocation and IM invagination. Interestingly, tethering the M protein to endomembranes, either by co‐expression with a transmembrane G protein CT domain or by artificial fusion with the G protein membrane targeting sequence, induces IM invagination in uninfected cells. Further evidence to support functions of G‐M interactions in virus budding came from dominant negative effects on SYNV‐induced IM invagination and viral infections that were elicited by expression of a soluble version of the G protein CT domain. Based on these data, we propose that cooperative G‐M interactions promote efficient SYNV budding.     

Assessing the impacts of imperfect detection on estimates of diversity and community structure through multispecies occupancy modeling

Detecting all species in a given survey is challenging, regardless of sampling effort. This issue, more commonly known as imperfect detection, can have negative impacts on data quality and interpretation, most notably leading to false absences for rare or difficult‐to‐detect species. It is important that this issue be addressed, as estimates of species richness are critical to many areas of ecological research and management. In this study, we set out to determine the impacts of imperfect detection, and decisions about thresholds for inclusion in occupancy, on estimates of species richness and community structure. We collected data from a stream fish assemblage in Algonquin Provincial Park to be used as a representation of ecological communities. We then used multispecies occupancy modeling to estimate species‐specific occurrence probabilities while accounting for imperfect detection, thus creating a more informed dataset. This dataset was then compared to the original to see where differences occurred. In our analyses, we demonstrated that imperfect detection can lead to large changes in estimates of species richness at the site level and summarized differences in the community structure and sampling locations, represented through correspondence analyses.     

A machine‐learning approach for extending classical wildlife resource selection analyses

Resource selection functions (RSFs) are tremendously valuable for ecologists and resource managers because they quantify spatial patterns in resource utilization by wildlife, thereby facilitating identification of critical habitat areas and characterizing specific habitat features that are selected or avoided. RSFs discriminate between known‐use resource units (e.g., telemetry locations) and available (or randomly selected) resource units based on an array of environmental features, and in their standard form are performed using logistic regression. As generalized linear models, standard RSFs have some notable limitations, such as difficulties in accommodating nonlinear (e.g., humped or threshold) relationships and complex interactions. Increasingly, ecologists are using flexible machine‐learning methods (e.g., random forests, neural networks) to overcome these limitations. Herein, we investigate the seasonal resource selection patterns of mule deer (Odocoileus hemionus) by comparing a logistic regression framework with random forest (RF), a popular machine‐learning algorithm. Random forest (RF) models detected nonlinear relationships (e.g., optimal ranges for slope and elevation) and complex interactions which would have been very challenging to discover and characterize using standard model‐based approaches. Compared with standard RSF models, RF models exhibited improved predictive skill, provided novel insights about resource selection patterns of mule deer, and, when projected across a relevant geographic space, manifested notable differences in predicted habitat suitability. We recommend that wildlife researchers harness the strengths of machine‐learning tools like RF in addition to “classical” tools (e.g., mixed‐effects logistic regression) for evaluating resource selection, especially in cases where extensive telemetry data sets are available.     

Small Interfering RNA-Mediated Control of Virus Replication in the CNS Is Therapeutic and Enables Natural Immunity to West Nile Virus

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A new genus and species of turtle blood fluke (Digenea: Schistosomatoidea) from the Mekong snail-eating turtle, <Emphasis Type="Italic">Malayemys subtrijuga</Emphasis> (Schlegel &amp; Müller) (Testudines: Geoemydidae) in Vietnam,with a reassessment of related Asiatic turtle blood flukes and molecular phylogeny

Platt sinuosus Roberts & Bullard n. g., n. sp. (type-species) infects the kidney and mesenteric blood vessels of Mekong snail-eating turtles, Malayemys subtrijuga (Schlegel & Müller), in the Mekong River Basin. Species of Platt Roberts & Bullard n. g. are unique by the combination of having a papillate ventral sucker, vasa efferentia that are dorsal to the gonads, a massive cirrus-sac that is directed anteriad or laterad, and a vitellarium that surrounds the intestinal caeca. The new species resembles Platt ocadiae (Takeuti, 1942) Roberts & Bullard n. comb. but differs from it by having an external seminal vesicle that overlaps with or is immediately posterior to the level of the ventral sucker. Seven species previously of Hapalorhynchus Stunkard, 1922 are reassigned herein to Platt: P. odhnerensis (Mehra, 1933) Roberts & Bullard n. comb.; P. yoshidai (Ozaki, 1939) Roberts & Bullard n. comb.; P. ocadiae; P. oschmarini (Belous, 1963) Roberts & Bullard n. comb.; P. sutlejensis (Mehrotra, 1973) Roberts & Bullard n. comb.; P. synderi (Platt & Sharma, 2012) Roberts & Bullard n. comb.; and P. tkachi (Platt & Sharma, 2012) Roberts & Bullard n. comb. A dichotomous key to Platt spp. is provided. Hapalorhynchus sheilae (Mehrotra, 1973) Bourgat, 1990 and Hapalorhynchus mica (Oshmarin, 1971) Bourgat, 1990 are considered as species inquirendae, and Hapalorhynchus indicus (Thapar, 1933) Price, 1934 and Hapalorhynchus macrotesticularis (Rohde, Lee, & Lim, 1968) Brooks & Sullivan, 1981 are considered as species incertae sedis. Phylogenetic analysis of the large subunit rDNA (28S) showed P. sinuosus and P. snyderi to be sister taxa distinct from a monophyletic Hapalorhynchus and Coeuritrema platti Roberts & Bullard, 2016.