Human disturbance and shifts in vertebrate community composition in a biodiversity hotspot.

Understanding how human modification of the landscape shapes vertebrate community composition is vital to understanding the current status and future trajectory of wildlife. Using a participatory approach, we deployed the largest camera-trap network in Mesoamerica to date to investigate how anthropogenic disturbance shapes the occupancy and co-occurrence of terrestrial vertebrate species in a tropical biodiversity hotspot: the Osa Peninsula, Costa Rica. We estimated species richness in different categories of land protection with rarefaction analysis and estimated the expected occupancy with a joint species distribution model that included covariates for anthropogenic disturbance, land protection, habitat quality, and habitat availability. Areas with the most stringent land-use protections (e.g., Corcovado National Park, 24 species [95% CI 23-25]) harbored significantly more species than unprotected areas (20 species [19.7-20.3]), mainly due to a reduced presence of large-bodied species of conservation concern in unprotected areas (e.g., jaguar Panthera onca and white-lipped peccary Tayassu pecari). Small-bodied generalist species, such as opossums (Didelphidae) and armadillos (Dasypus novemcinctus), in contrast, were more common at disturbed sites, resulting in a significant difference in vertebrate community composition between sites with low and high disturbance. Co-occurrence of species was also mainly associated with response to disturbance. Similar responses to disturbance create two groups of species, those whose site-level occupancy usually increased as anthropogenic disturbance increased and those whose estimated occupancy decreased. The absence of large-bodied species entails an important loss of ecological function in disturbed areas and can hinder forest development and maintenance. Efforts to protect and restore forested landscapes are likely having a positive effect on the abundance of some threatened species. These efforts, however, must be sustained and expanded to increase connectivity and ensure the long-term viability of the wildlife community.

Perturbaciones Humanas y Cambios en la Composición de la Comunidad de Vertebrados en un Punto Caliente de Biodiversidad Resumen El entendimiento de cómo las modificaciones humanas del paisaje conforman la composición de las comunidades de vertebrados es vital para entender el estado actual y la trayectoria futura de la fauna. Mediante una estrategia participativa, desplegamos la mayor red de cámaras trampa en Mesoamérica hasta la fecha para investigar cómo la perturbación antropogénica determina la ocupación y coocurrencia de las especies terrestres de vertebrados en un punto caliente de biodiversidad tropical: la Península de Osa, Costa Rica. Estimamos la riqueza de especies en diferentes categorías de protección de suelo con un análisis de rarefacción y estimamos la ocupación esperada con un modelo de distribución conjunta de especies que incluyó covariables para la perturbación antropogénica, la protección del suelo, la calidad del hábitat y la disponibilidad del hábitat. Las áreas con la protección más estricta de uso de suelo (p. ej.: Parque Nacional Corcovado, 24 especies [95% CI 23-25]) albergaron significativamente a más especies que las áreas desprotegidas (20 especies [19.7-20.3]), principalmente debido a la presencia reducida de especies de talla grande de interés para la conservación en las áreas desprotegidas (p. ej.: el jaguar Panthera onca, el pecarí de labios blancos, Tayassu pecari). Al contrario, las especies generalistas de talla pequeña, como las zarigüeyas (Didelphidae) y el armadillo (Dasypus novemcinctus) fueron más comunes en los sitios perturbados, lo que resulta en una diferencia significativa en la composición de las comunidades de vertebrados entre los sitios con una perturbación baja y alta. La coocurrencia de especies también estuvo asociada principalmente con la respuesta a la perturbación. Las respuestas similares a la perturbación crean dos grupos de especies: aquellas cuya ocupación a nivel de sitio generalmente incrementó conforme incrementó la perturbación antropogénica y aquellas cuya ocupación estimada disminuyó. La ausencia de especies de talla grande conlleva una pérdida importante de la función ecológica en las áreas perturbadas y puede dificultar el desarrollo y mantenimiento del bosque. Los esfuerzos para proteger y restaurar los paisajes forestales probablemente estén teniendo un efecto positivo sobre la abundancia de algunas especies amenazadas. Estos esfuerzos, sin embargo, deben ser sostenidos y expandidos para incrementar la conectividad y asegurar la viabilidad a largo plazo de la comunidad faunística.

Retroviral Gag protein-RNA interactions: Implications for specific genomic RNA packaging and virion assembly.

Retroviral Gag proteins are responsible for coordinating many aspects of virion assembly. Gag possesses two distinct nucleic acid binding domains, matrix (MA) and nucleocapsid (NC). One of the critical functions of Gag is to specifically recognize, bind, and package the retroviral genomic RNA (gRNA) into assembling virions. Gag interactions with cellular RNAs have also been shown to regulate aspects of assembly. Recent results have shed light on the role of MA and NC domain interactions with nucleic acids, and how they jointly function to ensure packaging of the retroviral gRNA. Here, we will review the literature regarding RNA interactions with NC, MA, as well as overall mechanisms employed by Gag to interact with RNA. The discussion focuses on human immunodeficiency virus type-1, but other retroviruses will also be discussed. A model is presented combining all of the available data summarizing the various factors and layers of selection Gag employs to ensure specific gRNA packaging and correct virion assembly.

HIV-1 Gag protein with or without p6 specifically dimerizes on the viral RNA packaging signal.

The HIV-1 Gag protein is responsible for genomic RNA (gRNA) packaging and immature viral particle assembly. Although the presence of gRNA in virions is required for viral infectivity, in its absence, Gag can assemble around cellular RNAs and form particles resembling gRNA-containing particles. When gRNA is expressed, it is selectively packaged despite the presence of excess host RNA, but how it is selectively packaged is not understood. Specific recognition of a gRNA packaging signal (Psi) has been proposed to stimulate the efficient nucleation of viral assembly. However, the heterogeneity of Gag-RNA interactions renders capturing this transient nucleation complex using traditional structural biology approaches challenging. Here, we used native MS to investigate RNA binding of wild-type (WT) Gag and Gag lacking the p6 domain (GagΔp6). Both proteins bind to Psi RNA primarily as dimers, but to a control RNA primarily as monomers. The dimeric complexes on Psi RNA require an intact dimer interface within Gag. GagΔp6 binds to Psi RNA with high specificity in vitro and also selectively packages gRNA in particles produced in mammalian cells. These studies provide direct support for the idea that Gag binding to Psi specifically promotes nucleation of Gag-Gag interactions at the early stages of immature viral particle assembly in a p6-independent manner.

A recovery network leads to the natural recolonization of an archipelago and a potential trailing edge refuge.

Rapid environmental change is reshaping ecosystems and driving species loss globally. Carnivore populations have declined and retracted rapidly and have been the target of numerous translocation projects. Success, however, is complicated when these efforts occur in novel ecosystems. Identifying refuges, locations that are resistant to environmental change, within a translocation framework should improve population recovery and persistence. American martens (Martes americana) are the most frequently translocated carnivore in North America. As elsewhere, martens were extirpated across much of the Great Lakes region by the 1930s and, despite multiple translocations beginning in the 1950s, martens remain of regional conservation concern. Surprisingly, martens were rediscovered in 2014 on the Apostle Islands of Lake Superior after a putative absence of >40 yr. To identify the source of martens to the islands and understand connectivity of the reintroduction network, we collected genetic data on martens from the archipelago and from all regional reintroduction sites. In total, we genotyped 483 individual martens, 43 of which inhabited the Apostle Islands (densities 0.42-1.46 km-2 ). Coalescent analyses supported the contemporary recolonization of the Apostle Islands with progenitors likely originating from Michigan, which were sourced from Ontario. We also identified movements by a first-order relative between the Apostle Islands and the recovery network. We detected some regional gene flow, but in an unexpected direction: individuals moving from the islands to the mainland. Our findings suggest that the Apostle Islands were naturally recolonized by progeny of translocated individuals and now act as a source back to the reintroduction sites on the mainland. We suggest that the Apostle Islands, given its protection from disturbance, complex forest structure, and reduced carnivore competition, will act as a potential refuge for marten along their trailing range boundary and a central node for regional recovery. Our work reveals that translocations, even those occurring along southern range boundaries, can create recovery networks that function like natural metapopulations. Identifying refuges, locations that are resistant to environmental change, within these recovery networks can further improve species recovery, even within novel environments. Future translocation planning should a priori identify potential refuges and sources to improve short-term recovery and long-term persistence.

A model of feedforward, global, and lateral inhibition in the locust visual system predicts responses to looming stimuli.

Detection of looming obstacles is a vital task for both natural and artificial systems. Locusts possess a visual nervous system with an extensively studied obstacle detection pathway, culminating in the lobula giant movement detector (LGMD) neuron. While numerous models of this system exist, none to date have incorporated recent data on the anatomy and function of feedforward and global inhibitory systems in the input network of the LGMD. Moreover, the possibility that global and lateral inhibition shape the feedforward inhibitory signals to the LGMD has not been investigated. To address these points, a novel model of feedforward inhibitory neurons in the locust optic lobe was developed based on the recent literature. This model also incorporated global and lateral inhibition into the afferent network of these neurons, based on their observed behaviour in existing data and the posited role of these mechanisms in the inputs to the LGMD. Tests with the model showed that it accurately replicates the behaviour of feedforward inhibitory neurons in locusts; the model accurately coded for stimulus angular size in an overall linear fashion, with decreasing response saturation and increasing linearity as stimulus size increased or approach velocity decreased. The model also exhibited only phasic responses to the appearance of a grating, along with sustained movement by it at constant speed. By observing the effects of altering inhibition schemes on these responses, it was determined that global inhibition serves primarily to normalize growing excitation as collision approaches, and keeps coding for subtense angle linear. Lateral inhibition was determined to suppress tonic responses to wide-field stimuli translating at constant speed. Based on these features being shared with characterizations of the LGMD input network, it was hypothesized that the feedforward inhibitory neurons and the LGMD share the same excitatory afferents; this necessitates further investigation.

Impacts of lake breeze meteorology on ozone gradient observations along Lake Michigan Shorelines in Wisconsin.

Daytime onshore lake breezes are a critical factor controlling ozone abundance at coastal sites around Lake Michigan. Coastal counties along the western shore of Lake Michigan have historically observed high ozone episodes dating to the 1970s. We classified ozone episode days based on the extent or absence of the lake breeze (i.e., "inland", "near-shore" or "no" lake breeze) to establish a climatology of these events. This work demonstrated variable gradients in ozone abundances based on these different types of meteorology, with the sharpest ozone concentration gradients on days with a near-shore lake breeze. On 76-82% of days in which ozone reached 70 ppb for at least 1 hour, a lake breeze was present. Evidence of ozone gradients from multiple observation platforms during the 2017 Lake Michigan Ozone Study (LMOS 2017) are shown for two days with different depths of lake breezes.

Preexisting Conditions That Kill Us.

To protect human life, science and public health need to guide public policy. We call for an end to the anti-science, anti-prevention, and anti-regulatory policies that have resulted in countless preexisting conditions and deaths. Reactive responses are not a substitute for primary prevention; we must invest in environmental and public health protections.

Conservation of tRNA mimicry in the 5'-untranslated region of distinct HIV-1 subtypes.

Human tRNALys3 serves as the primer for reverse transcription in human immunodeficiency virus type-1 (HIV-1) and anneals to the complementary primer binding site (PBS) in the genome. All tRNALys isoacceptors interact with human lysyl-tRNA synthetase (hLysRS) and are selectively packaged into virions. tRNALys3 must be released from hLysRS in order to anneal to the PBS, and this process is proposed to be facilitated by the interaction of hLysRS with a tRNA-like element (TLE) first identified in the HIV-1 5'-untranslated region (5'-UTR) of the subtype B NL4-3 virus. However, a significant subset of HIV-1 strains represented by the MAL isolate possess a different secondary structure in this region of the genome. Thus, to establish the conservation of this mechanism for primer targeting and release, we investigated the subtype A-like 5'-UTR of the MAL isolate. hLysRS bound to a 229-nt MAL RNA containing the PBS domain with high affinity (Kd = 47 nM), and to a 98-nt truncated construct with ∼10-fold reduced affinity. These results resemble previous studies using analogous NL4-3-derived RNAs. However, in contrast to studies with NL4-3, no binding was observed to smaller stem-loop elements within the MAL PBS domain. The tertiary structure of the 98-nt construct was analyzed using small-angle X-ray scattering, revealing remarkable global structural similarity to the corresponding NL4-3 PBS/TLE region. These results suggest that the tRNA-like structure within the 5'-UTR is conserved across distinct HIV-1 subtypes and that hLysRS recognition of the MAL isolate is likely not conferred by specific sequence elements but by 3D structure.

Inhibition of HIV-1 Gag-membrane interactions by specific RNAs.

HIV-1 particle assembly, which occurs at the plasma membrane (PM) of cells, is driven by the viral polyprotein Gag. Gag recognizes phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2], a PM-specific phospholipid, via the highly basic region (HBR) in its N-terminal matrix (MA) domain. The HBR is also known to bind to RNA. We have previously shown, using an in vitro liposome binding assay, that RNA inhibits Gag binding to membranes that lack PI(4,5)P2 If this RNA block is removed by RNase treatment, Gag can bind nonspecifically to other negatively charged membranes. In an effort to identify the RNA species that confer this inhibition of Gag membrane binding, we have tested the impact of purified RNAs on Gag interactions with negatively charged liposomes lacking PI(4,5)P2 We found that some tRNA species and RNAs containing stem-loop 1 of the psi region in the 5' untranslated region of the HIV-1 genome impose inhibition of Gag binding to membranes lacking PI(4,5)P2 In contrast, a specific subset of tRNAs, as well as an RNA sequence previously selected in vitro for MA binding, failed to suppress Gag-membrane interactions. Furthermore, switching the identity of charged residues in the HBR did not diminish the susceptibility of Gag-liposome binding for each of the RNAs tested, while deletion of most of the NC domain abrogates the inhibition of membrane binding mediated by the RNAs that are inhibitory to WT Gag-liposome binding. These results support a model in which NC facilitates binding of RNA to MA and thereby promotes RNA-based inhibition of Gag-membrane binding.

Acute management of pancreatitis: the key to best outcomes.

Acute pancreatitis (AP) accounts for over 230 000 US and 28 000 UK hospital admissions annually. Abdominal pain is the most common presenting symptom in AP but may not reflect severity. The clinical challenge is identifying the 20% of patients in whom AP will be severe. We summarise the common aetiologies, the risk stratification strategies including the simplified Bedside Index for Severity in Acute Pancreatitis, acute management approaches in the initial presentation setting, conditions for using advance imaging and opinions on antibiotic use. Some warning signs of impending complications are also discussed.

A landscape of overlapping risks for wolf-human conflict in Wisconsin, USA.

Managing risk requires an adequate understanding of risk-factors that influence the likelihood of a particular event occurring in time and space. Risk maps can be valuable tools for natural resource managers, allowing them to better understand spatial characteristics of risk. Risk maps can also support risk-avoidance efforts by identifying which areas are relatively riskier than others. However, risks, such as human-carnivore conflict, can be diverse, multi-faceted, and overlapping in space. Yet, efforts to describe risk typically focus on only one aspect of risk. We examined wolf complaints investigated in Wisconsin, USA for the period of 1999-2011. We described the spatial patterns of four types of wolf-human conflict: livestock depredation, depredation on hunting hounds, depredation on non-hound dogs, and human health and safety concerns (HHSC). Using predictive landscape models and discriminant functions analysis, we visualized the landscape of risk as a continuous surface of overlapping risks. Each type of conflict had its own unique landscape signature; however, the probability of any type of conflict increased closer to the center of wolf pack territories and with increased forest cover. Hunting hound depredations tended to occur in areas considered to be highly suitable wolf habitat, while livestock depredations occurred more regularly in marginal wolf habitat. HHSC and non-hound dog depredations were less predictable spatially but tended to occur in areas with low housing density adjacent to large wildland areas. Similar to other research evaluating the risk of human-carnivore conflict, our data suggests that human-carnivore conflict is most likely to occur where humans or human property and large carnivores co-occur. However, identifying areas of co-occurrence is only marginally valuable from a conservation standpoint and could be described using spatially-explicit human and carnivore data without complex analytical approaches. These results challenge our traditional understanding of risk and the standard approach used in describing risk. We suggest that a more comprehensive understanding of the risk of human-carnivore conflict can be achieved by examining the spatial and non-spatial factors influencing risk within areas of co-occurrence and by describing the landscape of risk as a continuous surface of multiple overlapping risks.

Three-dimensional shape and velocity changes affect responses of a locust visual interneuron to approaching objects.

Adaptive collision avoidance behaviours require accurate detection of complex spatiotemporal properties of an object approaching in an animal's natural, three-dimensional environment. Within the locust, the lobula giant movement detector and its postsynaptic partner, the descending contralateral movement detector (DCMD), respond robustly to images that emulate an approaching two-dimensional object and exhibit firing rate modulation correlated with changes in object trajectory. It is not known how this pathway responds to visual expansion of a three-dimensional object or an approaching object that changes velocity, both of which represent natural stimuli. We compared DCMD responses with images that emulate the approach of a sphere with those elicited by a two-dimensional disc. A sphere evoked later peak firing and decreased sensitivity to the ratio of the half size of the object to the approach velocity, resulting in an increased threshold subtense angle required to generate peak firing. We also presented locusts with an approaching sphere that decreased or increased in velocity. A velocity decrease resulted in transition-associated peak firing followed by a firing rate increase that resembled the response to a constant, slower velocity. A velocity increase resulted in an earlier increase in the firing rate that was more pronounced with an earlier transition. These results further demonstrate that this pathway can provide motor circuits for behaviour with salient information about complex stimulus dynamics.

Analysis of RNA structure using small-angle X-ray scattering.

In addition to their role in correctly attaching specific amino acids to cognate tRNAs, aminoacyl-tRNA synthetases (aaRS) have been found to possess many alternative functions and often bind to and act on other nucleic acids. In contrast to the well-defined 3D structure of tRNA, the structures of many of the other RNAs recognized by aaRSs have not been solved. Despite advances in the use of X-ray crystallography (XRC), nuclear magnetic resonance (NMR) spectroscopy and cryo-electron microscopy (cryo-EM) for structural characterization of biomolecules, significant challenges to solving RNA structures still exist. Recently, small-angle X-ray scattering (SAXS) has been increasingly employed to characterize the 3D structures of RNAs and RNA-protein complexes. SAXS is capable of providing low-resolution tertiary structure information under physiological conditions and with less intensive sample preparation and data analysis requirements than XRC, NMR and cryo-EM. In this article, we describe best practices involved in the process of RNA and RNA-protein sample preparation, SAXS data collection, data analysis, and structural model building.

Identification of distinct biological functions for four 3'-5' RNA polymerases.

The superfamily of 3'-5' polymerases synthesize RNA in the opposite direction to all other DNA/RNA polymerases, and its members include eukaryotic tRNA(His) guanylyltransferase (Thg1), as well as Thg1-like proteins (TLPs) of unknown function that are broadly distributed, with family members in all three domains of life. Dictyostelium discoideum encodes one Thg1 and three TLPs (DdiTLP2, DdiTLP3 and DdiTLP4). Here, we demonstrate that depletion of each of the genes results in a significant growth defect, and that each protein catalyzes a unique biological reaction, taking advantage of specialized biochemical properties. DdiTLP2 catalyzes a mitochondria-specific tRNA(His) maturation reaction, which is distinct from the tRNA(His) maturation reaction typically catalyzed by Thg1 enzymes on cytosolic tRNA. DdiTLP3 catalyzes tRNA repair during mitochondrial tRNA 5'-editing in vivo and in vitro, establishing template-dependent 3'-5' polymerase activity of TLPs as a bona fide biological activity for the first time since its unexpected discovery more than a decade ago. DdiTLP4 is cytosolic and, surprisingly, catalyzes robust 3'-5' polymerase activity on non-tRNA substrates, strongly implying further roles for TLP 3'-5' polymerases in eukaryotes.

Small-angle X-ray scattering-derived structure of the HIV-1 5' UTR reveals 3D tRNA mimicry.

The most conserved region of the HIV type 1 (HIV-1) genome, the ∼335-nt 5' UTR, is characterized by functional stem loop domains responsible for regulating the viral life cycle. Despite the indispensable nature of this region of the genome in HIV-1 replication, 3D structures of multihairpin domains of the 5' UTR remain unknown. Using small-angle X-ray scattering and molecular dynamics simulations, we generated structural models of the transactivation (TAR)/polyadenylation (polyA), primer-binding site (PBS), and Psi-packaging domains. TAR and polyA form extended, coaxially stacked hairpins, consistent with their high stability and contribution to the pausing of reverse transcription. The Psi domain is extended, with each stem loop exposed for interactions with binding partners. The PBS domain adopts a bent conformation resembling the shape of a tRNA in apo and primer-annealed states. These results provide a structural basis for understanding several key molecular mechanisms underlying HIV-1 replication.

Structurally distinct ligands rescue biogenesis defects of the KATP channel complex via a converging mechanism.

Small molecules that correct protein misfolding and misprocessing defects offer a potential therapy for numerous human diseases. However, mechanisms underlying pharmacological correction of such defects, especially in heteromeric complexes with structurally diverse constituent proteins, are not well understood. Here we investigate how two chemically distinct compounds, glibenclamide and carbamazepine, correct biogenesis defects in ATP-sensitive potassium (KATP) channels composed of sulfonylurea receptor 1 (SUR1) and Kir6.2. We present evidence that despite structural differences, carbamazepine and glibenclamide compete for binding to KATP channels, and both drugs share a binding pocket in SUR1 to exert their effects. Moreover, both compounds engage Kir6.2, in particular the distal N terminus of Kir6.2, which is involved in normal channel biogenesis, for their chaperoning effects on SUR1 mutants. Conversely, both drugs can correct channel biogenesis defects caused by Kir6.2 mutations in a SUR1-dependent manner. Using an unnatural, photocross-linkable amino acid, azidophenylalanine, genetically encoded in Kir6.2, we demonstrate in living cells that both drugs promote interactions between the distal N terminus of Kir6.2 and SUR1. These findings reveal a converging pharmacological chaperoning mechanism wherein glibenclamide and carbamazepine stabilize the heteromeric subunit interface critical for channel biogenesis to overcome defective biogenesis caused by mutations in individual subunits.

Mechanistic differences between HIV-1 and SIV nucleocapsid proteins and cross-species HIV-1 genomic RNA recognition.

BACKGROUND: The nucleocapsid (NC) domain of HIV-1 Gag is responsible for specific recognition and packaging of genomic RNA (gRNA) into new viral particles. This occurs through specific interactions between the Gag NC domain and the Psi packaging signal in gRNA. In addition to this critical function, NC proteins are also nucleic acid (NA) chaperone proteins that facilitate NA rearrangements during reverse transcription. Although the interaction with Psi and chaperone activity of HIV-1 NC have been well characterized in vitro, little is known about simian immunodeficiency virus (SIV) NC. Non-human primates are frequently used as a platform to study retroviral infection in vivo; thus, it is important to understand underlying mechanistic differences between HIV-1 and SIV NC. RESULTS: Here, we characterize SIV NC chaperone activity for the first time. Only modest differences are observed in the ability of SIV NC to facilitate reactions that mimic the minus-strand annealing and transfer steps of reverse transcription relative to HIV-1 NC, with the latter displaying slightly higher strand transfer and annealing rates. Quantitative single molecule DNA stretching studies and dynamic light scattering experiments reveal that these differences are due to significantly increased DNA compaction energy and higher aggregation capability of HIV-1 NC relative to the SIV protein. Using salt-titration binding assays, we find that both proteins are strikingly similar in their ability to specifically interact with HIV-1 Psi RNA. In contrast, they do not demonstrate specific binding to an RNA derived from the putative SIV packaging signal. CONCLUSIONS: Based on these studies, we conclude that (1) HIV-1 NC is a slightly more efficient NA chaperone protein than SIV NC, (2) mechanistic differences between the NA interactions of highly similar retroviral NC proteins are revealed by quantitative single molecule DNA stretching, and (3) SIV NC demonstrates cross-species recognition of the HIV-1 Psi RNA packaging signal.

Ureteral obstruction secondary to disseminated penicilliosis in a German shepherd dog.

Abdominal ultrasonographic evaluation of a 2-year-old male German shepherd dog evaluated for weight loss demonstrated a right ureteral mass with ipsilateral hydronephrosis, hypoechoic splenic nodules, and hypoechoic and rounded lymph nodes. A fungal mat extending from the renal pelvis into the ureter secondary to disseminated Penicillium was confirmed at necropsy.

Obstruction urétérale secondaire à une infection disséminée àPenicilliumchez un chien Berger allemand. L'évaluation abdominale par échographie d'un chien Berger allemand mâle âgé de 2 ans qui était évalué pour une perte de poids a révélé une masse urétrale droite avec de l'hydronéphrose ipsilatérale, des nodules spléniques hypoéchogènes et des ganglions lymphatiques arrondis et hypoéchogènes. Une masse fongique s'étendant du pelvis rénal jusqu'à l'urètre secondaire à une infection disséminée à Penicillium a été confirmée à la nécropsie.(Traduit par Isabelle Vallières).

Carbamazepine as a novel small molecule corrector of trafficking-impaired ATP-sensitive potassium channels identified in congenital hyperinsulinism.

ATP-sensitive potassium (KATP) channels consisting of sulfonylurea receptor 1 (SUR1) and the potassium channel Kir6.2 play a key role in insulin secretion by coupling metabolic signals to ß-cell membrane potential. Mutations in SUR1 and Kir6.2 that impair channel trafficking to the cell surface lead to loss of channel function and congenital hyperinsulinism. We report that carbamazepine, an anticonvulsant, corrects the trafficking defects of mutant KATP channels previously identified in congenital hyperinsulinism. Strikingly, of the 19 SUR1 mutations examined, only those located in the first transmembrane domain of SUR1 responded to the drug. We show that unlike that reported for several other protein misfolding diseases, carbamazepine did not correct KATP channel trafficking defects by activating autophagy; rather, it directly improved the biogenesis efficiency of mutant channels along the secretory pathway. In addition to its effect on channel trafficking, carbamazepine also inhibited KATP channel activity. Upon subsequent removal of carbamazepine, however, the function of rescued channels was recovered. Importantly, combination of the KATP channel opener diazoxide and carbamazepine led to enhanced mutant channel function without carbamazepine washout. The corrector effect of carbamazepine on mutant KATP channels was also demonstrated in rat and human ß-cells with an accompanying increase in channel activity. Our findings identify carbamazepine as a novel small molecule corrector that may be used to restore KATP channel expression and function in a subset of congenital hyperinsulinism patients.

A novel chemopreventive mechanism for a traditional medicine: East Indian sandalwood oil induces autophagy and cell death in proliferating keratinocytes.

One of the primary components of the East Indian sandalwood oil (EISO) is α-santalol, a molecule that has been investigated for its potential use as a chemopreventive agent in skin cancer. Although there is some evidence that α-santalol could be an effective chemopreventive agent, to date, purified EISO has not been extensively investigated even though it is widely used in cultures around the world for its health benefits as well as for its fragrance and as a cosmetic. In the current study, we show for the first time that EISO-treatment of HaCaT keratinocytes results in a blockade of cell cycle progression as well as a concentration-dependent inhibition of UV-induced AP-1 activity, two major cellular effects known to drive skin carcinogenesis. Unlike many chemopreventive agents, these effects were not mediated through an inhibition of signaling upstream of AP-1, as EISO treatment did not inhibit UV-induced Akt or MAPK activity. Low concentrations of EISO were found to induce HaCaT cell death, although not through apoptosis as annexin V and PARP cleavage were not found to increase with EISO treatment. However, plasma membrane integrity was severely compromised in EISO-treated cells, which may have led to cleavage of LC3 and the induction of autophagy. These effects were more pronounced in cells stimulated to proliferate with bovine pituitary extract and EGF prior to receiving EISO. Together, these effects suggest that EISO may exert beneficial effects upon skin, reducing the likelihood of promotion of pre-cancerous cells to actinic keratosis (AK) and skin cancer.