Hypothalamic GABAergic neurons expressing Cellular Retinoic Acid Binding Protein 1 (CRABP1) are sensitive to metabolic status and liraglutide in male mice.

INTRODUCTION: Owing to their privileged anatomical location, neurons of the arcuate nucleus of the hypothalamus (ARC) play critical roles in sensing and responding to metabolic signals such as leptin and glucagon-like peptide 1 (GLP-1). In addition to the well-known proopiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons, subpopulations of GABAergic neurons are emerging as key regulators of energy balance. However, the precise identity of these metabolic neurons is still elusive. Here, we identified and characterized the molecular signature of a novel population of GABAergic neurons of the ARC expressing Cellular retinoic acid binding protein 1 (Crabp1). METHODS: Using a combination of immunohistochemistry and in situ hybridization techniques, we investigated the expression of Crabp1 across the mouse brain and characterized the molecular identity of Crabp1ARC neurons. We also determined whether Crabp1ARC neurons are sensitive to fasting, leptin and GLP1R agonism by assessing cFOS immunoreactivity as a marker of neuronal activity. RESULTS: Crabp1ARC neurons represent a novel GABAergic neuronal population robustly enriched in the ARC and distinct from the prototypical melanocortin neurons. Crabp1ARC neurons overlap with three subpopulations of yet uncharacterized ARC neurons expressing Htr3b, Tbx19 and Tmem215, respectively. Notably, Crabp1ARC neurons express receptors for metabolic hormones and their activity is modulated by the nutritional state and GLP1R agonism. CONCLUSION: Crabp1ARC neurons represent a novel heterogenous population of GABAergic neurons sensitive to metabolic status.

[Implementing vascular access protection indicators (VAPI) in dialysis: an innovation in quality of care]. / Mise en place d'indicateurs de protection des abords vasculaires (IPAV) en dialyse : une innovation dans la qualité des soins.

Between 2013 and 2021, indicators of vascular access protection (IPAV) integrating a census of haematomas and multiple punctures were set up on the active file of chronic kidney failure patients with a vascular access dialyzed in Monaco's private haemodialysis center. They could help reduce the occurrence of complications and improve the quality of care offered to patients. This article reports on the results obtained before and after the introduction of this quality approach.

The effects of the ß1-adrenergic receptor antagonist bisoprolol administration on mirabegron-stimulated human brown adipose tissue thermogenesis.

AIM: Pharmacological stimulation of human brown adipose tissue (BAT) has been hindered by ineffective activation or undesirable off-target effects. Oral administration of the maximal allowable dose of mirabegron (200 mg), a ß3-adrenergic receptor (ß3-AR) agonist, has been effective in stimulating BAT thermogenesis and whole-body energy expenditure. However, this has been accompanied by undesirable cardiovascular effects. Therefore, we hypothesized that combining mirabegron with a ß1-AR antagonist could suppress these unwanted effects and increase the stimulation of the ß3-AR and ß2-AR in BAT. METHODS: We performed a randomized crossover trial (NCT04823442) in 8 lean men. Mirabegron (200 mg) was administered orally with or without the ß1-AR antagonist bisoprolol (10 mg). Dynamic [11C]-acetate and 2-deoxy-2-[18F]fluoro-d-glucose PET/CT scans were performed sequentially after oral administration of mirabegron ± bisoprolol. RESULTS: Compared to room temperature, mirabegron alone increased BAT oxidative metabolism (0.84 ± 0.46 vs. 1.79 ± 0.91 min-1, p = 0.0433), but not when combined with bisoprolol. The metabolic rate of glucose in BAT, measured using [18F]FDG PET, was significantly higher with mirabegron than mirabegron with bisoprolol (24 ± 10 vs. 16 ± 8 nmol/g/min, p = 0.0284). Bisoprolol inhibited the mirabegron-induced increase in systolic blood pressure and heart rate. CONCLUSION: The administration of bisoprolol decreases the adverse cardiovascular effects of mirabegron. However, the provided dose also blunted the mirabegron-stimulated increase in BAT lipolysis, thermogenesis, and glucose uptake. The attenuation in BAT blood flow induced by the large dose of bisoprolol may have limited BAT thermogenesis.

The evaluation of five serological assays in determining seroconversion to peste des petits ruminants virus in typical and atypical hosts.

Peste des petits ruminants (PPR) is an infectious viral disease, primarily of small ruminants such as sheep and goats, but is also known to infect a wide range of wild and domestic Artiodactyls including African buffalo, gazelle, saiga and camels. The livestock-wildlife interface, where free-ranging animals can interact with captive flocks, is the subject of scrutiny as its role in the maintenance and spread of PPR virus (PPRV) is poorly understood. As seroconversion to PPRV indicates previous infection and/or vaccination, the availability of validated serological tools for use in both typical (sheep and goat) and atypical species is essential to support future disease surveillance and control strategies. The virus neutralisation test (VNT) and enzyme-linked immunosorbent assay (ELISA) have been validated using sera from typical host species. Still, the performance of these assays in detecting antibodies from atypical species remains unclear. We examined a large panel of sera (n = 793) from a range of species from multiple countries (sourced 2015-2022) using three tests: VNT, ID VET N-ELISA and AU-PANVAC H-ELISA. A sub-panel (n = 30) was also distributed to two laboratories and tested using the luciferase immunoprecipitation system (LIPS) and a pseudotyped virus neutralisation assay (PVNA). We demonstrate a 75.0-88.0% agreement of positive results for detecting PPRV antibodies in sera from typical species between the VNT and commercial ELISAs, however this decreased to 44.4-62.3% in sera from atypical species, with an inter-species variation. The LIPS and PVNA strongly correlate with the VNT and ELISAs for typical species but vary when testing sera from atypical species.

Electrophysiological Comparison of Definitive Pro-opiomelanocortin Neurons in the Arcuate Nucleus and the Retrochiasmatic Area of Male and Female Mice.

Pro-opiomelanocortin (POMC)-expressing neurons in the arcuate nucleus of the hypothalamus (ARC) are considered a major site of leptin action. Due to increasing evidence that POMC neurons are highly heterogeneous and indications that the conventional molecular tools to study their functions have important limitations, a reassessment of leptin's effects on definitive POMC neurons is needed. POMC neurons are also expressed in the retrochiasmatic area (RCA), where their function is poorly understood. Furthermore, the response of POMC neurons to leptin in females is largely unknown. Therefore, the present study aimed to determine the differences in leptin responsiveness of POMC neurons in the ARC and the RCA using a mouse model allowing adult-inducible fluorescent labeling. We performed whole-cell patch clamp electrophysiology on 154 POMC neurons from male and female mice. We confirmed and extended the model by which leptin depolarizes POMC neurons, in both the ARC and the RCA. Furthermore, we characterized the electrophysiological properties of an underappreciated subpopulation representing ∼10% of hypothalamic POMC neurons that are inhibited by leptin. We also provide evidence that sex does not appear to be a major determinant of basal properties and leptin responsiveness of POMC neurons, but that females are overall less responsive to leptin compared to males.

Outcomes for 15 cats with bilateral sacroiliac luxation treated with transiliosacral toggle suture repair.

OBJECTIVE: To report a surgical technique and outcomes of transiliosacral toggle suture repair to treat feline bilateral sacroiliac luxation/fracture (SILF). STUDY DESIGN: Retrospective study. ANIMALS: Fifteen client-owned cats. METHODS: The medical records of cats with bilateral SILF treated using a transiliosacral toggle suture repair were reviewed. Short- and medium-term outcomes were assessed through standard postoperative clinical evaluation and radiographs, including measurements of angle of deviation (AoD), percentage of reduction (PoR), and pelvic canal width ratio (PCWR). Long-term functional follow up was obtained from a questionnaire derived from the Feline Musculoskeletal Pain Index (FMPI). RESULTS: Fifteen cats were enrolled retrospectively, among which 13 survived to discharge. One minor wound complication, treated by secondary intention healing, was encountered. No major complication was reported. Immediately postoperatively, the mean absolute PoR values were 88.1 ± 11.2% and 91 ± 11.6% on the right and left side, respectively. The mean absolute AoD was 3.1 ± 2.8°, and the mean PCWR was 1.24 ± 0.08. The medium-term radiographic follow up at a median of 205 (71-682) days postsurgery revealed the good stability of the repair. Excellent functional outcomes were identified upon the analysis of 12 long-term questionnaires at a median of 365 (119-798) days postsurgery. CONCLUSION: Anatomic reduction was satisfactory and comparable with previously described techniques with good implant placement documented. Functional outcomes based on FMPI-derived questionnaires were good to excellent in our population. CLINICAL SIGNIFICANCE: Transiliosacral toggle suture stabilization of bilateral SILF was associated with good outcomes in cats. Further studies are required to compare biomechanical properties and outcomes between this technique and previously described transiliosacral stabilization.

Long-term outcomes after arthroscopic treatment of dogs affected by osteochondrosis dissecans of the humeral trochlea, with or without medial coronoid disease: 23 cases (2012-2020).

The objective of this study was to report long-term clinical and radiographic outcomes following arthroscopic reparative treatment - flap removal, curettage, and osteostixis of subchondral bone - in dogs with humeral trochlea osteochondritis dissecans (OCD). Dogs were included in this retrospective multicenter case series if they had a computed tomography diagnostic of humeral trochlear OCD, with or without medial coronoid disease, that was treated by arthroscopic reparative technique, and a detailed follow-up at least 6 mo postoperatively. The latter included a clinical examination, assessment of lameness, measurement of the brachial circumference and elbow amplitude, International Elbow Working Group (IEWG) radiographic score, owner-completed canine brief pain inventory (CBPI) score, and visual analogue scale (VAS) rating. A generalized linear model and tests for symmetry and marginal homogeneity were used to compare data. Twenty-three dogs (30 affected elbows) were included. Long-term (median: 22 mo; range: 6 to 98 mo) postoperative lameness, CBPI, VAS, joint distension, and pain scores were significantly improved compared with the preoperative values. Long-term postoperative range of motion and brachial circumference did not reveal any significant difference between OCD-affected and unaffected elbows. Long-term IEWG scores were similar to preoperative values in 56% of elbows and had progressed by 1 grade in 44%. Long-term complications included persistent Grade-1 lameness and occurred in 23% of dogs. Long-term outcomes based on lameness and CBPI scores were considered excellent in 67% of dogs, good in 27%, and intermediate in 6%. Arthroscopic treatment is thus a suitable surgical procedure for OCD of the humeral trochlea in dogs and provides good long-term results.

Cette étude rapporte les résultats cliniques et radiographiques à long terme après un traitement arthroscopique chez des chiens atteints d'ostéochondrite disséquante (OCD) de la trochlée humérale. Les chiens inclus ont reçu un diagnostic d'OCD de la trochlée humérale par tomographie, un traitement réparateur par arthroscopie et un suivi post-opératoire d'au moins 6 mois. Ce dernier comprenant un examen clinique et orthopédique, la mesure de la circonférence brachiale et de l'amplitude du coude, le score radiographique de l'International Elbow Working Group (IEWG), le score Canine Brief Pain Inventory (CBPI) et l'échelle visuelle analogique (EVA). Un modèle linéaire généralisé et des tests de symétrie et d'homogénéité marginale ont permis de comparer les données. Vingt-trois chiens (30 coudes affectés) ont été inclus. Les scores postopératoires à long terme (médiane, 22 mois), de boiterie, de CBPI, d'EVA, de distension articulaire et de douleur étaient significativement améliorés. L'amplitude de mouvement et la circonférence brachiale postopératoires à long terme entre les coudes affectés et non affectés n'ont pas révélé de différence significative. Les scores IEWG à long terme étaient similaires aux valeurs préopératoires dans 56 % des coudes et avaient progressé d'un grade dans 44 %. Les résultats à long terme basés sur la boiterie et les scores CBPI ont été considérés comme excellents chez 67 % des chiens, bons chez 27 % et intermédiaires chez 6 %. Le traitement arthroscopique est donc une procédure chirurgicale appropriée pour l'OCD de la trochlée humérale chez le chien et donne de bons résultats à long terme.(Traduit par les auteurs).

Foraging and mating behaviors of Hypsignathus monstrosus at the bat-human interface in a central African rainforest.

Studying wildlife space use in human-modified environments contributes to characterize wildlife-human interactions to assess potential risks of zoonotic-pathogens transmission, and to pinpoint conservation issues. In central African rainforests with human dwelling and activities, we conducted a telemetry study on a group of males of Hypsignathus monstrosus, a lek-mating fruit bat identified as a potential maintenance host for Ebola virus. During a lekking season in 2020, we investigated the foraging-habitat selection and the individual nighttime space use during both mating and foraging activities close to villages and their surrounding agricultural landscape. At night, marked individuals strongly selected agricultural lands and more generally areas near watercourses to forage, where they spent more time compared to forest ones. Furthermore, the probability and duration of the presence of bats in the lek during nighttime decreased with the distance to their roost site but remained relatively high within a 10 km radius. Individuals adjusted foraging behaviors according to mating activity by reducing both the overall time spent in foraging areas and the number of forest areas used to forage when they spent more time in the lek. Finally, the probability of a bat revisiting a foraging area in the following 48 hours increased with the previous time spent in that foraging area. These behaviors occurring close to or in human-modified habitats can trigger direct and indirect bat-human contacts, which could thus facilitate pathogen transmission such as Ebola virus.

Histaminergic regulation of food intake.

Histamine is a biogenic amine that acts as a neuromodulator within the brain. In the hypothalamus, histaminergic signaling contributes to the regulation of numerous physiological and homeostatic processes, including the regulation of energy balance. Histaminergic neurons project extensively throughout the hypothalamus and two histamine receptors (H1R, H3R) are strongly expressed in key hypothalamic nuclei known to regulate energy homeostasis, including the paraventricular (PVH), ventromedial (VMH), dorsomedial (DMH), and arcuate (ARC) nuclei. The activation of different histamine receptors is associated with differential effects on neuronal activity, mediated by their different G protein-coupling. Consequently, activation of H1R has opposing effects on food intake to that of H3R: H1R activation suppresses food intake, while H3R activation mediates an orexigenic response. The central histaminergic system has been implicated in atypical antipsychotic-induced weight gain and has been proposed as a potential therapeutic target for the treatment of obesity. It has also been demonstrated to interact with other major regulators of energy homeostasis, including the central melanocortin system and the adipose-derived hormone leptin. However, the exact mechanisms by which the histaminergic system contributes to the modification of these satiety signals remain underexplored. The present review focuses on recent advances in our understanding of the central histaminergic system's role in regulating feeding and highlights unanswered questions remaining in our knowledge of the functionality of this system.

COMPARING ANTIBIOTIC RESISTANCE IN FREE-RANGING VS. CAPTIVE AFRICAN WILD HERBIVORES.

Antimicrobial resistance (AMR) is a critical challenge of the 21st century for public and animal health. The role of host biodiversity and the environment in the evolution and transmission of resistant bacteria between populations and species, and specifically at the wildlife-livestock-human interface, needs to be further investigated. We evaluated the AMR of commensal Escherichia coli in three mammalian herbivore species-impala (Aepyceros melampus), greater kudu (Tragelaphus strepsiceros), and plains zebra (Equus quagga)-targeting populations living under two conditions: captivity (French zoos) and free ranging (natural and private parks in Zimbabwe). From 137 fecal samples from these three host species, 328 E. coli isolates were isolated. We measured the AMR of each isolate against eight antibiotics, and we assessed the presence of AMR genes and mobile genetic element class 1 integrons (int1). Isolates obtained from captive hosts had a higher probability of being resistant than those obtained from free-ranging hosts (odds ratio, 293.8; confidence interval, 10-94,000). This statistically higher proportion of AMR bacteria in zoos than in natural parks was especially observed for bacteria resistant to amoxicillin. The percentage of int1 detection was higher when isolates were obtained from captive hosts, particularly captive impalas. Ninety percent of bacterial isolates with genes involved in antibiotic resistance also had the int1 gene. The sul1, sul2, blaTEM, and stra genes were found in 14, 19, 0, and 31%, respectively, of E. coli with respective antibiotic resistance. Finally, plains zebra carried AMR significantly more often than the other species.

A critical update on the leptin-melanocortin system.

The discovery of leptin in 1994 was an "eureka moment" in the field of neurometabolism that provided new opportunities to better understand the central control of energy balance and glucose metabolism. Rapidly, a prevalent model in the field emerged that pro-opiomelanocortin (POMC) neurons were key in promoting leptin's anorexigenic effects and that the arcuate nucleus of the hypothalamus (ARC) was a key region for the regulation of energy homeostasis. While this model inspired many important discoveries, a growing body of literature indicates that this model is now outdated. In this review, we re-evaluate the hypothalamic leptin-melanocortin model in light of recent advances that directly tackle previous assumptions, with a particular focus on the ARC. We discuss how segregated and heterogeneous these neurons are, and examine how the development of modern approaches allowing spatiotemporal, intersectional, and chemogenetic manipulations of melanocortin neurons has allowed a better definition of the complexity of the leptin-melanocortin system. We review the importance of leptin in regulating glucose homeostasis, but not food intake, through direct actions on ARC POMC neurons. We further highlight how non-POMC, GABAergic neurons mediate leptin's direct effects on energy balance and influence POMC neurons.

Photoperiodic Remodeling of Adiposity and Energy Metabolism in Non-Human Mammals.

Energy homeostasis and metabolism in mammals are strongly influenced by seasonal changes. Variations in photoperiod patterns drive adaptations in body weight and adiposity, reflecting changes in the regulation of food intake and energy expenditure. Humans also show distinct patterns of energy balance depending on the season, being more susceptible to gaining weight during a specific time of the year. Changes in body weight are mainly reflected by the adipose tissue, which is a key metabolic tissue and is highly affected by circannual rhythms. Mostly, in summer-like (long-active) photoperiod, adipocytes adopt a rather anabolic profile, more predisposed to store energy, while food intake increases and energy expenditure is reduced. These metabolic adaptations involve molecular modifications, some of which have been studied during the last years and are summarized in this review. In addition, there is a bidirectional relation between obesity and the seasonal responses, with obesity disrupting some of the seasonal responses observed in healthy mammals, and altered seasonality being highly associated with increased risk of developing obesity. This suggests that changes in photoperiod produce important metabolic alterations in healthy organisms. Biological rhythms impact the regulation of metabolism to different extents, some of which are already known, but further research is needed to fully understand the relationship between energy balance and seasonality.

DEPTOR loss impairs brown adipocyte development in vitro but has limited impacts in mice.

OBJECTIVES: The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth and metabolism. In mice, activation of mTOR controls cold adaptation by promoting the recruitment and the activation of brown adipose tissue (BAT). DEP-domain containing mTOR-interacting protein (DEPTOR) interacts with mTOR to modulate its activity. Whether DEPTOR levels are modulated by cold in BAT and whether this protein regulates brown adipocyte development and thermogenic activation has never been tested. METHODS: DEPTOR levels were measured in mouse tissues upon cold exposure and in brown preadipocytes following the induction of adipogenesis. Lentiviruses expressing short-hairpin RNA were used to repress DEPTOR expression in brown preadipocytes in vitro. Conditional deletion of DEPTOR in brown preadipocytes and in mature brown fat cells was achieved by crossing DEPTOR floxed mice with either Myf5-Cre or Ucp1-CreERT2 mice. These animals were exposed to cold and extensively phenotyped. RESULTS: DEPTOR is highly expressed in BAT and its levels are induced by chronic cold exposure, a condition that triggers BAT expansion and activation. Supporting a role for DEPTOR in brown fat cell recruitment, we found that DEPTOR is induced during brown adipocyte development and that its depletion impairs adipogenesis in vitro. This adipogenic lesion was associated with defects in both Akt activation and the expression of key adipogenic regulators. Conditional deletion of DEPTOR in brown preadipocytes or mature brown fat cells did not impact BAT recruitment and thermogenesis in mice but slightly reduced the expression of adipogenic and lipogenic genes. CONCLUSIONS: DEPTOR is highly expressed in BAT and its levels are dynamically regulated during brown fat cell development and upon cold exposure. Although DEPTOR depletion severely represses brown fat adipogenesis in vitro, its deletion is dispensable for BAT development, recruitment, and thermogenic activation in mice.

The sympathetic nervous system in the 21st century: Neuroimmune interactions in metabolic homeostasis and obesity.

The sympathetic nervous system maintains metabolic homeostasis by orchestrating the activity of organs such as the pancreas, liver, and white and brown adipose tissues. From the first renderings by Thomas Willis to contemporary techniques for visualization, tracing, and functional probing of axonal arborizations within organs, our understanding of the sympathetic nervous system has started to grow beyond classical models. In the present review, we outline the evolution of these findings and provide updated neuroanatomical maps of sympathetic innervation. We offer an autonomic framework for the neuroendocrine loop of leptin action, and we discuss the role of immune cells in regulating sympathetic terminals and metabolism. We highlight potential anti-obesity therapeutic approaches that emerge from the modern appreciation of SNS as a neural network vis a vis the historical fear of sympathomimetic pharmacology, while shifting focus from post- to pre-synaptic targeting. Finally, we critically appraise the field and where it needs to go.

Do POMC neurons have a sweet tooth for leptin? Special issue: Role of nutrients in nervous control of energy balance.

Coordinated detection of changes in metabolic state by the nervous system is fundamental for survival. Hypothalamic pro-opiomelanocortin (POMC) neurons play a critical role in integrating metabolic signals, including leptin levels. They also coordinate adaptative responses and thus represent an important relay in the regulation of energy balance. Despite a plethora of work documenting the effects of individual hormones, nutrients, and neuropeptides on POMC neurons, the importance for crosstalk and additive effects between such signaling molecules is still underexplored. The ability of the metabolic state and the concentrations of nutrients, such as glucose, to influence leptin's effects on POMC neurons appears critical for understanding the function and complexity of this regulatory network. Here, we summarize the current knowledge on the effects of leptin on POMC neuron electrical excitability and discuss factors potentially contributing to variability in these effects, with a particular focus on the mouse models that have been developed and the importance of extracellular glucose levels. This review highlights the importance of the metabolic "environment" for determining hypothalamic neuronal responsiveness to metabolic cues and for determining the fundamental effects of leptin on the activity of hypothalamic POMC neurons.

The Optimal Sample Size for Usability Testing, From the Manufacturer's Perspective: A Value-of-Information Approach.

OBJECTIVES: For medical devices, a usability assessment is mandatory for market access; the objective is to detect potentially harmful use errors that stem from the device's design. The manufacturer assesses the final version of the device and determines the risk-benefit ratio for remaining errors. Nevertheless, the decision rule currently used to determine the sample size for this testing has statistical limitations and the lack of a clear decision-making perspective. METHODS: As an alternative, we developed a value-of-information analysis from the medical device manufacturer's perspective. The consequences of use errors not detected during usability testing and the errors' probability of occurrence were embedded in a loss function. The value of further testing was assessed as a reduction in the expected loss for the manufacturer. The optimal sample size was determined using the expected net benefit of sampling (ENBS) (the difference between the value provided by new participants and the cost of their inclusion). RESULTS: The value-of-information approach was applied to a real usability test of a needle-free adrenaline autoinjector. The initial estimate (performed on the first n = 20 participants) gave an optimal sample size of 100 participants and an ENBS of €255 453. This estimation was updated iteratively as new participants were included. After the inclusion of 90 participants, the ENBS was null for any sample size; hence, the cost of adding more participants outweighed the expected value of information, and therefore, the study could be stopped. CONCLUSIONS: On the basis of these results, our method seems to be highly suitable for sample size estimation in the usability testing of medical devices before market access.

Detection and genetic diversity of Mopeia virus in Mastomys natalensis from different habitats in the Limpopo National Park, Mozambique.

Mammarenaviruses have been a growing concern for public health in Africa since the 1970s when Lassa virus cases in humans were first described in west Africa. In southern Africa, a single outbreak of Lujo virus was reported to date in South Africa in 2008 with a case fatality rate of 80%. The natural reservoir of Lassa virus is Mastomys natalensis while for the Lujo virus the natural host has yet to be identified. Mopeia virus was described for the first time in M. natalensis in the central Mozambique in 1977 but few studies have been conducted in the region. In this study, rodents were trapped between March and November 2019in villages, croplands fields and mopane woodland forest. The aim was to assess the potential circulation and to evaluate the genetic diversity of mammarenaviruses in M. natalensis trapped in the Limpopo National Park and its buffer zone in Massingir district, Mozambique. A total of 534 M. natalensis were screened by RT-PCR and the overall proportion of positive individuals was 16.9%. No significant differences were detected between the sampled habitats (χ2 = 0.018; DF = 1; p = 0.893). The Mopeia virus (bootstrap value 91%) was the Mammarenavirus circulating in the study area sites, forming a specific sub-clade with eight different sub-clusters. We concluded that Mopeia virus circulates in all habitats investigated and it forms a different sub-clade to the one reported in central Mozambique in 1977.

Pathophysiological Mechanisms That Alter the Autonomic Brain-Liver Communication in Metabolic Diseases.

The brain influences liver metabolism through many neuroendocrine and autonomic mechanisms that have evolved to protect the organism against starvation and hypoglycemia. Unfortunately, this effective way of preventing death has become dysregulated in modern obesogenic environments, although the pathophysiological mechanisms behind metabolic dyshomeostasis are still unclear. In this Mini-Review, we provide our thoughts regarding obesity and type 2 diabetes as diseases of the autonomic nervous system. We discuss the pathophysiological mechanisms that alter the autonomic brain-liver communication in these diseases, and how they could represent important targets to prevent or treat metabolic dysfunctions. We discuss how sympathetic hyperactivity to the liver may represent an early event in the progression of metabolic diseases and could progressively lead to hepatic neuropathy. We hope that this discussion will inspire and help to frame a model based on better understanding of the chronology of autonomic dysfunctions in the liver, enabling the application of the right strategy at the right time.

Mapping of Ebola virus spillover: Suitability and seasonal variability at the landscape scale.

The unexpected Ebola virus outbreak in West Africa in 2014 involving the Zaire ebolavirus made clear that other regions outside Central Africa, its previously documented niche, were at risk of future epidemics. The complex transmission cycle and a lack of epidemiological data make mapping areas at risk of the disease challenging. We used a Geographic Information System-based multicriteria evaluation (GIS-MCE), a knowledge-based approach, to identify areas suitable for Ebola virus spillover to humans in regions of Guinea, Congo and Gabon where Ebola viruses already emerged. We identified environmental, climatic and anthropogenic risk factors and potential hosts from a literature review. Geographical data layers, representing risk factors, were combined to produce suitability maps of Ebola virus spillover at the landscape scale. Our maps show high spatial and temporal variability in the suitability for Ebola virus spillover at a fine regional scale. Reported spillover events fell in areas of intermediate to high suitability in our maps, and a sensitivity analysis showed that the maps produced were robust. There are still important gaps in our knowledge about what factors are associated with the risk of Ebola virus spillover. As more information becomes available, maps produced using the GIS-MCE approach can be easily updated to improve surveillance and the prevention of future outbreaks.

Dual Glycolate Oxidase/Lactate Dehydrogenase A Inhibitors for Primary Hyperoxaluria.

Both glycolate oxidase (GO) and lactate dehydrogenase A (LDHA) influence the endogenous synthesis of oxalate and are clinically validated targets for treatment of primary hyperoxaluria (PH). We investigated whether dual inhibition of GO and LDHA may provide advantage over single agents in treating PH. Utilizing a structure-based drug design (SBDD) approach, we developed a series of novel, potent, dual GO/LDHA inhibitors. X-ray crystal structures of compound 15 bound to individual GO and LDHA proteins validated our SBDD strategy. Dual inhibitor 7 demonstrated an IC50 of 88 nM for oxalate reduction in an Agxt-knockdown mouse hepatocyte assay. Limited by poor liver exposure, this series of dual inhibitors failed to demonstrate significant PD modulation in an in vivo mouse model. This work highlights the challenges in optimizing in vivo liver exposures for diacid containing compounds and limited benefit seen with dual GO/LDHA inhibitors over single agents alone in an in vitro setting.