Pharmacological and genetic activation of cAMP synthesis disrupts cholesterol utilization in Mycobacterium tuberculosis

There is a growing appreciation for the idea that bacterial utilization of host-derived lipids, including cholesterol, supports Mycobacterium tuberculosis (Mtb) pathogenesis. This has generated interest in identifying novel antibiotics that can disrupt cholesterol utilization by Mtb in vivo. Here we identify a novel small molecule agonist (V-59) of the Mtb adenylyl cyclase Rv1625c, which stimulates 3’, 5’-cyclic adenosine monophosphate (cAMP) synthesis and inhibits cholesterol utilization by Mtb. Similarly, using a complementary genetic approach that induces bacterial cAMP synthesis independent of Rv1625c, we demonstrate that inducing cAMP synthesis is sufficient to inhibit cholesterol utilization in Mtb. Although the physiological roles of individual adenylyl cyclase enzymes in Mtb are largely unknown, here we demonstrate that the transmembrane region of Rv1625c is required during cholesterol metabolism. Finally, the pharmacokinetic properties of Rv1625c agonists have been optimized, producing an orally-available Rv1625c agonist that impairs Mtb pathogenesis in infected mice. Collectively, this work demonstrates a role for Rv1625c and cAMP signaling in controlling cholesterol metabolism in Mtb and establishes that cAMP signaling can be pharmacologically manipulated for the development of new antibiotic strategies.     

Seroepidemiology of Crimean-Congo Haemorrhagic Fever among cattle in Cameroon: Implications from a One Health perspective

BackgroundCrimean-Congo Haemorrhagic Fever (CCHF) is a tick-borne viral zoonotic disease distributed across several continents and recognized as an ongoing health threat. In humans, the infection can progress to a severe disease with high fatality, raising public health concerns due to the limited prophylactic and therapeutic options available. Animal species, clinically unaffected by the virus, serve as viral reservoirs and amplifier hosts, and can be a valuable tool for surveillance. Little is known about the occurrence and prevalence of Crimean-Congo Haemorrhagic Fever Virus (CCHFV) in Cameroon. Knowledge on CCHFV exposure and the factors associated with its presence in sentinel species are a valuable resource to better understand transmission dynamics and assess local risks for zoonotic disease emergence.Methods and findingsWe conducted a CCHFV serological survey and risk factor analysis for animal level seropositivity in pastoral and dairy cattle in the North West Region (NWR) and the Vina Division (VD) of the Adamawa Region in Cameroon. Seroprevalence estimates were adjusted for sampling design-effects and test performance. In addition, explanatory multivariable logistic regression mixed-effects models were fit to estimate the effect of animal characteristics, husbandry practices, risk contacts and ecological features on the serological status of pastoral cattle. The overall seroprevalence was 56.0% (95% CI 53.5–58.6) and 6.7% (95% CI 2.6–16.1) among pastoral and dairy cattle, respectively. Animals going on transhumance had twice the odds of being seropositive (OR 2.0, 95% CI 1.1–3.8), indicating that animal movements could be implicated in disease expansion. From an ecological perspective, absolute humidity (OR 0.6, 95% CI 0.4–0.9) and shrub density (OR 2.1, 95% CI 1.4–3.2) were associated with seropositivity, which suggests an underlying viral dynamic connecting vertebrate host and ticks in a complex transmission network.ConclusionsThis study demonstrated high seroprevalence levels of CCHFV antibodies in cattle in Cameroon indicating a potential risk to human populations. However, current understanding of the underlying dynamics of CCHFV locally and the real risk for human populations is incomplete. Further studies designed using a One Health approach are required to improve local knowledge of the disease, host interactions and environmental risk factors. This information is crucial to better project the risks for human populations located in CCHFV-suitable ecological niches.     

Linear and nonlinear relationships between neuronal activity, oxygen metabolism, and hemodynamic responses

We investigated the relationship between neuronal activity, oxygen metabolism, and hemodynamic responses in rat somatosensory cortex with simultaneous optical intrinsic signal imaging and spectroscopy, laser Doppler flowmetry, and local field potential recordings. Changes in cerebral oxygen consumption increased linearly with synaptic activity but with a threshold effect consistent with the existence of a tissue oxygen buffer. Modeling analysis demonstrated that the coupling between neuronal activity and hemodynamic response magnitude may appear linear over a narrow range but incorporates nonlinear effects that are better described by a threshold or power law relationship. These results indicate that caution is required in the interpretation of perfusion-based indicators of brain activity, such as functional magnetic resonance imaging (fMRI), and may help to refine quantitative models of neurovascular coupling.     

Phytochemical intake and relationship to past health history in Japanese women

We calculated functional food factor (FFF) intakes using a new database and examined their relationship to health conditions commonly affecting Japanese women in midlife. One-day DRs were collected weekly for 6 months from 67 Japanese women, aged 45-55 yr, living in Kyoto prefecture, Japan. Macro- and micronutrient and FFF intake were calculated from the resulting 1528 DRs. Factor analysis and logistic regression were performed to identify relationships between FFFs and past health history. Fourteen of 17 FFF factors, as well as age, BMI and menopausal status, exhibited both positive and negative correlations with past history of hypertension, diabetes, allergy, migraine, and menopausal syndrome.     

"Culture shock" from the bone cell's perspective: emulating physiological conditions for mechanobiological investigations

Bone physiology can be examined on multiple length scales. Results of cell-level studies, typically carried out in vitro, are often extrapolated to attempt to understand tissue and organ physiology. Results of organ- or organism-level studies are often analyzed to deduce the state(s) of the cells within the larger system(s). Although phenomena on all of these scales—cell, tissue, organ, system, organism—are interlinked and contribute to the overall health and function of bone tissue, it is difficult to relate research among these scales. For example, groups of cells in an exogenous, in vitro environment that is well defined by the researcher would not be expected to function similarly to those in a dynamic, endogenous environment, dictated by systemic as well as organismal physiology. This review of the literature on bone cell culture describes potential causes and components of cell "culture shock," i.e., behavioral variations associated with the transition from in vivo to in vitro environment, focusing on investigations of mechanotransduction and experimental approaches to mimic aspects of bone tissue on a macroscopic scale. The state of the art is reviewed, and new paradigms are suggested to begin bridging the gap between two-dimensional cell cultures in petri dishes and the three-dimensional environment of living bone tissue. osteoblast; osteocyte; tissue engineering; mechanobiology; mechanochemical transduction; fluid flow