Phytocannabinoid-dependent mTORC1 regulation is dependent upon inositol polyphosphate multikinase activity

BACKGROUND AND PURPOSE: Cannabidiol (CBD) has been shown to differentially regulate the mechanistic target of rapamycin complex 1 (mTORC1) in preclinical models of disease, where it reduces activity in models of epilepsies and cancer and increases it in models of multiple sclerosis (MS) and psychosis. Here, we investigate the effects of phytocannabinoids on mTORC1 and define a molecular mechanism. EXPERIMENTAL APPROACH: A novel mechanism for phytocannabinoids was identified using the tractable model system, Dictyostelium discoideum. Using mouse embryonic fibroblasts, we further validate this new mechanism of action. We demonstrate clinical relevance using cells derived from healthy individuals and from people with MS (pwMS). KEY RESULTS: Both CBD and the more abundant cannabigerol (CBG) enhance mTORC1 activity in D. discoideum. We identify a mechanism for this effect involving inositol polyphosphate multikinase (IPMK), where elevated IPMK expression reverses the response to phytocannabinoids, decreasing mTORC1 activity upon treatment, providing new insight on phytocannabinoids' actions. We further validated this mechanism using mouse embryonic fibroblasts. Clinical relevance of this effect was shown in primary human peripheral blood mononuclear cells, where CBD and CBG treatment increased mTORC1 activity in cells derived from healthy individuals and decreased mTORC1 activity in cells derived from pwMS. CONCLUSION AND IMPLICATIONS: Our findings suggest that both CBD and the abundant CBG differentially regulate mTORC1 signalling through a mechanism dependent on the activity of the upstream IPMK signalling pathway, with potential relevance to the treatment of mTOR-related disorders, including MS

Influence of Microbial Biofilms on the Preservation of Primary Soft Tissue in Fossil and Extant Archosaurs

Background: Mineralized and permineralized bone is the most common form of fossilization in the vertebrate record. Preservation of gross soft tissues is extremely rare, but recent studies have suggested that primary soft tissues and biomolecules are more commonly preserved within preserved bones than had been presumed. Some of these claims have been challenged, with presentation of evidence suggesting that some of the structures are microbial artifacts, not primary soft tissues. The identification of biomolecules in fossil vertebrate extracts from a specimen of Brachylophosaurus canadensis has shown the interpretation of preserved organic remains as microbial biofilm to be highly unlikely. These discussions also propose a variety of potential mechanisms that would permit the preservation of soft-tissues in vertebrate fossils over geologic time. Methodology/Principal Findings: This study experimentally examines the role of microbial biofilms in soft-tissue preservation in vertebrate fossils by quantitatively establishing the growth and morphology of biofilms on extant archosaur bone. These results are microscopically and morphologically compared with soft-tissue extracts from vertebrate fossils from the Hell Creek Formation of southeastern Montana (Latest Maastrichtian) in order to investigate the potential role of microbial biofilms on the preservation of fossil bone and bound organic matter in a variety of taphonomic settings. Base

Nuclear resonant scattering from 193Ir as a probe of the electronic and magnetic properties of iridates

The high brilliance of modern synchrotron radiation sources facilitates experiments with high-energy x-rays across a range of disciplines, including the study of the electronic and magnetic correlations using elastic and inelastic scattering techniques. Here we report on Nuclear Resonance Scattering at the 73 keV nuclear level in 193Ir. The transitions between the hyperfine split levels show an untypically high E2/M1 multi-polarity mixing ratio combined with an increased sensitivity to certain changes in the hyperfine field direction compared to non-mixing transitions. The method opens a new way for probing local magnetic and electronic properties of correlated materials containing iridium and provides novel insights into anisotropic magnetism in iridates. In particular, unexpected out-of-plane components of magnetic hyperfine fields and non-zero electric field gradients in Sr2IrO4 have been detected and attributed to the strong spin-orbit interaction in this iridate. Due to the high, 62% natural abundance of the 193Ir isotope, no isotopic enrichment of the samples is required, qualifying the method for a broad range of applications

The convective storm initiation project

Copyright @ 2007 AMSThe Convective Storm Initiation Project (CSIP) is an international project to understand precisely where, when, and how convective clouds form and develop into showers in the mainly maritime environment of southern England. A major aim of CSIP is to compare the results of the very high resolution Met Office weather forecasting model with detailed observations of the early stages of convective clouds and to use the newly gained understanding to improve the predictions of the model. A large array of ground-based instruments plus two instrumented aircraft, from the U.K. National Centre for Atmospheric Science (NCAS) and the German Institute for Meteorology and Climate Research (IMK), Karlsruhe, were deployed in southern England, over an area centered on the meteorological radars at Chilbolton, during the summers of 2004 and 2005. In addition to a variety of ground-based remote-sensing instruments, numerous rawin-sondes were released at one- to two-hourly intervals from six closely spaced sites. The Met Office weather radar network and Meteosat satellite imagery were used to provide context for the observations made by the instruments deployed during CSIP. This article presents an overview of the CSIP field campaign and examples from CSIP of the types of convective initiation phenomena that are typical in the United Kingdom. It shows the way in which certain kinds of observational data are able to reveal these phenomena and gives an explanation of how the analyses of data from the field campaign will be used in the development of an improved very high resolution NWP model for operational use.This work is funded by the National Environment Research Council following an initial award from the HEFCE Joint Infrastructure Fund

The Effect of Intermittent Fasting on Appetite: A Systematic Review and Meta-Analysis

This is the final version. Available on open access from MDPI via the DOI in this recordData Availability Statement: Data sharing not applicablePreviously, narrative reviews have considered the effects of intermittent fasting on appetite. One suggestion is that intermittent fasting attenuates an increase in appetite that typically accompanies weight loss. Here, we conducted the first systematic review and meta-analysis to quantify the effects of intermittent fasting on appetite, when compared to a continuous energy restriction intervention. Five electronic databases and trial registers were searched in February 2021 and February 2022. Abstracts (N = 2800) were screened and 17 randomized controlled trials (RCTs), consisting of a variety of intermittent fasting regimes, met our inclusion criteria. The total number of participants allocated to interventions was 1111 and all RCTs were judged as having either some concerns or a high risk of bias (Cochrane RoB 2.0 tool). Random effects meta-analyses were conducted on change-from-baseline appetite ratings. There was no clear evidence that intermittent fasting affected hunger (WMD = -3.03; 95% CI [-8.13, 2.08]; p = 0.25; N = 13), fullness (WMD = 3.11; 95% CI [-1.46, 7.69]; p = 0.18; N = 10), desire to eat (WMD = -3.89; 95% CI [-12.62, 4.83]; p = 0.38; N = 6), or prospective food consumption (WMD = -2.82; 95% CI [-3.87, 9.03]; p = 0.43; N = 5), differently to continuous energy restriction interventions. Our results suggest that intermittent fasting does not mitigate an increase in our drive to eat that is often associated with continuous energy restriction.Medical Research Council (MRC)National Institute for Health and Care Research (NIHR

A systematic review of randomised controlled trials on the effectiveness of exercise programs on lumbo pelvic pain among postnatal women

Background: A substantial number of women tend to be affected by Lumbo Pelvic Pain (LPP) following child birth. Physical exercise is indicated as a beneficial method to relieve LPP, but individual studies appear to suggest mixed findings about its effectiveness. This systematic review aimed to synthesise evidence from randomised controlled trials on the effectiveness of exercise on LPP among postnatal women to inform policy, practice and future research. Methods: A systematic review was conducted of all randomised controlled trials published between January 1990 and July 2014, identified through a comprehensive search of following databases: PubMed, PEDro, Embase, Cinahl, Medline, SPORTDiscus, Cochrane Pregnancy and Childbirth Group’s Trials Register, and electronic libraries of authors’institutions. Randomised controlled trials were eligible for inclusion if the intervention comprised of postnatal exercise for women with LPP onset during pregnancy or within 3 months after delivery and the outcome measures included changes in LPP. Selected articles were assessed using the PEDro Scale for methodological quality and findings were synthesised narratively as meta-analysis was found to be inappropriate due to heterogeneity among included studies. Results: Four randomised controlled trials were included, involving 251 postnatal women. Three trials were rated as of ‘good’ methodological quality. All trials, except one, were at low risk of bias. The trials included physical exercise programs with varying components, differing modes of delivery, follow up times and outcome measures. Intervention in one trial, involving physical therapy with specific stabilising exercises, proved to be effective in reducing LPP intensity. An improvement in gluteal pain on the right side was reported in another trial and a significant difference in pain frequency in another. Conclusion: Our review indicates that only few randomised controlled trials have evaluated the effectiveness of exercise on LPP among postnatal women. There is also a great amount of variability across existing trials in the components of exercise programs, modes of delivery, follow up times and outcome measures. While there is some evidence to indicate the effectiveness of exercise for relieving LPP, further good quality trials are needed to ascertain the most effective elements of postnatal exercise programs suited for LPP treatment

Building Babies - Chapter 16

In contrast to birds, male mammals rarely help to raise the offspring. Of all mammals, only among rodents, carnivores, and primates, males are sometimes intensively engaged in providing infant care (Kleiman and Malcolm 1981). Male caretaking of infants has long been recognized in nonhuman primates (Itani 1959). Given that infant care behavior can have a positive effect on the infant’s development, growth, well-being, or survival, why are male mammals not more frequently involved in “building babies”? We begin the chapter defining a few relevant terms and introducing the theory and hypotheses that have historically addressed the evolution of paternal care. We then review empirical findings on male care among primate taxa, before focusing, in the final section, on our own work on paternal care in South American owl monkeys (Aotus spp.). We conclude the chapter with some suggestions for future studies.Deutsche Forschungsgemeinschaft (HU 1746/2-1) Wenner-Gren Foundation, the L.S.B. Leakey Foundation, the National Geographic Society, the National Science Foundation (BCS-0621020), the University of Pennsylvania Research Foundation, the Zoological Society of San Dieg

Hepatic Sarcoidosis Mimicking Hilar Cholangiocarcinoma: Case Report and Review of the Literature

Sarcoidosis is a multisystemic granulomatous disease of unknown etiology. Hepatic involvement was reported in about 11% of patients with sarcoidosis. However, cases of sarcoidosis in which the granuloma is solitary and limited in the liver are very rare. A 51-year-old woman with tumors in the liver underwent extended left lobectomy with caudate lobectomy and bile duct resection. The tumor was located between segment 4 and the hilar region. Some daughter nodules were found in the left lobe, which were regarded as intrahepatic metastasis. Our case displayed clinical and radiologically distinct findings, which are very similar to those of hilar cholangiocarcinoma restricted to the liver. This report demonstrates that sarcoidosis can show solitary hepatic involvement in the absence of thoracic lymphadenopathy. In such a case, it is difficult to distinguish the diagnosis from other malignant neoplasms. In conclusion, the diagnosis of hepatic sarcoidosis has to be made through prudent and comprehensive investigations that include a full clinical history of sarcoidosis in other organs. Despite utilizing several detailed diagnostic modalities, the definitive diagnosis of cases of solitary sarcoidosis may remain difficult. In these cases, surgical treatment including liver resection should be considered in order to avoid missing a suitable opportunity for treatment

Can sacrificial feeding areas protect aquatic plants from herbivore grazing? Using behavioural ecology to inform wildlife management

Effective wildlife management is needed for conservation, economic and human well-being objectives. However, traditional population control methods are frequently ineffective, unpopular with stakeholders, may affect non-target species, and can be both expensive and impractical to implement. New methods which address these issues and offer effective wildlife management are required. We used an individual-based model to predict the efficacy of a sacrificial feeding area in preventing grazing damage by mute swans (Cygnus olor) to adjacent river vegetation of high conservation and economic value. The accuracy of model predictions was assessed by a comparison with observed field data, whilst prediction robustness was evaluated using a sensitivity analysis. We used repeated simulations to evaluate how the efficacy of the sacrificial feeding area was regulated by (i) food quantity, (ii) food quality, and (iii) the functional response of the forager. Our model gave accurate predictions of aquatic plant biomass, carrying capacity, swan mortality, swan foraging effort, and river use. Our model predicted that increased sacrificial feeding area food quantity and quality would prevent the depletion of aquatic plant biomass by swans. When the functional response for vegetation in the sacrificial feeding area was increased, the food quantity and quality in the sacrificial feeding area required to protect adjacent aquatic plants were reduced. Our study demonstrates how the insights of behavioural ecology can be used to inform wildlife management. The principles that underpin our model predictions are likely to be valid across a range of different resource-consumer interactions, emphasising the generality of our approach to the evaluation of strategies for resolving wildlife management problems

Cortisol secretion after adrenocorticotrophin (ACTH) and Dexamethasone tests in healthy female and male dogs

<p>Abstract</p> <p>Background</p> <p>For the conclusive diagnosis of Cushing's Syndrome, a stimulating ACTH test or a low suppressive Dexamethasone test is used. Reports in other species than the dog indicate that plasma cortisol concentration after ACTH administration is affected by gender. We investigated the effect of gender on the cortisol response to ACTH and Dexamethasone tests in dogs.</p> <p>Methods</p> <p>Seven healthy adult Cocker Spaniels (4 females and 3 males) were assigned to a two by two factorial design: 4 dogs (2 females and 2 males) received IV Dexamethasone 0.01 mg/kg, while the other 3 dogs received an IV saline solution (control group). Two weeks later the treatments were reversed. After one month, ACTH was given IV (250 μg/animal) to 4 dogs (2 female and 2 males) while the rest was treated with saline solution (control group). Cortisol concentrations were determined by a direct solid-phase radioimmunoassay and cholesterol and triglycerides by commercial kits.</p> <p>Results and Discussion</p> <p>No effect of treatment was observed in metabolite concentrations, but females presented higher cholesterol concentrations. ACTH-treated dogs showed an increase in cortisol levels in the first hour after sampling until 3 hours post injection. Cortisol concentrations in Dexamethasone-treated dogs decreased one hour post injection and remained low for 3 hours, thereafter cortisol concentrations increased. The increase in cortisol levels from one to two hours post ACTH injection was significantly higher in females than males. In Dexamethasone-treated males cortisol levels decreased one hour post injection up to 3 hours; in females the decrease was more pronounced and prolonged, up to 5 hours post injection.</p> <p>Conclusion</p> <p>We have demonstrated that cortisol response to ACTH and Dexamethasone treatment in dogs differs according to sex.</p