All You Need Is Fats-for Seizure Control: Using Amoeba to Advance Epilepsy Research

Since the original report of seizure control through starvation in the 1920s, the ketogenic diet has been considered an energy-related therapy. The diet was assumed to be functioning through the effect of reduced carbohydrate intake regulating cellular energy state, thus giving rise to seizure control. From this assumption, the generation of ketones during starvation provided an attractive mechanism for this altered energy state; however, many years of research has sought and largely failed to correlate seizure control and ketone levels. Due to this focus on ketones, few studies have examined a role for free fatty acids, as metabolic intermediates between the triglycerides provided in the diet and ketones, in seizure control. Recent discoveries have now suggested that the medium-chain fats, delivered through the medium-chain triglyceride (MCT) ketogenic diet, may provide a key therapeutic mechanism of the diet in seizure control. Here we describe an unusual pathway leading to this discovery, beginning with the use of a tractable non-animal model—Dictyostelium, through to the demonstration that medium-chain fats play a direct role in seizure control, and finally the identification of a mechanism of action of these fats and related congeners leading to reduced neural excitability and seizure control

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

Appetite, gut hormone and energy intake responses to low volume sprint interval and traditional endurance exercise.

Sprint interval exercise improves several health markers but the appetite and energy balance response is unknown. This study compared the effects of sprint interval and endurance exercise on appetite, energy intake and gut hormone responses. Twelve healthy males [mean (SD): age 23 (3) years, body mass index 24.2 (2.9) kg m(-2), maximum oxygen uptake 46.3 (10.2) mL kg(-1) min(-1)] completed three 8 h trials [control (CON), endurance exercise (END), sprint interval exercise (SIE)] separated by 1 week. Trials commenced upon completion of a standardised breakfast. Sixty minutes of cycling at 68.1 (4.3) % of maximum oxygen uptake was performed from 1.75-2.75 h in END. Six 30-s Wingate tests were performed from 2.25-2.75 h in SIE. Appetite ratings, acylated ghrelin and peptide YY (PYY) concentrations were measured throughout each trial. Food intake was monitored from buffet meals at 3.5 and 7 h and an overnight food bag. Appetite (P 0.05). Therefore, relative energy intake (energy intake minus the net energy expenditure of exercise) was lower in END than that in CON (15.7 %; P = 0.006) and SIE (11.5 %; P = 0.082). An acute bout of endurance exercise resulted in lower appetite perceptions in the hours after exercise than sprint interval exercise and induced a greater 24 h energy deficit due to higher energy expenditure during exercise

A scalable analytical framework for spatio-temporal analysis of neighborhood change: A sequence analysis approach

© Springer Nature Switzerland AG 2020. Spatio-temporal changes reflect the complexity and evolution of demographic and socio-economic processes. Changes in the spatial distribution of population and consumer demand at urban and rural areas are expected to trigger changes in future housing and infrastructure needs. This paper presents a scalable analytical framework for understanding spatio-temporal population change, using a sequence analysis approach. This paper uses gridded cell Census data for Great Britain from 1971 to 2011 with 10-year intervals, creating neighborhood typologies for each Census year. These typologies are then used to analyze transitions of grid cells between different types of neighborhoods and define representative trajectories of neighborhood change. The results reveal seven prevalent trajectories of neighborhood change across Great Britain, identifying neighborhoods which have experienced stable, upward and downward pathways through the national socioeconomic hierarchy over the last four decades

Constructing large DNA segments by iterative clone recombination

Methods for constructing large contiguous segments of DNA will be enabling for Synthetic Biology, where the assembly of genes encoding circuits, biosynthetic pathways or even whole microbial organisms is of interest. Currently, in vitro approaches to DNA synthesis are adequate for generating DNAs that are up to 10s of kbp in length, and in vivo recombination strategies are more suitable for building DNA constructs that are 100 kbp or larger. We have developed a vector system for efficient assembly of large DNA molecules by iterative in vivo recombination of fosmid clones. Two custom fosmid vectors have been built, pFOSAMP and pFOSKAN, that support antibiotic switching. Using this technique we rebuilt two non-contiguous regions of the Haemophilus influenzae genome as episomes in recombinogenic Escherichia coli host cells. These regions together comprise190 kbp, or 10.4% of the H. influenze genome

Frameshift mutation hotspot identified in Smith-Magenis syndrome: case report and review of literature

Smith-Magenis syndrome (SMS) is a complex syndrome involving intellectual disabilities, sleep disturbance, behavioural problems, and a variety of craniofacial, skeletal, and visceral anomalies. While the majority of SMS cases harbor an ~3.5 Mb common deletion on 17p11.2 that encompasses the retinoic acid induced-1 (RAI1) gene, some patients carry small intragenic deletions or point mutations in RAI1. We present data on two cases of Smith-Magenis syndrome with mutation of RAI1. Both cases are phenotypically consistent with SMS and RAI1 mutation but also have other anomalies not previously reported in SMS, including spontaneous pneumothoraces. These cases also illustrate variability in the SMS phenotype not previously shown for RAI1 mutation cases, including hearing loss, absence of self-abusive behaviours, and mild global delays. Sequencing of RAI1 revealed mutation of the same heptameric C-tract (CCCCCCC) in exon 3 in both cases (c.3103delC one case and and c.3103insC in the other), resulting in frameshift mutations. Of the seven reported frameshift mutations occurring in poly C-tracts in RAI1, four cases (~57%) occur at this heptameric C-tract. Collectively, these results indicate that this heptameric C-tract is a preferential hotspot for single nucleotide insertion/deletions (SNindels) and therefore, should be considered a primary target for analysis in patients suspected for mutations in RAI1. We expect that as more patients are sequenced for mutations in RAI1, the incidence of frameshift mutations in this hotspot will become more evident

Monkey Steering Responses Reveal Rapid Visual-Motor Feedback

The neural mechanisms underlying primate locomotion are largely unknown. While behavioral and theoretical work has provided a number of ideas of how navigation is controlled, progress will require direct physiolgical tests of the underlying mechanisms. In turn, this will require development of appropriate animal models. We trained three monkeys to track a moving visual target in a simple virtual environment, using a joystick to control their direction. The monkeys learned to quickly and accurately turn to the target, and their steering behavior was quite stereotyped and reliable. Monkeys typically responded to abrupt steps of target direction with a biphasic steering movement, exhibiting modest but transient overshoot. Response latencies averaged approximately 300 ms, and monkeys were typically back on target after about 1 s. We also exploited the variability of responses about the mean to explore the time-course of correlation between target direction and steering response. This analysis revealed a broad peak of correlation spanning approximately 400 ms in the recent past, during which steering errors provoke a compensatory response. This suggests a continuous, visual-motor loop controls steering behavior, even during the epoch surrounding transient inputs. Many results from the human literature also suggest that steering is controlled by such a closed loop. The similarity of our results to those in humans suggests the monkey is a very good animal model for human visually guided steering

SHIELD: Neutral Gas Kinematics and Dynamics

We present kinematic analyses of the 12 galaxies in the "Survey of HI in Extremely Low-mass Dwarfs" (SHIELD). We use multi-configuration interferometric observations of the HI 21cm emission line from the Karl G. Jansky Very Large Array (VLA) to produce image cubes at a variety of spatial and spectral resolutions. Both two- and three-dimensional fitting techniques are employed in an attempt to derive inclination-corrected rotation curves for each galaxy. In most cases, the comparable magnitudes of velocity dispersion and projected rotation result in degeneracies that prohibit unambiguous circular velocity solutions. We thus make spatially resolved position-velocity cuts, corrected for inclination using the stellar components, to estimate the circular rotation velocities. We find circular velocities <30 km/s for the entire survey population. Baryonic masses are calculated using single-dish HI fluxes from Arecibo and stellar masses derived from HST and Spitzer imaging. Comparison is made with total dynamical masses estimated from the position-velocity analysis. The SHIELD galaxies are then placed on the baryonic Tully-Fisher relation. There exists an empirical threshold rotational velocity <15 km/s, below which current observations cannot differentiate coherent rotation from pressure support. The SHIELD galaxies are representative of an important population of galaxies whose properties cannot be described by current models of rotationally-dominated galaxy dynamics

SHIELD: Comparing Gas and Star Formation in Low Mass Galaxies

We analyze the relationships between atomic, neutral hydrogen (HI) and star formation (SF) in the 12 low-mass SHIELD galaxies. We compare high spectral (~0.82 km/s/channel) and spatial resolution (physical resolutions of 170 pc - 700 pc) HI imaging from the VLA with H\alpha and far-ultraviolet imaging. We quantify the degree of co-spatiality between star forming regions and regions of high HI column densities. We calculate the global star formation efficiencies (SFE, $\Sigma_{\rm SFR}$ / $\Sigma_{\rm HI}$), and examine the relationships among the SFE and HI mass, HI column density, and star formation rate (SFR). The systems are consuming their cold neutral gas on timescales of order a few Gyr. While we derive an index for the Kennicutt-Schmidt relation of N ~ 0.68 $\pm$ 0.04 for the SHIELD sample as a whole, the values of N vary considerably from system to system. By supplementing SHIELD results with those from other surveys, we find that HI mass and UV-based SFR are strongly correlated over five orders of magnitude. Identification of patterns within the SHIELD sample allows us to bin the galaxies into three general categories: 1) mainly co-spatial HI and SF regions, found in systems with highest peak HI column densities and highest total HI masses, 2) moderately correlated HI and SF regions, found in systems with moderate HI column densities, and 3) obvious offsets between HI and SF peaks, found in systems with the lowest total HI masses. SF in these galaxies is dominated by stochasticity and random fluctuations in their ISM

Presence of Helicobacter pylori in betel chewers and non betel chewers with and without oral cancers

<p>Abstract</p> <p>Background</p> <p>Betel chewing has been shown to predispose to periodontal disease and oral cancer. Studies show that people with gum disease are more likely to test positive for <it>Helicobacter pylori (H. pylori)</it>. It is not known if the lesions produced by betel quid and the resulting, chemical changes predispose to colonization by <it>H. pylori</it>. Further the role of this organism in oral cancer is not known. Our objective was to determine the presence of <it>H. pylori </it>in oral lesions of thirty oral cancer patients and to determine the presence of IgG antibodies to <it>H. pylori </it>in oral cancer patients who are betel chewers and non betel chewers, healthy betel chewers and healthy non-betel chewers and to compare the presence of <it>H</it>. <it>pylori </it>in these four groups. This case control study was conducted at the Cancer Institute Maharagama and the Department of Microbiology, Faculty of Medical Sciences, University of Sri Jayewardenepura.</p> <p>Methods</p> <p>One hundred and seventy three subjects, of whom fifty three were patients presenting with oral cancer to the Cancer Institute Maharagama, sixty healthy betel chewers and sixty healthy non-betel chewers from the Religious and Welfare Service Centre Maharagama were tested for <it>H. pylori </it>by serology. Thirty oral biopsies from oral cancer patients were cultured under microaerophilic condition to isolate <it>H. pylori</it>. The statistic used was Chi-square test.</p> <p>Results</p> <p>Of the fifty-three oral cancer patients, forty-four were betel chewers. Among the 53 oral cancer patients examined, ten of forty-four (10/44 = 22.7%) patients who are betel chewers and four of nine (4/9 = 44.4%) patients who are non-betel chewers were detected positive for IgG antibody against <it>H. pylori</it>. In the healthy group (betel chewers and non betel chewers) ten (16.7%) of the healthy betel chewers tested positive for <it>H. pylori </it>by serology. None of the healthy non-betel chewers tested positive for <it>H. pylori</it></p> <p>Fourteen [26.4%] of oral cancer patients tested positive for <it>H. pylori </it>by serology, of which two were also culture positive (Only thirty samples were cultured). The presence of <it>H. pylori </it>in betel chewers (with or without cancer) compared to non-betel chewers was statistically significant. (Chi-square test p < 0.05) The use of tobacco and areca nut in betel chewers was significant with the presence of <it>H. pylori </it>(p < 0.05).</p> <p>Conclusion</p> <p>There is a significant higher proportion of <it>H. pylori </it>in betel chewers compared to non-betel chewers but not between oral cancer patients compared to patients without oral cancer. Hence Betel chewing may predispose to colonisation with <it>H. pylori </it>in the digestive tract through swallowing the quid or during betel chewing.</p