CARMA1 is a novel regulator of T-ALL disease and leukemic cell migration to the CNS

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Effect of parasympathetic stimulation on brain activity during appraisal of fearful expressions

Autonomic nervous system activity is an important component of human emotion. Mental processes influence bodily physiology, which in turn feeds back to influence thoughts and feelings. Afferent cardiovascular signals from arterial baroreceptors in the carotid sinuses are processed within the brain and contribute to this two-way communication with the body. These carotid baroreceptors can be stimulated non-invasively by externally applying focal negative pressure bilaterally to the neck. In an experiment combining functional neuroimaging (fMRI) with carotid stimulation in healthy participants, we tested the hypothesis that manipulating afferent cardiovascular signals alters the central processing of emotional information (fearful and neutral facial expressions). Carotid stimulation, compared with sham stimulation, broadly attenuated activity across cortical and brainstem regions. Modulation of emotional processing was apparent as a significant expression-by-stimulation interaction within left amygdala, where responses during appraisal of fearful faces were selectively reduced by carotid stimulation. Moreover, activity reductions within insula, amygdala, and hippocampus correlated with the degree of stimulation-evoked change in the explicit emotional ratings of fearful faces. Across participants, individual differences in autonomic state (heart rate variability, a proxy measure of autonomic balance toward parasympathetic activity) predicted the extent to which carotid stimulation influenced neural (amygdala) responses during appraisal and subjective rating of fearful faces. Together our results provide mechanistic insight into the visceral component of emotion by identifying the neural substrates mediating cardiovascular influences on the processing of fear signals, potentially implicating central baroreflex mechanisms for anxiolytic treatment targets

Changes in agonist neural drive, hypertrophy and pre-training strength all contribute to the individual strength gains after resistance training.

PURPOSE: Whilst neural and morphological adaptations following resistance training (RT) have been investigated extensively at a group level, relatively little is known about the contribution of specific physiological mechanisms, or pre-training strength, to the individual changes in strength following training. This study investigated the contribution of multiple underpinning neural [agonist EMG (QEMGMVT), antagonist EMG (HEMGANTAG)] and morphological variables [total quadriceps volume (QUADSVOL), and muscle fascicle pennation angle (QUADSθ p)], as well as pre-training strength, to the individual changes in strength after 12 weeks of knee extensor RT. METHODS: Twenty-eight healthy young men completed 12 weeks of isometric knee extensor RT (3/week). Isometric maximum voluntary torque (MVT) was assessed pre- and post-RT, as were simultaneous neural drive to the agonist (QEMGMVT) and antagonist (HEMGANTAG). In addition QUADSVOL was determined with MRI and QUADSθ p with B-mode ultrasound. RESULTS: Percentage changes (∆) in MVT were correlated to ∆QEMGMVT (r = 0.576, P = 0.001), ∆QUADSVOL (r = 0.461, P = 0.014), and pre-training MVT (r = -0.429, P = 0.023), but not ∆HEMGANTAG (r = 0.298, P = 0.123) or ∆QUADSθ p (r = -0.207, P = 0.291). Multiple regression analysis revealed 59.9% of the total variance in ∆MVT after RT to be explained by ∆QEMGMVT (30.6%), ∆QUADSVOL (18.7%), and pre-training MVT (10.6%). CONCLUSIONS: Changes in agonist neural drive, quadriceps muscle volume and pre-training strength combined to explain the majority of the variance in strength changes after knee extensor RT (~60%) and adaptations in agonist neural drive were the most important single predictor during this short-term intervention

A hierarchical kinetic theory of birth, death, and fission in age-structured interacting populations

We study mathematical models describing the evolution of stochastic age-structured populations. After reviewing existing approaches, we develop a complete kinetic framework for age-structured interacting populations undergoing birth, death and fission processes in spatially dependent environments. We define the full probability density for the population-size age chart and find results under specific conditions. Connections with more classical models are also explicitly derived. In particular, we show that factorial moments for non-interacting processes are described by a natural generalization of the McKendrick-von Foerster equation, which describes mean-field deterministic behavior. Our approach utilizes mixed-type, multidimensional probability distributions similar to those employed in the study of gas kinetics and with terms that satisfy BBGKY-like equation hierarchies

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse

Cardiovascular and renal outcomes with canagliflozin in patients with peripheral arterial disease: Data from the CANVAS Program and CREDENCE trial

Aim: To define the proportional and absolute benefits of the sodium-glucose co-transporter-2 inhibitor canagliflozin in patients with type 2 diabetes (T2D) with and without peripheral arterial disease (PAD). Materials and Methods: We pooled individual participant data from the CANVAS Program (n = 10 142) and CREDENCE trial (n = 4401). In this post hoc analysis, the main outcomes of interest were major adverse cardiovascular events (MACE: non-fatal myocardial infarction, non-fatal stroke or cardiovascular death), kidney outcomes, and extended major adverse limb events (MALE). Cox proportional hazards models were used to assess canagliflozin treatment effects in those with and without PAD. Absolute risk reductions per 1000 patients treated for 2.5 years were estimated using Poisson regression. Results: Of 14 543 participants, 3159 (21.7%) had PAD at baseline. In patients with PAD, canagliflozin reduced MACE (hazard ratio, 0.76; 95% confidence interval, 0.62-0.92), with similar relative benefits for other cardiovascular and kidney outcomes in participants with or without PAD at baseline (all Pinteraction >.268). There was no increase in the relative risk of extended MALE with canagliflozin, irrespective of baseline PAD history (Pinteraction >.864). The absolute benefits of canagliflozin were greater in those with PAD. Conclusions: Patients with T2D and PAD derived similar relative cardiorenal benefits from canagliflozin treatment but higher absolute benefits compared with those without PAD, with no increase in extended MALE

Verbal thinking and inner speech use in autism spectrum disorder

The extent to which cognition is verbally mediated in neurotypical individuals is the subject of debate in cognitive neuropsychology, as well as philosophy and psychology. Studying “verbal thinking” in developmental/neuropsychological disorders provides a valuable opportunity to inform theory building, as well as clinical practice. In this paper, we provide a comprehensive, critical review of such studies among individuals with autism spectrum disorder (ASD). ASD involves severe social-communication deficits and limitations in cognitive/behavioural flexibility. The prevailing view in the field is that neither cognition nor behaviour is mediated verbally in ASD, and that this contributes to diagnostic features. However, our review suggests that, on the contrary, most studies to date actually find that among people with ASD cognitive task performance is either a) mediated verbally in a typical fashion, or b) not mediated verbally, but at no obvious cost to overall task performance. Overall though, these studies have methodological limitations and thus clear-cut conclusions are not possible at this stage. The aim of the review is to take stock of existing empirical findings, as well as to help develop the directions for future research that will resolve the many outstanding issues in this field

Gene family expansions and contractions are associated with host range in plant pathogens of the genus Colletotrichum

Background: Many species belonging to the genus Colletotrichum cause anthracnose disease on a wide range of plant species. In addition to their economic impact, the genus Colletotrichum is a useful model for the study of the evolution of host specificity, speciation and reproductive behaviors. Genome projects of Colletotrichum species have already opened a new era for studying the evolution of pathogenesis in fungi. Results: We sequenced and annotated the genomes of four strains in the Colletotrichum acutatum species complex (CAsc), a clade of broad host range pathogens within the genus. The four CAsc proteomes and secretomes along with those representing an additional 13 species (six Colletotrichum spp. and seven other Sordariomycetes) were classified into protein families using a variety of tools. Hierarchical clustering of gene family and functional domain assignments, and phylogenetic analyses revealed lineage specific losses of carbohydrate-active enzymes (CAZymes) and proteases encoding genes in Colletotrichum species that have narrow host range as well as duplications of these families in the CAsc. We also found a lineage specific expansion of necrosis and ethylene-inducing peptide 1 (Nep1)-like protein (NLPs) families within the CAsc. Conclusions: This study illustrates the plasticity of Colletotrichum genomes, and shows that major changes in host range are associated with relatively recent changes in gene content

Genome-Wide Identification of R2R3-MYB Genes and Expression Analyses During Abiotic Stress in

The R2R3-MYB is one of the largest families of transcription factors, which have been implicated in multiple biological processes. There is great diversity in the number of R2R3-MYB genes in different plants. However, there is no report on genome-wide characterization of this gene family in cotton. In the present study, a total of 205 putative R2R3-MYB genes were identified in cotton D genome (Gossypium raimondii), that are much larger than that found in other cash crops with fully sequenced genomes. These GrMYBs were classified into 13 groups with the R2R3-MYB genes from Arabidopsis and rice. The amino acid motifs and phylogenetic tree were predicted and analyzed. The sequences of GrMYBs were distributed across 13 chromosomes at various densities. The results showed that the expansion of the G. Raimondii R2R3-MYB family was mainly attributable to whole genome duplication and segmental duplication. Moreover, the expression pattern of 52 selected GrMYBs and 46 GaMYBs were tested in roots and leaves under different abiotic stress conditions. The results revealed that the MYB genes in cotton were differentially expressed under salt and drought stress treatment. Our results will be useful for determining the precise role of the MYB genes during stress responses with crop improvement

Effects of canagliflozin on hyperkalaemia and serum potassium in people with diabetes and chronic kidney disease: insights from the CREDENCE trial

Hyperkalaemia is a common complication of type 2 diabetes mellitus (T2DM) and limits the optimal use of agents that block the renin-angiotensin aldosterone system (RAAS), particularly in patients with chronic kidney disease (CKD). In patients with CKD, sodium glucose cotransporter 2 (SGLT2) inhibitors provide cardiorenal protection, but whether they affect the risk of hyperkalaemia remains uncertain. We sought to assess the effect of canagliflozin on hyperkalaemia and other potassium-related outcomes in people with T2DM and CKD by conducting a post-hoc analysis of the CREDENCE trial. The CREDENCE trial randomized 4401 participants with T2DM and CKD to the SGLT2 inhibitor canagliflozin or matching placebo. In this post-hoc analysis using an intention-to-treat approach, we assessed the effect of canagliflozin on a composite outcome of time to either investigator-reported hyperkalaemia or the initiation of potassium binders. We also analysed effects on central laboratory-determined hyper- and hypokalaemia (serum potassium ≥6.0 and <3.5 mmol/L, respectively) and change in serum potassium. At baseline the mean serum potassium in canagliflozin and placebo arms was 4.5 mmol/L; 4395 (99.9%) participants were receiving renin angiotensin system blockade. Canagliflozin reduced the risk of investigator-reported hyperkalaemia or initiation of potassium binders (HR 0.78, 95% CI 0.64–0.95, p=0.014; Figure 1). The incidence of laboratory-determined hyperkalaemia was similarly reduced (HR 0.77, 95% CI 0.61–0.98, p=0.031; Figure 2); the risk of hypokalaemia (HR 0.92, 95% CI 0.71–1.20, p=0.53) was not increased. Mean serum potassium over time with canagliflozin was similar to that of placebo. Among patients treated with RAAS inhibitors, SGLT2 inhibition with canagliflozin may reduce the risk of hyperkalaemia in people with T2DM and CKD without increasing the risk of hypokalaemia