Enhanced c-Fos expression in the central amygdala correlates with increased thigmotaxis in rats with peripheral nerve injury

Pain is associated with affective, cognitive and sensory dysfunction. Animal models can be used to observe ethologically relevant behaviours such as thigmotaxis, giving insight into how ongoing sensory abnormalities influence natural rodent behaviours. The amygdala is a complex group of nuclei implicated in the integration and generation of emotional behavioural responses, including those associated with pain, and a region known as the central amygdala is particularly associated with generation of behavioural responses, due to its links to the descending pain modulation pathways; as such, study of amygdalar c-Fos immunoreactivity can help identify the neuronal circuits involved.This study investigated changes in both nociceptive evoked responses and open field behaviour following spinal nerve transection (SNT) in male Wistar rats, and attempted to correlate these with changes in central amygdala c-Fos immunoreactivity.Fourteen days after SNT, mechanical hypersensitivity was present in the hind paw ipsilateral to site of injury. Thigmotactic behaviour was significantly increased in both SNT and sham surgery animals, with c-Fos immunoreactivity in the central amygdala significantly greater in SNT animals compared to both sham and naive groups. Activation was greatest in the capsular and lateral subnuclei of the central amygdala, and in the caudal-most regions. There was a strong correlation between thigmotactic behaviour and central amygdala activation following SNT surgery not seen in sham animals suggesting a role for the amygdala in behavioural responses to peripheral nerve injury.This study provides evidence to support the role of the amygdala in thigmotactic open field behaviour following SNT. WHAT DOES THIS STUDY ADD?: Thigmotaxis and amygdala activation are positively correlated in rats following spinal nerve transection. Behavioural changes seen in sham animals did not correlate with amygdala activation, suggesting amygdala activation is related to nociceptive input. Evoked measures, such as hindpaw withdrawal, are not correlated with either thigmotaxis or amygdala activation, emphasizing the importance of complex behaviours when studying pain

IKKα negatively regulates ASC-dependent inflammasome activation.

The inflammasomes are multiprotein complexes that activate caspase-1 in response to infections and stress, resulting in the secretion of pro-inflammatory cytokines. Here we report that IκB kinase α (IKKα) is a critical negative regulator of apoptosis-associated specklike protein containing a C-terminal caspase-activation-andrecruitment (CARD) domain (ASC)-dependent inflammasomes. IKKα controls the inflammasome at the level of the adaptor ASC, which interacts with IKKα in the nucleus of resting macrophages in an IKKα kinase-dependent manner. Loss of IKKα kinase activity results in inflammasome hyperactivation. Mechanistically, the downstream nuclear effector IKK-related kinase (IKKi) facilitates translocation of ASC from the nucleus to the perinuclear area during inflammasome activation. ASC remains under the control of IKKα in the perinuclear area following translocation of the ASC/IKKα complex. Signal 2 of NLRP3 activation leads to inhibition of IKKα kinase activity through the recruitment of PP2A, allowing ASC to participate in NLRP3 inflammasome assembly. Taken together, these findings reveal a IKKi-IKKα-ASC axis that serves as a common regulatory mechanism for ASC-dependent inflammasomes

Exosomes from Human Adipose Tissue-Derived Mesenchymal Stem Cells Promote Epidermal Barrier Repair by Inducing de Novo Synthesis of Ceramides in Atopic Dermatitis.

Atopic dermatitis (AD) is a multifactorial, heterogeneous disease associated with epidermal barrier disruption and intense systemic inflammation. Previously, we showed that exosomes derived from human adipose tissue-derived mesenchymal stem cells (ASC-exosomes) attenuate AD-like symptoms by reducing multiple inflammatory cytokine levels. Here, we investigated ASC-exosomes' effects on skin barrier restoration by analyzing protein and lipid contents. We found that subcutaneous injection of ASC-exosomes in an oxazolone-induced dermatitis model remarkably reduced trans-epidermal water loss, while enhancing stratum corneum (SC) hydration and markedly decreasing the levels of inflammatory cytokines such as IL-4, IL-5, IL-13, TNF-α, IFN-γ, IL-17, and TSLP, all in a dose-dependent manner. Interestingly, ASC-exosomes induced the production of ceramides and dihydroceramides. Electron microscopic analysis revealed enhanced epidermal lamellar bodies and formation of lamellar layer at the interface of the SC and stratum granulosum with ASC-exosomes treatment. Deep RNA sequencing analysis of skin lesions demonstrated that ASC-exosomes restores the expression of genes involved in skin barrier, lipid metabolism, cell cycle, and inflammatory response in the diseased area. Collectively, our results suggest that ASC-exosomes effectively restore epidermal barrier functions in AD by facilitating the de novo synthesis of ceramides, resulting in a promising cell-free therapeutic option for treating AD

Why Are Autism Spectrum Conditions More Prevalent in Males?

Autism Spectrum Conditions (ASC) are much more common in males, a bias that may offer clues to the etiology of this condition. Although the cause of this bias remains a mystery, we argue that it occurs because ASC is an extreme manifestation of the male brain. The extreme male brain (EMB) theory, first proposed in 1997, is an extension of the Empathizing-Systemizing (E-S) theory of typical sex differences that proposes that females on average have a stronger drive to empathize while males on average have a stronger drive to systemize. In this first major update since 2005, we describe some of the evidence relating to the EMB theory of ASC and consider how typical sex differences in brain structure may be relevant to ASC. One possible biological mechanism to account for the male bias is the effect of fetal testosterone (fT). We also consider alternative biological theories, the X and Y chromosome theories, and the reduced autosomal penetrance theory. None of these theories has yet been fully confirmed or refuted, though the weight of evidence in favor of the fT theory is growing from converging sources (longitudinal amniocentesis studies from pregnancy to age 10 years old, current hormone studies, and genetic association studies of SNPs in the sex steroid pathways). Ultimately, as these theories are not mutually exclusive and ASC is multi-factorial, they may help explain the male prevalence of ASC.</p

AUV/ASC cooperative survey

In this paper we describe a solution to perform autonomous surveys taking advantage of a cooperative multivehicle setup. In the proposed configuration, an ASC provides –through an USBL- absolute positioning and communications to an AUV. Thus, by following the AUV with the surface vehicle we facilitate the reception of USBL measurements in the AUV regardless of the extent of the mission. This turns into an improved navigation on the AUV’s side, with the drift bounded thanks to the absolute measurements. Experimental results show that the proposed algorithm is able to maintain the ASC at a close distance and improve the navigation of the AUV. Moreover, the bathymetric maps built from the AUV data are consistent enough to enable the automatic detection of present targets and program further localized missions in the area.Peer Reviewe

Government involvement in high performance sport: An Australian national sporting organisation perspective

The purpose of this paper is to examine the relationship between the Australian Sports Commission (ASC) and Summer Olympic National Sporting Organisations (NSOs) to determine the effect the relationship has on Olympic performance outcomes. Five Olympic NSOs were examined: Athletics Australia, Cycling Australia, Rowing Australia, Swimming Australia and Yachting Australia. All five NSOs represent sports in which Australia has consistently achieved strong results at previous Olympic Games. These NSOs receive significant funding from the ASC and, as such, are expected to achieve success at the Olympic Games. The ASC–NSO relationship was examined through an agency theory framework whereby the ‘contracts’ between the ASC (principal) and the NSOs (agents) were investigated through a survey, interviews and document analysis to identify potential management issues that may affect Olympic performance outcomes, such as agent or principal opportunism. The findings identified a lack of a collaborative high performance sport system in Australia, with the findings emphasising concerns over the ASC’s management of NSO programmes. While the ASC staff identified their organisation as the leader of high performance sport in Australia, the study’s NSO participants did not believe that the ASC had the capacity, capability and knowledge to fulfil this role.No Full Tex

ASC filament formation serves as a signal amplification mechanism for inflammasomes

A hallmark of inflammasome activation is the ASC speck, a micrometre-sized structure formed by the inflammasome adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD), which consists of a pyrin domain (PYD) and a caspase recruitment domain (CARD). Here we show that assembly of the ASC speck involves oligomerization of ASC(PYD) into filaments and cross-linking of these filaments by ASC(CARD). ASC mutants with a non-functional CARD only assemble filaments but not specks, and moreover disrupt endogenous specks in primary macrophages. Systematic site-directed mutagenesis of ASC(PYD) is used to identify oligomerization-deficient ASC mutants and demonstrate that ASC speck formation is required for efficient processing of IL-1β, but dispensable for gasdermin-D cleavage and pyroptosis induction. Our results suggest that the oligomerization of ASC creates a multitude of potential caspase-1 activation sites, thus serving as a signal amplification mechanism for inflammasome-mediated cytokine production

Accelerating Stochastic Composition Optimization

Consider the stochastic composition optimization problem where the objective is a composition of two expected-value functions. We propose a new stochastic first-order method, namely the accelerated stochastic compositional proximal gradient (ASC-PG) method, which updates based on queries to the sampling oracle using two different timescales. The ASC-PG is the first proximal gradient method for the stochastic composition problem that can deal with nonsmooth regularization penalty. We show that the ASC-PG exhibits faster convergence than the best known algorithms, and that it achieves the optimal sample-error complexity in several important special cases. We further demonstrate the application of ASC-PG to reinforcement learning and conduct numerical experiments