Microglial regulation of satiety and cognition

Microglia have been known for decades as key immune cells that shape the central nervous system (CNS) during development and respond to brain pathogens and injury in adult life. Recent findings now suggest that these cells also play a highly complex role in several other functions of the CNS. In this review, we provide a brief overview of the established microglial functions in development and disease. We also discuss emerging research suggesting that microglia are important for both cognitive function and the regulation of food intake. With respect to cognitive function, current data suggest microglia are not indispensable for neurogenesis, synaptogenesis or cognition in the healthy young adult, although they crucially modulate and support these functions. In doing so, they are likely important in supporting the balance between apoptosis and survival of newborn neurones and in orchestrating appropriate synaptic remodelling in response to a learning stimulus. We also explore the possibility of a role for microglia in feeding and satiety. Microglia have been implicated in both appetite suppression with sickness and obesity and in promoting feeding under some conditions and we discuss these findings here, highlighting the contribution of these cells to healthy brain function

The Relationship between Squat Jump Performance and Sprint Profile in Collegiate Track and Field Athletes

The squat jump (SJ) necessitates the inter-play of various biomechanical components for better jump performance. Good sprint performance requires the inter-play of many of the same biomechanical components. Researchers have previously examined how the speed, force, velocity, and power interact during sprinting, but have yet to examine how these measures are associated with SJ performance measures. PURPOSE: Examine the relationship between squat jump performance measures and the sprint profile measurements of collegiate track and field athletes. METHODS: Twenty-five athletes (18 males and 7 females) completed two squat jump trials with a linear encoder attached to a 45 lbs. bar placed on the athlete’s upper back. Measures of interest during the concentric phase of the SJ included jump height, maximum force, maximum velocity, maximum power, and rate of force development. Athletes then completed two 30-meter acceleration sprints. The MySprint mobile application was used to acquire the athlete’s sprint profile and to assess maximal theoretical horizontal force, maximal theoretical velocity, optimal velocity, maximal theoretical power, maximal speed, maximal ratio of force, force-velocity slope, and decrease in ratio of force. The best trial was used for statistical analysis. Pearson’s or Spearman’s correlation coefficients were conducted between SJ measures and sprint profile measures. RESULTS: There was a positive correlation between SJ height and maximal speed (r = 0.402; p = 0.042). Maximal power during the SJ was positively correlated with maximal speed (r = 0.476; p = 0.014); optimal velocity (r = 0.469; p = 0.018); maximal theoretical power (r = 0.462; p = 0.018); maximal theoretical velocity (r = 0.452; p = 0.021); theoretical horizontal force (r = 0.431; p = 0.028); and maximal ratio force (r = 0.428; p = 0.029). Maximal velocity during the SJ was correlated with maximal speed (r = 0.519; p = 0.007); maximal theoretical velocity (r = 0.499; p = 0.010); optimal velocity (r = 0.486; p = 0.014); and maximal theoretical power (r = 0.484; p = 0.012). No other correlations were significant. CONCLUSION: Maximal velocity and power during the concentric phase of the SJ are moderately to strongly correlated with maximal sprinting speed, velocity, and power. SJ height is positively correlated with maximum sprint speed. There is a lack of significant correlations between other measures of the SJ and sprint profile measures. SJ power and velocity are correlated with sprint performance, therefore power and velocity improved through plyometric SJ training may be transferable to achieve better sprint performance

Immunotherapeutic targeting of LIGHT/LTβR/HVEM pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells.

Tumor necrosis factor (TNF)/TNF receptor (TNFR) superfamily members play essential roles in the development of the different phases of the immune response. Mouse LIGHT (TNFSF14) is a type II transmembrane protein with a C-terminus extracellular TNF homology domain (THD) that assembles in homotrimers and regulates the course of the immune responses by signaling through 2 receptors, the herpes virus entry mediator (HVEM, TNFSFR14) and the lymphotoxin β receptor (LTβR, TNFSFR3). LIGHT is a membrane-bound protein transiently expressed on activated T cells, natural killer (NK) cells and immature dendritic cells that can be proteolytically cleaved by a metalloprotease and released to the extracellular milieu. The immunotherapeutic potential of LIGHT blockade was evaluated in vivo. Administration of an antagonist of LIGHT interaction with its receptors attenuated the course of graft-versus-host reaction and recapitulated the reduced cytotoxic activity of LIGHT-deficient T cells adoptively transferred into non-irradiated semiallogeneic recipients. The lack of LIGHT expression on donor T cells or blockade of LIGHT interaction with its receptors slowed down the rate of T cell proliferation and decreased the frequency of precursor alloreactive T cells, retarding T cell differentiation toward effector T cells. The blockade of LIGHT/LTβR/HVEM pathway was associated with delayed downregulation of interleukin-7Rα and delayed upregulation of inducible costimulatory molecule expression on donor alloreactive CD8 T cells that are typical features of impaired T cell differentiation. These results expose the relevance of LIGHT/LTβR/HVEM interaction for the potential therapeutic control of the allogeneic immune responses mediated by alloreactive CD8 T cells that can contribute to prolong allograft survival

Desensitization to carboplatin in low-grade glioma. A revision of 100 treatments in children

info:eu-repo/semantics/publishedVersio

Therapeutic implications of NK cell regulation of allogeneic CD8 T cell-mediated immune responses stimulated through the direct pathway of antigen presentation in transplantation.

Natural killer (NK) cells are a population of innate type I lymphoid cells essential for early anti-viral responses and are known to modulate the course of humoral and cellular-mediated T cell responses. We assessed the role of NK cells in allogeneic CD8 T cell-mediated responses in an immunocompetent mouse model across an MHC class I histocompatibility barrier to determine its impact in therapeutic clinical interventions with polyclonal or monoclonal antibodies (mAbs) targeting lymphoid cells in transplantation. The administration of an NK cell depleting antibody to either CD8 T cell replete or CD8 T cell-depleted naïve C57BL/6 immunocompetent mice accelerated graft rejection. This accelerated rejection response was associated with an in vivo increased cytotoxic activity of CD8 T cells against bm1 allogeneic hematopoietic cells and bm1 skin allografts. These findings show that NK cells were implicated in the control host anti-donor cytotoxic responses, likely by competing for common cell growth factors in both CD8 T cell replete and CD8 T cell-depleted mice, the latter reconstituting in response to lymphopenia. Our data calls for precaution in solid organ transplantation under tolerogenic protocols involving extensive depletion of lymphocytes. These pharmacological biologics with depleting properties over NK cells may accelerate graft rejection and promote aggressive CD8 T cell cytotoxic alloresponses refractory to current immunosuppression

SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis

Dephosphorylation of the inhibitory “S259” site on RAF kinases (S259 on CRAF, S365 on BRAF) plays a key role in RAF activation. The MRAS GTPase, a close relative of RAS oncoproteins, interacts with SHOC2 and protein phosphatase 1 (PP1) to form a heterotrimeric holoenzyme that dephosphorylates this S259 RAF site. MRAS and SHOC2 function as PP1 regulatory subunits providing the complex with striking specificity against RAF. MRAS also functions as a targeting subunit as membrane localization is required for efficient RAF dephosphorylation and ERK pathway regulation in cells. SHOC2’s predicted structure shows remarkable similarities to the A subunit of PP2A, suggesting a case of convergent structural evolution with the PP2A heterotrimer. We have identified multiple regions in SHOC2 involved in complex formation as well as residues in MRAS switch I and the interswitch region that help account for MRAS’s unique effector specificity for SHOC2–PP1. MRAS, SHOC2, and PPP1CB are mutated in Noonan syndrome, and we show that syndromic mutations invariably promote complex formation with each other, but not necessarily with other interactors. Thus, Noonan syndrome in individuals with SHOC2, MRAS, or PPPC1B mutations is likely driven at the biochemical level by enhanced ternary complex formation and highlights the crucial role of this phosphatase holoenzyme in RAF S259 dephosphorylation, ERK pathway dynamics, and normal human development

Distinctive Expression and Amplification of Genes at 11q13 in Relation to HPV Status with Impact on Survival in Head and Neck Cancer Patients

Clear differences have been established between head and neck squamous cell carcinomas (HNSCC) depending on human papillomavirus (HPV) infection status. This study specifically investigated the status of the CTTN, CCND1 and ANO1 genes mapping at the 11q13 amplicon in relation to the HPV status in HNSCC patients. CTTN, CCND1 and ANO1 protein expression and gene amplification were respectively analyzed by immunohistochemistry and real-time PCR in a homogeneous cohort of 392 surgically treated HNSCC patients. The results were further confirmed using an independent cohort of 279 HNSCC patients from The Cancer Genome Atlas (TCGA). The impact on patient survival was also evaluated. CTTN, CCND1 and ANO1 gene amplification and protein expression were frequent in HPV-negative tumors, while absent or rare in HPV-positive tumors. Using an independent validation cohort of 279 HNSCC patients, we consistently found that these three genes were frequently co-amplified (28%) and overexpressed (39-46%) in HPV-negative tumors, whereas almost absent in HPV-positive tumors. Remarkably, these alterations (in particular CTTN and ANO1 overexpression) were associated with poor prognosis. Taken together, the distinctive expression and amplification of these genes could cooperatively contribute to the differences in prognosis and clinical outcome between HPV-positive and HPV-negative tumors. These findings could serve as the basis to design more personalized therapeutic strategies for HNSCC patients

Latin American chronic urticaria registry (CUR) contribution to the understanding and knowledge of the disease in the region

Chronic urticaria (CU) has a widespread spectrum on causal or exacerbating factors, clinical manifestations, therapeutic response and quality of life affectation. Registries are useful tools in several real-life diagnosis and management approach. We aimed to evaluate the characteristics of CU patients living in Latin America through an original cross-sectional registry with data entered by regional allergologists. Results: Three hundred patients were included, being 72% female, with median age of 36 years (1\u201385) and 20 months of CU median evolution time. The cause of CU was reported as unknown in 72% of them. Thirty-nine percent of suspected cases presented positive serology for Mycoplasma, positive autologous serum skin test (ASST) was reported in 47%, and occasional presence of thyroid or antinuclear autoantibodies and parasites. The impact of pruritus in their quality of life was moderate to severe in 60% of patients, with almost 3 out of four patients having partial or lack of urticaria control with anti-histamines. Conclusions: Our registry provides retrospective data on the real-life assistance of a large number of patients from the region. Continuous search for associated conditions and better treatment possibilities are needed, in order to control the significant impact on quality of life and the length of disease

NO, ROS, and cell death associated with caspase-like activity increase in stress-induced microspore embryogenesis of barley

Under specific stress treatments (cold, starvation), in vitro microspores can be induced to deviate from their gametophytic development and switch to embryogenesis, forming haploid embryos and homozygous breeding lines in a short period of time. The inductive stress produces reactive oxygen species (ROS) and nitric oxide (NO), signalling molecules mediating cellular responses, and cell death, modifying the embryogenic microspore response and therefore, the efficiency of the process. This work analysed cell death, caspase 3-like activity, and ROS and NO production (using fluorescence probes and confocal analysis) after inductive stress in barley microspore cultures and embryogenic suspension cultures, as an in vitro system which permitted easy handling for comparison. There was an increase in caspase 3-like activity and cell death after stress treatment in microspore and suspension cultures, while ROS increased in non-induced microspores and suspension cultures. Treatments of the cultures with a caspase 3 inhibitor, DEVD-CHO, significantly reduced the cell death percentages. Stress-treated embryogenic suspension cultures exhibited high NO signals and cell death, while treatment with S-nitrosoglutathione (NO donor) in control suspension cultures resulted in even higher cell death. In contrast, in microspore cultures, NO production was detected after stress, and, in the case of 4-day microspore cultures, in embryogenic microspores accompanying the initiation of cell divisions. Subsequent treatments of stress-treated microspore cultures with ROS and NO scavengers resulted in a decreasing cell death during the early stages, but later they produced a delay in embryo development as well as a decrease in the percentage of embryogenesis in microspores. Results showed that the ROS increase was involved in the stress-induced programmed cell death occurring at early stages in both non-induced microspores and embryogenic suspension cultures; whereas NO played a dual role after stress in the two in vitro systems, one involved in programmed cell death in embryogenic suspension cultures and the other in the initiation of cell division leading to embryogenesis in reprogrammed microspores

Where myth and archaeology meet: Discovering the Gorgon Medusa's Lair.

Here we report the discovery of ceramic fragments that form part of a Gorgoneion, a ceramic image representation of the Gorgon Medusa. The fragments were found in a deep part of Gorham's Cave, well known to ancient mariners as a natural shrine, between the 8th and 2nd century BCE. We discuss the context of this discovery, both within the inner topography of the cave itself, and also the broader geographical context. The discovery is situated at the extreme western end of the Mediterranean Sea, where it meets the Atlantic Ocean. The location was known to ancient mariners as the northern Pillar of Herakles, which marked the end of the known world. We relate the discovery, and its geographical and chronological context, to Greek legends that situated the lair of the Gorgon sisters at a location which coincides with the physical attributes and geographical position of Gorham's Cave. We thus provide, uniquely, a geographical and archaeological context to the myth of Perseus and the slaying of the Gorgon Medusa