The rockefeller university

In animals, stress and corticosteroid excess are associated with decreases in memory performance and hippocampal volume that may be prevented with agents that decrease glutamate release. Humans also demonstrate changes in memory and hippocampus with corticosteroids. In this report the effects of glutamate-release inhibitor lamotrigine on hippocampal structure and memory were examined in people receiving medically needed prescription corticosteroid therapy. A total of 54 outpatient adults (n = 28 women) receiving chronic (>= 6 months) oral corticosteroid therapy were randomized to lamotrigine or placebo for 48 weeks. Declarative memory was assessed using the Rey Auditory Verbal Learning Test (RAVLT); structural magnetic resonance imaging (MRI) as well as single-voxel proton MR spectroscopy ((HMRS)-H-1) focused on hippocampus were obtained at baseline and week 48. Utilizing a mixed-model approach, structural and biochemical data were examined by separate ANOVAs, and memory was assessed with a multi-level longitudinal model. RAVLT total scores demonstrated significantly better declarative memory performance with lamotrigine than placebo (p = 0.047). Hippocampal subfield volumes were not significantly different between the treatment groups. In summary, lamot-rigine was associated with less decline in declarative memory performance than placebo in corticosteroid-treated patients. Findings suggest that, in humans as well as in animal models, glutamate release inhibitors may attenuate some of the effects on the human memory associated with corticosteroids. (c) 2018 Published by Elsevier B.V.

Cardio-oncology has organically developed as a new discipline within cardiovascular medicine as a result of the cardiac and vascular adverse sequelae of the major advances in cancer treatment. Patients with cancer and cancer survivors are at increased risk of vascular disease for a number of reasons. First, many new cancer therapies, including several targeted therapies, are associated with vascular and metabolic complications. Second, cancer itself serves as a risk factor for vascular disease, especially by increasing the risk for thromboembolic events. Finally, recent data suggest that common modifiable and genetic risk factors predispose to both malignancies and cardiovascular disease. Vascular complications in patients with cancer represent a new challenge for the clinician and a new frontier for research and investigation. Indeed, vascular sequelae of novel targeted therapies may provide insights into vascular signaling in humans. Clinically, emerging challenges are best addressed by a multidisciplinary approach in which cardiovascular medicine specialists and vascular biologists work closely with oncologists in the care of patients with cancer and cancer survivors. This novel approach realizes the goal of providing superior care through the creation of cardio-oncology consultative services and the training of a new generation of cardiovascular specialists with a broad understanding of cancer treatments.

The cross sections for gamma(1S), gamma(2S), and gamma(3S) production in lead-lead (PbPb) and proton-proton (pp) collisions at root s(NN) = 5.02 TeV have been measured using the CMS detector at the LHC. The nuclear modification factors, R-AA, derived from the PbPb-to-pp ratio of yields for each state, are studied as functions of meson rapidity and transverse momentum, as well as PbPb collision centrality. The yields of all three states are found to be significantly suppressed, and compatible with a sequential ordering of the suppression, R-AA(T(1S)) > R-AA(gamma(2S)) > R-AA(gamma(3S)). The suppression of gamma(1S) is larger than that seen at root s(NN) = 2.76 TeV, although the two are compatible within uncertainties. The upper limit on the R-AA of gamma(3S) integrated over p(T), rapidity and centrality is 0.096 at 95% confidence level, which is the strongest suppression observed for a quarkonium state in heavy ion collisions to date. (C) 2019 The Author(s). Published by Elsevier B.V.

The mechanism by which gamma-secretase activating protein (GSAP) regulates gamma-secretase activity has not yet been elucidated. Here, we show that knockout of GSAP in cultured cells directly reduces gamma-secretase activity for A beta production, but not for Notch1 cleavage, suggesting that GSAP may induce a conformational change contributing to the specificity of gamma-secretase. Furthermore, using an active-site-directed photoprobe with double cross-linking moieties, we demonstrate that GSAP modifies the orientation and/or distance of the PS1 N-terminal fragment and the PS1 C-terminal fragment, a region containing the active site of gamma-secretase. This work offers insight into how GSAP regulates gamma-secretase specificity.

Cellular proteins continuously undergo non-enzymatic covalent modifications (NECMs) that accumulate under normal physiological conditions and are stimulated by changes in the cellular microenvironment. Glycation, the hallmark of diabetes, is a prevalent NECM associated with an array of pathologies. Histone proteins are particularly susceptible to NECMs due to their long half-lives and nucleophilic disordered tails that undergo extensive regulatory modifications; however, histone NECMs remain poorly understood. Here we perform a detailed analysis of histone glycation in vitro and in vivo and find it has global ramifications on histone enzymatic PTMs, the assembly and stability of nucleosomes, and chromatin architecture. Importantly, we identify a physiologic regulation mechanism, the enzyme DJ-1, which functions as a potent histone deglycase. Finally, we detect intense histone glycation and DJ-1 overexpression in breast cancer tumors. Collectively, our results suggest an additional mechanism for cellular metabolic damage through epigenetic perturbation, with implications in pathogenesis.

Linked Article: Kanni et al. Br J Dermatol 2018; 179:413-19.

Despite being a minor component of cells, phosphoinositides are essential for eukaryotic membrane biology, serving as markers of organelle identity and involved in several signaling cascades. Their many functions, combined with alternative synthesis pathways, make in vivo study very difficult. In vitro studies are limited by their inability to fully recapitulate the complexities of membranes in living cells. We engineered the biosynthetic pathway for the most abundant phosphoinositides into the bacterium Escherichia coli, which is naturally devoid of this class of phospholipids. These modified E. coli, when grown in the presence of myo-inositol, incorporate phosphatidylinositol (PI), phosphatidylinositol-4-phosphate (PI4P), phosphatidylinositol-4,5-bisphosphate (PIP2), and phosphatidylinositol-3,4,5-trisphosphate (PIP3) into their plasma membrane. We tested models of biophysical mechanisms with these phosphoinositides in a living membrane, using our system to evaluate the role of PIP2 in nonconventional protein export of human basic fibroblast growth factor 2. We found that PI alone is sufficient for the process.

In daily life, in the operating room and in the laboratory, the operational way to assess wakefulness and consciousness is through responsiveness. A number of studies suggest that the awake, conscious state is not the default behavior of an assembly of neurons, but rather a very special state of activity that has to be actively maintained and curated to support its functional properties. Thus responsiveness is a feature that requires active maintenance, such as a homeostatic mechanism to balance excitation and inhibition. In this work we developed a method for monitoring such maintenance processes, focusing on a specific signature of their behavior derived from the theory of dynamical systems: stability analysis of dynamical modes. When such mechanisms are at work, their modes of activity are at marginal stability, neither damped (stable) nor exponentially growing (unstable) but rather hovering in between. We have previously shown that, conversely, under induction of anesthesia those modes become more stable and thus less responsive, then reversed upon emergence to wakefulness. We take advantage of this effect to build a single-trial classifier which detects whether a subject is awake or unconscious achieving high performance. We show that our approach can be developed into a means for intra-operative monitoring of the depth of anesthesia, an application of fundamental importance to modern clinical practice.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease of the skin, manifesting in chronic, recurrent painful pustules, nodules, boils and purulent draining abscesses. Our current understanding of the pathogenesis of the disease is incomplete. This review aims to identify available treatment options in HS and discuss the pharmacological mechanisms through which such agents function. Identifying common pathways may inform our understanding of the pathogenesis of HS as well as identify future therapeutic targets. The pharmacological mechanisms implicated in topical therapies, antibiotic, hormonal, systemic immunomodulatory and biologic therapies for HS are discussed. Significant differences exist between agents and implicated pathways in therapy for mild and severe disease. This is an expression of the possible dichotomy in inflammatory pathways (and treatment responses) in HS. Studies involving monoclonal antibodies provide the greatest insight into what these specific mechanisms may be. Their variable levels of clinical efficacy compared with placebo bolsters the suggestion that differential inflammatory pathways may be involved in different presentations and severity of disease. Nuclear factor kappa B (NF-kappa B), tumor necrosis factor (TNF)-alpha and other innate immune mechanisms are strongly represented in treatments which are effective in mild to moderate disease in the absence of scarring or draining fistulae, however complex feed-forward mechanisms in severe disease respond to interleukin (IL)-1 inhibition but are less likely to respond to innate immune inhibition (through NF-kappa B or TNF-alpha) alone. It is unclear whether IL-17 inhibition will parallel TNF-alpha or IL-1 inhibition in effect, however it is plausible that small molecule targets (Janus kinase1 and phosphodiesterase 4) may provide effective new strategies for treatment of HS.