The rockefeller university

Medicinal mushrooms have been used for centuries in Asian countries owing to their beneficial effects on health and longevity. Previous studies have reported that a single medicinal mushroom may produce both stimulatory and inhibitory effects on immune cells, depending on conditions, but the factors responsible for this apparent dichotomy remain obscure. We show here that water and ethanol extracts of cultured mycelium from various species (Agaricus blazei Murrill, Antrodia cinnamomea, Ganoderma lucidum and Hirsutella sinensis) produce opposite effects on NK cells. Water extracts enhance NK cell cytotoxic activity against cancer cells, whereas ethanol extracts inhibit cytotoxicity. Water extracts stimulate the expression and production of cytolytic proteins (perforin and granulysin) and NKG2D/NCR cell surface receptors, and activate intracellular signaling kinases (ERK, JNK and p38). In contrast, ethanol extracts inhibit expression of cytolytic and cell surface receptors. Our results suggest that the mode of extraction of medicinal mushrooms may determine the nature of the immunomodulatory effects produced on immune cells, presumably owing to the differential solubility of stimulatory and inhibitory mediators. These findings have important implications for the preparation of medicinal mushrooms to prevent and treat human diseases.

Elevated levels of circulating asymmetric and symmetric dimethylarginines (ADMA and SDMA) predict and potentially contribute to end organ damage in cardiovascular diseases. Alanine-glyoxylate aminotransferase 2 (AGXT2) regulates systemic levels of ADMA and SDMA, and also of beta-aminoisobutyric acid (BAIB)-a modulator of lipid metabolism. We identified a putative binding site for hepatic nuclear factor 4 alpha (HNF4 alpha in AGXT2 promoter sequence. In a luciferase reporter assay we found a 75% decrease in activity of Agxt2 core promoter after disruption of the HNF4 alpha binding site. Direct binding of HNF4 alpha to Agxt2 promoter was confirmed by chromatin immunoprecipitation assay. siRNA-mediated knockdown of Hnf4a led to an almost 50% reduction in Agxt2 mRNA levels in Hepa 1-6 cells. Liver-specific Hnf4a knockout mice exhibited a 90% decrease in liver Agxt2 expression and activity, and elevated plasma levels of ADMA, SDMA and BAIB, compared to wild-type littermates. Thus we identified HNF4 alpha as a major regulator of Agxt2 expression. Considering a strong association between human HNF4A polymorphisms and increased risk of type 2 diabetes our current findings suggest that downregulation of AGXT2 and subsequent impairment in metabolism of dimethylarginines and BAIB caused by HNF4 alpha deficiency might contribute to development of cardiovascular complications in diabetic patients.

Remote activation of specific cells of a heterogeneous population can provide a useful research tool for clinical and therapeutic applications. Here, we demonstrate that photostimulation of gold nanorods (AuNRs) using a tunable near-infrared (NIR) laser at specific longitudinal surface plasmon resonance wavelengths can induce the selective and temporal internalization of calcium in HEK 293T cells. Biotin-PEG-Au nanorods coated with streptavidin Alexa Fluor-633 and biotinylated anti-His antibodies were used to decorate cells genetically modified with His-tagged TRPV1 temperature-sensitive ion channel and AuNRs conjugated to biotinylated RGD peptide were used to decorate integrins in unmodified cells. Plasmonic activation can be stimulated at weak laser power (0.7-4.0 W/cm(2)) without causing cell damage. Selective activation of TRPV1 channels could be controlled by laser power between 1.0 and 1.5 W/cm(2). Integrin targeting robustly stimulated calcium signaling due to a dense cellular distribution of nanoparticles. Such an approach represents a functional tool for combinatorial activation of cell signaling in heterogeneous cell populations. Our results suggest that it is possible to induce cell activation via NIR-induced gold nanorod heating through the selective targeting of membrane proteins in unmodified cells to produce calcium signaling and downstream expression of specific genes with significant relevance for both in vitro and therapeutic applications. (C) 2016 Wiley Periodicals, Inc.

Microtubule-organizing centers (MTOCs) nucleate microtubules that can grow autonomously in any direction. To generate bundles of parallel microtubules originating from a single MTOC, the growth of multiple microtubules needs to coordinated, but the underlying mechanism is unknown. Here, we show that a conserved two-component system consisting of the plus-end tracker EB1 and the minus-end-directed molecular motor Kinesin-14 is sufficient to promote parallel microtubule growth. The underlying mechanism relies on the ability of Kinesin-14 to guide growing plus ends along existing microtubules. The generality of this finding is supported by yeast, Drosophila, and human EB1/Kinesin-14 pairs. We demonstrate that plus-end guiding involves a directional switch of the motor due to a force applied via a growing microtubule end. The described mechanism can account for the generation of parallel microtubule networks required for a broad range of cellular functions such as spindle assembly or cell polarization.

Parkinson's disease (PD) is characterized by the selective loss of dopamine neurons in the substantia nigra; however, the mechanism of neurodegeneration in PD remains unclear. A subset of familial PD is linked to mutations in PARK2 and PINK1, which lead to dysfunctional mitochondria-related proteins Parkin and PINK1, suggesting that pathways implicated in these monogenic forms could play a more general role in PD. We demonstrate that the identification of disease-related phenotypes in PD-patient-specific induced pluripotent stem cell (iPSC)-derived midbrain dopamine (mDA) neurons depends on the type of differentiation protocol utilized. In a floor-plate-based but not a neural-rosette-based directed differentiation strategy, iPSC-derived mDA neurons recapitulate PD phenotypes, including pathogenic protein accumulation, cell-type-specific vulnerability, mitochondrial dysfunction, and abnormal neurotransmitter homeostasis. We propose that these form a pathogenic loop that contributes to disease. Our study illustrates the promise of iPSC technology for examining PD pathogenesis and identifying therapeutic targets.

Purpose of reviewTo evaluate how the genomic, transcriptomic, and proteomic profiles of allergic skin diseases, like atopic dermatitis and allergic contact dermatitis, contribute to their understanding and promote their therapeutic development.Recent findingsThe -omics' revolution has facilitated the quantification of inflammatory skin diseases at the molecular level, expanding our understanding of disease pathogenesis. It has also greatly expanded once-limited treatment options and improved the ability to define posttreatment improvements, beyond clinical scores. The findings on the genomic/transcriptomic level are also complemented by proteomic data, contributing to the understanding of the later changes taking place in the final stages of protein formation. Atopic dermatitis is defined as a Th2/Th22 polarized disease with some contributions of Th17 and Th1 pathways. In atopic dermatitis, studies of biologics and small molecules, targeting specific pathways upregulated in atopic dermatitis, seem to provide well tolerated alternatives to conventional immunosuppressive therapies (i.e. corticosteroids and cyclosporine A), particularly for severe patients. Allergic contact dermatitis is defined as having Th1/Th17-centered inflammation, especially with nickel-induced disease, but additional pathways, including Th2 and Th22, are upregulated with other allergens (i.e. fragrance).SummarySupplementing studies of allergic skin diseases with -omics' approaches are transforming the pathogenic understanding, diagnosis and, perhaps, also the treatment of these diseases.

Protein-facilitated shape and topology changes of cell membranes are crucial for many biological processes, such as cell division, protein trafficking, and cell signaling. However, the inherently multiscale nature of membrane remodeling presents a considerable challenge for understanding the mechanisms and physics that drive this process. To address this problem, a multiscale approach that makes use of a diverse set of computational and experimental techniques is required. The atomistic simulations provide high-resolution information on protein-membrane interactions. Experimental techniques, like electron microscopy, on the other hand, resolve high-order organization of proteins on the membrane. Coarse-grained (CG) and mesoscale computational techniques provide the intermediate link between the two scales and can give new insights into the underlying mechanisms. In this Review, we present the recent advances in multiscale computational approaches established in our group. We discuss various CG and mesoscale approaches in studying the protein-mediated large-scale membrane remodeling. (C) 2016 Elsevier Inc. All rights reserved.

Normal brain function depends on the interaction between highly specialized neurons that operate within anatomically and functionally distinct brain regions. Neuronal specification is driven by transcriptional programs that are established during early neuronal development and remain in place in the adult brain. The fidelity of neuronal specification depends on the robustness of the transcriptional program that supports the neuron type-specific gene expression patterns. Here we show that polycomb repressive complex 2 (PRC2), which supports neuron specification during differentiation, contributes to the suppression of a transcriptional program that is detrimental to adult neuron function and survival. We show that PRC2 deficiency in striatal neurons leads to the de-repression of selected, predominantly bivalent PRC2 target genes that are dominated by self-regulating transcription factors normally suppressed in these neurons. The transcriptional changes in PRC2-deficient neurons lead to progressive and fatal neurodegeneration in mice. Our results point to a key role of PRC2 in protecting neurons against degeneration.

In the 2015 David Kopf Lecture on Neuroethics of the Society for Neuroscience, Dr. Joseph Fins presents his work on neuroethics and disorders of consciousness through the experience of Maggie and Nancy Worthen, a young woman who sustained a severe brain injury and her mother who cared for her. The central protagonists in his book, Rights Come to Mind: Brain Injury, Ethics and the Struggle for Consciousness (Cambridge University Press, 2015), their experience is emblematic of the challenges faced by families touched by severe brain injury and the possibility for improved diagnosis and treatment offered by progress in neuroscience. By telling their story, and those of other families interviewed as part of the research for Rights Come to Mind, Fins calls for improved care for this population arguing that this is both an access to care issue and a civil and disability rights issue worthy of greater societal attention.