Prostasomes (Exosomes) Mediate Functional Abilities to Recipient Cells through Transfer of Proteins and Nucleic Acids: A Comprehensive Model for Exosomal Intercellular Communication

The prostasome is the first described exosome and constitutes the third communication system between cells mediating messages besides gap junctions and soluble compounds such as hormones. Exosomes are nanometer vesicles surrounded by a lipid bilayered membrane and released by most cell types including malignant cells. The exosomal messenger system reaches distant cells even on the other side of the blood brain barrier. In this way they are able to interact with their target cells for delivery of their cargo. We here describe prostasomal properties in more detail thus exemplifying common exosomal characteristics. Myocardial derived exosomes (cardiosomes), are also described in order to highlight other common biological functions including damaged tissue, i.e. tissue repair. Abnormal tissue such as malignant progression can be driven by cancer cell derived exosomes, believed mainly to be mediated by different forms of short RNAs exerting their action through specific signaling pathways related to metastases, therapeutic resistance and immunosuppression.

Enhancement in Phospholipase D Activity as a New Proposed Molecular Mechanism of Haloperidol-Induced Neurotoxicity

Membrane phospholipase D (PLD) is associated with numerous neuronal functions, such as axonal growth, synaptogenesis, formation of secretory vesicles, neurodegeneration, and apoptosis. PLD acts mainly on phosphatidylcholine, from which phosphatidic acid (PA) and choline are formed. In turn, PA is a key element of the PLD-dependent secondary messenger system. Changes in PLD activity are associated with the mechanism of action of olanzapine, an atypical antipsychotic. The aim of the present study was to assess the effect of short-term administration of the first-generation antipsychotic drugs haloperidol, chlorpromazine, and fluphenazine on membrane PLD activity in the rat brain. Animals were sacrificed for a time equal to the half-life of the antipsychotic drug in the brain, then the membranes in which PLD activity was determined were isolated from the tissue. The results indicate that only haloperidol in a higher dose increases the activity of phospholipase D. Such a mechanism of action of haloperidol has not been described previously. Induction of PLD activity by haloperidol may be related to its mechanism of cytotoxicity. The finding could justify the use of PLD inhibitors as protective drugs against the cytotoxicity of first-generation antipsychotic drugs like haloperidol.

Taming the Dragon-King of a Day-Ahead Smart Grid Blackout

Dragon-King a is introduced in this paper as the manifestation of a disaster incident for a Smart Grid’s blackout for a day-ahead. The quintessential incident is being generated by an artificial black hole, it then spreads quickly into transmission lines. Consequently, it bursts into space-time transition regions. This paper reveals all the essential characteristics of the Dragon-King, it has non-isotropic stochastic kinematics. Regardless of its huge manifestation of unwanted phenomena, the Dragon-King is controllable. We also describe the mechanism of an updated complexity, spinning cosmic string and a messenger system in this paper. Furthermore, the control strategy of the feedback controller which ultimately leads to a stable normal operation is also reported in this paper.

Induction and catabolite repression of alpha-amylase synthesis in Bacilluslicheniformis SKB4

Microbial amylases have an exciting potentiality and are being used extensively in different industries. In this study, regulation of amylase biosynthesis was examined in Bacillus licheniformis SKB4 (wild type) and its mutant strain (8b). The mutant strain was developed by using UV exposure. Expression of the a-amylase gene of Bacillus licheniformis was activated by inducer and subject to catabolite repression. Addition of exogenous glucose or sucrose repressed bio-synthesis of a-amylase which was concentration (0.05-1.0% w/v) dependent. However, mutant strain could enable to overrule the glucose mediated repressive effect. Supplementation of second messenger like cyclic adenosine 3',5'-monophosphate (cAMP, 5 mM) along with glucose could a little bit improve amylase synthesis in wild strain. Antibiotics like rifampicin and tetracycline (ribonucleic acid and protein synthesis inhibitor; 100mg/ml) had stopped the release of enzyme in both wild and mutant strain. Amylase production was also inhibited in presence of respiratory inhibitor 2,4-dinitrophenol (uncoupler) at (5mM) concentration. Thus, the pattern of regulation of a-amylase production in the present strain was in multiple forms; it showed the classical glucose effect without stimulation of second messenger system.

Systematic Reconstruction of Autism Biology with Multi-Level Whole Exome Analysis

Whole exome/genome studies on autism spectrum disorder (ASD) identified thousands of variants, yet not a coherent and systematic disease mechanism. We conduct novel integrated analyses across multiple levels on ASD exomes. These mutations do not recur or replicate at variant level, but significantly and increasingly so at gene and pathway level. Genetic association reveals a novel gene+pathway dual-hit model, better explaining ASD risk than the well-accepted mutation burden model.In multiple analyses with independent datasets, hundreds of variants or genes consistently converge to several canonical pathways. Unlike the reported gene groups or networks, these pathways define novel, relevant, recurrent and systematic ASD biology. At sub-pathway level, most variants disrupt the pathway-related gene functions, and multiple interacting variants spotlight key modules, e.g. cAMP second-messenger system and mGluR signaling regulation by GRK in synapses. At super-pathway level, these distinct pathways are highly interconnected, and further converge to a few biology themes, i.e. synaptic function, morphology and plasticity. Therefore, ASD is a not just multi-genic but a multi-pathway disease.

60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH

The pituitary adrenocorticotropic hormone (ACTH) plays a pivotal role in homeostasis and stress response and is thus the major component of the hypothalamo–pituitary–adrenal axis. After a brief summary of ACTH production from proopiomelanocortin (POMC) and on ACTH receptor properties, the first part of the review covers the role of ACTH in steroidogenesis and steroid secretion. We highlight the mechanisms explaining the differential acute vs chronic effects of ACTH on aldosterone and glucocorticoid secretion. The second part summarizes the effects of ACTH on adrenal growth, addressing its role as either a mitogenic or a differentiating factor. We then review the mechanisms involved in steroid secretion, from the classical Cyclic adenosine monophosphate second messenger system to various signaling cascades. We also consider how the interaction between the extracellular matrix and the cytoskeleton may trigger activation of signaling platforms potentially stimulating or repressing the steroidogenic potency of ACTH. Finally, we consider the extra-adrenal actions of ACTH, in particular its role in differentiation in a variety of cell types, in addition to its known lipolytic effects on adipocytes. In each section, we endeavor to correlate basic mechanisms of ACTH function with the pathological consequences of ACTH signaling deficiency and of overproduction of ACTH.