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Sample records for molecular pathogenetic mechanisms

  1. Pseudohyperaldosteronism: pathogenetic mechanisms.

    PubMed

    Armanini, Decio; Calò, Lorenzo; Semplicini, Andrea

    2003-06-01

    Pseudohyperaldosteronism is characterized by a clinical picture of hyperaldosteronism with suppression of plasma renin activity and aldosterone. Pseudohyperaldosteronism can be due to a direct mineralocorticoid effect, as with desoxycorticosterone, fluorohydrocortisone, fluoroprednisolone, estrogens, and the ingestion of high amounts of glycyrrhetinic acid. A block of 11-hydroxysteroid-dehydrogenase type 2 (11HSD2), the enzyme that converts cortisol into cortisone, at the level of epithelial target tissues of aldosterone, is involved in other cases. This mechanism is related either to a mutation of the gene, which encodes 11HSD2 (apparent mineralocorticoid excess syndrome and some cases of low renin hypertension) or to an acquired reduction of the activity of the enzyme due to glycyrrhetinic acid, carbenoxolone, and grapefruit juice. In other cases saturation of 11HSD2 may be involved as in severe Cushing's syndrome and chronic therapy with some corticosteroids. Recently, an activating mutation of the mineralocorticoid receptor gene has been described. Another genetic cause of pseudohyperaldosteronism is the syndrome of Liddle, which is due to a mutation of the gene encoding for beta and gamma subunits of the sodium channels. PMID:12892318

  2. PATHOGENETIC MECHANISMS OF FOCAL CORTICAL DYSPLASIA

    PubMed Central

    Marin-Valencia, Isaac; Guerrini, Renzo; Gleeson, Joseph G.

    2014-01-01

    SUMMARY Objective Focal cortical dysplasias (FCDs) constitute a prevalent cause of intractable epilepsy in children, and one of the leading conditions requiring epilepsy surgery. Despite the recent advances on the cellular and molecular biology of these conditions, the pathogenetic mechanisms of FCDs remain largely unknown. The purpose if this work is to review the molecular underpinnings of FCDs and to highlight potential therapeutic targets. Methods A systematic review of the literature regarding the histological, molecular, and electrophysiological aspects of FCDs was conducted. Results Disruption of the mTOR signaling comprises a common pathway underlying the structural and electrical disturbances of some FCDs. Other mechanisms such as viral infections, prematurity, head trauma, and brain tumors are also posited. mTOR inhibitors (i.e., rapamycin) have shown positive results on seizure management in animal models and in a small cohort of patients with FCD. Significance Encouraging progresses have been achieved on the molecular and electrophysiological basis of constitutive cells in the dysplastic tissue. Despite the promising results of mTOR inhibitors, large-scale randomized trials are in need to evaluate their efficacy and side effects, along with additional mechanistic studies for the development of novel, molecular-based diagnostic and therapeutic approaches. PMID:24861491

  3. Pathogenetic Mechanisms of Deep Infiltrating Endometriosis.

    PubMed

    Tosti, Claudia; Pinzauti, Serena; Santulli, Pietro; Chapron, Charles; Petraglia, Felice

    2015-09-01

    Endometriosis is a benign gynecologic disease, affecting women of reproductive age associated with chronic pelvic pain, dysmenorrhea, dyspareunia and infertility. Ovarian endometrioma (OMA), superficial peritoneal endometriosis (SPE), and deep infiltrating endometriosis (DIE) are, till now, recognized as major phenotypes. The discussion is to know whether they share the same pathogenetic mechanisms. Till today, DIE is recognized as the most severe clinical form of endometriosis and has a complex clinical management. The DIE lesions have been considered in the present article, without distinguishing between the anterior (bladder) or the posterior (vagina, uterosacral ligaments, rectum, and ureter) compartment. The present knowledge indicates that hormonal function (estrogen and progesterone receptors) and immunological factors, such as peritoneal macrophages, natural killer cells, and lymphocytes, are critically altered in DIE. The aggressive behavior of DIE may be explained by the highly decreased apoptosis (nuclear factor kappa-light-chain-enhancer of activated B cells [NF-kB], B-cell lymphoma 2 [Blc-2], and anti-Mullerian hormone) and by the increased proliferation activity related to oxidative stress (NF-kB, reactive oxygen species, extracellular regulated kinase (ERK), advanced oxidation protein product). Invasive mechanisms are more expressed (matrix metalloproteinases and activins) in DIE in comparison to the OMA and SPE. Correlated with the increased invasiveness are the data on very high expression of neuroangiogenesis (nerve growth factor, vascular endothelial growth factor, and intercellular adhesion molecule) genes in DIE. Therefore, at the present time, several of the DIE pathogenetic features result specific in comparison to other endometriosis phenotypes, pleading for the existence of a specific entity. These evidence of specific pathogenetic features of DIE may explain the more severe symptomatology related to this form of endometriosis and suggest

  4. Ameloblastoma: A Review of Recent Molecular Pathogenetic Discoveries

    PubMed Central

    Brown, Noah A.; Betz, Bryan L.

    2015-01-01

    Ameloblastoma is an odontogenic neoplasm whose molecular pathogenesis has only recently been elucidated. The discovery of recurrent activating mutations in FGFR2, BRAF, and RAS in a large majority of ameloblastomas has implicated dysregulation of MAPK pathway signaling as a critical step in the pathogenesis of this tumor. Some degree of controversy exists regarding the role of mutations affecting the sonic hedgehog (SHH) pathway, specifically Smoothened (SMO), which have been postulated to serve as either an alternative pathogenetic mechanism or secondary mutations. Here, we review recent advances in our understanding of the molecular pathogenesis of ameloblastoma as well as the diagnostic, prognostic, and therapeutic implications of these discoveries. PMID:26483612

  5. [Pathogenetic mechanisms of phantom-pain syndrome].

    PubMed

    Reshetnyak, V K; Kukushkin, M L; Gurko, N C

    2015-01-01

    This review considers the literature data on the epidemiology of phantom-pain syndrome (PPS) presents the results of numerous clinical studies demonstrating the lack of effectiveness of the vast majority of modem non-pharmacological and pharmacological methods of treatment of PPS. Detail presents data on the patho genetic mechanisms underlying the PPS. According to most researchers, the major role in the patho genesis of the PPS has the reorganization of the somatosensory area of the cerebral cortex of the brain. At the same time discusses the views of researchers who believe that the main reason PPS is to strengthen nociceptive and nonnociceptive afferentation in the peripheral newous system. The comparison of these conflicting data it is concluded that in the genesis of the PPS plays the role of both primary and secondary sensitization. Leading important dysfunction of the central nervous system. Details the modern understanding of the mechanisms underlying the high efficiency of suppression of PPS during stimulation of motor cortex. PMID:27116887

  6. Pathogenetic mechanisms in B27 associated diseases.

    PubMed

    Moll, J M

    1983-11-01

    Various aspects of pathogenesis, or more broadly, aetiopathogenesis, in the field of B27 related disorders are considered. The main conclusions can be expressed as follows: Genetic factors are involved in the causation of the spondarthritides, although there is still controversy within individual disorders concerning the precise mode of inheritance. For instance, in some conditions evidence appears stronger for a Mendelian mechanism, in others for a multifactorial process. The mode of the HLA-B27-receptor interaction is not yet fully established, but there is strong support for the one gene cross-tolerance theory, in ankylosing spondylitis at least. It is likely that environmental factors 'collaborate' with genetic factors in causing spondarthritic disease. The factors in the environment have yet to be proved, but there is some evidence that micro-organisms such as Klebsiella and Yersinia are involved (e.g. ankylosing spondylitis, Reiter's disease, reactive arthritis). Of noninfective environmental factors, trauma could play a part, as suggested by the mode of onset and pattern of development of some examples of ankylosing spondylitis and psoriatic arthritis. PMID:6418260

  7. Neuroferritinopathy: From ferritin structure modification to pathogenetic mechanism

    PubMed Central

    Levi, Sonia; Rovida, Ermanna

    2015-01-01

    Neuroferritinopathy is a rare, late-onset, dominantly inherited movement disorder caused by mutations in L-ferritin gene. It is characterized by iron and ferritin aggregate accumulation in brain, normal or low serum ferritin levels and high variable clinical feature. To date, nine causative mutations have been identified and eight of them are frameshift mutations determined by nucleotide(s) insertion in the exon 4 of L-ferritin gene altering the structural conformation of the C-terminus of the L-ferritin subunit. Acting in a dominant negative manner, mutations are responsible for an impairment of the iron storage efficiency of ferritin molecule. Here, we review the main characteristics of neuroferritinopathy and present a computational analysis of some representative recently defined mutations with the purpose to gain new information about the pathogenetic mechanism of the disorder. This is particularly important as neuroferritinopathy can be considered an interesting model to study the relationship between iron, oxidative stress and neurodegeneration. PMID:25772441

  8. [Basic etiological factors, pathogenetic mechanisms, and clinical forms of meteopathic reactions].

    PubMed

    Zunnunov, Z P

    2002-01-01

    The paper reviews basic etiological factors of meteopathic reactions, presents a scheme of pathogenetic mechanisms of the development and clinical classification. Meteopathic reactions are attributed to the following causing factors: atmospheric electromagnetic impacts ("storms"), change of thermobaric situation ("hypoxic weather for "spastic"), weather situation of the intermediate type. Pathogenetic mechanisms of meteopathic reactions provoke the following developments: electromagnetic impacts irritate the cells of afferent nervous ends, weather hypoxic conditions aggravate lack of oxygen of affected organs and tissues, spasm of vascular smooth muscles worsens transport of oxygen to organs and tissues causing capillary-trophic insufficiency. Clinically, meteopathic reactions run latently or manifest as aggrevation of preexisting diseases. Hence, meteopathic reactions are divided into cerebral, cardial, respiratory, peripheral, abdominal (visceral) and combined; mild, moderate and severe. PMID:12592895

  9. Osteolysis around total knee arthroplasty: a review of pathogenetic mechanisms.

    PubMed

    Gallo, J; Goodman, S B; Konttinen, Y T; Wimmer, M A; Holinka, M

    2013-09-01

    Aseptic loosening and other wear-related complications are some of the most frequent late reasons for revision of total knee arthroplasty (TKA). Periprosthetic osteolysis (PPOL) pre-dates aseptic loosening in many cases, indicating the clinical significance of this pathogenic mechanism. A variety of implant-, surgery- and host-related factors have been delineated to explain the development of PPOL. These factors influence the development of PPOL because of changes in mechanical stresses within the vicinity of the prosthetic device, excessive wear of the polyethylene liner, and joint fluid pressure and flow acting on the peri-implant bone. The process of aseptic loosening is initially governed by factors such as implant/limb alignment, device fixation quality and muscle coordination/strength. Later, large numbers of wear particles detached from TKA trigger and perpetuate particle disease, as highlighted by progressive growth of inflammatory/granulomatous tissue around the joint cavity. An increased accumulation of osteoclasts at the bone-implant interface, impairment of osteoblast function, mechanical stresses and increased production of joint fluid contribute to bone resorption and subsequent loosening of the implant. In addition, hypersensitivity and adverse reactions to metal debris may contribute to aseptic TKA failure, but should be determined more precisely. Patient activity level appears to be the most important factor when the long-term development of PPOL is considered. Surgical technique, implant design and material factors are the most important preventative factors, because they influence both the generation of wear debris and excessive mechanical stresses. New generations of bearing surfaces and designs for TKA should carefully address these important issues in extensive preclinical studies. Currently, there is little evidence that PPOL can be prevented by pharmacological intervention. PMID:23669623

  10. OSTEOLYSIS AROUND TOTAL KNEE ARTHOPLASTY: A REVIEW OF PATHOGENETIC MECHANISMS

    PubMed Central

    Gallo, Jiri; Goodman, Stuart B.; Konttinen, Yrjö T.; Wimmer, Markus A.; Holinka, Martin

    2014-01-01

    Aseptic loosening and other wear-related complications are one of the most frequent late reasons for revision of total knee arthroplasty (TKA). Periprosthetic osteolysis (PPOL) predates aseptic loosening in many cases indicating the clinical significance of this pathogenic mechanism. A variety of implant-, surgery-, and host-related factors have been delineated to explain the development of PPOL. These factors influence the development of PPOL due to changes in mechanical stresses within the vicinity of the prosthetic device, excessive wear of the polyethylene liner, and joint fluid pressure and flow acting on the peri-implant bone. The process of aseptic loosening is initially governed by factors such as implant/limb alignment, device fixation quality, and muscle coordination/strength. Later large numbers of wear particles detached from TKAs trigger and perpetuate particle disease, as highlighted by progressive growth of inflammatory/granulomatous tissue around the joint cavity. An increased accumulation of osteoclasts at the bone-implant interface, an impairment of osteoblast function, mechanical stresses, and an increased production of joint fluid contribute to bone resorption and subsequent loosening of the implant. In addition, hypersensitivity and adverse reactions to metal debris may contribute to aseptic TKA failure but should be determined more precisely. Patient activity level appears to be the most important factor when the long-term development of PPOL is considered. Surgical technique, implant design, and material factors are the most important preventative factors because they influence both the generation of wear debris and excessive mechanical stresses. New generations of bearing surfaces and designs for TKA should carefully address these important issues in extensive preclinical studies. Currently, there is little evidence that PPOL can be prevented with pharmacological interventions. PMID:23669623

  11. Cofilin-2 Phosphorylation and Sequestration In Myocardial Aggregates: Novel Pathogenetic Mechanisms For Idiopathic Dilated Cardiomyopathy

    PubMed Central

    Subramanian, Khaushik; Gianni, Davide; Balla, Cristina; Assenza, Gabriele Egidy; Joshi, Mugdha; Semigran, Marc J.; Macgillivray, Thomas E.; Van Eyk, Jennifer E.; Agnetti, Giulio; Paolocci, Nazareno; Bamburg, James R.; Agrawal, Pankaj B.; del Monte, Federica

    2015-01-01

    BACKGROUND Recently, tangles and plaque-like aggregates have been identified in certain cases of dilated cardiomyopathy (DCM). This suggests a potential underlying cause for the one-third of cases, traditionally labeled idiopathic (iDCM), where there is no specific diagnostic test or targeted therapy. OBJECTIVE We sought to identify the make-up of myocardial aggregates to understand the molecular mechanisms of these cases of DCM; this strategy has been central to understanding Alzheimer’s disease. METHODS Aggregates were extracted from human iDCM samples with high congophilic reactivity (an indication of plaque presence) and the findings validated in a larger cohort of samples. We tested the expression, distribution, and activity of cofilin in human tissue and generated a cardiac-specific knockout mouse model to investigate the functional impact of the human findings. We also modeled cofilin inactivity in vitro using pharmacological and genetic gain and loss of function approaches. RESULTS Aggregates in the human myocardium were enriched for cofilin-2, an actin-depolymerizing protein known to participate in neurodegenerative diseases and nemaline myopathy. Cofilin-2 was predominantly phosphorylated, rendering it inactive. Cardiac-specific haploinsufficiency of cofilin-2 in mice recapitulated the human disease’s morphological, functional, and structural phenotype. Pharmacological stimulation of cofilin-2 phosphorylation and genetic overexpression of the phosphomimetic protein promoted the accumulation of “stress-like” fibers and severely impaired cardiomyocyte contractility. CONCLUSIONS Our study provides the first biochemical characterization of prefibrillar myocardial aggregates in humans and the first report to link cofilin-2 to cardiomyopathy. The findings suggest a common pathogenetic mechanism between certain iDCMs and other chronic degenerative diseases, laying the groundwork for new therapeutic strategies. PMID:25814227

  12. Calcific Aortic Valve Disease: Part 1-Molecular Pathogenetic Aspects, Hemodynamics, and Adaptive Feedbacks.

    PubMed

    Pasipoularides, Ares

    2016-04-01

    Aortic valvular stenosis (AVS), produced by calcific aortic valve disease (CAVD) causing reduced cusp opening, afflicts mostly older persons eventually requiring valve replacement. CAVD had been considered "degenerative," but newer investigations implicate active mechanisms similar to atherogenesis-genetic predisposition and signaling pathways, lipoprotein deposits, chronic inflammation, and calcification/osteogenesis. Consequently, CAVD may eventually be controlled/reversed by lifestyle and pharmacogenomics remedies. Its management should be comprehensive, embracing not only the valve but also the left ventricle and the arterial system with their interdependent morphomechanics/hemodynamics, which underlie the ensuing diastolic and systolic LV dysfunction. Compared to even a couple of decades ago, we now have an increased appreciation of genomic and cytomolecular pathogenetic mechanisms underlying CAVD. Future pluridisciplinary studies will characterize better and more completely its pathobiology, evolution, and overall dynamics, encompassing intricate feedback processes involving specific signaling molecules and gene network cascades. They will herald more effective, personalized medicine treatments of CAVD/AVS. PMID:26891845

  13. Frontotemporal lobar degeneration: old knowledge and new insight into the pathogenetic mechanisms of tau mutations

    PubMed Central

    Rossi, Giacomina; Tagliavini, Fabrizio

    2015-01-01

    Frontotemporal lobar degeneration (FTLD) is a group of heterogeneous neurodegenerative diseases which includes tauopathies. In the central nervous system (CNS) tau is the major microtubule-associated protein (MAP) of neurons, promoting assembly and stabilization of microtubules (MTs) required for morphogenesis and axonal transport. Primary tauopathies are characterized by deposition of abnormal fibrils of tau in neuronal and glial cells, leading to neuronal death, brain atrophy and eventually dementia. In genetic tauopathies mutations of tau gene impair the ability of tau to bind to MTs, alter the normal ratio among tau isoforms and favor fibril formation. Recently, additional functions have been ascribed to tau and different pathogenetic mechanisms are then emerging. In fact, a role of tau in DNA protection and genome stability has been reported and chromosome aberrations have been found associated with tau mutations. Furthermore, newly structurally and functionally characterized mutations have suggested novel pathological features, such as a tendency to form oligomeric rather than fibrillar aggregates. Tau mutations affecting axonal transport and plasma membrane interaction have also been described. In this article, we will review the pathogenetic mechanisms underlying tau mutations, focusing in particular on the less common aspects, so far poorly investigated. PMID:26528178

  14. Molecular association of pathogenetic contributors to pre-eclampsia (pre-eclampsia associome)

    PubMed Central

    2015-01-01

    Background Pre-eclampsia is the most common complication occurring during pregnancy. In the majority of cases, it is concurrent with other pathologies in a comorbid manner (frequent co-occurrences in patients), such as diabetes mellitus, gestational diabetes and obesity. Providing bronchial asthma, pulmonary tuberculosis, certain neurodegenerative diseases and cancers as examples, we have shown previously that pairs of inversely comorbid pathologies (rare co-occurrences in patients) are more closely related to each other at the molecular genetic level compared with randomly generated pairs of diseases. Data in the literature concerning the causes of pre-eclampsia are abundant. However, the key mechanisms triggering this disease that are initiated by other pathological processes are thus far unknown. The aim of this work was to analyse the characteristic features of genetic networks that describe interactions between comorbid diseases, using pre-eclampsia as a case in point. Results The use of ANDSystem, Pathway Studio and STRING computer tools based on text-mining and database-mining approaches allowed us to reconstruct associative networks, representing molecular genetic interactions between genes, associated concurrently with comorbid disease pairs, including pre-eclampsia, diabetes mellitus, gestational diabetes and obesity. It was found that these associative networks statistically differed in the number of genes and interactions between them from those built for randomly chosen pairs of diseases. The associative network connecting all four diseases was composed of 16 genes (PLAT, ADIPOQ, ADRB3, LEPR, HP, TGFB1, TNFA, INS, CRP, CSRP1, IGFBP1, MBL2, ACE, ESR1, SHBG, ADA). Such an analysis allowed us to reveal differential gene risk factors for these diseases, and to propose certain, most probable, theoretical mechanisms of pre-eclampsia development in pregnant women. The mechanisms may include the following pathways: [TGFB1 or TNFA]-[IL1B]-[pre-eclampsia]; [TNFA

  15. Molecular Mechanics

    PubMed Central

    Vanommeslaeghe, Kenno; Guvench, Olgun; MacKerell, Alexander D.

    2014-01-01

    Molecular Mechanics (MM) force fields are the methods of choice for protein simulations, which are essential in the study of conformational flexibility. Given the importance of protein flexibility in drug binding, MM is involved in most if not all Computational Structure-Based Drug Discovery (CSBDD) projects. This section introduces the reader to the fundamentals of MM, with a special emphasis on how the target data used in the parametrization of force fields determine their strengths and weaknesses. Variations and recent developments such as polarizable force fields are discussed. The section ends with a brief overview of common force fields in CSBDD. PMID:23947650

  16. Peripheral neuropathies in Sjögren's syndrome: a critical update on clinical features and pathogenetic mechanisms.

    PubMed

    Pavlakis, P P; Alexopoulos, H; Kosmidis, M L; Mamali, I; Moutsopoulos, H M; Tzioufas, A G; Dalakas, M C

    2012-08-01

    Sjögren's syndrome is a systemic autoimmune disease that, apart from exocrine glands, may affect every organ or system. Involvement of different sections of the peripheral nervous system results in a wide spectrum of neuropathic manifestations. Based on distinct clinical, electrophysiological and histological criteria, the types of neuropathies seen in Sjögren's syndrome include: a) pure sensory which presents with distal symmetric sensory loss due to axonal degeneration of sensory fibers; sensory ataxia due to loss of proprioceptive large fibers (ganglionopathy); or with painful dysethesias (small fiber sensory neuropathy) due to degeneration of cutaneous axons. The latter appears to be the most common neuropathy in Sjögren's syndrome and requires skin biopsy for diagnosis to document loss or reduction of nerve fiber density; b) sensorimotor polyneuropathy affecting sensory and motor axons, often associated with severe systemic or pro-lymhomatous manifestations, such as palpable purpura and cryoglobulinemia, and c) rare types that include autoimmune demyelinating neuropathy, mononeuropathy, mononeuropathy multiplex and autonomic neuropathy. In this review, the frequency, prevalence and diagnostic criteria for each neuropathy subset are discussed and possible pathogenetic mechanisms are outlined. PMID:22318209

  17. Melanin targets LC3-associated phagocytosis (LAP): A novel pathogenetic mechanism in fungal disease.

    PubMed

    Chamilos, Georgios; Akoumianaki, Tonia; Kyrmizi, Irene; Brakhage, Axel; Beauvais, Anne; Latge, Jean-Paul

    2016-05-01

    Intracellular swelling of conidia of the major human airborne fungal pathogen Aspergillus fumigatus results in surface exposure of immunostimulatory pathogen-associated molecular patterns (PAMPs) and triggers activation of a specialized autophagy pathway called LC3-associated phagocytosis (LAP) to promote fungal killing. We have recently discovered that, apart from PAMPs exposure, cell wall melanin removal during germination of A. fumigatus is a prerequisite for activation of LAP. Importantly, melanin promotes fungal pathogenicity via targeting LAP, as a melanin-deficient A. fumigatus mutant restores its virulence upon conditional inactivation of Atg5 in hematopoietic cells of mice. Mechanistically, fungal cell wall melanin selectively excludes the CYBA/p22phox subunit of NADPH oxidase from the phagosome to inhibit LAP, without interfering with signaling regulating cytokine responses. Notably, inhibition of LAP is a general property of melanin pigments, a finding with broad physiological implications. PMID:27028978

  18. Defective angiogenesis delays thrombus resolution: a potential pathogenetic mechanism underlying chronic thromboembolic pulmonary hypertension

    PubMed Central

    Panzenboeck, Adelheid; Winter, Max P; Schubert, Uwe; Voswinckel, Robert; Frey, Maria K; Jakowitsch, Johannes; Alimohammadi, Arman; Hobohm, Lukas; Mangold, Andreas; Bergmeister, Helga; Sibilia, Maria; Wagner, Erwin F; Mayer, Eckhard; Klepetko, Walter; Hoelzenbein, Thomas J; Preissner, Klaus T; Lang, Irene M

    2015-01-01

    Objective Restoration of patency is a natural target of vascular remodeling following venous thrombosis that involves vascular endothelial cells and smooth muscle cells as well as leukocytes. Acute pulmonary emboli usually resolve within six months. However, in some instances, thrombi transform into fibrous vascular obstructions, resulting in occlusion of the deep veins, or in chronic thromboembolic pulmonary hypertension (CTEPH). We proposed that dysregulated thrombus angiogenesis may contribute to thrombus persistence. Approach and Results Mice with an endothelial-cell-specific conditional deletion of vascular endothelial growth factor receptor 2/kinase insert domain protein receptor (VEGF-R2/Kdr) were utilized in a model of stagnant flow venous thrombosis closely resembling human deep vein thrombosis. Biochemical and functional analyses were performed on pulmonary endarterectomy specimens from patients with CTEPH, a human model of non-resolving venous thromboembolism. Endothelial cell-specific deletion of Kdr and subsequent ablation of thrombus vascularization delayed thrombus resolution. In accordance with these findings, organized human CTEPH thrombi were largely devoid of vascular structures. Several vessel-specific genes such as KDR, vascular endothelial cadherin and podoplanin were expressed at lower levels in white CTEPH thrombi than in organizing deep vein thrombi and organizing thrombi from aortic aneurysms. In addition, red CTEPH thrombi attenuated the angiogenic response induced by VEGF. Conclusions In the present work, we propose a mechanism of thrombus non-resolution demonstrating that endothelial cell-specific deletion of Kdr abates thrombus vessel formation, misguiding thrombus resolution. Medical conditions associated with the development of CTEPH may be compromising early thrombus angiogenesis. PMID:24526692

  19. [Pathogenetic approaches to treating constipations].

    PubMed

    Luzina, E V

    2014-01-01

    Constipation affects 15-25% of people. Its mechanisms are various. There are constipations due to intestinal dyskinesia (functional constipation, irritated bowel syndrome), slow transit (colonic inertia), and muscular apparatus discoordination ensuring defecation (dyssynergic defecation). The treatment of different types of constipation uses prokinetics (type 4 serotonin receptor agonists, chlorine channels activators and guanylate cyclase C channel activators) or spasmolytics, among which pinaverium bromide (dicetel) has demonstrated its high efficacy. Biofeedback therapy or surgical techniques may be used. There is a need to prescribe laxatives in any type of constipation. A pathogenetic approach to treating constipation is most efficient. The paper characterizes stimulant, osmotic, volume, and emollient laxatives and agents stimulating the urge to defecate. It also gives the data of meta-analyses evaluating the efficacy of different drug groups. Particular emphasis is laid of the effect of lactulose and its first preparation--duphalac. PMID:25306754

  20. Study of Molecular Mechanisms Involved in the Pathogenesis of Immune-Mediated Inflammatory Diseases, using Psoriasis As a Model

    PubMed Central

    Sobolev, V.V.; Abdeev, R.M.; Zolotarenko, A.D.; Nikolaev, A.A.; Sarkisova, M.K.; Sautin, M.E.; Ishkin, A.A.; Piruzyan, An.L.; Ilyina, S.A.; Korsunskaya, I.M.; Rahimova, O.Y.; Bruskin, S.A.

    2009-01-01

    Psoriasis was used as a model to analyze the pathogenetic pathways of immune-mediated inflammatory diseases, and the results of bioinformatic, molecular-genetic and proteomic studies are provided. Cell mechanisms, common for the pathogenesis of psoriasis, as well as Crohn's disease, are identified. New approaches for immune-mediated diseases are discussed. PMID:22649625

  1. Molecular mechanisms of epilepsy

    PubMed Central

    Staley, Kevin

    2015-01-01

    Decades of experimental work have established an imbalance of excitation and inhibition as the leading mechanism of the transition from normal brain function to seizure. In epilepsy, these transitions are rare and abrupt. Transition processes incorporating positive feedback, such as activity-dependent disinhibition, could provide these unique timing features. A rapidly expanding array of genetic etiologies will help delineate the molecular mechanism(s). This delineation will entail quite a bit of cell biology. The genes discovered to date are currently more remarkable for their diversity than their similarities. PMID:25710839

  2. Quantitative differences in biosynthesis and extracellular deposition of fibrillin in cultured fibroblasts distinguish five groups of Marfan syndrome patients and suggest distinct pathogenetic mechanisms.

    PubMed Central

    Aoyama, T; Francke, U; Dietz, H C; Furthmayr, H

    1994-01-01

    Pulse-chase studies of [35S]cysteine-labeled fibrillin were performed on fibroblast strains from 55 patients with Marfan syndrome (MFS), including 13 with identified mutations in the fibrillin-1 gene and 10 controls. Quantitation of the soluble intracellular and insoluble extracellular fibrillin allowed discrimination of five groups. Groups I (n = 8) and II (n = 19) synthesize reduced amounts of normal-sized fibrillin, while synthesis is normal in groups III (n = 6), IV (n = 18), and V (n = 4). When extracellular fibrillin deposition is measured, groups I and III deposit between 35 and 70% of control values, groups II and IV < 35%, and group V > 70%. A deletion mutant with a low transcript level from the mutant allele and seven additional patients have the group I protein phenotype. Disease in these patients is caused by a reduction in microfibrils associated with either a null allele, an unstable transcript, or an altered fibrillin product synthesized in low amounts. In 68% of the MFS individuals (groups II and IV), a dominant negative effect is invoked as the main pathogenetic mechanism. Products made by the mutant allele in these fibroblasts are proposed to interfere with microfibril formation. Insertion, deletion, and exon skipping mutations, resulting in smaller fibrillin products, exhibit the group II phenotype. A truncated form of fibrillin of 60 kD was identified with specific fibrillin antibodies in one of the group II cell culture media. Seven of the nine known missense mutations, giving rise to abnormal, but normal-sized fibrillin molecules, are in group IV. Images PMID:8040255

  3. A new structural model of the acid-labile subunit: pathogenetic mechanisms of short stature-causing mutations.

    PubMed

    David, Alessia; Kelley, Lawrence A; Sternberg, Michael J E

    2012-12-01

    The acid-labile subunit (ALS) is the main regulator of IGF1 and IGF2 bioavailability. ALS deficiency caused by mutations in the ALS (IGFALS) gene often results in mild short stature in adulthood. Little is known about the ALS structure-function relationship. A structural model built in 1999 suggested a doughnut shape, which has never been observed in the leucine-rich repeat (LRR) superfamily, to which ALS belongs. In this study, we built a new ALS structural model, analysed its glycosylation and charge distribution and studied mechanisms by which missense mutations affect protein structure. We used three structure prediction servers and integrated their results with information derived from ALS experimental studies. The ALS model was built at high confidence using Toll-like receptor protein templates and resembled a horseshoe with an extensively negatively charged concave surface. Enrichment in prolines and disulphide bonds was found at the ALS N- and C-termini. Moreover, seven N-glycosylation sites were identified and mapped. ALS mutations were predicted to affect protein structure by causing loss of hydrophobic interactions (p.Leu134Gln), alteration of the amino acid backbone (p.Leu241Pro, p.Leu172Phe and p.Leu244Phe), loss of disulphide bridges (p.Cys60Ser and p.Cys540Arg), change in structural constrains (p.Pro73Leu), creation of novel glycosylation sites (p.Asp440Asn) or alteration of LRRs (p.Asn276Ser). In conclusion, our ALS structural model was identified as a highly confident prediction by three independent methods and disagrees with the previously published ALS model. The new model allowed us to analyse the ALS core and its caps and to interpret the potential structural effects of ALS mutations. PMID:22991227

  4. Moving beyond molecular mechanisms

    PubMed Central

    2015-01-01

    A major goal in cell biology is to bridge the gap in our understanding of how molecular mechanisms contribute to cell and organismal physiology. Approaches well established in the physical sciences could be instrumental in achieving this goal. A better integration of the physical sciences with cell biology will therefore be an important step in our quest to decipher how cells work together to construct a living organism. PMID:25601400

  5. BCR-ABL negative myeloproliferative neoplasia: a review of involved molecular mechanisms.

    PubMed

    Koopmans, Suzanne M; Schouten, Harry C; van Marion, Ariënne M W

    2015-02-01

    The clonal bone marrow stem cell disorders essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF) belong to the group of Philadelphia chromosome negative myeloproliferative neoplasia (Ph- MPN). In 2005 the JAK2(V617F) mutation was discovered which has generated more insight in the pathogenetic mechanism of the MPNs. More mutations have been detected in MPN patients since. However, the underlying cause of MPN has not been discovered so far. The mechanism of increased angiogenesis in MPNs and the development of fibrosis in the bone marrow in PMF patients and in some ET and PV patients is still not known. This review will focus on the most important molecular pathogenetic mechanisms in MPN patients. PMID:25196073

  6. MOLECULAR MECHANISMS OF PREECLAMPSIA

    PubMed Central

    Mutter, Walter P.; Karumanchi, S. Ananth

    2008-01-01

    Preeclampsia is a major cause of maternal, fetal, and neonatal mortality worldwide. The mechanisms that initiate preeclampsia in humans have been elusive, but some parts of the puzzle have begun to come together. A key discovery in the field was the realization that its major phenotypes, such as hypertension and proteinuria, are due to excess circulating soluble fms-like tyrosine kinase-1 (sFlt-1, also referred to as sVEGFR-1). sFlt-1 is an endogenous anti-angiogenic protein that is made by the placenta and acts by neutralizing the pro-angiogenic proteins vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). More recently, soluble endoglin, another circulating anti-angiogenic protein was found to synergize with sFlt1 and contribute to the pathogenesis of preeclampsia. Abnormalities in these circulating angiogenic proteins are not only present during clinical preeclampsia, but also antedate clinical symptoms by several weeks. This review will summarize our current understanding of the molecular mechanism of preeclampsia, with an emphasis on the recently characterized circulating anti-angiogenic proteins. PMID:17553534

  7. Molecular mechanisms of cancer.

    PubMed Central

    Koeffler, H. P.; McCormick, F.; Denny, C.

    1991-01-01

    Cancer is caused by specific DNA damage. Several common mechanisms that cause DNA damage result in specific malignant disorders: First, proto-oncogenes can be activated by translocations. For example, translocation of the c-myc proto-oncogene from chromosome 8 to one of the immunoglobulin loci on chromosomes 2, 14, or 22 results in Burkitt's lymphomas. Translocation of the c-abl proto-oncogene from chromosome 9 to the BCR gene located on chromosome 22 produces a hybrid BCR/ABL protein resulting in chronic myelogenous leukemia. Second, proto-oncogenes can be activated by point mutations. For example, point mutations of genes coding for guanosine triphosphate-binding proteins, such as H-, K-, or N-ras or G proteins, can be oncogenic as noted in a large variety of malignant neoplasms. Proteins from these mutated genes are constitutively active rather than being faithful second messengers of periodic extracellular signals. Third, mutations that inactivate a gene can result in tumors if the product of the gene normally constrains cellular proliferation. Functional loss of these "tumor suppressor genes" is found in many tumors such as colon and lung cancers. The diagnosis, classification, and treatment of cancers will be greatly enhanced by understanding their abnormalities at the molecular level. PMID:1815390

  8. Whither pathogenetic treatments for diabetic polyneuropathy?

    PubMed

    Boulton, Andrew J M; Kempler, Peter; Ametov, Alexander; Ziegler, Dan

    2013-07-01

    Diabetic distal symmetric polyneuropathy (DSPN) occurs in around one-third of patients with diabetes and is associated with significant morbidity and increased mortality. Diagnosis and clinical assessment of DSPN remain a challenge, not only for the physician in clinical practice but also for clinical trials. Optimal diabetes control is generally considered an essential first step in the prevention and management of DSPN. However, glycaemic control alone may be insufficient to prevent the development or progression of DSPN, especially in type 2 diabetes. Near-normoglycaemia is also difficult to achieve in a significant proportion of patients. Although considerable advances have been made in symptomatic pain management, these have not addressed the problem of sensory deficits and have no impact on the underlying pathogenesis of DSPN. There remains a lack of treatment options that effectively target the natural history of the disease. Several pathogenetic treatment approaches have been investigated, but evidence from clinical trials is limited with a number of treatments having shown disappointing results. However, some pathogenetic therapies have shown clinically relevant improvements in neuropathic endpoints in randomised controlled trials, in particular α-lipoic acid and Actovegin. These advances in DSPN disease modification need to be confirmed with further robust evidence from clinical trials together with a better understanding of the mechanisms of action of promising treatments. PMID:23381942

  9. von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy

    PubMed Central

    2013-01-01

    von Willebrand disease (VWD) is the most common autosomally inherited bleeding disorder. The disease represents a range of quantitative and qualitative pathologies of the adhesive glycoprotein von Willebrand factor (VWF). The pathogenic mechanisms responsible for the type 2 qualitative variants of VWF are now well characterized, with most mutations representing missense substitutions influencing VWF multimer structure and interactions with platelet GPIbα and collagen and with factor VIII. The molecular pathology of type 3 VWD has been similarly well characterized, with an array of different mutation types producing either a null phenotype or the production of VWF that is not secreted. In contrast, the pathogenetic mechanisms responsible for type 1 VWD remain only partially resolved. In the hemostasis laboratory, the measurement of VWF:Ag and VWF:RCo are key components in the diagnostic algorithm for VWD, although the introduction of direct GPIbα-binding assays may become the functional assay of choice. Molecular genetic testing can provide additional benefit, but its utility is currently limited to type 2 and 3 VWD. The treatment of bleeding in VWD involves the use of desmopressin and plasma-derived VWF concentrates and a variety of adjunctive agents. Finally, a new recombinant VWF concentrate has just completed clinical trial evaluation and has demonstrated excellent hemostatic efficacy and safety. PMID:24065240

  10. Molecular mechanism of preconditioning.

    PubMed

    Das, Manika; Das, Dipak K

    2008-04-01

    During the last 20 years, since the appearance of the first publication on ischemic preconditioning (PC), our knowledge of this phenomenon has increased exponentially. PC is defined as an increased tolerance to ischemia and reperfusion induced by previous sublethal period ischemia. This is the most powerful mechanism known to date for limiting the infract size. This adaptation occurs in a biphasic pattern (i) early preconditioning (lasts for 2-3 h) and (ii) late preconditioning (starting at 24 h lasting until 72-96 h after initial ischemia). Early preconditioning is more potent than delayed preconditioning in reducing infract size. Late preconditioning attenuates myocardial stunning and requires genomic activation with de novo protein synthesis. Early preconditioning depends on adenosine, opioids and to a lesser degree, on bradykinin and prostaglandins, released during ischemia. These molecules activate G-protein-coupled receptor, initiate activation of K(ATP) channel and generate oxygen-free radicals, and stimulate a series of protein kinases, which include protein kinase C, tyrosine kinase, and members of MAP kinase family. Late preconditioning is triggered by a similar sequence of events, but in addition essentially depends on newly synthesized proteins, which comprise iNOS, COX-2, manganese superoxide dismutase, and possibly heat shock proteins. The final mechanism of PC is still not very clear. The present review focuses on the possible role signaling molecules that regulate cardiomyocyte life and death during ischemia and reperfusion. PMID:18344203

  11. The GH-IGF-SST system in hepatocellular carcinoma: biological and molecular pathogenetic mechanisms and therapeutic targets

    PubMed Central

    2014-01-01

    Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide. Different signalling pathways have been identified to be implicated in the pathogenesis of HCC; among these, GH, IGF and somatostatin (SST) pathways have emerged as some of the major pathways implicated in the development of HCC. Physiologically, GH-IGF-SST system plays a crucial role in liver growth and development since GH induces IGF1 and IGF2 secretion and the expression of their receptors, involved in hepatocytes cell proliferation, differentiation and metabolism. On the other hand, somatostatin receptors (SSTRs) are exclusively present on the biliary tract. Importantly, the GH-IGF-SST system components have been indicated as regulators of hepatocarcinogenesis. Reduction of GH binding affinity to GH receptor, decreased serum IGF1 and increased serum IGF2 production, overexpression of IGF1 receptor, loss of function of IGF2 receptor and appearance of SSTRs are frequently observed in human HCC. In particular, recently, many studies have evaluated the correlation between increased levels of IGF1 receptors and liver diseases and the oncogenic role of IGF2 and its involvement in angiogenesis, migration and, consequently, in tumour progression. SST directly or indirectly influences tumour growth and development through the inhibition of cell proliferation and secretion and induction of apoptosis, even though SST role in hepatocarcinogenesis is still opened to argument. This review addresses the present evidences suggesting a role of the GH-IGF-SST system in the development and progression of HCC, and describes the therapeutic perspectives, based on the targeting of GH-IGF-SST system, which have been hypothesised and experimented in HCC. PMID:25225571

  12. Autoimmune uveitis: clinical, pathogenetic, and therapeutic features.

    PubMed

    Prete, Marcella; Dammacco, Rosanna; Fatone, Maria Celeste; Racanelli, Vito

    2016-05-01

    Autoimmune uveitis (AU), an inflammatory non-infectious process of the vascular layer of the eye, can lead to visual impairment and, in the absence of a timely diagnosis and suitable therapy, can even result in total blindness. The majority of AU cases are idiopathic, whereas fewer than 20 % are associated with systemic diseases. The clinical severity of AU depends on whether the anterior, intermediate, or posterior part of the uvea is involved and may range from almost asymptomatic to rapidly sight-threatening forms. Race, genetic background, and environmental factors can also influence the clinical picture. The pathogenetic mechanism of AU is still poorly defined, given its remarkable heterogeneity and the many discrepancies between experimental and human uveitis. Even so, the onset of AU is thought to be related to an aberrant T cell-mediated immune response, triggered by inflammation and directed against retinal or cross-reactive antigens. B cells may also play a role in uveal antigen presentation and in the subsequent activation of T cells. The management of AU remains a challenge for clinicians, especially because of the paucity of randomized clinical trials that have systematically evaluated the effectiveness of different drugs. In addition to topical treatment, several different therapeutic options are available, although a standardized regimen is thus far lacking. Current guidelines recommend corticosteroids as the first-line therapy for patients with active AU. Immunosuppressive drugs may be subsequently required to treat steroid-resistant AU and for steroid-sparing purposes. The recent introduction of biological agents, such as those targeting tumor necrosis factor-α, is expected to remarkably increase the percentages of responders and to prevent irreversible sight impairment. This paper reviews the clinical features of AU and its crucial pathogenetic targets in relation to the current therapeutic perspectives. Also, the largest clinical trials

  13. Molecular Mechanism of Water Evaporation

    NASA Astrophysics Data System (ADS)

    Nagata, Yuki; Usui, Kota; Bonn, Mischa

    2015-12-01

    Evaporation is the process by which water changes from a liquid to a gas or vapor, and is a key step in Earth's water cycle. At the molecular level, evaporation requires breaking at least one very strong intermolecular bond between two water molecules at the interface. Despite the importance of this process the molecular mechanism by which an evaporating water molecule gains sufficient energy to escape from the surface has remained elusive. Here, we show, using molecular dynamics simulations at the water-air interface with polarizable classical force field models, that the high kinetic energy of the evaporated water molecule is enabled by a well-timed making and breaking of hydrogen bonds involving at least three water molecules at the interface, the recoil of which allows one of the molecules to escape. The evaporation of water is thus enabled by concerted, ultrafast hydrogen-bond dynamics of interfacial water, and follows one specific molecular pathway.

  14. Molecular Mechanisms of Arterial Stiffening

    PubMed Central

    Cecelja, Marina; Chowienczyk, Phil

    2016-01-01

    Stiffening of large arteries is a hallmark of vascular aging and one of the most important determinants of the age-related increase in blood pressure and cardiovascular disease events. Despite a substantial genetic component, the molecular mechanisms underlying phenotypic variability in arterial stiffness remain unknown. Previous genetic studies have identified several genetic variants that are associated with measures of arterial stiffness. Here, we review the relevant advances in the identification of pathways underlying arterial stiffness from genomic studies. PMID:27493903

  15. Molecular Mechanisms of Nickel Allergy

    PubMed Central

    Saito, Masako; Arakaki, Rieko; Yamada, Akiko; Tsunematsu, Takaaki; Kudo, Yasusei; Ishimaru, Naozumi

    2016-01-01

    Allergic contact hypersensitivity to metals is a delayed-type allergy. Although various metals are known to produce an allergic reaction, nickel is the most frequent cause of metal allergy. Researchers have attempted to elucidate the mechanisms of metal allergy using animal models and human patients. Here, the immunological and molecular mechanisms of metal allergy are described based on the findings of previous studies, including those that were recently published. In addition, the adsorption and excretion of various metals, in particular nickel, is discussed to further understand the pathogenesis of metal allergy. PMID:26848658

  16. Superspreading: mechanisms and molecular design.

    PubMed

    Theodorakis, Panagiotis E; Müller, Erich A; Craster, Richard V; Matar, Omar K

    2015-03-01

    The intriguing ability of certain surfactant molecules to drive the superspreading of liquids to complete wetting on hydrophobic substrates is central to numerous applications that range from coating flow technology to enhanced oil recovery. Despite significant experimental efforts, the precise mechanisms underlying superspreading remain unknown to date. Here, we isolate these mechanisms by analyzing coarse-grained molecular dynamics simulations of surfactant molecules of varying molecular architecture and substrate affinity. We observe that for superspreading to occur, two key conditions must be simultaneously satisfied: the adsorption of surfactants from the liquid-vapor surface onto the three-phase contact line augmented by local bilayer formation. Crucially, this must be coordinated with the rapid replenishment of liquid-vapor and solid-liquid interfaces with surfactants from the interior of the droplet. This article also highlights and explores the differences between superspreading and conventional surfactants, paving the way for the design of molecular architectures tailored specifically for applications that rely on the control of wetting. PMID:25658859

  17. Molecular Mechanism of TRP Channels

    PubMed Central

    Zheng, Jie

    2013-01-01

    Transient receptor potential (TRP) channels are cellular sensors for a wide spectrum of physical and chemical stimuli. They are involved in the formation of sight, hearing, touch, smell, taste, temperature, and pain sensation. TRP channels also play fundamental roles in cell signaling and allow the host cell to respond to benign or harmful environmental changes. As TRP channel activation is controlled by very diverse processes and, in many cases, exhibits complex polymodal properties, understanding how each TRP channel responds to its unique forms of activation energy is both crucial and challenging. The past two decades witnessed significant advances in understanding the molecular mechanisms that underlie TRP channels activation. This review focuses on our current understanding of the molecular determinants for TRP channel activation. PMID:23720286

  18. Molecular Mechanisms of Synaptic Specificity

    PubMed Central

    Margeta, Milica A.; Shen, Kang

    2011-01-01

    Synapses are specialized junctions that mediate information flow between neurons and their targets. A striking feature of the nervous system is the specificity of its synaptic connections: an individual neuron will form synapses only with a small subset of available presynaptic and postsynaptic partners. Synaptic specificity has been classically thought to arise from homophilic or heterophilic interactions between adhesive molecules acting across the synaptic cleft. Over the past decade, many new mechanisms giving rise to synaptic specificity have been identified. Synapses can be specified by secreted molecules that promote or inhibit synaptogenesis, and their source can be a neighboring guidepost cell, not just presynaptic and postsynaptic neurons. Furthermore, lineage, fate, and timing of development can also play critical roles in shaping neural circuits. Future work utilizing large-scale screens will aim to elucidate the full scope of cellular mechanisms and molecular players that can give rise to synaptic specificity. PMID:19969086

  19. Anticancer Molecular Mechanisms of Resveratrol

    PubMed Central

    Varoni, Elena M.; Lo Faro, Alfredo Fabrizio; Sharifi-Rad, Javad; Iriti, Marcello

    2016-01-01

    Resveratrol is a pleiotropic phytochemical belonging to the stilbene family. Though it is only significantly present in grape products, a huge amount of preclinical studies investigated its anticancer properties in a plethora of cellular and animal models. Molecular mechanisms of resveratrol involved signaling pathways related to extracellular growth factors and receptor tyrosine kinases; formation of multiprotein complexes and cell metabolism; cell proliferation and genome instability; cytoplasmic tyrosine kinase signaling (cytokine, integrin, and developmental pathways); signal transduction by the transforming growth factor-β super-family; apoptosis and inflammation; and immune surveillance and hormone signaling. Resveratrol also showed a promising role to counteract multidrug resistance: in adjuvant therapy, associated with 5-fluoruracyl and cisplatin, resveratrol had additive and/or synergistic effects increasing the chemosensitization of cancer cells. Resveratrol, by acting on diverse mechanisms simultaneously, has been emphasized as a promising, multi-target, anticancer agent, relevant in both cancer prevention and treatment. PMID:27148534

  20. Molecular mechanisms of temperature adaptation.

    PubMed

    Bagriantsev, Sviatoslav N; Gracheva, Elena O

    2015-08-15

    Thermal perception is a fundamental physiological process pertaining to the vast majority of organisms. In vertebrates, environmental temperature is detected by the primary afferents of the somatosensory neurons in the skin, which express a 'choir' of ion channels tuned to detect particular temperatures. Nearly two decades of research have revealed a number of receptor ion channels that mediate the perception of several temperature ranges, but most still remain molecularly orphaned. Yet even within this well-researched realm, most of our knowledge largely pertains to two closely related species of rodents, mice and rats. While these are standard biomedical research models, mice and rats provide a limited perspective to elucidate the general principles that drive somatosensory evolution. In recent years, significant advances have been made in understanding the molecular mechanism of temperature adaptation in evolutionarily distant vertebrates and in organisms with acute thermal sensitivity. These studies have revealed the remarkable versatility of the somatosensory system and highlighted adaptations at the molecular level, which often include changes in biophysical properties of ion channels from the transient receptor potential family. Exploiting non-standard animal models has the potential to provide unexpected insights into general principles of thermosensation and thermoregulation, unachievable using the rodent model alone. PMID:25433072

  1. Molecular mechanisms of temperature adaptation

    PubMed Central

    Bagriantsev, Sviatoslav N; Gracheva, Elena O

    2015-01-01

    Thermal perception is a fundamental physiological process pertaining to the vast majority of organisms. In vertebrates, environmental temperature is detected by the primary afferents of the somatosensory neurons in the skin, which express a ‘choir’ of ion channels tuned to detect particular temperatures. Nearly two decades of research have revealed a number of receptor ion channels that mediate the perception of several temperature ranges, but most still remain molecularly orphaned. Yet even within this well-researched realm, most of our knowledge largely pertains to two closely related species of rodents, mice and rats. While these are standard biomedical research models, mice and rats provide a limited perspective to elucidate the general principles that drive somatosensory evolution. In recent years, significant advances have been made in understanding the molecular mechanism of temperature adaptation in evolutionarily distant vertebrates and in organisms with acute thermal sensitivity. These studies have revealed the remarkable versatility of the somatosensory system and highlighted adaptations at the molecular level, which often include changes in biophysical properties of ion channels from the transient receptor potential family. Exploiting non-standard animal models has the potential to provide unexpected insights into general principles of thermosensation and thermoregulation, unachievable using the rodent model alone. PMID:25433072

  2. Negative regulation of erythroblast maturation by Fas-L(+)/TRAIL(+) highly malignant plasma cells: a major pathogenetic mechanism of anemia in multiple myeloma.

    PubMed

    Silvestris, Franco; Cafforio, Paola; Tucci, Marco; Dammacco, Franco

    2002-02-15

    Multiple myeloma (MM) is associated with severe normochromic/normocytic anemia. This study demonstrates that the abnormal up-regulation of apoptogenic receptors, including both Fas ligand (L) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), by highly malignant myeloma cells is involved in the pathogenesis of the ineffective erythropoiesis and chronic exhaustion of the erythroid matrix. By measuring Fas-L and TRAIL in plasma cells and the content of glycophorin A (GpA) in erythroblasts from a cohort of 28 untreated, newly diagnosed patients with MM and 7 with monoclonal gammopathy of undetermined significance (MGUS), selected in relation to their peripheral hemoglobin values, results showed that both receptors occurred at high levels in 15 severely anemic MM patients. Their marrow erythropoietic component was low and included predominantly immature GpA(+dim) erythroblasts, in contrast with the higher relative numbers of mature GpA(+bright) erythroid cells observed in the nonanemic patients and those with MGUS. In cocultures with autologous Fas-L(+)/TRAIL(+) myeloma cells, the expanded GpA(+dim) erythroid population underwent prompt apoptosis after direct exposure to malignant plasma cells, whereas erythroblasts from nonanemic patients were scarcely affected. The evidence that Fas-L(+)/TRAIL(+) malignant plasma cells prime erythroblast apoptosis by direct cytotoxicity was also supported by the increase of FLICE in fresh immature GpA(+dim) erythroid cells, whereas ICE and caspase-10 increased in subsequent maturative forms. In addition, GATA-1, a survival factor for erythroid precursors, was remarkably down-regulated in fresh erythroblasts from the severely anemic patients. These results indicate that progressive destruction of the erythroid matrix in aggressive MM is due to cytotoxic mechanisms based on the up-regulation in myeloma cells of Fas-L, TRAIL, or both. It is conceivable that the altered regulation of these receptors defines a peculiar

  3. Molecular mechanisms of microglial activation.

    PubMed

    Zielasek, J; Hartung, H P

    1996-01-01

    Microglial cells are brain macrophages which serve specific functions in the defense of the central nervous system (CNS) against microorganisms, the removal of tissue debris in neurodegenerative diseases or during normal development, and in autoimmune inflammatory disorders of the brain. In cultured microglial cells, several soluble inflammatory mediators such as cytokines and bacterial products like lipopolysaccharide (LPS) were demonstrated to induce a wide range of microglial activities, e.g. increased phagocytosis, chemotaxis, secretion of cytokines, activation of the respiratory burst and induction of nitric oxide synthase. Since heightened microglial activation was shown to play a role in the pathogenesis of experimental inflammatory CNS disorders, understanding the molecular mechanisms of microglial activation may lead to new treatment strategies for neurodegenerative disorders, multiple sclerosis and bacterial or viral infections of the nervous system. PMID:8876774

  4. Molecular Mechanisms of Bacterial Pathogenicity

    NASA Astrophysics Data System (ADS)

    Fuchs, Thilo Martin

    Cautious optimism has arisen over recent decades with respect to the long struggle against bacteria, viruses, and parasites. This has been offset, however, by a fatal complacency stemming from previous successes such as the development of antimicrobial drugs, the eradication of smallpox, and global immunization programs. Infectious diseases nevertheless remain the world's leading cause of death, killing at least 17 million persons annually [61]. Diarrheal diseases caused by Vibrio cholerae or Shigella dysenteriae kill about 3 million persons every year, most of them young children: Another 4 million die of tuberculosis or tetanus. Outbreaks of diphtheria in Eastern Europe threatens the population with a disease that had previously seemed to be overcome. Efforts to control infectious diseases more comprehensively are undermined not only by socioeconomic conditions but also by the nature of the pathogenic organisms itself; some isolates of Staphylococcus aureus and Enterobacter have become so resistant to drugs by horizontal gene transfer that they are almost untreatable. In addition, the mechanism of genetic variability helps pathogens to evade the human immune system, thus compromising the development of powerful vaccines. Therefore detailed knowledge of the molecular mechanisms of microbial pathogenicity is absolutely necessary to develop new strategies against infectious diseases and thus to lower their impact on human health and social development.

  5. [Pathogenetic mechanisms of tick-borne encephalitis].

    PubMed

    Panov, A G; Il'enko, V I; Komandenko, N I

    1977-01-01

    The main cause of progressive forms of tickborne encephalitis is a prolonged persistence of certain viral strains in the brain. Although there are no virals with a selective capability to lead only to an acute or chronic encephalitis, nevertheless in the epidemiological process there is a selection of virals capable of bringing on chronic forms of the disease. In cases of an incapacity of immunological factors bor a defence during the initial phase of the infectious process there may be prerequisites to a fixation of the virals in the brain and a chronic development of the neuroinfections. It is necessary to differentiate active neuroinfectious processes due to persistent virals and postencephalitic reparative-dystrophical syndromes. This permits to avoid a hyperdiagnosis and more reasonably select therapeutical measures in the evaluation of their effectivity. PMID:402756

  6. Molecular mechanisms of pancreatic carcinogenesis.

    PubMed

    Furukawa, Toru; Sunamura, Makoto; Horii, Akira

    2006-01-01

    Pancreatic ductal adenocarcinoma is one of the most fatal malignancies. Intensive investigation of molecular pathogenesis might lead to identifying useful molecules for diagnosis and treatment of the disease. Pancreatic ductal adenocarcinoma harbors complicated aberrations of alleles including losses of 1p, 6q, 9p, 12q, 17p, 18q, and 21q, and gains of 8q and 20q. Pancreatic cancer is usually initiated by mutation of KRAS and aberrant expression of SHH. Overexpression of AURKA mapping on 20q13.2 may significantly enhance overt tumorigenesity. Aberrations of tumor suppressor genes synergistically accelerate progression of the carcinogenic pathway through pancreatic intraepithelial neoplasia (PanIN) to invasive ductal adenocarcinoma. Abrogation of CDKN2A occurs in low-grade/early PanIN, whereas aberrations of TP53 and SMAD4 occur in high-grade/late PanIN. SMAD4 may play suppressive roles in tumorigenesis by inhibition of angiogenesis. Loss of 18q precedes SMAD4 inactivation, and restoration of chromosome 18 in pancreatic cancer cells results in tumor suppressive phenotypes regardless of SMAD4 status, indicating the possible existence of a tumor suppressor gene(s) other than SMAD4 on 18q. DUSP6 at 12q21-q22 is frequently abrogated by loss of expression in invasive ductal adenocarcinomas despite fairly preserved expression in PanIN, which suggests that DUSP6 works as a tumor suppressor in pancreatic carcinogenesis. Restoration of chromosome 12 also suppresses growths of pancreatic cancer cells despite the recovery of expression of DUSP6; the existence of yet another tumor suppressor gene on 12q is strongly suggested. Understanding the molecular mechanisms of pancreatic carcinogenesis will likely provide novel clues for preventing, detecting, and ultimately curing this life-threatening disease. PMID:16367914

  7. Coronaviridae, pathogenetic and clinical aspects: an update.

    PubMed

    Möstl, K

    1990-01-01

    A review is given about pathogenetic and clinical aspects of the well-known as well as of recently detected members of the family Coronaviridae. Special attention is paid to coronavirus infections of domestic cattle and pets, whereas avian, murine, rat and human coronaviruses are summarized briefly. PMID:1963836

  8. Molecular mechanisms of statin intolerance

    PubMed Central

    Franczyk, Beata; Toth, Peter P.; Rysz, Jacek; Banach, Maciej

    2016-01-01

    Statins reduce cardiovascular morbidity and mortality in primary and secondary prevention. Despite their efficacy, many persons are unable to tolerate statins due to adverse events such as hepatotoxicity and myalgia/myopathy. In the case of most patients, it seems that mild-to-moderate abnormalities in liver and muscle enzymes are not serious adverse effects and do not outweigh the benefits of coronary heart disease risk reduction. The risk for mortality or permanent organ damage ascribed to statin use is very small and limited to cases of myopathy and rhabdomyolysis. Statin-induced muscle-related adverse events comprise a highly heterogeneous clinical disorder with numerous, complex etiologies and a variety of genetic backgrounds. Every patient who presents with statin-related side effects cannot undergo the type of exhaustive molecular characterization that would include all of these mechanisms. Frequently the only solution is to either discontinue statin therapy/reduce the dose or attempt intermittent dosing strategies at a low dose. PMID:27279860

  9. Atopic dermatitis: molecular mechanisms, clinical aspects and new therapeutical approaches.

    PubMed

    Galli, E; Cicconi, R; Rossi, P; Casati, A; Brunetti, E; Mancino, G

    2003-03-01

    Atopic dermatitis (AD) is a genetically determinated, chronic inflammatory skin disorder associated with cutaneous erythema and severe pruritus, affecting 10-15% of children with increasing incidence and socio-economical relevance. Frequently, AD is associated with development of allergic rhinitis and/or asthma later in childhood. In most of patients AD is associated with a sensitization to food and/or environmental allergens and increased serum-IgE, while only a fewer percentage missed links to the classical atopic diathesis. Currently investigated pathogenetic aspects of AD include imbalanced Th1/Th2 responses, altered prostaglandin metabolism, intrinsic defects in the keratinocyte function, delayed eosinophil apoptosis, and IgE-mediated facilitated antigen presentation by epidermal dendritic cells. An inflammatory response of the two-phase-type and the effects of staphylococcal superantigens (SAgs) are also reported. At present a standardized cure of AD and a consensus on therapeutical approach of the severe form of the disease have not been established. Current management of AD is directed to the reduction of cutaneous inflammation and infection, mainly by S. aureus, and to the elimination of exacerbating factors (irritants, allergens, emotional stresses). Since patient with AD show abnormalities in immunoregulation, therapy directed to adjustment of their immune function could represent an alternative approach, particularly in the severe form of the disease. In this review, we analyse the clinical and genetic aspects of AD, the related molecular mechanisms, and the immunobiology of the disease, focusing our attention on current treatments and future perspectives on this topic. PMID:12630559

  10. Molecular Mechanics: Illustrations of Its Application.

    ERIC Educational Resources Information Center

    Cox, Philip J.

    1982-01-01

    The application of molecular mechanics (a nonquantum mechanical method for solving problems concerning molecular geometries) to calculate force fields for n-butane and cyclohexane is discussed. Implications regarding the stable conformations of the example molecules are also discussed. (Author/SK)

  11. The pathogenetic bases of sarcopenia

    PubMed Central

    Budui, Simona L.; Rossi, Andrea P.; Zamboni, Mauro

    2015-01-01

    Summary Aging is accompanied by involuntary loss of skeletal muscle mass, strength and function, called sarcopenia. The mechanisms underlying the development of sarcopenia are not completely understood and most likely multi-factorial, but significant progress has been made over the past few years to identify some of the major contributors. Besides life style-related factors, as diet and physical activity, sarcopenia seems to be also determined by hormonal dysregulation, chronic inflammatory status, ectopic adipose tissue accumulation, neurological and vascular changes associated with aging. The present mini-review focused on the basic factors that primarily impact muscle homeostasis in older subjects. A better understanding of cellular mechanism leading to sarcopenia is required to establish evidence-based intervention in order to prevent onset of symptoms associated with sarcopenia and to extend the time free from disability in older adults. PMID:26136791

  12. [The pathogenetic bases of cardiorenal syndrome].

    PubMed

    Beloglazova, I P; Mogutova, P A; Poteshkina, N G

    2012-01-01

    The term "cardiorenal syndrome" has been introduced to denote the mutual influences of the cardiovascular system and kidneys. According to the definition, the cardiorenal syndrome is a pathophysiological condition of the heart and kidney, in which acute or chronic dysfunction of one of these organs leads to that of the other. The community of pathogenetic components allows one to apply a comprehensive approach to diagnosing, treating, and preventing cardiovascular and renal diseases. PMID:23091862

  13. Polarization effects in molecular mechanical force fields

    PubMed Central

    Cieplak, Piotr; Dupradeau, François-Yves; Duan, Yong; Wang, Junmei

    2014-01-01

    The focus here is on incorporating electronic polarization into classical molecular mechanical force fields used for macromolecular simulations. First, we briefly examine currently used molecular mechanical force fields and the current status of intermolecular forces as viewed by quantum mechanical approaches. Next, we demonstrate how some components of quantum mechanical energy are effectively incorporated into classical molecular mechanical force fields. Finally, we assess the modeling methods of one such energy component—polarization energy—and present an overview of polarizable force fields and their current applications. Incorporating polarization effects into current force fields paves the way to developing potentially more accurate, though more complex, parameterizations that can be used for more realistic molecular simulations. PMID:21828594

  14. Polarization effects in molecular mechanical force fields.

    PubMed

    Cieplak, Piotr; Dupradeau, François-Yves; Duan, Yong; Wang, Junmei

    2009-08-19

    The focus here is on incorporating electronic polarization into classical molecular mechanical force fields used for macromolecular simulations. First, we briefly examine currently used molecular mechanical force fields and the current status of intermolecular forces as viewed by quantum mechanical approaches. Next, we demonstrate how some components of quantum mechanical energy are effectively incorporated into classical molecular mechanical force fields. Finally, we assess the modeling methods of one such energy component-polarization energy-and present an overview of polarizable force fields and their current applications. Incorporating polarization effects into current force fields paves the way to developing potentially more accurate, though more complex, parameterizations that can be used for more realistic molecular simulations. PMID:21828594

  15. Driving Mechanisms for Molecular Outflows

    NASA Astrophysics Data System (ADS)

    Downes, Turlough P.

    Molecular outflows are observed to be closely associated with star formation. The cumulative momentum and the momentum injection rate in these outflows are important parameters in theories of star formation. The cumulative momentum in an outflow is a measure of the feed-back from star formation on molecular cloud turbulence. The level of turbulence in a cloud also effects the formation of further stars and, indeed, the survival of the cloud itself (e.g. [15]). In addition the rate of injection of momentum is an important constraint for theoretical models of outflows from young stars [10, 18]. Hence, while these outflows are interesting in themselves, it is also critical to understand their origin and behaviour as part of the general study of how stars themselves form.

  16. Molecular mechanisms of hepatic apoptosis

    PubMed Central

    Wang, K

    2014-01-01

    Apoptosis is a prominent feature of liver diseases. Causative factors such as alcohol, viruses, toxic bile acids, fatty acids, drugs, and immune response, can induce apoptotic cell death via membrane receptors and intracellular stress. Apoptotic signaling network, including membrane death receptor-mediated cascade, reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress, lysosomal permeabilization, and mitochondrial dysfunction, is intermixed each other, but one mechanism may dominate at a particular stage. Mechanisms of hepatic apoptosis are complicated by multiple signaling pathways. The progression of liver disease is affected by the balance between apoptotic and antiapoptotic capabilities. Therapeutic options of liver injury are impacted by the clear understanding toward mechanisms of hepatic apoptosis. PMID:24434519

  17. Molecular Mechanisms Underlying Pituitary Pathogenesis.

    PubMed

    Sapochnik, Melanie; Nieto, Leandro Eduardo; Fuertes, Mariana; Arzt, Eduardo

    2016-04-01

    During the last years, progress has been made on the identification of mechanisms involved in anterior pituitary cell transformation and tumorigenesis. Oncogene activation, tumor suppressor gene inactivation, epigenetic changes, and microRNAs deregulation contribute to the initiation of pituitary tumors. Despite the high prevalence of pituitary adenomas, they are mostly benign, indicating that intrinsic mechanisms may regulate pituitary cell expansion. Senescence is characterized by an irreversible cell cycle arrest and represents an important protective mechanism against malignancy. Pituitary tumor transforming gene (PTTG) is an oncogene involved in early stages of pituitary tumor development, and also triggers a senescence response by activating DNA-damage signaling pathway. Cytokines, as well as many other factors, play an important role in pituitary physiology, affecting not only cell proliferation but also hormone secretion. Special interest is focused on interleukin-6 (IL-6) because its dual function of stimulating pituitary tumor cell growth but inhibiting normal pituitary cells proliferation. It has been demonstrated that IL-6 has a key role in promoting and maintenance of the senescence program in tumors. Senescence, triggered by PTTG activation and mediated by IL-6, may be a mechanism for explaining the benign nature of pituitary tumors. PMID:26718581

  18. Cellular and molecular mechanisms in kidney fibrosis

    PubMed Central

    Duffield, Jeremy S.

    2014-01-01

    Fibrosis is a characteristic feature of all forms of chronic kidney disease. Deposition of pathological matrix in the interstitial space and within the walls of glomerular capillaries as well as the cellular processes resulting in this deposition are increasingly recognized as important factors amplifying kidney injury and accelerating nephron demise. Recent insights into the cellular and molecular mechanisms of fibrogenesis herald the promise of new therapies to slow kidney disease progression. This review focuses on new findings that enhance understanding of cellular and molecular mechanisms of fibrosis, the characteristics of myofibroblasts, their progenitors, and molecular pathways regulating both fibrogenesis and its resolution. PMID:24892703

  19. Molecular mechanisms of induced pluripotency

    PubMed Central

    Wróblewska, Joanna; Mazurek, Sylwia; Liszewska, Ewa

    2015-01-01

    Growing knowledge concerning transcriptional control of cellular pluripotency has led to the discovery that the fate of differentiated cells can be reversed, which has resulted in the generation, by means of genetic manipulation, of induced pluripotent stem cells. Overexpression of just four pluripotency-related transcription factors, namely Oct3/4, Sox2, Klf4, and c-Myc (Yamanaka factors, OKSM), in fibroblasts appears sufficient to produce this new cell type. Currently, we know that these factors induce several changes in genetic program of differentiated cells that can be divided in two general phases: the initial one is stochastic, and the subsequent one is highly hierarchical and organised. This review briefly discusses the molecular events leading to induction of pluripotency in response to forced presence of OKSM factors in somatic cells. We also discuss other reprogramming strategies used thus far as well as the advantages and disadvantages of laboratory approaches towards pluripotency induction in different cell types. PMID:25691818

  20. Molecular pathogenesis and mechanisms of thyroid cancer

    PubMed Central

    Xing, Mingzhao

    2013-01-01

    Thyroid cancer is a common endocrine malignancy. There has been exciting progress in understanding its molecular pathogenesis in recent years, as best exemplified by the elucidation of the fundamental role of several major signalling pathways and related molecular derangements. Central to these mechanisms are the genetic and epigenetic alterations in these pathways, such as mutation, gene copy-number gain and aberrant gene methylation. Many of these molecular alterations represent novel diagnostic and prognostic molecular markers and therapeutic targets for thyroid cancer, which provide unprecedented opportunities for further research and clinical development of novel treatment strategies for this cancer. PMID:23429735

  1. Molecular mechanism of sweetness sensation.

    PubMed

    DuBois, Grant E

    2016-10-01

    The current understanding of peripheral molecular events involved in sweet taste sensation in humans is reviewed. Included are discussions of the sweetener receptor T1R2/T1R3, its agonists, antagonists, positive allosteric modulators, the transduction of its activation in taste bud cells and the coding of its signaling to the CNS. Areas of incomplete understanding include 1) signal communication with afferent nerve fibers, 2) contrasting concentration/response (C/R) functions for high-potency (HP) sweeteners (hyperbolic) and carbohydrate (CHO) sweeteners (linear), 3) contrasting temporal profiles for HP sweeteners (delayed onset and extinction) and CHO sweeteners (rapid onset and extinction) and 4) contrasting adaptation behaviors for HP sweeteners (moderate to strong adaptation) and CHO sweeteners (low adaptation). Evidence based on the sweet water aftertastes of several novel sweetness inhibitors is presented providing new support for constitutive activity in T1R2/T1R3. And a model is developed to rationalize the linear C/R functions of CHO sweeteners and hyperbolic C/R functions of HP sweeteners, where the former may activate T1R2/T1R3 by both binding and constitutive activity modulation (i.e., without binding) and the latter activate T1R2/T1R3 only by binding. PMID:26992959

  2. Molecular mechanism of cholangiocarcinoma carcinogenesis.

    PubMed

    Maemura, Kosei; Natsugoe, Shoji; Takao, Sonshin

    2014-10-01

    Cholangiocarcinoma (CCA) is a highly malignant cancer of the biliary tract with a poor prognosis, which often arises from conditions causing long-term inflammation, injury, and reparative biliary epithelial cell proliferation. Several conditions are known to be major risk factors for cancer in the biliary tract or gallbladder, including primary sclerosing cholangitis, liver fluke infection, pancreaticobiliary maljunction, and chemical exposure in proof-printing workers. Abnormalities in various signaling cascades, molecules, and genetic mutations are involved in the pathogenesis of CCA. CCA is characterized by a series of highly recurrent mutations in genes, including KRAS, BRF, TP53, Smad, and p16(INK4a) . Cytokines that are affected by inflammatory environmental conditions, such as interleukin-6 (IL-6), transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), and platelet-derived growth factor (PDGF), play an important role in cancer pathogenesis. Prominent signaling pathways important in carcinogenesis include TGF-β/Smad, IL-6/STAT-3, PI3K/AKT, Wnt, RAF/MEK/MAPK, and Notch. Additionally, some microRNAs regulate targets in critical pathways of CCA development and progression. This review article provides the understanding of the genetic and epigenetic mechanism(s) of carcinogenesis in CCA, which leads to the development of new therapeutic targets for the prevention and treatment of this devastating cancer. PMID:24895231

  3. Molecular mechanisms of ventricular hypoplasia.

    PubMed

    Srivastava, D; Gottlieb, P D; Olson, E N

    2002-01-01

    We have established the beginnings of a road map to understand how ventricular cells become specified, differentiate, and expand into a functional cardiac chamber (Fig. 5). The transcriptional networks described here provide clear evidence that disruption of pathways affecting ventricular growth could be the underlying etiology in a subset of children born with malformation of the right or left ventricle. As we learn details of the precise mechanisms through which the critical factors function, the challenge will lie in devising innovative methods to augment or modify the effects of gene mutations on ventricular development. Because most congenital heart disease likely occurs in a setting of heterozygous, predisposing mutations of one or more genes, modulation of activity of critical pathways in a preventive fashion may be useful in averting disease in genetically susceptible individuals. PMID:12858532

  4. A molecular mechanics force field for lignin

    SciTech Connect

    Petridis, Loukas; Smith, Jeremy C

    2009-02-01

    A CHARMM molecular mechanics force field for lignin is derived. Parameterization is based on reproducing quantum mechanical data of model compounds. Partial atomic charges are derived using the RESP electrostatic potential fitting method supplemented by the examination of methoxybenzene:water interactions. Dihedral parameters are optimized by fitting to critical rotational potentials and bonded parameters are obtained by optimizing vibrational frequencies and normal modes. Finally, the force field is validated by performing a molecular dynamics simulation of a crystal of a lignin fragment molecule and comparing simulation-derived structural features with experimental results. Together with the existing force field for polysaccharides, this lignin force field will enable full simulations of lignocellulose.

  5. [Feasibility of pathogenetic therapy for hysteria].

    PubMed

    Semke, V Ia

    1981-01-01

    On the basis of combined clinico-dynamic and neurophysiological examinations of 371 patients with hysteria and 180 patients with hysteriform disturbances a concept on the necessity of their pathogenetic treatment with consideration of the stage and degree of the emotional disturbances is proposed. In cases of an acute or subacute course of the disease, combinations of hypnosuggestive therapy with modified autogenic training are shown to be effective. For patients with a lingering course combinations of psychotherapeutic and biological methods with the use of central cholinolytics (for relaxing the high tone of the cholinergic system), psychostimulants and antidepressants (for strengthening the tone of the serotoninergic structures) are indicated. In resistant cases, medicinal therapy with median and high doses of atropine is recommended. An individualized, staged complex approach to the therapy of hysteria with indispensable consideration of the age factor is shown to bae the most advisable. PMID:6114603

  6. Osteoarthritis Pathogenesis: A Review of Molecular Mechanisms

    PubMed Central

    Xia, Bingjiang; Chen, Di; Zhang, Jushi; Hu, Songfeng; Jin, Hongting; Tong, Peijian

    2016-01-01

    Osteoarthritis (OA), the most prevalent chronic joint disease, increases in prevalence with age, and affects majority of individuals over the age of 65 and is a leading musculoskeletal cause of impaired mobility in the elderly. Because the precise molecular mechanisms which are involved in the degradation of cartilage matrix and development of OA are poorly understood and there are currently no effective interventions to decelerate the progression of OA or retard the irreversible degradation of cartilage except for total joint replacement surgery. In this paper, the important molecular mechanisms related to OA pathogenesis will be summarized and new insights into potential molecular targets for the prevention and treatment of OA will be provided. PMID:25311420

  7. Gene Fusions in Soft Tissue Tumors: Recurrent and Overlapping Pathogenetic Themes

    PubMed Central

    Mertens, Fredrik; Antonescu, Cristina R.; Mitelman, Felix

    2016-01-01

    Gene fusions have been described in approximately one-third of soft tissue tumors (STT); of the 142 different fusions that have been reported, more than half are recurrent in the same histologic subtype. These gene fusions constitute pivotal driver mutations, and detailed studies of their cellular effects have provided important knowledge about pathogenetic mechanisms in STT. Furthermore, most fusions are strongly associated with a particular histotype, serving as ideal molecular diagnostic markers. In recent years, it has also become apparent that some chimeric proteins, directly or indirectly, constitute excellent treatment targets, making the detection of gene fusions in STT ever more important. Indeed, pharmacological treatment of STT displaying fusions that activate protein kinases, such as ALK and ROS1, or growth factors, such as PDGFB, is already in clinical use. However, the vast majority (52/78) of recurrent gene fusions create structurally altered and/or deregulated transcription factors, and a small but growing subset develops through rearranged chromatin regulators. The present review provides an overview of the spectrum of currently recognized gene fusions in STT, and, on the basis of the protein class involved, the mechanisms by which they exert their oncogenic effect are discussed. PMID:26684580

  8. Disease resistance: Molecular mechanisms and biotechnological applications

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This special issue “Disease resistance: molecular mechanisms and biotechnological applications” contains 11 review articles and four original research papers. Research in the area of engineering for disease resistance continues to progress although only 10% of the transgenic plants registered for ...

  9. Ocular diseases: immunological and molecular mechanisms

    PubMed Central

    Song, Jing; Huang, Yi-Fei; Zhang, Wen-Jing; Chen, Xiao-Fei; Guo, Yu-Mian

    2016-01-01

    Many factors, such as environmental, microbial and endogenous stress, antigen localization, can trigger the immunological events that affect the ending of the diverse spectrum of ocular disorders. Significant advances in understanding of immunological and molecular mechanisms have been researched to improve the diagnosis and therapy for patients with ocular inflammatory diseases. Some kinds of ocular diseases are inadequately responsive to current medications; therefore, immunotherapy may be a potential choice as an alternative or adjunctive treatment, even in the prophylactic setting. This article first provides an overview of the immunological and molecular mechanisms concerning several typical and common ocular diseases; second, the functions of immunological roles in some of systemic autoimmunity will be discussed; third, we will provide a summary of the mechanisms that dictate immune cell trafficking to ocular local microenvironment in response to inflammation. PMID:27275439

  10. [Molecular mechanisms for AMPA receptor trafficking].

    PubMed

    Fukata, Masaki; Fukata, Yuko

    2008-06-01

    Finely tuned synaptic transmission in the brain provides the molecular basis for learning and memory. The misregulation of synaptic transmission is involved in the pathogenesis of various neurological disorders like epilepsy. AMPA-typed glutamate receptors (AMPARs) mediate the most prominent form of excitatory neurotransmission in the brain. Dynamic regulation of AMPARs is thought to be a primary mechanism for controlling synaptic strength. We have analyzed the molecular mechanism for AMPAR-trafficking and function by focusing on PSD-95, a major postsynaptic scaffolding protein. Here, we review the novel regulatory mechanisms of AMPARs by 1) the PSD-95 palmitoylating enzyme, which determines the position of PSD-95 at postsynapses, and 2) the epilepsy related ligand/receptor, LGI1/ADAM22, identified as the PSD-95-interacting protein. PMID:18646599

  11. Mutagenesis and cardiovascular diseases Molecular mechanisms, risk factors, and protective factors.

    PubMed

    De Flora, Silvio; Izzotti, Alberto

    2007-08-01

    Although no generalization can be made, it is of interest that cancer, cardiovascular diseases, and other chronic conditions often share common risk factors and common protective factors as well as common pathogenetic determinants, such as DNA damage, oxidative stress, and chronic inflammation. Atherosclerosis is the most important cause of vascular forms representing the major cause of death in the population of many geographical areas. A great deal of studies support the "response-to-injury" theory. A variety of experimental and epidemiological findings are also in favor of the somatic mutation theory, which maintains that the earliest event in the atherogenic process is represented by mutations in arterial smooth muscle cells, akin to formation of a benign tumor. These two theories can be harmonized, also taking into account the highly diversified nature of atherosclerotic lesions. Molecular epidemiology studies performed in our laboratory and other laboratories have shown that DNA adducts are systematically present in arterial smooth muscle cells, and their levels are correlated with atherogenic risk factors known from traditional epidemiology. Oxidative DNA damage was also consistently detected in these cells. The role of glutathione S-transferase polymorphisms on the frequency of the above molecular alterations and of arterial diseases is rather controversial. Prevention of both cancer and atherosclerosis is based on avoidance of exposure to risk factors and on fortification of the host defense mechanisms by means of dietary principles and chemopreventive drugs. PMID:17383689

  12. Sampling Molecular Conformers in Solution with Quantum Mechanical Accuracy at a Nearly Molecular-Mechanics Cost.

    PubMed

    Rosa, Marta; Micciarelli, Marco; Laio, Alessandro; Baroni, Stefano

    2016-09-13

    We introduce a method to evaluate the relative populations of different conformers of molecular species in solution, aiming at quantum mechanical accuracy, while keeping the computational cost at a nearly molecular-mechanics level. This goal is achieved by combining long classical molecular-dynamics simulations to sample the free-energy landscape of the system, advanced clustering techniques to identify the most relevant conformers, and thermodynamic perturbation theory to correct the resulting populations, using quantum-mechanical energies from density functional theory. A quantitative criterion for assessing the accuracy thus achieved is proposed. The resulting methodology is demonstrated in the specific case of cyanin (cyanidin-3-glucoside) in water solution. PMID:27494227

  13. Geochemical Reaction Mechanism Discovery from Molecular Simulation

    SciTech Connect

    Stack, Andrew G.; Kent, Paul R. C.

    2014-11-10

    Methods to explore reactions using computer simulation are becoming increasingly quantitative, versatile, and robust. In this review, a rationale for how molecular simulation can help build better geochemical kinetics models is first given. We summarize some common methods that geochemists use to simulate reaction mechanisms, specifically classical molecular dynamics and quantum chemical methods and discuss their strengths and weaknesses. Useful tools such as umbrella sampling and metadynamics that enable one to explore reactions are discussed. Several case studies wherein geochemists have used these tools to understand reaction mechanisms are presented, including water exchange and sorption on aqueous species and mineral surfaces, surface charging, crystal growth and dissolution, and electron transfer. The impact that molecular simulation has had on our understanding of geochemical reactivity are highlighted in each case. In the future, it is anticipated that molecular simulation of geochemical reaction mechanisms will become more commonplace as a tool to validate and interpret experimental data, and provide a check on the plausibility of geochemical kinetic models.

  14. Geochemical Reaction Mechanism Discovery from Molecular Simulation

    DOE PAGESBeta

    Stack, Andrew G.; Kent, Paul R. C.

    2014-11-10

    Methods to explore reactions using computer simulation are becoming increasingly quantitative, versatile, and robust. In this review, a rationale for how molecular simulation can help build better geochemical kinetics models is first given. We summarize some common methods that geochemists use to simulate reaction mechanisms, specifically classical molecular dynamics and quantum chemical methods and discuss their strengths and weaknesses. Useful tools such as umbrella sampling and metadynamics that enable one to explore reactions are discussed. Several case studies wherein geochemists have used these tools to understand reaction mechanisms are presented, including water exchange and sorption on aqueous species and mineralmore » surfaces, surface charging, crystal growth and dissolution, and electron transfer. The impact that molecular simulation has had on our understanding of geochemical reactivity are highlighted in each case. In the future, it is anticipated that molecular simulation of geochemical reaction mechanisms will become more commonplace as a tool to validate and interpret experimental data, and provide a check on the plausibility of geochemical kinetic models.« less

  15. Molecular mechanisms underlying alcohol-drinking behaviours.

    PubMed

    Ron, Dorit; Barak, Segev

    2016-09-01

    The main characteristic of alcohol use disorder is the consumption of large quantities of alcohol despite the negative consequences. The transition from the moderate use of alcohol to excessive, uncontrolled alcohol consumption results from neuroadaptations that cause aberrant motivational learning and memory processes. Here, we examine studies that have combined molecular and behavioural approaches in rodents to elucidate the molecular mechanisms that keep the social intake of alcohol in check, which we term 'stop pathways', and the neuroadaptations that underlie the transition from moderate to uncontrolled, excessive alcohol intake, which we term 'go pathways'. We also discuss post-transcriptional, genetic and epigenetic alterations that underlie both types of pathways. PMID:27444358

  16. Molecular Mechanisms of Inherited Demyelinating Neuropathies

    PubMed Central

    SCHERER, STEVEN S.; WRABETZ, LAWRENCE

    2008-01-01

    The past 15 years have witnessed the identification of more than 25 genes responsible for inherited neuropathies in humans, many associated with primary alterations of the myelin sheath. A remarkable body of work in patients, as well as animal and cellular models, has defined the clinical and molecular genetics of these illnesses and shed light on how mutations in associated genes produce the heterogeneity of dysmyelinating and demyelinating phenotypes. Here, we review selected recent developments from work on the molecular mechanisms of these disorders and their implications for treatment strategies. PMID:18803325

  17. Cellular and molecular mechanisms underlying presynapse formation

    PubMed Central

    Chia, Poh Hui; Li, Pengpeng

    2013-01-01

    Synapse formation is a highly regulated process that requires the coordination of many cell biological events. Decades of research have identified a long list of molecular components involved in assembling a functioning synapse. Yet how the various steps, from transporting synaptic components to adhering synaptic partners and assembling the synaptic structure, are regulated and precisely executed during development and maintenance is still unclear. With the improvement of imaging and molecular tools, recent work in vertebrate and invertebrate systems has provided important insight into various aspects of presynaptic development, maintenance, and trans-synaptic signals, thereby increasing our understanding of how extrinsic organizers and intracellular mechanisms contribute to presynapse formation. PMID:24127213

  18. Cellular and molecular mechanisms underlying muscular dystrophy

    PubMed Central

    2013-01-01

    The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle. Since the discovery of the first muscular dystrophy gene encoding dystrophin, a large number of genes have been identified that are involved in various muscle-wasting and neuromuscular disorders. Human genetic studies complemented by animal model systems have substantially contributed to our understanding of the molecular pathomechanisms underlying muscle degeneration. Moreover, these studies have revealed distinct molecular and cellular mechanisms that link genetic mutations to diverse muscle wasting phenotypes. PMID:23671309

  19. Nonlinear vibrational excitations in molecular crystals molecular mechanics calculations

    NASA Astrophysics Data System (ADS)

    Pumilia, P.; Abbate, S.; Baldini, G.; Ferro, D. R.; Tubino, R.

    1992-03-01

    The coupling constant for vibrational solitons χ has been examined in a molecular mechanics model for acetanilide (ACN) molecular crystal. According to A.C. Scott, solitons can form and propagate in solid acetanilide over a threshold energy value. This can be regarded as a structural model for the spines of hydrogen bond chains stabilizing the α helical structure of proteins. A one dimensional hydrogen bond chain of ACN has been built, for which we have found that, even though experimental parameters are correctly predicted, the excessive rigidity of the isolated chain prevents the formation of a localized distortion around the excitation. Yet, C=O coupling value with softer lattice modes could be rather high, allowing self-trapping to take place.

  20. Molecular mechanisms of membrane interaction at implantation.

    PubMed

    Davidson, Lien M; Coward, Kevin

    2016-03-01

    Successful pregnancy is dependent upon the implantation of a competent embryo into a receptive endometrium. Despite major advancement in our understanding of reproductive medicine over the last few decades, implantation failure still occurs in both normal pregnancies and those created artificially by assisted reproductive technology (ART). Consequently, there is significant interest in elucidating the etiology of implantation failure. The complex multistep process of implantation begins when the developing embryo first makes contact with the plasma membrane of epithelial cells within the uterine environment. However, although this biological interaction marks the beginning of a fundamental developmental process, our knowledge of the intricate physiological and molecular processes involved remains sparse. In this synopsis, we aim to provide an overview of our current understanding of the morphological changes which occur to the plasma membrane of the uterine endothelium, and the molecular mechanisms that control communication between the early embryo and the endometrium during implantation. A multitude of molecular factors have been implicated in this complex process, including endometrial integrins, extracellular matrix molecules, adhesion molecules, growth factors, and ion channels. We also explore the development of in vitro models for embryo implantation to help researchers investigate mechanisms which may underlie implantation failure. Understanding the precise molecular pathways associated with implantation failure could help us to generate new prognostic/diagnostic biomarkers, and may identify novel therapeutic targets. PMID:26969610

  1. Autocatalytic Decomposition Mechanisms in Energetic Molecular Crystals

    NASA Astrophysics Data System (ADS)

    Kuklja, Maija; Rashkeev, Sergey

    2009-06-01

    Atomic scale mechanisms of the initiation of chemical processes in energetic molecular crystals, which lead to the decomposition and ultimately to an explosive chain reaction, are still far from being understood. In this work, we investigate the onset of the initiation processes in two high explosive crystals - diamino-dinitroethylene (DADNE) and triamino- trinitrobenzene (TATB). We found that an autocatalytic decomposition mechanism is likely to take place in DADNE crystal that consists of corrugated, dashboard-shaped molecular layers. The presence of a dissociated NO2 group in the interstitial space between two layers induces a significant shear-strain between these layers, which, in turn, facilitates the further dissociation of NO2 groups from surrounding molecules through lowering the C-NO2 decomposition barrier. Unlike this, in TATB (that consists of flat, graphite-like molecular layers), an interstitial NO2 group positioned between two layers tends to produce a tensile stress (rather than a shear-strain), which leads to local molecular disorder in these layers without any significant modification of the C-NO2 decomposition barrier. The observed differences between the two materials are discussed in terms of their structural, electronic, and chemical properties.

  2. Mechanisms and Molecular Probes of Sirtuins

    PubMed Central

    Smith, Brian C.; Hallows, William C.; Denu, John M.

    2008-01-01

    Summary Sirtuins are critical regulators of many cellular processes including insulin secretion, the cell cycle, and apoptosis. Sirtuins are associated with a variety of age-associated diseases such as type II diabetes, obesity, and Alzheimer’s disease. A thorough understanding of sirtuin chemical mechanisms will aid toward developing novel therapeutics that regulate metabolic disorders and combat associated diseases. In this review, we discuss the unique deacetylase mechanism of sirtuins and how this information might be employed to develop inhibitors and other molecular probes for therapeutic and basic research applications. We also cover physiological regulation of sirtuin activity and how these modes of regulation may be exploited to manipulate sirtuin activity in live cells. Development of molecular probes and drugs that specifically target sirtuins will further understanding of sirtuin biology and potentially afford new treatments of several human diseases. PMID:18940661

  3. Molecular Mechanism of Biological Proton Transport

    SciTech Connect

    Pomes, R.

    1998-09-01

    Proton transport across lipid membranes is a fundamental aspect of biological energy transduction (metabolism). This function is mediated by a Grotthuss mechanism involving proton hopping along hydrogen-bonded networks embedded in membrane-spanning proteins. Using molecular simulations, the authors have explored the structural, dynamic, and thermodynamic properties giving rise to long-range proton translocation in hydrogen-bonded networks involving water molecules, or water wires, which are emerging as ubiquitous H{sup +}-transport devices in biological systems.

  4. Molecular regulatory mechanism of tooth root development

    PubMed Central

    Huang, Xiao-Feng; Chai, Yang

    2012-01-01

    The root is crucial for the physiological function of the tooth, and a healthy root allows an artificial crown to function as required clinically. Tooth crown development has been studied intensively during the last few decades, but root development remains not well understood. Here we review the root development processes, including cell fate determination, induction of odontoblast and cementoblast differentiation, interaction of root epithelium and mesenchyme, and other molecular mechanisms. This review summarizes our current understanding of the signaling cascades and mechanisms involved in root development. It also sets the stage for de novo tooth regeneration. PMID:23222990

  5. Molecular mechanism of magnet formation in bacteria.

    PubMed

    Matsunaga, T; Sakaguchi, T

    2000-01-01

    Magnetic bacteria have an ability to synthesize intracellular ferromagnetic crystalline particles consisting of magnetite (Fe3O4) or greigite (Fe3S4) which occur within a specific size range (50-100 nm). Bacterial magnetic particles (BMPs) can be distinguished by the regular morphology and the presence of an thin organic membrane enveloping crystals from abiologically formed magnetite. The particle is the smallest magnetic crystal that has a regular morphology within the single domain size. Therefore, BMPs have an unfathomable amount of potential value for various technological applications not only scientific interests. However, the molecular and genetic mechanism of magnetite biomineralization is hardly understood although iron oxide formation occurs widely in many higher animals as well as microorganisms. In order to elucidate the molecular and genetic mechanisms of magnetite biomineralization, a magnetic bacterium Magnetospirillum sp. AMB-1, for which gene transfer and transposon mutagenesis techniques had been recently developed, has been used as a model organism. Several findings and information on the BMPs formation process have been obtained within this decade by means of studies with this model organism and its related one. Biomineralization mechanism and potential availability in biotechnology of bacterial magnets have been elucidated through molecular and genetic approach. PMID:16232810

  6. Molecular and cellular mechanisms of cardiotoxicity.

    PubMed Central

    Kang, Y J

    2001-01-01

    Cardiotoxicity resulting from detrimental environmental insults has been recognized for a long time. However, extensive studies of the mechanisms involved had not been undertaken until recent years. Advances in molecular biology provide powerful tools and make such studies possible. We are gathering information about cellular events, signaling pathways, and molecular mechanisms of myocardial toxicologic responses to environmental toxicants and pollutants. Severe acute toxic insults cause cardiac cell death instantly. In the early response to mild environmental stimuli, biochemical changes such as alterations in calcium homeostasis occur. These may lead to cardiac arrhythmia, which most often is reversible. Prolonged stimuli activate transcription factors such as activator protein-1 through elevation of intracellular calcium and the subsequent activation of calcineurin. Upregulation by activated transcription factors of hypertrophic genes results in heart hypertrophy, which is a short-term adaptive response to detrimental factors. However, further development of hypertrophy will lead to severe and irreversible cardiomyopathy, and eventually heart failure. From cardiac hypertrophy to heart failure, myocardial cells undergo extensive biochemical and molecular changes. Cardiac hypertrophy causes tissue hypoperfusion, which activates compensatory mechanisms such as production of angiotensin II and norepinephrine. Both further stimulate cardiac hypertrophy and, importantly, activate counterregulatory mechanisms including overexpression of atrial natriuretic peptide and b-type natriuretic peptide, and production of cytokines such as tumor necrosis factor-alpha. This counterregulation leads to myocardial remodeling as well as cell death through apoptosis and necrosis. Cell death through activation of mitochondrial factors and other pathways constitutes an important cellular mechanism of heart failure. Our current knowledge of cardiotoxicity is limited. Further extensive

  7. Molecular mechanics of mussel adhesion proteins

    NASA Astrophysics Data System (ADS)

    Qin, Zhao; Buehler, Markus J.

    2014-01-01

    Mussel foot protein (mfp), a natural glue produced by marine mussel, is an intriguing material because of its superior ability for adhesion in various environments. For example, a very small amount of this material is sufficient to affix a mussel to a substrate in water, providing structural support under extreme forces caused by the dynamic effects of waves. Towards a more complete understanding of its strength and underwater workability, it is necessary to understand the microscropic mechanisms by which the protein structure interacts with various substrates. However, none of the mussel proteins' structure is known, preventing us from directly using atomistic modeling to probe their structural and mechanical properties. Here we use an advanced molecular sampling technique to identify the molecular structures of two mussel foot proteins (mfp-3 and mfp-5) and use those structures to study their mechanics of adhesion, which is then incorporated into a continuum model. We calculate the adhesion energy of the mussel foot protein on a silica substrate, compute the adhesion strength based on results obtained from molecular modeling, and compare with experimental data. Our results show good agreement with experimental measurements, which validates the multiscale model. We find that the molecular structure of the folded mussel foot protein (ultimately defined by its genetic sequence) favors strong adhesion to substrates, where L-3,4-dihydroxyphenylalanine (or DOPA) protein subunits work in a cooperative manner to enhance adhesion. Our experimental data suggests a peak attachment force of 0.4±0.1 N, which compares favorably with the prediction from the multiscale model of Fc=0.21-0.33 N. The principles learnt from those results could guide the fabrication of new interfacial materials (e.g. composites) to integrate organic with inorganic surfaces in an effective manner.

  8. A mechanical micro molecular mass sensor

    PubMed Central

    Kurhekar, A. S.; Apte, P. R.

    2014-01-01

    One of the bio-sensing mechanisms is mechanical. Rather than measuring shift in resonance frequency, we adopt to measure the change in spring constant due to adsorption, as one of the fundamental sensing mechanism. This study explains determination of spring constant of a surface functionalized micro machined micro cantilever, which resonates in a trapezoidal cavity-on Silicon <100> wafer, with the resonating frequency of 7000 cycles per second. This thin-flimsy-oxide micro-cantilever has a typical shape, and the tip of the micro-cantilever is dip-coated with chemically and biologically active material. The change in mass, due to adsorption, is detected by measuring the change in spring constant. The Force-Distance spectroscopy is used to detect the change in spring constant. The experimental results, show that the mechanical sensing scheme used, permit this surface functionalized micro machined micro cantilever to be used as a molecular mass sensor. The mechanical spring behaviour of a micro-cantilever, a micro-mechanical device can be used to develop ultra-tech micro-mechanical system using computer interface. PMID:24459585

  9. Molecular Mechanisms of Renal Ischemic Conditioning Strategies.

    PubMed

    Kierulf-Lassen, Casper; Nieuwenhuijs-Moeke, Gertrude J; Krogstrup, Nicoline V; Oltean, Mihai; Jespersen, Bente; Dor, Frank J M F

    2015-01-01

    Ischemia-reperfusion injury is the leading cause of acute kidney injury in a variety of clinical settings such as renal transplantation and hypovolemic and/or septic shock. Strategies to reduce ischemia-reperfusion injury are obviously clinically relevant. Ischemic conditioning is an inherent part of the renal defense mechanism against ischemia and can be triggered by short periods of intermittent ischemia and reperfusion. Understanding the signaling transduction pathways of renal ischemic conditioning can promote further clinical translation and pharmacological advancements in this era. This review summarizes research on the molecular mechanisms underlying both local and remote ischemic pre-, per- and postconditioning of the kidney. The different types of conditioning strategies in the kidney recruit similar powerful pro-survival mechanisms. Likewise, renal ischemic conditioning mobilizes many of the same protective signaling pathways as in other organs, but differences are recognized. PMID:26330099

  10. Molecular mechanisms for protein-encoded inheritance

    SciTech Connect

    Wiltzius, Jed J.W.; Landau, Meytal; Nelson, Rebecca; Sawaya, Michael R.; Apostol, Marcin I.; Goldschmidt, Lukasz; Soriaga, Angela B.; Cascio, Duilio; Rajashankar, Kanagalaghatta; Eisenberg, David

    2009-12-01

    In prion inheritance and transmission, strains are phenotypic variants encoded by protein 'conformations'. However, it is unclear how a protein conformation can be stable enough to endure transmission between cells or organisms. Here we describe new polymorphic crystal structures of segments of prion and other amyloid proteins, which offer two structural mechanisms for the encoding of prion strains. In packing polymorphism, prion strains are encoded by alternative packing arrangements (polymorphs) of {beta}-sheets formed by the same segment of a protein; in segmental polymorphism, prion strains are encoded by distinct {beta}-sheets built from different segments of a protein. Both forms of polymorphism can produce enduring conformations capable of encoding strains. These molecular mechanisms for transfer of protein-encoded information into prion strains share features with the familiar mechanism for transfer of nucleic acid-encoded information into microbial strains, including sequence specificity and recognition by noncovalent bonds.

  11. Mechanically induced luminescence changes in molecular assemblies.

    PubMed

    Sagara, Yoshimitsu; Kato, Takashi

    2009-11-01

    Altering the shape and properties of a material through external factors such as heat, light, pressure, pH, electric or magnetic fields, or the introduction of a guest molecule, is an attractive prospect. In this Perspective, piezochromic luminescent materials - which change the colour of their luminescence in response to mechanical stimuli - are described. Such piezochromism has been observed for a few molecular materials that contain luminescent cores in liquid-crystalline and crystalline solid states, as well as for polymeric materials doped with dyes. These changes in photoluminescent colour can be activated by various types of mechanical pressure such as shearing, grinding or elongation, which can trigger different mechanisms of producing the colour. Such stimuli-responsive materials have potential for various applications, including sensors, memory and displays. PMID:21378953

  12. Molecular mechanisms of curcumin action: gene expression.

    PubMed

    Shishodia, Shishir

    2013-01-01

    Curcumin derived from the tropical plant Curcuma longa has a long history of use as a dietary agent, food preservative, and in traditional Asian medicine. It has been used for centuries to treat biliary disorders, anorexia, cough, diabetic wounds, hepatic disorders, rheumatism, and sinusitis. The preventive and therapeutic properties of curcumin are associated with its antioxidant, anti-inflammatory, and anticancer properties. Extensive research over several decades has attempted to identify the molecular mechanisms of curcumin action. Curcumin modulates numerous molecular targets by altering their gene expression, signaling pathways, or through direct interaction. Curcumin regulates the expression of inflammatory cytokines (e.g., TNF, IL-1), growth factors (e.g., VEGF, EGF, FGF), growth factor receptors (e.g., EGFR, HER-2, AR), enzymes (e.g., COX-2, LOX, MMP9, MAPK, mTOR, Akt), adhesion molecules (e.g., ELAM-1, ICAM-1, VCAM-1), apoptosis related proteins (e.g., Bcl-2, caspases, DR, Fas), and cell cycle proteins (e.g., cyclin D1). Curcumin modulates the activity of several transcription factors (e.g., NF-κB, AP-1, STAT) and their signaling pathways. Based on its ability to affect multiple targets, curcumin has the potential for the prevention and treatment of various diseases including cancers, arthritis, allergies, atherosclerosis, aging, neurodegenerative disease, hepatic disorders, obesity, diabetes, psoriasis, and autoimmune diseases. This review summarizes the molecular mechanisms of modulation of gene expression by curcumin. PMID:22996381

  13. Molecular mechanism of viscoelasticity in aligned polyethylene

    NASA Astrophysics Data System (ADS)

    Hammad, Ali; Hasan, Hikmatyar; Swinburne, Thomas; Del Rosso, Stefano; Iannucci, Lorenzo; Sutton, Adrian

    2014-03-01

    Aligned polyethylene is used in industrial and medical applications due to its low density and high tensile strength. Extensive experimental work has been done to determine its mechanical properties, notably its viscoelasticity. However, the molecular processes that underlie these macroscopic properties are poorly understood. We develop a united atom model of aligned chains, in which intermolecular interactions are modelled by a Lennard-Jones potential, and the elastic energy within chains is modelled with harmonic springs. Using this simple model, we demonstrate the nucleation of solitons from chain ends, as one molecular chain is stretched with respect to another, and how load is transferred between chains in disregistry by intermolecular interactions. We develop an equation of motion for the movement of solitons along molecular chains, allowing us to replace a collection of aligned chains with a gas of solitons. Although solitons have been invoked to account for dielectric relaxation in crystalline regions of polyethylene, we believe this may be the first time they are discussed in the context of mechanical properties of aligned polyethylene.

  14. Molecular Mechanisms of Prolactin and Its Receptor

    PubMed Central

    2012-01-01

    Prolactin and the prolactin receptors are members of a family of hormone/receptor pairs which include GH, erythropoietin, and other ligand/receptor pairs. The mechanisms of these ligand/receptor pairs have broad similarities, including general structures, ligand/receptor stoichiometries, and activation of several common signaling pathways. But significant variations in the structural and mechanistic details are present among these hormones and their type 1 receptors. The prolactin receptor is particularly interesting because it can be activated by three sequence-diverse human hormones: prolactin, GH, and placental lactogen. This system offers a unique opportunity to compare the detailed molecular mechanisms of these related hormone/receptor pairs. This review critically evaluates selected literature that informs these mechanisms, compares the mechanisms of the three lactogenic hormones, compares the mechanism with those of other class 1 ligand/receptor pairs, and identifies information that will be required to resolve mechanistic ambiguities. The literature describes distinct mechanistic differences between the three lactogenic hormones and their interaction with the prolactin receptor and describes more significant differences between the mechanisms by which other related ligands interact with and activate their receptors. PMID:22577091

  15. Molecular pathways mediating mechanical signaling in bone

    PubMed Central

    Rubin, Janet; Rubin, Clinton; Jacobs, Christopher Rae

    2013-01-01

    Bone tissue has the capacity to adapt to its functional environment such that its morphology is “optimized” for the mechanical demand. The adaptive nature of the skeleton poses an interesting set of biological questions (e.g., how does bone sense mechanical signals, what cells are the sensing system, what are the mechanical signals that drive the system, what receptors are responsible for transducing the mechanical signal, what are the molecular responses to the mechanical stimuli). Studies of the characteristics of the mechanical environment at the cellular level, the forces that bone cells recognize, and the integrated cellular responses are providing new information at an accelerating speed. This review first considers the mechanical factors that are generated by loading in the skeleton, including strain, stress and pressure. Mechanosensitive cells placed to recognize these forces in the skeleton, osteoblasts, osteoclasts, osteocytes and cells of the vasculature are reviewed. The identity of the mechanoreceptor(s) is approached, with consideration of ion channels, integrins, connexins, the lipid membrane including caveolar and noncaveolar lipid rafts and the possibility that altering cell shape at the membrane or cytoskeleton alters integral signaling protein associations. The distal intracellular signaling systems on-line after the mechanoreceptor is activated are reviewed, including those emanating from G-proteins (e.g., intracellular calcium shifts), MAPKs, and nitric oxide. The ability to harness mechanical signals to improve bone health through devices and exercise is broached. Increased appreciation of the importance of the mechanical environment in regulating and determining the structural efficacy of the skeleton makes this an exciting time for further exploration of this area. PMID:16361069

  16. Cellular and Molecular Mechanisms of AKI.

    PubMed

    Agarwal, Anupam; Dong, Zheng; Harris, Raymond; Murray, Patrick; Parikh, Samir M; Rosner, Mitchell H; Kellum, John A; Ronco, Claudio

    2016-05-01

    In this article, we review the current evidence for the cellular and molecular mechanisms of AKI, focusing on epithelial cell pathobiology and related cell-cell interactions, using ischemic AKI as a model. Highlighted are the clinical relevance of cellular and molecular targets that have been investigated in experimental models of ischemic AKI and how such models might be improved to optimize translation into successful clinical trials. In particular, development of more context-specific animal models with greater relevance to human AKI is urgently needed. Comorbidities that could alter patient susceptibility to AKI, such as underlying diabetes, aging, obesity, cancer, and CKD, should also be considered in developing these models. Finally, harmonization between academia and industry for more clinically relevant preclinical testing of potential therapeutic targets and better translational clinical trial design is also needed to achieve the goal of developing effective interventions for AKI. PMID:26860342

  17. Molecular mechanisms of ageing and related diseases.

    PubMed

    Liu, Jun-Ping

    2014-07-01

    Human and other multicellular life species age, and ageing processes become dominant during the late phase of life. Recent studies challenge this dogma, suggesting that ageing does not occur in some animal species. In mammals, cell replicative senescence occurs as early as before birth (i.e. in embryos) under physiological conditions. How the molecular machinery operates and why ageing cells dominate under some circumstances are intriguing questions. Recent studies show that cell ageing involves extensive cellular remodelling, including telomere attrition, heterochromatin formation, endoplasmic reticulum stress, mitochondrial disorders and lysosome processing organelles and chromatins. This article provides an update on the molecular mechanisms underlying the ageing of various cell types, the newly described developmental and programmed replicative senescence and the critical roles of cellular organelles and effectors in Parkinson's disease, diabetes, hypertension and dyskeratosis congenita. PMID:24798238

  18. Molecular mechanics conformational analysis of tylosin

    NASA Astrophysics Data System (ADS)

    Ivanov, Petko M.

    1998-01-01

    The conformations of the 16-membered macrolide antibiotic tylosin were studied with molecular mechanics (AMBER∗ force field) including modelling of the effect of the solvent on the conformational preferences (GB/SA). A Monte Carlo conformational search procedure was used for finding the most probable low-energy conformations. The present study provides complementary data to recently reported analysis of the conformations of tylosin based on NMR techniques. A search for the low-energy conformations of protynolide, a 16-membered lactone containing the same aglycone as tylosin, was also carried out, and the results were compared with the observed conformation in the crystal as well as with the most probable conformations of the macrocyclic ring of tylosin. The dependence of the results on force field was also studied by utilizing the MM3 force field. Some particular conformations were computed with the semiempirical molecular orbital methods AM1 and PM3.

  19. Molecular mechanisms of the EHF bioeffect

    SciTech Connect

    Serikov, A.A.

    1994-07-01

    A generalizing theoretical analysis of models of mechanisms of interaction of biological macromolecules with EHF electromagnetic fields is performed. It is shown that nonthermal EHF radiation has a biological effect when the dipole-active oscillation Q of the primary receptors is greater than or equal to 10{sup 3}-10{sup 4}, which is of the same magnitude as the corresponding characteristic of individual peaks in the radiation spectrum. From the analysis of model equations of the kinetics of synthesis and dissociation of molecular associates, an explanation of the EHF bioeffect is proposed that is based on the phenomenon of high sensitivity to external actions of responses in which high-molecular-weight aggregates participate.

  20. Molecular Mechanics of Tip-Link Cadherins

    NASA Astrophysics Data System (ADS)

    Sotomayor, Marcos; Weihofen, Wilhelm A.; Gaudet, Rachelle; Corey, David P.

    2011-11-01

    The hair-cell tip link, a fine filament directly conveying force to mechanosensitive transduction channels, is likely composed of two proteins, protocadherin-15 and cadherin-23, whose mutation causes deafness. However, their complete molecular structure, elasticity, and deafness-related structural defects remain largely unknown. We present crystal structures of extracellular (EC) tip-link cadherin repeats involved in hereditary deafness and tip link formation. In addition, we show that the deafness mutation D101G, in the linker region between the repeats EC1 and EC2 of cadherin-23, causes a slight bend between repeats and decreases Ca2+ affinity. Molecular dynamics simulations suggest that tip-link cadherin repeats are stiff and that either removing Ca2+ or mutating Ca2+-binding residues reduces rigidity and unfolding strength. The structures and simulations also suggest mechanisms underlying inherited deafness and how cadherin-23 may bind with protocadherin-15 to form the tip link.

  1. Molecular Mechanisms of Sex Determination in Reptiles

    PubMed Central

    Rhen, T.; Schroeder, A.

    2010-01-01

    Charles Darwin first provided a lucid explanation of how gender differences evolve nearly 140 years ago. Yet, a disconnect remains between his theory of sexual selection and the mechanisms that underlie the development of males and females. In particular, comparisons between representatives of different phyla (i.e., flies and mice) reveal distinct genetic mechanisms for sexual differentiation. Such differences are hard to comprehend unless we study organisms that bridge the phylogenetic gap. Analysis of variation within monophyletic groups (i.e., amniotes) is just as important if we hope to elucidate the evolution of mechanisms underlying sexual differentiation. Here we review the molecular, cellular, morphological, and physiological changes associated with sex determination in reptiles. Most research on the molecular biology of sex determination in reptiles describes expression patterns for orthologs of mammalian sex-determining genes. Many of these genes have evolutionarily conserved expression profiles (i.e., DMRT1 and SOX9 are expressed at a higher level in developing testes vs. developing ovaries in all species), which suggests functional conservation. However, expression profiling alone does not test gene function and will not identify novel sex-determining genes or gene interactions. For that reason, we provide a prospectus on various techniques that promise to reveal new sex-determining genes and regulatory interactions among these genes. We offer specific examples of novel candidate genes and a new signaling pathway in support of these techniques. PMID:20145384

  2. Molecular Mechanisms of Chemoresistance in Oral Cancer.

    PubMed

    Wang, Cheng; Liu, Xi Qiang; Hou, Jin Song; Wang, Jian Ning; Huang, Hong Zhang

    2016-03-01

    Oral cancer is an aggressive disease with the propensity for local recurrence and distal metastasis in the head and neck region. Currently, cisplatin-based chemotherapy or concurrent radiochemotherapy is still the first choice to treat the advanced stage cancers, in particular, the unresectable tumours. Unfortunately, innate and acquired resistance to chemotherapy agent greatly limited its effectiveness and often led to treatment failure in these patients. Hence, it is urgent to clarify the mechanisms underlying the development of chemoresistance in patients with oral cancer. In this article, the current understandings on molecular mechanisms of chemoresistance in oral cancer were reviewed, including drug efflux, apoptosis, DNA damage and repair, epithelial mesenchymal transition, autophagy and miRNA. PMID:26981604

  3. Emerging paramyxoviruses: molecular mechanisms and antiviral strategies

    PubMed Central

    Aguilar, Hector C.; Lee, Benhur

    2011-01-01

    In recent years, several paramyxoviruses have emerged to infect humans, including previously unidentified zoonoses. Hendra and Nipah virus (henipavirus (HNV)) zoonoses were first identified in 1994 or 1998, causing deaths in animals and humans in Australia or Malaysia, respectively. Other paramyxoviruses, such as menangle virus, tioman virus, human metapneumovirus, and avian paramyxovirus-1, with less morbidity in humans, have also been recently identified. Although the Paramyxoviridae family of viruses has been previously recognized as biomedically and veterinarily important, the recent emergence of these paramyxoviruses has increased our attention to this family. Antiviral drugs can be designed to target specific important determinants of the viral/cell life cycle. Therefore, identifying and understanding the mechanistic underpinnings of viral entry, replication, assembly, and budding will be critical in the development of antiviral therapeutic agents. This review focuses on the molecular mechanisms discovered and the antiviral strategies pursued in recent years for emerging paramyxoviruses, with a concentration on viral entry and exit mechanisms. PMID:21345285

  4. Molecular inhibitory mechanism of tricin on tyrosinase.

    PubMed

    Mu, Yan; Li, Lin; Hu, Song-Qing

    2013-04-15

    Tricin was evaluated as a type of tyrosinase inhibitor with good efficacy compared to arbutin. Tricin functioned as a non-competitive inhibitor of tyrosinase, with an equilibrium constant of 2.30 mmol/L. The molecular mechanisms underlying the inhibition of tyrosinase by tricin were investigated by means of circular dichroism spectra, fluorescence quenching and molecular docking. These assays demonstrated that the interactions between tricin and tyrosinase did not change the secondary structure. The interaction of tricin with residues in the hydrophobic pocket of tyrosinase was revealed by fluorescence quenching; the complex was stabilized by hydrophobic associations and hydrogen bonding (with residues Asn80 and Arg267). Docking results implied that the possible inhibitory mechanisms may be attributed to the stereospecific blockade effects of tricin on substrates or products and flexible conformation alterations in the tyrosinase active center caused by weak interactions between tyrosinase and tricin. The application of this type of flavonoid as a tyrosinase inhibitor will lead to significant advances in the field of depigmentation. PMID:23434549

  5. Molecular Mechanisms of Thoracic Aortic Dissection

    PubMed Central

    Wu, Darrell; Shen, Ying H.; Russell, Ludivine; Coselli, Joseph S.; LeMaire, Scott A.

    2013-01-01

    Thoracic aortic dissection (TAD) is a highly lethal vascular disease. In many patients with TAD, the aorta progressively dilates and ultimately ruptures. Dissection formation, progression, and rupture cannot be reliably prevented pharmacologically because the molecular mechanisms of aortic wall degeneration are poorly understood. The key histopathologic feature of TAD is medial degeneration, a process characterized by smooth muscle cell depletion and extracellular matrix degradation. These structural changes have a profound impact on the functional properties of the aortic wall and can result from excessive protease-mediated destruction of the extracellular matrix, altered signaling pathways, and altered gene expression. Review of the literature reveals differences in the processes that lead to ascending versus descending and sporadic versus hereditary TAD. These differences add to the complexity of this disease. Although tremendous progress has been made in diagnosing and treating TAD, a better understanding of the molecular, cellular, and genetic mechanisms that cause this disease is necessary to developing more effective preventative and therapeutic treatment strategies. PMID:23856125

  6. Molecular inhibitory mechanism of tricin on tyrosinase

    NASA Astrophysics Data System (ADS)

    Mu, Yan; Li, Lin; Hu, Song-Qing

    2013-04-01

    Tricin was evaluated as a type of tyrosinase inhibitor with good efficacy compared to arbutin. Tricin functioned as a non-competitive inhibitor of tyrosinase, with an equilibrium constant of 2.30 mmol/L. The molecular mechanisms underlying the inhibition of tyrosinase by tricin were investigated by means of circular dichroism spectra, fluorescence quenching and molecular docking. These assays demonstrated that the interactions between tricin and tyrosinase did not change the secondary structure. The interaction of tricin with residues in the hydrophobic pocket of tyrosinase was revealed by fluorescence quenching; the complex was stabilized by hydrophobic associations and hydrogen bonding (with residues Asn80 and Arg267). Docking results implied that the possible inhibitory mechanisms may be attributed to the stereospecific blockade effects of tricin on substrates or products and flexible conformation alterations in the tyrosinase active center caused by weak interactions between tyrosinase and tricin. The application of this type of flavonoid as a tyrosinase inhibitor will lead to significant advances in the field of depigmentation.

  7. Hyperinsulinemic Hypoglycemia – The Molecular Mechanisms

    PubMed Central

    Nessa, Azizun; Rahman, Sofia A.; Hussain, Khalid

    2016-01-01

    Under normal physiological conditions, pancreatic β-cells secrete insulin to maintain fasting blood glucose levels in the range 3.5–5.5 mmol/L. In hyperinsulinemic hypoglycemia (HH), this precise regulation of insulin secretion is perturbed so that insulin continues to be secreted in the presence of hypoglycemia. HH may be due to genetic causes (congenital) or secondary to certain risk factors. The molecular mechanisms leading to HH involve defects in the key genes regulating insulin secretion from the β-cells. At this moment, in time genetic abnormalities in nine genes (ABCC8, KCNJ11, GCK, SCHAD, GLUD1, SLC16A1, HNF1A, HNF4A, and UCP2) have been described that lead to the congenital forms of HH. Perinatal stress, intrauterine growth retardation, maternal diabetes mellitus, and a large number of developmental syndromes are also associated with HH in the neonatal period. In older children and adult’s insulinoma, non-insulinoma pancreatogenous hypoglycemia syndrome and post bariatric surgery are recognized causes of HH. This review article will focus mainly on describing the molecular mechanisms that lead to unregulated insulin secretion. PMID:27065949

  8. Understanding the molecular mechanisms of reprogramming.

    PubMed

    Krause, Marie N; Sancho-Martinez, Ignacio; Izpisua Belmonte, Juan Carlos

    2016-05-01

    Despite the profound and rapid advancements in reprogramming technologies since the generation of the first induced pluripotent stem cells (iPSCs) in 2006[1], the molecular basics of the process and its implications are still not fully understood. Recent work has suggested that a subset of TFs, so called "Pioneer TFs", play an important role during the stochastic phase of iPSC reprogramming [2-6]. Pioneer TFs activities differ from conventional transcription factors in their mechanism of action. They bind directly to condensed chromatin and elicit a series of chromatin remodeling events that lead to opening of the chromatin. Chromatin decondensation by pioneer factors progressively occurs during cell division and in turn exposes specific gene promoters in the DNA to which TFs can now directly bind to promoters that are readily accessible[2, 6]. Here, we will summarize recent advancements on our understanding of the molecular mechanisms underlying reprogramming to iPSC as well as the implications that pioneer Transcription Factor activities might play during different lineage conversion processes. PMID:26655812

  9. Molecular mechanisms regulating macrophage response to hypoxia.

    PubMed

    Rahat, Michal A; Bitterman, Haim; Lahat, Nitza

    2011-01-01

    Monocytes and Macrophages (Mo/Mɸ) exhibit great plasticity, as they can shift between different modes of activation and, driven by their immediate microenvironment, perform divergent functions. These include, among others, patrolling their surroundings and maintaining homeostasis (resident Mo/Mɸ), combating invading pathogens and tumor cells (classically activated or M1 Mo/Mɸ), orchestrating wound healing (alternatively activated or M2 Mo/Mɸ), and restoring homeostasis after an inflammatory response (resolution Mɸ). Hypoxia is an important factor in the Mɸ microenvironment, is prevalent in many physiological and pathological conditions, and is interdependent with the inflammatory response. Although Mo/Mɸ have been studied in hypoxia, the mechanisms by which hypoxia influences the different modes of their activation, and how it regulates the shift between them, remain unclear. Here we review the current knowledge about the molecular mechanisms that mediate this hypoxic regulation of Mɸ activation. Much is known about the hypoxic transcriptional regulatory network, which includes the master regulators hypoxia-induced factor-1 and NF-κB, as well as other transcription factors (e.g., AP-1, Erg-1), but we also highlight the role of post-transcriptional and post-translational mechanisms. These mechanisms mediate hypoxic induction of Mɸ pro-angiogenic mediators, suppress M1 Mɸ by post-transcriptionally inhibiting pro-inflammatory mediators, and help shift the classically activated Mɸ into an activation state which approximate the alternatively activated or resolution Mɸ. PMID:22566835

  10. Molecular Mechanisms Regulating Macrophage Response to Hypoxia

    PubMed Central

    Rahat, Michal A.; Bitterman, Haim; Lahat, Nitza

    2011-01-01

    Monocytes and Macrophages (Mo/Mɸ) exhibit great plasticity, as they can shift between different modes of activation and, driven by their immediate microenvironment, perform divergent functions. These include, among others, patrolling their surroundings and maintaining homeostasis (resident Mo/Mɸ), combating invading pathogens and tumor cells (classically activated or M1 Mo/Mɸ), orchestrating wound healing (alternatively activated or M2 Mo/Mɸ), and restoring homeostasis after an inflammatory response (resolution Mɸ). Hypoxia is an important factor in the Mɸ microenvironment, is prevalent in many physiological and pathological conditions, and is interdependent with the inflammatory response. Although Mo/Mɸ have been studied in hypoxia, the mechanisms by which hypoxia influences the different modes of their activation, and how it regulates the shift between them, remain unclear. Here we review the current knowledge about the molecular mechanisms that mediate this hypoxic regulation of Mɸ activation. Much is known about the hypoxic transcriptional regulatory network, which includes the master regulators hypoxia-induced factor-1 and NF-κB, as well as other transcription factors (e.g., AP-1, Erg-1), but we also highlight the role of post-transcriptional and post-translational mechanisms. These mechanisms mediate hypoxic induction of Mɸ pro-angiogenic mediators, suppress M1 Mɸ by post-transcriptionally inhibiting pro-inflammatory mediators, and help shift the classically activated Mɸ into an activation state which approximate the alternatively activated or resolution Mɸ. PMID:22566835

  11. Cytokeratin and protein expression patterns in squamous cell carcinoma of the oral cavity provide evidence for two distinct pathogenetic pathways

    PubMed Central

    FROHWITTER, GESCHE; BUERGER, HORST; VAN DIEST, PAUL J.; KORSCHING, EBERHARD; KLEINHEINZ, JOHANNES; FILLIES, THOMAS

    2016-01-01

    Squamous cell carcinoma (SCC) of the oral cavity is a morphological heterogeneous disease. Various cytokeratin (CK) expression patterns with different prognostic values have been described, but little is known concerning the underlying biological cell mechanisms. Therefore, the present study investigated 193 cases of oral SCCs using immunohistochemistry for α/β/γ-catenin, glucose transporter 1, caspase-3, X-linked inhibitor of apoptosis protein, hypoxia inducible factor-1α, carbonic anhydrase 9, heat shock protein (hsp) 70, mast/stem cell growth factor receptor, p21, p27, p16, p53, B-cell lymphoma 6, epidermal growth factor receptor, cyclin D1 and CK1, 5/6, 8/18, 10, 14 and 19. Expression patterns were analyzed with biomathematical permutation analysis. The present results revealed a significant association between the expression of low-molecular weight CK8/18 and 19 and a high-tumor grade, β and γ-catenin expression, deregulated cell cycle proteins and a predominant localization of the tumor on the floor of the mouth. By contrast, expression of high-molecular weight CK1, 5/6, 10 and 14 was significantly associated with the expression of p21 and hsp70. In conclusion, the current study presents evidence for the existence of two parallel pathogenetic pathways in oral SCCs, characterized by the expression of low- and high-molecular weight CKs. Additional studies are required to demonstrate the extent that these results may be used to improve therapeutic regimens. PMID:27347109

  12. Cellular and molecular mechanisms of fibrosis.

    PubMed

    Wynn, T A

    2008-01-01

    Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen-producing cell. Myofibroblasts are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial-mesenchymal (EMT/EndMT) transition, as well as from circulating fibroblast-like cells called fibrocytes that are derived from bone-marrow stem cells. Myofibroblasts are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine factors secreted by myofibroblasts, and pathogen-associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on fibroblasts. Cytokines (IL-13, IL-21, TGF-beta1), chemokines (MCP-1, MIP-1beta), angiogenic factors (VEGF), growth factors (PDGF), peroxisome proliferator-activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin-angiotensin-aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being

  13. Cellular and molecular mechanisms of fibrosis

    PubMed Central

    Wynn, TA

    2009-01-01

    Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen-producing cell. Myofibroblasts are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial-mesenchymal (EMT/EndMT) transition, as well as from circulating fibroblast-like cells called fibrocytes that are derived from bone-marrow stem cells. Myofibroblasts are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine factors secreted by myofibroblasts, and pathogen-associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on fibroblasts. Cytokines (IL-13, IL-21, TGF-β1), chemokines (MCP-1, MIP-1β), angiogenic factors (VEGF), growth factors (PDGF), peroxisome proliferator-activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin–angiotensin–aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being

  14. Molecular and cellular mechanisms of anthracycline cardiotoxicity.

    PubMed

    Chen, Billy; Peng, Xuyang; Pentassuglia, Laura; Lim, Chee Chew; Sawyer, Douglas B

    2007-01-01

    The molecular and cellular mechanisms that cause cumulative dose-dependent anthracycline-cardiotoxicity remain controversial and incompletely understood. Studies examining the effects of anthracyclines in cardiac myocytes inA vitro have demonstrated several forms of cellular injury. Cell death in response to anthracyclines can be observed by one of several mechanisms including apoptosis and necrosis. Cell death by apoptosis can be inhibited by dexrazoxane, the iron chelator that is known to prevent clinical development of heart failure at high cumulative anthracycline exposure. Together with clinical evidence for myocyte death after anthracycline exposure, in the form of elevations in serum troponin, make myocyte cell death a probable mechanism for anthracycline-induced cardiac injury. Other mechanisms of myocyte injury include the development of cellular \\'sarcopenia\\' characterized by disruption of normal sarcomere structure. Anthracyclines suppress expression of several cardiac transcription factors, and this may play a role in the development of myocyte death as well as sarcopenia. Degradation of the giant myofilament protein titin may represent an important proximal step that leads to accelerated myofilament degradation. Titin is an entropic spring element in the sarcomere that regulates length-dependent calcium sensitivity. Thus titin degradation may lead to impaired diastolic as well as systolic dysfunction, as well as potentiate the effect of suppression of transcription of sarcomere proteins. An interesting interaction has been noted clinically between anthracyclines and newer cancer therapies that target the erbB2 receptor tyrosine kinase. Studies of erbB2 function in viro suggest that signaling through erbB2 by the growth factor neuregulin may regulate cardiac myocyte sarcomere turnover, as well as myocyte-myocyte/myocyte-matrix force coupling. A combination of further in vitro studies, with more careful monitoring of cardiac function after exposure to

  15. Screened Electrostatic Interactions in Molecular Mechanics.

    PubMed

    Wang, Bo; Truhlar, Donald G

    2014-10-14

    In a typical application of molecular mechanics (MM), the electrostatic interactions are calculated from parametrized partial atomic charges treated as point charges interacting by radial Coulomb potentials. This does not usually yield accurate electrostatic interactions at van der Waals distances, but this is compensated by additional parametrized terms, for example Lennard-Jones potentials. In the present work, we present a scheme involving radial screened Coulomb potentials that reproduces the accurate electrostatics much more accurately. The screening accounts for charge penetration of one subsystem's charge cloud into that of another subsystem, and it is incorporated into the interaction potential in a way similar to what we proposed in a previous article (J. Chem. Theory Comput. 2010, 6, 3330) for combined quantum mechanical and molecular mechanical (QM/MM) simulations, but the screening parameters are reoptimized for MM. The optimization is carried out with electrostatic-potential-fitted partial atomic charges, but the optimized parameters should be useful with any realistic charge model. In the model we employ, the charge density of an atom is approximated as the sum of a point charge representing the nucleus and inner electrons and a smeared charge representing the outermost electrons; in particular, for all atoms except hydrogens, the smeared charge represents the two outermost electrons in the present model. We find that the charge penetration effect can cause very significant deviations from the popular point-charge model, and by comparison to electrostatic interactions calculated by symmetry-adapted perturbation theory, we find that the present results are considerably more accurate than point-charge electrostatic interactions. The mean unsigned error in electrostatics for a large and diverse data set (192 interaction energies) decreases from 9.2 to 3.3 kcal/mol, and the error in the electrostatics for 10 water dimers decreases from 1.7 to 0.5 kcal

  16. Measuring the mechanical properties of molecular conformers

    PubMed Central

    Jarvis, S. P.; Taylor, S.; Baran, J. D.; Champness, N. R.; Larsson, J. A.; Moriarty, P.

    2015-01-01

    Scanning probe-actuated single molecule manipulation has proven to be an exceptionally powerful tool for the systematic atomic-scale interrogation of molecular adsorbates. To date, however, the extent to which molecular conformation affects the force required to push or pull a single molecule has not been explored. Here we probe the mechanochemical response of two tetra(4-bromophenyl)porphyrin conformers using non-contact atomic force microscopy where we find a large difference between the lateral forces required for manipulation. Remarkably, despite sharing very similar adsorption characteristics, variations in the potential energy surface are capable of prohibiting probe-induced positioning of one conformer, while simultaneously permitting manipulation of the alternative conformational form. Our results are interpreted in the context of dispersion-corrected density functional theory calculations which reveal significant differences in the diffusion barriers for each conformer. These results demonstrate that conformational variation significantly modifies the mechanical response of even simple porpyhrins, potentially affecting many other flexible molecules. PMID:26388232

  17. Molecular Mechanisms of Neonatal Brain Injury

    PubMed Central

    Thornton, Claire; Rousset, Catherine I.; Kichev, Anton; Miyakuni, Yasuka; Vontell, Regina; Baburamani, Ana A.; Fleiss, Bobbi; Gressens, Pierre; Hagberg, Henrik

    2012-01-01

    Fetal/neonatal brain injury is an important cause of neurological disability. Hypoxia-ischemia and excitotoxicity are considered important insults, and, in spite of their acute nature, brain injury develops over a protracted time period during the primary, secondary, and tertiary phases. The concept that most of the injury develops with a delay after the insult makes it possible to provide effective neuroprotective treatment after the insult. Indeed, hypothermia applied within 6 hours after birth in neonatal encephalopathy reduces neurological disability in clinical trials. In order to develop the next generation of treatment, we need to know more about the pathophysiological mechanism during the secondary and tertiary phases of injury. We review some of the critical molecular events related to mitochondrial dysfunction and apoptosis during the secondary phase and report some recent evidence that intervention may be feasible also days-weeks after the insult. PMID:22363841

  18. [Molecular mechanisms of niclosamide antitumor activity].

    PubMed

    Moskaleva, E Yu; Perevozchikova, V G; Zhirnik, A S; Severin, S E

    2015-01-01

    In this review the recent data regarding the antitumor activity of niclosamide and the molecular mechanisms of its antitumor activity are presented. Niclosamide has been used in the clinic for the treatment of intestinal parasite infections. In recent years in several screening investigations of various drugs and chemical compounds niclosamide was identified as a potential anticancer agent. Niclosamide not only inhibits the Wnt/β-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways, but also targets mitochondria in cancer cells to induce growth inhibition and apoptosis. A number of studies have established the anticancer activity of niclosamide in both in vitro and in vivo in xenotransplantation models using human tumors and immunodeficient mice. It is important that niclosamide is active not only against tumor cells but also cancer stem cells. Normal cells are resistant to niclosamide. The accumulated experimental data suggest niclosamide is a promising drug for the treatment of various types of cancer. PMID:26716739

  19. Molecular Mechanisms of Mouse Skin Tumor Promotion

    PubMed Central

    Rundhaug, Joyce E.; Fischer, Susan M.

    2010-01-01

    Multiple molecular mechanisms are involved in the promotion of skin carcinogenesis. Induction of sustained proliferation and epidermal hyperplasia by direct activation of mitotic signaling pathways or indirectly in response to chronic wounding and/or inflammation, or due to a block in terminal differentiation or resistance to apoptosis is necessary to allow clonal expansion of initiated cells with DNA mutations to form skin tumors. The mitotic pathways include activation of epidermal growth factor receptor and Ras/Raf/mitogen-activated protein kinase signaling. Chronic inflammation results in inflammatory cell secretion of growth factors and cytokines such as tumor necrosis factor-α and interleukins, as well as production of reactive oxygen species, all of which can stimulate proliferation. Persistent activation of these pathways leads to tumor promotion. PMID:21297902

  20. Pilocytic astrocytoma: pathology, molecular mechanisms and markers.

    PubMed

    Collins, V Peter; Jones, David T W; Giannini, Caterina

    2015-06-01

    Pilocytic astrocytomas (PAs) were recognized as a discrete clinical entity over 70 years ago. They are relatively benign (WHO grade I) and have, as a group, a 10-year survival of over 90%. Many require merely surgical removal and only very infrequently do they progress to more malignant gliomas. While most show classical morphology, they may present a spectrum of morphological patterns, and there are difficult cases that show similarities to other gliomas, some of which are malignant and require aggressive treatment. Until recently, almost nothing was known about the molecular mechanisms involved in their development. The use of high-throughput sequencing techniques interrogating the whole genome has shown that single abnormalities of the mitogen-activating protein kinase (MAPK) pathway are exclusively found in almost all cases, indicating that PA represents a one-pathway disease. The most common mechanism is a tandem duplication of a ≈2 Mb-fragment of #7q, giving rise to a fusion between two genes, resulting in a transforming fusion protein, consisting of the N-terminus of KIAA1549 and the kinase domain of BRAF. Additional infrequent fusion partners have been identified, along with other abnormalities of the MAP-K pathway, affecting tyrosine kinase growth factor receptors at the cell surface (e.g., FGFR1) as well as BRAF V600E, KRAS, and NF1 mutations among others. However, while the KIAA1549-BRAF fusion occurs in all areas, the incidence of the various other mutations identified differs in PAs that develop in different regions of the brain. Unfortunately, from a diagnostic standpoint, almost all mutations found have been reported in other brain tumor types, although some retain considerable utility. These molecular abnormalities will be reviewed, and the difficulties in their potential use in supporting a diagnosis of PA, when the histopathological findings are equivocal or in the choice of individualized therapy, will be discussed. PMID:25792358

  1. Molecular mechanism of phototropin light signaling.

    PubMed

    Okajima, Koji

    2016-03-01

    Phototropin (phot) is a blue light (BL) receptor kinase involved in the BL responses of several species, ranging from green algae to higher plants. Phot converts BL signals from the environment into biochemical signals that trigger cellular responses. In phot, the LOV1 and LOV2 domains of the N-terminal region utilize BL for cyclic photoreactions and regulate C-terminal serine/threonine kinase (STK) activity. LOV2-STK peptides are the smallest functional unit of phot and are useful for understanding regulation mechanisms. The combined analysis of spectroscopy and STK activity assay in Arabidopsis phots suggests that the decay speed of the photo-intermediate S390 in LOV2 is one of the factors contributing to light sensitive kinase activity. LOV2 and STK are thought to be adjacent to each other in LOV2-STK with small angle scattering (SAXS). BL irradiation induces LOV2-STK elongation, resulting in LOV2 shifting away from STK. The N- and C-terminal lateral regions of LOV2, A'α-helix, Jα-helix, and A'α/Aβ gap are responsible for the propagation of the BL signal to STK via conformational changes. The comparison between LOV2-STK and full-length phot from Chlamydomonas suggests that LOV1 is directly adjacent to LOV2 in LOV2-STK; therefore, LOV1 may indirectly regulate STK. The molecular mechanism of phot is discussed. PMID:26815763

  2. Insulin Resistance and Heart Failure: Molecular Mechanisms

    PubMed Central

    Aroor, Annayya R.; Mandavia, Chirag H.; Sowers, James R.

    2012-01-01

    Insulin resistance and associated reductions in cardiac insulin metabolic signaling is emerging as a major factor for the development of heart failure and assumes more importance because of an epidemic increase in obesity and the cardiorenal metabolic syndrome and our aging population. Major factors contributing to the development of cardiac insulin resistance are oxidative stress, hyperglycemia, hyperlipidemia, dysregulated secretion of adipokines/cytokines and inappropriate activation of renin-angiotensin II-aldosterone system (RAAS) and the sympathetic nervous system. The effects of cardiac insulin resistance are exacerbated by metabolic, endocrine and cytokine alterations associated with systemic insulin resistance. The aggregate of these various alterations leads to an insulin resistant phenotype with metabolic inflexibility, impaired calcium handling, mitochondrial dysfunction and oxidative stress, dysregulated myocardial-endothelial interactions resulting in energy deficiency, impaired diastolic dysfunction, myocardial cell death and cardiac fibrosis. Therefore, understanding the molecular mechanisms linking insulin resistance and heart failure may help to design new and more effective mechanism-based drugs to improve myocardial and systemic insulin resistance. PMID:22999243

  3. Molecular mechanisms of muscle plasticity with exercise.

    PubMed

    Hoppeler, Hans; Baum, Oliver; Lurman, Glenn; Mueller, Matthias

    2011-07-01

    The skeletal muscle phenotype is subject to considerable malleability depending on use. Low-intensity endurance type exercise leads to qualitative changes of muscle tissue characterized mainly by an increase in structures supporting oxygen delivery and consumption. High-load strength-type exercise leads to growth of muscle fibers dominated by an increase in contractile proteins. In low-intensity exercise, stress-induced signaling leads to transcriptional upregulation of a multitude of genes with Ca(2+) signaling and the energy status of the muscle cells sensed through AMPK being major input determinants. Several parallel signaling pathways converge on the transcriptional co-activator PGC-1α, perceived as being the coordinator of much of the transcriptional and posttranscriptional processes. High-load training is dominated by a translational upregulation controlled by mTOR mainly influenced by an insulin/growth factor-dependent signaling cascade as well as mechanical and nutritional cues. Exercise-induced muscle growth is further supported by DNA recruitment through activation and incorporation of satellite cells. Crucial nodes of strength and endurance exercise signaling networks are shared making these training modes interdependent. Robustness of exercise-related signaling is the consequence of signaling being multiple parallel with feed-back and feed-forward control over single and multiple signaling levels. We currently have a good descriptive understanding of the molecular mechanisms controlling muscle phenotypic plasticity. We lack understanding of the precise interactions among partners of signaling networks and accordingly models to predict signaling outcome of entire networks. A major current challenge is to verify and apply available knowledge gained in model systems to predict human phenotypic plasticity. PMID:23733647

  4. Decomposition of Amino Diazeniumdiolates (NONOates): Molecular Mechanisms

    SciTech Connect

    Shaikh, Nizamuddin; Valiev, Marat; Lymar, Sergei V.

    2014-08-23

    Although diazeniumdiolates (X[N(O)NO]-) are extensively used in biochemical, physiological, and pharmacological studies due to their ability to slowly release NO and/or its congeneric nitroxyl, the mechanisms of these processes remain obscure. In this work, we used a combination of spectroscopic, kinetic, and computational techniques to arrive at a qualitatively consistent molecular mechanism for decomposition of amino diazeniumdiolates (amino NONOates: R2N[N(O)NO]-, where R = -N(C2H5)2 (1), -N(C3H4NH2)2 (2), or -N(C2H4NH2)2 (3)). Decomposition of these NONOates is triggered by protonation of their [NN(O)NO]- group with apparent pKa and decomposition rate constants of 4.6 and 1 s-1 for 1-H, 3.5 and 83 x 10-3 s-1 for 2-H, and 3.8 and 3.3 x 10-3 s-1 for 3-H. Although protonation occurs mainly on the O atoms of the functional group, only the minor R2N(H)N(O)NO tautomer (population ~0.01%, for 1) undergoes the N-N heterolytic bond cleavage (k ~102 s-1 for 1) leading to amine and NO. Decompositions of protonated amino NONOates are strongly temperature-dependent; activation enthalpies are 20.4 and 19.4 kcal/mol for 1 and 2, respectively, which includes contributions from both the tautomerization and bond cleavage. The bond cleavage rates exhibit exceptional sensitivity to the nature of R substituents which strongly modulate activation entropy. At pH < 2, decompositions of all these NONOates are subject to additional acid catalysis that occurs through di-protonation of the [NN(O)NO]- group.

  5. Decomposition of amino diazeniumdiolates (NONOates): Molecular mechanisms

    DOE PAGESBeta

    Shaikh, Nizamuddin; Valiev, Marat; Lymar, Sergei V.

    2014-08-23

    Although diazeniumdiolates (X[N(O)NO]-) are extensively used in biochemical, physiological, and pharmacological studies due to their ability to release NO and/or its congeneric nitroxyl, the mechanisms of these processes remain obscure. In this work, we used a combination of spectroscopic, kinetic, and computational techniques to arrive at a quantitatively consistent molecular mechanism for decomposition of amino diazeniumdiolates (amino NONOates: R2N[N(O)NO]-, where R = —N(C2H5)2(1), —N(C3H4NH2)2(2), or —N(C2H4NH2)2(3)). Decomposition of these NONOates is triggered by protonation of their [NN(O)NO]- group with the apparent pKa and decomposition rate constants of 4.6 and 1 s-1 for 1; 3.5 and 0.083 s-1 for 2; andmore » 3.8 and 0.0033 s-1 for 3. Although protonation occurs mainly on the O atoms of the functional group, only the minor R2N(H)N(O)NO tautomer (population ~ 10-7, for 1) undergoes the N—N heterolytic bond cleavage (kd ~ 107 s-1 for 1) leading to amine and NO. Decompositions of protonated amino NONOates are strongly temperature-dependent; activation enthalpies are 20.4 and 19.4 kcal/mol for 1 and 2, respectively, which includes contributions from both the tautomerization and bond cleavage. Thus, the bond cleavage rates exhibit exceptional sensitivity to the nature of R substituents which strongly modulate activation entropy. At pH < 2, decompositions of all three NONOates that have been investigated are subject to additional acid catalysis that occurs through di-protonation of the [NN(O)NO]- group.« less

  6. Molecular mechanism of pore formation by actinoporins.

    PubMed

    Kristan, Katarina Crnigoj; Viero, Gabriella; Dalla Serra, Mauro; Macek, Peter; Anderluh, Gregor

    2009-12-15

    Actinoporins are effective pore-forming toxins produced by sea anemones. These extremely potent, basic 20 kDa proteins readily form pores in membranes that contain sphingomyelin. Much has been learned about the molecular basis of their pore-forming mechanism in recent years. Pore formation is a multi-step process that involves recognition of membrane sphingomyelin, firm binding to the membrane accompanied by the transfer of the N-terminal region to the lipid-water interface and finally pore formation after oligomerisation of three to four monomers. The final conductive pathway is formed by amphipathic alpha-helices, hence actinoporins are an important example of so-called alpha-helical pore-forming toxins. Actinoporins have become useful model proteins to study protein-membrane interactions, specific recognition of lipids in the membrane, and protein oligomerisation in the lipid milieu. Recent sequence and structural data of proteins similar to actinoporins indicate that they are not a unique family restricted to sea anemones as was long believed. An AF domain superfamily (abbreviated from actinoporin-like proteins and fungal fruit-body lectins) was defined and shown to contain members from three animal and two plant phyla. On the basis of functional properties of some members we hypothesise that AF domain proteins are peripheral membrane proteins. Finally, ability of actinoporins to form transmembrane pores has been exploited in some novel biomedical applications. PMID:19268680

  7. Molecular Mechanisms Underlying Peritoneal EMT and Fibrosis

    PubMed Central

    Strippoli, Raffaele; Moreno-Vicente, Roberto; Battistelli, Cecilia; Cicchini, Carla; Noce, Valeria; Amicone, Laura; Marchetti, Alessandra; del Pozo, Miguel Angel; Tripodi, Marco

    2016-01-01

    Peritoneal dialysis is a form of renal replacement alternative to the hemodialysis. During this treatment, the peritoneal membrane acts as a permeable barrier for exchange of solutes and water. Continual exposure to dialysis solutions, as well as episodes of peritonitis and hemoperitoneum, can cause acute/chronic inflammation and injury to the peritoneal membrane, which undergoes progressive fibrosis, angiogenesis, and vasculopathy, eventually leading to discontinuation of the peritoneal dialysis. Among the different events controlling this pathological process, epithelial to mesenchymal transition of mesothelial cells plays a main role in the induction of fibrosis and in subsequent functional deterioration of the peritoneal membrane. Here, the main extracellular inducers and cellular players are described. Moreover, signaling pathways acting during this process are elucidated, with emphasis on signals delivered by TGF-β family members and by Toll-like/IL-1β receptors. The understanding of molecular mechanisms underlying fibrosis of the peritoneal membrane has both a basic and a translational relevance, since it may be useful for setup of therapies aimed at counteracting the deterioration as well as restoring the homeostasis of the peritoneal membrane. PMID:26941801

  8. Molecular Mechanisms Underlying Psychological Stress and Cancer.

    PubMed

    Shin, Kyeong Jin; Lee, Yu Jin; Yang, Yong Ryoul; Park, Seorim; Suh, Pann-Ghill; Follo, Matilde Yung; Cocco, Lucio; Ryu, Sung Ho

    2016-01-01

    Psychological stress is an emotion experienced when people are under mental pressure or encounter unexpected problems. Extreme or repetitive stress increases the risk of developing human disease, including cardiovascular disease (CVD), immune diseases, mental disorders, and cancer. Several studies have shown an association between psychological stress and cancer growth and metastasis in animal models and case studies of cancer patients. Stress induces the secretion of stress-related mediators, such as catecholamine, cortisol, and oxytocin, via the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis or the sympathetic nervous system (SNS). These stress-related hormones and neurotransmitters adversely affect stress-induced tumor progression and cancer therapy. Catecholamine is the primary factor that influences tumor progression. It can regulate diverse cellular signaling pathways through adrenergic receptors (ADRs), which are expressed by several types of cancer cells. Activated ADRs enhance the proliferation and invasion abilities of cancer cells, alter cell activity in the tumor microenvironment, and regulate the interaction between cancer and its microenvironment to promote tumor progression. Additionally, other stress mediators, such as glucocorticoids and oxytocin, and their cognate receptors are involved in stress-induced cancer growth and metastasis. Here, we will review how each receptor-mediated signal cascade contributes to tumor initiation and progression and discuss how we can use these molecular mechanisms for cancer therapy. PMID:26916018

  9. Cellular and molecular mechanisms in liver fibrogenesis.

    PubMed

    Novo, Erica; Cannito, Stefania; Paternostro, Claudia; Bocca, Claudia; Miglietta, Antonella; Parola, Maurizio

    2014-04-15

    Liver fibrogenesis is a dynamic and highly integrated molecular, tissue and cellular process, potentially reversible, that drives the progression of chronic liver diseases (CLD) towards liver cirrhosis and hepatic failure. Hepatic myofibroblasts (MFs), the pro-fibrogenic effector cells, originate mainly from activation of hepatic stellate cells and portal fibroblasts being characterized by a proliferative and survival attitude. MFs also contract in response to vasoactive agents, sustain angiogenesis and recruit and modulate activity of cells of innate or adaptive immunity. Chronic activation of wound healing and oxidative stress as well as derangement of epithelial-mesenchymal interactions are "major" pro-fibrogenic mechanisms, whatever the etiology. However, literature has outlined a complex network of pro-fibrogenic factors and mediators proposed to modulate CLD progression, with some of them being at present highly debated in the field, including the role of epithelial to mesenchymal transition and Hedgehog signaling pathways. Hypoxia and angiogenesis as well as inflammasomes are recently emerged as ubiquitous pro-inflammatory and pro-fibrogenic determinants whereas adipokines are mostly involved in CLD related to metabolic disturbances (metabolic syndrome and/or obesity and type 2 diabetes). Finally, autophagy as well as natural killer and natural killer-T cells have been recently proposed to significantly affect fibrogenic CLD progression. PMID:24631571

  10. Molecular mechanism of anaerobic ammonium oxidation.

    PubMed

    Kartal, Boran; Maalcke, Wouter J; de Almeida, Naomi M; Cirpus, Irina; Gloerich, Jolein; Geerts, Wim; Op den Camp, Huub J M; Harhangi, Harry R; Janssen-Megens, Eva M; Francoijs, Kees-Jan; Stunnenberg, Hendrik G; Keltjens, Jan T; Jetten, Mike S M; Strous, Marc

    2011-11-01

    Two distinct microbial processes, denitrification and anaerobic ammonium oxidation (anammox), are responsible for the release of fixed nitrogen as dinitrogen gas (N(2)) to the atmosphere. Denitrification has been studied for over 100 years and its intermediates and enzymes are well known. Even though anammox is a key biogeochemical process of equal importance, its molecular mechanism is unknown, but it was proposed to proceed through hydrazine (N(2)H(4)). Here we show that N(2)H(4) is produced from the anammox substrates ammonium and nitrite and that nitric oxide (NO) is the direct precursor of N(2)H(4). We resolved the genes and proteins central to anammox metabolism and purified the key enzymes that catalyse N(2)H(4) synthesis and its oxidation to N(2). These results present a new biochemical reaction forging an N-N bond and fill a lacuna in our understanding of the biochemical synthesis of the N(2) in the atmosphere. Furthermore, they reinforce the role of nitric oxide in the evolution of the nitrogen cycle. PMID:21964329

  11. Therapeutic and pathogenetic animal models for Dolichos pruriens.

    PubMed

    de Paula Coelho, C; D'Almeida, V; Pedrazzolli-Neto, M; Duran-Filho, C; Florio, J C; Zincaglia, L M C; Bonamin, L V

    2006-07-01

    The therapeutic and pathogenetic effects of Dolichos pruriens were evaluated using experimental models in rats. In the therapeutic experiment Wistar rats were housed in a heated environment (25+/-3 degrees C) to induce itch, and treated with ascending potencies D. pruriens (6 cH, 9 cH, 12 cH and 30 cH), each for 10 days. The positive control group received vehicle (ethanol 30% in water). The negative control group received no treatment and were kept at a standard temperature. In the pathogenetic experiment, all animals were kept at a temperature of 20+/-3 degrees C and treated for 30 consecutive days with D. pruriens 6 or 30 cH, or ethanol vehicle, or no treatment. The experiments were performed blind. The statistical analysis used Bartlett's test, followed by ANOVA/Tuckey-Krammer or Kruskal-Wallis/Dunn. The results point to the existence of therapeutic effects, with inhibition of the itching, skin lesions and fur thinning produced by heat, more evident in later observations, with the 9 12, and 30 cH potencies (Kruskal-Wallis/Dunn; P=0.001). No changes were observed in the other parameters, such as open field activity and laterality of the itching. In the pathogenetic experiment, no changes were observed in any parameters examined. We conclude that the proposed experimental model demonstrates the therapeutic effect of D. pruriens, but not its pathogenetic effects. PMID:16815516

  12. Silica Synthesis by Sponges: Unanticipated Molecular Mechanism

    NASA Astrophysics Data System (ADS)

    Morse, D. E.; Weaver, J. C.

    2001-12-01

    substitutions of specific amino acid sidechains, in conjunction with computer-assisted molecular modeling and biomimetic synthesis, allowed us to probe the determinants of catalytic activity and confirm the identification of the amino acid sidechains required for hydrolysis of the silicon alkoxides. If, as suggested by the data of others, silicic acid is conjugated with organic moieties after its transport into the cell, the catalytic mechanism described here may be important in biosilicification by sponges. As is often the case, we have been better able to answer mechanistic questions about "how" silica can be formed biologically, than "why" the diversity of structures is elaborated. Studies of spicule formation during cellular regeneration in Tethya aurantia reveal that synthesis of the larger silica needles (megascleres) and smaller starburst-shaped microscleres may be independently regulated, presumably at the genetic level. The spatial segregation of these morphologically-distinct spicule types within the sponge further suggests an adaptive significance of the different skeletal elements.

  13. Molecular Mechanics: The Method and Its Underlying Philosophy.

    ERIC Educational Resources Information Center

    Boyd, Donald B.; Lipkowitz, Kenny B.

    1982-01-01

    Molecular mechanics is a nonquantum mechanical method for solving problems concerning molecular geometries and energy. Methodology based on: the principle of combining potential energy functions of all structural features of a particular molecule into a total force field; derivation of basic equations; and use of available computer programs is…

  14. Mechanism of a molecular electronic photoswitch

    NASA Astrophysics Data System (ADS)

    Zhuang, Min; Ernzerhof, Matthias

    2005-08-01

    We present a simple non-self-consistent method for the calculation of the molecular conductance under finite bias voltage. Our approach is applied to a molecular photoswitch that has recently been investigated in break junction experiments [D. Dulić , Phys. Rev. Lett. 91, 207402 (2003)]. We obtain I-V characteristics that are qualitatively in agreement with experimental measurements. Employing our electronic structure calculations, we provide a detailed explanation for the switching behavior observed in experiment.

  15. The cognitive life of mechanical molecular models.

    PubMed

    Charbonneau, Mathieu

    2013-12-01

    The use of physical models of molecular structures as research tools has been central to the development of biochemistry and molecular biology. Intriguingly, it has received little attention from scholars of science. In this paper, I argue that these physical models are not mere three-dimensional representations but that they are in fact very special research tools: they are cognitive augmentations. Despite the fact that they are external props, these models serve as cognitive tools that augment and extend the modeler's cognitive capacities and performance in molecular modeling tasks. This cognitive enhancement is obtained because of the way the modeler interacts with these models, the models' materiality contributing to the solving of the molecule's structure. Furthermore, I argue that these material models and their component parts were designed, built and used specifically to serve as cognitive facilitators and cognitive augmentations. PMID:23910718

  16. Hybrid Quantum Mechanical/Molecular Mechanical Molecular Dynamics Simulations of HIV-1 Integrase/Inhibitor Complexes

    PubMed Central

    Nunthaboot, Nadtanet; Pianwanit, Somsak; Parasuk, Vudhichai; Ebalunode, Jerry O.; Briggs, James M.; Kokpol, Sirirat

    2007-01-01

    Human immunodeficiency virus (HIV)-1 integrase (IN) is an attractive target for development of acquired immunodeficiency syndrome chemotherapy. In this study, conventional and coupled quantum mechanical and molecular mechanical (QM/MM) molecular dynamics (MD) simulations of HIV-1 IN complexed with 5CITEP (IN-5CITEP) were carried out. In addition to differences in the bound position of 5CITEP, significant differences at the two levels of theory were observed in the metal coordination geometry and the areas involving residues 116–119 and 140–166. In the conventional MD simulation, the coordination of Mg2+ was found to be a near-perfect octahedral geometry whereas a distorted octahedral complex was observed in QM/MM. All of the above reasons lead to a different pattern of protein-ligand salt link formation that was not observed in the classical MD simulation. Furthermore to provide a theoretical understanding of inhibition mechanisms of 5CITEP and its derivative (DKA), hybrid QM/MM MD simulations of the two complexes (IN-5CITEP and IN-DKA) have been performed. The results reveal that areas involving residues 60–68, 116–119, and 140–149 were substantially different among the two systems. The two systems show similar pattern of metal coordination geometry, i.e., a distorted octahedron. In IN-DKA, both OD1 and OD2 of Asp-64 coordinate the Mg2+ in a monodentate fashion whereas only OD1 is chelated to the metal as observed in IN-5CITEP. The high potency of DKA as compared to 5CITEP is supported by a strong salt link formed between its carboxylate moiety and the ammonium group of Lys-159. Detailed comparisons between HIV-1 IN complexed with DKA and with 5CITEP provide information about ligand structure effects on protein-ligand interactions in particular with the Lys-159. This is useful for the design of new selective HIV-1 IN inhibitors. PMID:17693479

  17. Developing accurate molecular mechanics force fields for conjugated molecular systems.

    PubMed

    Do, Hainam; Troisi, Alessandro

    2015-10-14

    A rapid method to parameterize the intramolecular component of classical force fields for complex conjugated molecules is proposed. The method is based on a procedure of force matching with a reference electronic structure calculation. It is particularly suitable for those applications where molecular dynamics simulations are used to generate structures that are therefore analysed by electronic structure methods, because it is possible to build force fields that are consistent with electronic structure calculations that follow classical simulations. Such applications are commonly encountered in organic electronics, spectroscopy of complex systems and photobiology (e.g. photosynthetic systems). We illustrate the method by parameterizing the force fields of a molecule used in molecular semiconductors (2,2-dicyanovinyl-capped S,N-heteropentacene or DCV-SN5), a polymeric semiconductor (thieno[3,2-b]thiophene-diketopyrrolopyrrole TT-DPP) and a chromophore embedded in a protein environment (15,16-dihydrobiliverdin or DBV) where several hundreds of parameters need to be optimized in parallel. PMID:26349916

  18. [Pathogenetic mechanisms in the treatment of periodontitis using xenogeneic peritoneum].

    PubMed

    Borovskiĭ, E V; Volozhin, A I; Lavrova, V S; Seksenova, L Sh

    1990-01-01

    Water-free cattle parietal peritoneum was used in surgical treatment of 62 patients with severe periodontitis. Use of xenoperitoneum in multiple-modality treatment of periodontitis was conducive to bone tissue regeneration in bone pockets, to a more rapid recovery of gingival temperature round incisors and molars. PMID:2389266

  19. Oro-facial gangrene (noma/cancrum oris): pathogenetic mechanisms.

    PubMed

    Enwonwu, C O; Falkler, W A; Idigbe, E O

    2000-01-01

    Cancrum oris (Noma) is a devastating infectious disease which destroys the soft and hard tissues of the oral and para-oral structures. The dehumanizing oro-facial gangrenous lesion affects predominantly children ages 2 to 16 years, particularly in sub-Saharan Africa, where the estimated frequency in some communities varies from 1 to 7 cases per 1000 population. The risk factors are poverty, malnutrition, poor oral hygiene, residential proximity to livestock in unsanitary environments, and infectious diseases, particularly measles and those due to the herpesviridae. Infections and malnutrition impair the immune system, and this is the common denominator for the occurrence of noma. Acute necrotizing gingivitis (ANG) and oral herpetic ulcers are considered the antecedent lesions, and ongoing studies suggest that the rapid progression of these precursor lesions to noma requires infection by a consortium of micro-organisms, with Fusobacterium necrophorum (Fn) and Prevotella intermedia (Pi) as the suspected key players. Additional to production of a growth-stimulating factor for Pi, Fn displays a classic endotoxin, a dermonecrotic toxin, a cytoplasmic toxin, and a hemolysin. Without appropriate treatment, the mortality rate from noma is 70-90%. Survivors suffer the two-fold afflictions of oro-facial mutilation and functional impairment, which require a time-consuming, financially prohibitive surgical reconstruction. PMID:12002813

  20. Citrullinated Autoantigens: From Diagnostic Markers to Pathogenetic Mechanisms.

    PubMed

    Muller, Sylviane; Radic, Marko

    2015-10-01

    The conversion of an arginine residue in a protein to a citrulline residue, a reaction carried out by enzymes called peptidylarginine deiminases (PADs), is rather subtle. One of the terminal imide groups in arginine is replaced by oxygen in citrulline, thus resulting in the loss of positive charge and the gain of 1 dalton. This post-translational modification by PAD enzymes is conserved in vertebrates and affects specific substrates during development and in various mature cell lineages. Citrullination offers a unique perspective on autoimmunity because PAD activity is stringently regulated, yet autoantibodies to citrullinated proteins predictably arise. Autoantigens recognized by anti-citrullinated protein antibodies (ACPA) include extracellular proteins such as filaggrin, collagen II, fibrinogen, and calreticulin; membrane-associated proteins such as myelin basic protein; cytoplasmic proteins such as vimentin and enolase; and even nuclear proteins such as histones. Some ACPA are remarkably effective as diagnostics in autoimmune disorders, most notably rheumatoid arthritis (RA). Several ACPA can be observed before other clinical RA manifestations are apparent. In patients with RA, ACPA may attain a sensitivity that exceeds 70 % and specificity that approaches 96-98 %. The biological context that may account for the induction of ACPA emerges from studies of the cellular response of the innate immune system to acute or chronic stimuli. In response to infections or inflammation, neutrophil granulocytes activate PAD, citrullinate multiple autoantigens, and expel chromatin from the cell. The externalized chromatin is called a neutrophil extracellular "trap" (NET). Citrullination of core and linker histones occurs prior to the release of chromatin from neutrophils, thus implicating the regulation of citrullinated chromatin release in the development of autoreactivity. The citrullination of extracellular autoantigens likely follows the release of NETs and associated PADs. Autoantibodies to citrullinated histones arise in RA, systemic lupus erythematosus, and Felty's syndrome patients. The citrullination of linker histone H1 may play a key role in NET release because the H1 histone regulates the entry and exit of DNA from the nucleosome. Juxtaposition of citrullinated histones with infectious pathogens and complement and immune complexes may compromise tolerance of nuclear autoantigens and promote autoimmunity. PMID:25355199

  1. TOPICAL REVIEW: Polarization effects in molecular mechanical force fields

    NASA Astrophysics Data System (ADS)

    Cieplak, Piotr; Dupradeau, François-Yves; Duan, Yong; Wang, Junmei

    2009-08-01

    The focus here is on incorporating electronic polarization into classical molecular mechanical force fields used for macromolecular simulations. First, we briefly examine currently used molecular mechanical force fields and the current status of intermolecular forces as viewed by quantum mechanical approaches. Next, we demonstrate how some components of quantum mechanical energy are effectively incorporated into classical molecular mechanical force fields. Finally, we assess the modeling methods of one such energy component—polarization energy—and present an overview of polarizable force fields and their current applications. Incorporating polarization effects into current force fields paves the way to developing potentially more accurate, though more complex, parameterizations that can be used for more realistic molecular simulations.

  2. Identifying the mechanisms of polymer friction through molecular dynamics simulation.

    PubMed

    Dai, Ling; Minn, M; Satyanarayana, N; Sinha, Sujeet K; Tan, V B C

    2011-12-20

    Mechanisms governing the tribological behavior of polymer-on-polymer sliding were investigated by molecular dynamics simulations. Three main mechanisms governing frictional behavior were identified. Interfacial "brushing" of molecular chain ends over one another was observed as the key contribution to frictional forces. With an increase of the sliding speed, fluctuations in frictional forces reduced in both magnitude and periodicity, leading to dynamic frictional behavior. While "brushing" remained prevalent, two additional irreversible mechanisms, "combing" and "chain scission", of molecular chains were observed when the interfaces were significantly diffused. PMID:22044344

  3. Pathogenetic considerations of pica in lead poisoning.

    PubMed

    Pueschel, S M; Cullen, S M; Howard, R B; Cullinane, M M

    An important factor associated with lead poisoning in children is the habit of eating non-food substances, a condition termed pica. In search for underlying mechanisms involved in the pathogenesis of pica, this investigation presents evidence in support of the hypothesis that in many families failure of normal mother-child interaction, paternal deprivation, culturally dependent maternal oral interests and significant stress factors in the home where abundant lead-containing material is available are etiologically related to the development of pica in lead poisoning. Other factors, which have been thought to be associated with pica, are nutritional deficiencies and maladaptive behavior patterns. A multifocal treatment approach is considered to be most effective. PMID:649261

  4. Molecular mechanisms involved in convergent crop domestication.

    PubMed

    Lenser, Teresa; Theißen, Günter

    2013-12-01

    Domestication has helped to understand evolution. We argue that, vice versa, novel insights into evolutionary principles could provide deeper insights into domestication. Molecular analyses have demonstrated that convergent phenotypic evolution is often based on molecular changes in orthologous genes or pathways. Recent studies have revealed that during plant domestication the causal mutations for convergent changes in key traits are likely to be located in particular genes. These insights may contribute to defining candidate genes for genetic improvement during the domestication of new plant species. Such efforts may help to increase the range of arable crops available, thus increasing crop biodiversity and food security to help meet the predicted demands of the continually growing global population under rapidly changing environmental conditions. PMID:24035234

  5. Molecular chaperones: functional mechanisms and nanotechnological applications.

    PubMed

    Fernández-Fernández, M Rosario; Sot, Begoña; Valpuesta, José María

    2016-08-12

    Molecular chaperones are a group of proteins that assist in protein homeostasis. They not only prevent protein misfolding and aggregation, but also target misfolded proteins for degradation. Despite differences in structure, all types of chaperones share a common general feature, a surface that recognizes and interacts with the misfolded protein. This and other, more specialized properties can be adapted for various nanotechnological purposes, by modification of the original biomolecules or by de novo design based on artificial structures. PMID:27363314

  6. Molecular chaperones: functional mechanisms and nanotechnological applications

    NASA Astrophysics Data System (ADS)

    Rosario Fernández-Fernández, M.; Sot, Begoña; María Valpuesta, José

    2016-08-01

    Molecular chaperones are a group of proteins that assist in protein homeostasis. They not only prevent protein misfolding and aggregation, but also target misfolded proteins for degradation. Despite differences in structure, all types of chaperones share a common general feature, a surface that recognizes and interacts with the misfolded protein. This and other, more specialized properties can be adapted for various nanotechnological purposes, by modification of the original biomolecules or by de novo design based on artificial structures.

  7. Perifollicular fibrosis: pathogenetic role in androgenetic alopecia.

    PubMed

    Yoo, Hyeon Gyeong; Kim, Jin Sook; Lee, Se Rah; Pyo, Hyun Keol; Moon, Hyung In; Lee, Jong Hee; Kwon, Oh Sang; Chung, Jin Ho; Kim, Kyu Han; Eun, Hee Chul; Cho, Kwang Hyun

    2006-06-01

    Androgenetic alopecia (AGA) is a dihydrotestosterone (DHT)-mediated process, characterized by continuous miniaturization of androgen reactive hair follicles and accompanied by perifollicular fibrosis of follicular units in histological examination. Testosterone (T: 10(-9)-10(-7) M) treatment increased the expression of type I procollagen at mRNA and protein level. Pretreatment of finasteride (10(-8) M) inhibited the T-induced type I procollagen expression at mRNA (40.2%) and protein levels (24.9%). T treatment increased the expression of transforming growth factor-beta 1 (TGF-beta1) at protein levels by 81.9% in the human scalp dermal fibroblasts (DFs). Pretreatment of finasteride decreased the expression of TGF-beta1 protein induced by an average of T (30.4%). The type I procollagen expression after pretreatment of neutralizing TGF-beta1 antibody (10 microg/ml) was inhibited by an average of 54.3%. Our findings suggest that T-induced TGF-beta1 and type I procollagen expression may contribute to the development of perifollicular fibrosis in the AGA, and the inhibitory effects on T-induced procollagen and TGF-beta1 expression may explain another possible mechanism how finasteride works in AGA. PMID:16755026

  8. Molecular Mechanisms of External Genitalia Development

    PubMed Central

    Blaschko, Sarah D.; Cunha, Gerald R.; Baskin, Laurence S.

    2012-01-01

    External genitalia development occurs through a combination of hormone independent, hormone dependent, and endocrine pathways. Perturbation of these pathways can lead to abnormal external genitalia development. We review human and animal mechanisms of normal and abnormal external genitalia development, and we evaluate abnormal mechanisms that lead to hypospadias. We also discuss recent laboratory findings that further our understanding of animal models of hypospadias. PMID:22790208

  9. Symposium on molecular and cellular mechanisms of mutagenesis

    SciTech Connect

    Not Available

    1981-01-01

    These proceedings contain abstracts only of the 21 papers presented at the Sympsoium. The papers dealt with molecular mechanisms of mutagenesis and cellular responses to chemical and physical mutagenic agents. (ERB)

  10. Molecular and cellular mechanisms of pulmonary fibrosis

    PubMed Central

    2012-01-01

    Pulmonary fibrosis is a chronic lung disease characterized by excessive accumulation of extracellular matrix (ECM) and remodeling of the lung architecture. Idiopathic pulmonary fibrosis is considered the most common and severe form of the disease, with a median survival of approximately three years and no proven effective therapy. Despite the fact that effective treatments are absent and the precise mechanisms that drive fibrosis in most patients remain incompletely understood, an extensive body of scientific literature regarding pulmonary fibrosis has accumulated over the past 35 years. In this review, we discuss three broad areas which have been explored that may be responsible for the combination of altered lung fibroblasts, loss of alveolar epithelial cells, and excessive accumulation of ECM: inflammation and immune mechanisms, oxidative stress and oxidative signaling, and procoagulant mechanisms. We discuss each of these processes separately to facilitate clarity, but certainly significant interplay will occur amongst these pathways in patients with this disease. PMID:22824096

  11. Molecular mechanisms of STIM/Orai communication

    PubMed Central

    Derler, Isabella; Jardin, Isaac

    2016-01-01

    Ca2+ entry into the cell via store-operated Ca2+ release-activated Ca2+ (CRAC) channels triggers diverse signaling cascades that affect cellular processes like cell growth, gene regulation, secretion, and cell death. These store-operated Ca2+ channels open after depletion of intracellular Ca2+ stores, and their main features are fully reconstituted by the two molecular key players: the stromal interaction molecule (STIM) and Orai. STIM represents an endoplasmic reticulum-located Ca2+ sensor, while Orai forms a highly Ca2+-selective ion channel in the plasma membrane. Functional as well as mutagenesis studies together with structural insights about STIM and Orai proteins provide a molecular picture of the interplay of these two key players in the CRAC signaling cascade. This review focuses on the main experimental advances in the understanding of the STIM1-Orai choreography, thereby establishing a portrait of key mechanistic steps in the CRAC channel signaling cascade. The focus is on the activation of the STIM proteins, the subsequent coupling of STIM1 to Orai1, and the consequent structural rearrangements that gate the Orai channels into the open state to allow Ca2+ permeation into the cell. PMID:26825122

  12. Molecular mechanisms of STIM/Orai communication.

    PubMed

    Derler, Isabella; Jardin, Isaac; Romanin, Christoph

    2016-04-15

    Ca(2+)entry into the cell via store-operated Ca(2+)release-activated Ca(2+)(CRAC) channels triggers diverse signaling cascades that affect cellular processes like cell growth, gene regulation, secretion, and cell death. These store-operated Ca(2+)channels open after depletion of intracellular Ca(2+)stores, and their main features are fully reconstituted by the two molecular key players: the stromal interaction molecule (STIM) and Orai. STIM represents an endoplasmic reticulum-located Ca(2+)sensor, while Orai forms a highly Ca(2+)-selective ion channel in the plasma membrane. Functional as well as mutagenesis studies together with structural insights about STIM and Orai proteins provide a molecular picture of the interplay of these two key players in the CRAC signaling cascade. This review focuses on the main experimental advances in the understanding of the STIM1-Orai choreography, thereby establishing a portrait of key mechanistic steps in the CRAC channel signaling cascade. The focus is on the activation of the STIM proteins, the subsequent coupling of STIM1 to Orai1, and the consequent structural rearrangements that gate the Orai channels into the open state to allow Ca(2+)permeation into the cell. PMID:26825122

  13. Molecular and Mechanical Behavior of Elastomers.

    ERIC Educational Resources Information Center

    Etzel, A. J.; And Others

    1986-01-01

    Describes an experiment in which stretching a rubber band can be used to compare the statistical theory of rubber elasticity with its continuum mechanics counterpart. Employs the use of the equation of the state of rubber elasticity and the Mooney-Rivlin equation. (TW)

  14. Molecular Mechanisms of Action of BPA

    PubMed Central

    Acconcia, Filippo; Pallottini, Valentina

    2015-01-01

    Bisphenol A (BPA) exposure has been associated with serious endocrine-disrupting effects in humans and wildlife. Toxicological and epidemiological studies evidenced that BPA increases body mass index and disrupts normal cardiovascular physiology by interfering with endogenous hormones in rodents, nonhuman primates, and cell culture test systems. The BPA concentration derived from these experiments were used by government regulatory agencies to determine the safe exposure levels of BPA in humans. However, accumulating literature in vivo and in vitro indicate that at concentrations lower than that reported in toxicological studies, BPA could elicit a different endocrine-disrupting capacity. To further complicate this picture, BPA effects rely on several and diverse mechanisms that converge upon endocrine and reproductive systems. If all or just few of these mechanisms concur to the endocrine-disrupting potential of low doses of BPA is at present still unclear. Thus, taking into account that the incidence and/or prevalence of health problems associated with endocrine disruption have increased worldwide, the goal of the present review is to give an overview of the many mechanisms of BPA action in order to decipher whether different mechanisms are at the root of the effect of low dose of BPA on endocrine system. PMID:26740804

  15. Selectivity and molecular mechanisms of toxicity

    SciTech Connect

    DeMatteis, F. ); Lock, E. A. )

    1987-01-01

    This book contains 11 chapters. Some of the titles are: Mechanisms of genotoxicity of chlorinated aliphatic hydrocarbons; Drugs as suicide substrates of cytochrome P-450; Cellular specific toxicity in the lung; The nephrotoxicity of haloalkane and haloalkene glutathione conjugates; and dioxin and organotin compounds as model immunotoxic chemicals.

  16. Emerging mechanisms of molecular pathology in ALS

    PubMed Central

    Peters, Owen M.; Ghasemi, Mehdi; Brown, Robert H.

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a devastating degenerative disease characterized by progressive loss of motor neurons in the motor cortex, brainstem, and spinal cord. Although defined as a motor disorder, ALS can arise concurrently with frontotemporal lobal dementia (FTLD). ALS begins focally but disseminates to cause paralysis and death. About 10% of ALS cases are caused by gene mutations, and more than 40 ALS-associated genes have been identified. While important questions about the biology of this disease remain unanswered, investigations of ALS genes have delineated pathogenic roles for (a) perturbations in protein stability and degradation, (b) altered homeostasis of critical RNA- and DNA-binding proteins, (c) impaired cytoskeleton function, and (d) non-neuronal cells as modifiers of the ALS phenotype. The rapidity of progress in ALS genetics and the subsequent acquisition of insights into the molecular biology of these genes provide grounds for optimism that meaningful therapies for ALS are attainable. PMID:25932674

  17. Molecular mechanisms in multiple myeloma drug resistance

    PubMed Central

    Nikesitch, Nicholas; Ling, Silvia C W

    2016-01-01

    Multiple myeloma (MM) is predominantly an incurable malignancy despite high-dose chemotherapy, autologous stem cell transplant and novel agents. MM is a genetically heterogeneous disease and the complexity increases as the disease progresses to a more aggressive stage. MM arises from a plasma cell, which produces and secretes non-functioning immunoglobulins. Most MM cells are sensitive to proteasome inhibitors (PIs), which have become the main drug in the treatment of newly diagnosed and relapsed MM. However, not all MM is sensitive to PIs. This review summarises the literature regarding molecular biology of MM with a focus on the unfolded protein response and explores how this could affect drug sensitivity and progression of disease. PMID:26598624

  18. Molecular mechanisms of polyploidy and hybrid vigor

    PubMed Central

    Chen, Z. Jeffrey

    2010-01-01

    Hybrids such as maize (Zea mays) or domestic dog (Canis lupus familiaris) grow bigger and stronger than their parents. This is also true for allopolyploids such as wheat (Triticum spp.) or frog (i.e. Xenopus and Silurana) that contain two or more sets of chromosomes from different species. The phenomenon, known as hybrid vigor or heterosis, was systematically characterized by Charles Darwin (1876). The rediscovery of heterosis in maize a century ago has revolutionized plant and animal breeding and production. Although genetic models for heterosis have been rigorously tested, the molecular bases remain elusive. Recent studies have determined the roles of nonadditive gene expression, small RNAs, and epigenetic regulation, including circadian-mediated metabolic pathways, in hybrid vigor and incompatibility, which could lead to better use and exploitation of the increased biomass and yield in hybrids and allopolyploids for food, feed, and biofuels. PMID:20080432

  19. How Molecular Structure Affects Mechanical Properties of an Advanced Polymer

    NASA Technical Reports Server (NTRS)

    Nicholson, Lee M.; Whitley, Karen S.; Gates, Thomas S.; Hinkley, Jeffrey A.

    2000-01-01

    density was performed over a range of temperatures below the glass transition temperature. The physical characterization, elastic properties and notched tensile strength all as a function of molecular weight and test temperature were determined. For the uncrosslinked SI material, it was shown that notched tensile strength is a strong function of both temperature and molecular weight, whereas stiffness is only a strong function of temperature. For the crosslinked PETI-SI material, it was shown that the effect of crosslinking significantly enhances the mechanical performance of the low molecular weight material; comparable to that exhibited by the high molecular weight material.

  20. Shared Molecular Mechanisms of Membrane Transporters.

    PubMed

    Drew, David; Boudker, Olga

    2016-06-01

    The determination of the crystal structures of small-molecule transporters has shed light on the conformational changes that take place during structural isomerization from outward- to inward-facing states. Rather than using a simple rocking movement of two bundles around a central substrate-binding site, it has become clear that even the most simplistic transporters utilize rearrangements of nonrigid bodies. In the most dramatic cases, one bundle is fixed while the other, structurally divergent, bundle carries the substrate some 18 Å across the membrane, which in this review is termed an elevator alternating-access mechanism. Here, we compare and contrast rocker-switch, rocking-bundle, and elevator alternating-access mechanisms to highlight shared features and novel refinements to the basic alternating-access model. PMID:27023848

  1. Molecular mechanisms regulating NLRP3 inflammasome activation

    PubMed Central

    Jo, Eun-Kyeong; Kim, Jin Kyung; Shin, Dong-Min; Sasakawa, Chihiro

    2016-01-01

    Inflammasomes are multi-protein signaling complexes that trigger the activation of inflammatory caspases and the maturation of interleukin-1β. Among various inflammasome complexes, the NLRP3 inflammasome is best characterized and has been linked with various human autoinflammatory and autoimmune diseases. Thus, the NLRP3 inflammasome may be a promising target for anti-inflammatory therapies. In this review, we summarize the current understanding of the mechanisms by which the NLRP3 inflammasome is activated in the cytosol. We also describe the binding partners of NLRP3 inflammasome complexes activating or inhibiting the inflammasome assembly. Our knowledge of the mechanisms regulating NLRP3 inflammasome signaling and how these influence inflammatory responses offers further insight into potential therapeutic strategies to treat inflammatory diseases associated with dysregulation of the NLRP3 inflammasome. PMID:26549800

  2. Vancomycin Molecular Interactions: Antibiotic and Enantioselective Mechanisms

    NASA Astrophysics Data System (ADS)

    Ward, Timothy J.; Gilmore, Aprile; Ward, Karen; Vowell, Courtney

    Medical studies established that vancomycin and other related macrocyclic antibiotics have an enhanced antimicrobial activity when they are associated as dimers. The carbohydrate units attached to the vancomycin basket have an essential role in the dimerization reaction. Covalently synthesized dimers were found active against vancomycin-resistant bacterial strains. A great similarity between antibiotic potential and enantioselectivity was established. A covalent vancomycin dimer was studied in capillary electrophoresis producing excellent chiral separation of dansyl amino acids. Balhimycin is a macrocyclic glycopeptide structurally similar to vancomycin. The small differences are, however, responsible for drastic differences in enantioselectivity in the same experimental conditions. Contributions from studies examining vancomycin's mechanism for antimicrobial activity have substantially aided our understanding of its mechanism in chiral recognition.

  3. Molecular mechanisms of bone formation in spondyloarthritis.

    PubMed

    González-Chávez, Susana Aideé; Quiñonez-Flores, Celia María; Pacheco-Tena, César

    2016-07-01

    Spondyloarthritis comprise a group of inflammatory rheumatic diseases characterized by its association to HLA-B27 and the presence of arthritis and enthesitis. The pathogenesis involves both an inflammatory process and new bone formation, which eventually lead to ankylosis of the spine. To date, the intrinsic mechanisms of the pathogenic process have not been fully elucidated, and our progress is remarkable in the identification of therapeutic targets to achieve the control of the inflammatory process, yet our ability to inhibit the excessive bone formation is still insufficient. The study of new bone formation in spondyloarthritis has been mostly conducted in animal models of the disease and only few experiments have been done using human biopsies. The deregulation and overexpression of molecules involved in the osteogenesis process have been observed in bone cells, mesenchymal cells, and fibroblasts. The signaling associated to the excessive bone formation is congruent with those involved in the physiological processes of bone remodeling. Bone morphogenetic proteins and Wnt pathways have been found deregulated in this disease; however, the cause for uncontrolled stimulation remains unknown. Mechanical stress appears to play an important role in the pathological osteogenesis process; nevertheless, the association of other important factors, such as the presence of HLA-B27 and environmental factors, remains uncertain. The present review summarizes the experimental findings that describe the signaling pathways involved in the new bone formation process in spondyloarthritis in animal models and in human biopsies. The role of mechanical stress as the trigger of these pathways is also reviewed. PMID:26838262

  4. Molecular mechanisms for tumour resistance to chemotherapy.

    PubMed

    Pan, Shu-Ting; Li, Zhi-Ling; He, Zhi-Xu; Qiu, Jia-Xuan; Zhou, Shu-Feng

    2016-08-01

    Chemotherapy is one of the prevailing methods used to treat malignant tumours, but the outcome and prognosis of tumour patients are not optimistic. Cancer cells gradually generate resistance to almost all chemotherapeutic drugs via a variety of distinct mechanisms and pathways. Chemotherapeutic resistance, either intrinsic or acquired, is caused and sustained by reduced drug accumulation and increased drug export, alterations in drug targets and signalling transduction molecules, increased repair of drug-induced DNA damage, and evasion of apoptosis. In order to better understand the mechanisms of chemoresistance, this review highlights our current knowledge of the role of altered drug metabolism and transport and deregulation of apoptosis and autophagy in the development of tumour chemoresistance. Reduced intracellular activation of prodrugs (e.g. thiotepa and tegafur) or enhanced drug inactivation by Phase I and II enzymes contributes to the development of chemoresistance. Both primary and acquired resistance can be caused by alterations in the transport of anticancer drugs which is mediated by a variety of drug transporters such as P-glycoprotein (P-gp), multidrug resistance associated proteins, and breast cancer resistance protein. Presently there is a line of evidence indicating that deregulation of programmed cell death including apoptosis and autophagy is also an important mechanism for tumour resistance to anticancer drugs. Reversal of chemoresistance is likely via pharmacological and biological approaches. Further studies are warranted to grasp the full picture of how each type of cancer cells develop resistance to anticancer drugs and to identify novel strategies to overcome it. PMID:27097837

  5. Molecular Mechanisms of Circadian Regulation During Spaceflight

    NASA Technical Reports Server (NTRS)

    Zanello, Susana; Boyle, Richard

    2011-01-01

    Disruption of the regular environmental circadian cues in addition to stringent and demanding operational schedules are two main factors that undoubtedly impact sleep patterns and vigilant performance in the astronaut crews during spaceflight. Most research is focused on the behavioral aspects of the risk of circadian desynchronization, characterized by fatigue and health and performance decrement. A common countermeasure for circadian re-entrainment utilizes blue-green light to entrain the circadian clock and mitigate this risk. However, an effective countermeasure targeting the photoreceptor system requires that the basic circadian molecular machinery remains intact during spaceflight. The molecular clock consists of sets of proteins that perform different functions within the clock machinery: circadian oscillators (genes whose expression levels cycle during the day, keep the pass of cellular time and regulate downstream effector genes), the effector or output genes (those which impact the physiology of the tissue or organism), and the input genes (responsible for sensing the environmental cues that allow circadian entrainment). The main environmental cue is light. As opposed to the known photoreceptors (rods and cones), the non-visual light stimulus is received by a subset of the population of retinal ganglion cells called intrinsically photosensitive retinal ganglion cells (ipRGC) that express melanopsin (opsin 4 -Opn4-) as the photoreceptor. We hypothesize that spaceflight may affect ipRGC and melanopsin expression, which may be a contributing cause of circadian disruption during spaceflight. To answer this question, eyes from albino Balb/cJ mice aboard STS-133 were collected for histological analysis and gene expression profiling of the retina at 1 and 7 days after landing. Both vivarium and AEM (animal enclosure module) mice were used as ground controls. Opn4 expression was analyzed by real time RT/qPCR and retinal sections were stained for Opn4

  6. [Mechanism and clinical progress of molecular targeted cancer therapy].

    PubMed

    Hu, Hong-xiang; Wang, Xue-qing; Zhang, Hua; Zhang, Qiang

    2015-10-01

    Molecular target-based cancer therapy is playing a more and more important role in cancer therapy because of its high specificity, good tolerance and so on. There are different kinds of molecular targeted drugs such as monoclonal antibodies and small molecular kinase inhibitors, and more than 50 drugs have been approved since 1997. When the first monoclonal antibody, rituximab, was on the market. The development of molecular target-based cancer therapeutics has become the main approach. Based on this, we summarized the drugs approved by FDA and introduced their mechanism of actions and clinical applications. In order to incorporate most molecular targeted drugs and describe clearly various characteristics, we divided them into four categories: drugs related to EGFR, drugs related to antiangiogenesis, drugs related to specific antigen and other targeted drugs. The purpose of this review is to provide a current status of this field and discover the main problems in the molecular targeted therapy. PMID:26837167

  7. Brief Homeopathic Pathogenetic Experimentation: A Unique Educational Tool in Brazil

    PubMed Central

    2009-01-01

    In homeopathy, many difficulties are encountered in understanding theoretical presuppositions because they represent different paradigms from those of hegemonic science. In our medical school, we developed a brief homeopathic pathogenetic experimentation course to be added as curricular content and a didactic method in homeopathic disciplines to add practical experience to the theoretical approach of homeopathic presuppositions. In accordance with the premises laid out by Hahnemann, the father of homeopathy, brief pathogenetic experimentation was offered on a voluntary basis for students who were free of chronic diseases and who had not regularly used medication in the last 3 months. The clinical test, either crossed or sequential (randomized and blind), was used as a study model. Single weekly doses of a homeopathic medicine of 30 cH or placebo were taken by participants during 4 weeks after which crossover of the experimented substances took place for another 4 weeks. Polycrest medicines were used so that symptoms developed by the participants could be compared to those described in Homeopathic Materia Medica. Thirty-three of the 50 students who studied homeopathy as an elective discipline over the last 4 years at the School of Medicine of the University of São Paulo (FMUSP) participated. Participants described symptoms according to specific methodology including many comments with peculiar characteristics and notable idiosyncrasies. All these students endorsed the course because it contributed to their understanding of how dynamized substances produced symptoms in healthy participants as well as the cure of symptoms according to the casual similitude principle. Brief homeopathic pathogenetic experimentation proved to be an effective method to observe the idiosyncratic manifestations of human individuality based on qualitative methodology, thus building a basis of understanding of homeopathy. PMID:18955242

  8. Uncouplers and the molecular mechanism of uncoupling in mitochondria.

    PubMed Central

    Kessler, R J; Vande Zande, H; Tyson, C A; Blondin, G A; Fairfield, J; Glasser, P; Green, D E

    1977-01-01

    Uncouplers are molecules with protonophoric and ionophoric capabilities that mediate coupled cyclical transport of cations--a transport that takes precedence over all other coupled processes. Uncouplers form cation-containing complexes with electrogenic ionophores that potentiate cyclical transport of cations. The molecular mechanism of uncoupling sheds strong light on the mechanism of coupling. PMID:142250

  9. Plant regeneration: cellular origins and molecular mechanisms.

    PubMed

    Ikeuchi, Momoko; Ogawa, Yoichi; Iwase, Akira; Sugimoto, Keiko

    2016-05-01

    Compared with animals, plants generally possess a high degree of developmental plasticity and display various types of tissue or organ regeneration. This regenerative capacity can be enhanced by exogenously supplied plant hormones in vitro, wherein the balance between auxin and cytokinin determines the developmental fate of regenerating organs. Accumulating evidence suggests that some forms of plant regeneration involve reprogramming of differentiated somatic cells, whereas others are induced through the activation of relatively undifferentiated cells in somatic tissues. We summarize the current understanding of how plants control various types of regeneration and discuss how developmental and environmental constraints influence these regulatory mechanisms. PMID:27143753

  10. Multiple Sclerosis: Molecular Mechanisms and Therapeutic Opportunities

    PubMed Central

    Miljković, Djordje; Spasojević, Ivan

    2013-01-01

    Abstract The pathophysiology of multiple sclerosis (MS) involves several components: redox, inflammatory/autoimmune, vascular, and neurodegenerative. All of them are supported by the intertwined lines of evidence, and none of them should be written off. However, the exact mechanisms of MS initiation, its development, and progression are still elusive, despite the impressive pace by which the data on MS are accumulating. In this review, we will try to integrate the current facts and concepts, focusing on the role of redox changes and various reactive species in MS. Knowing the schedule of initial changes in pathogenic factors and the key turning points, as well as understanding the redox processes involved in MS pathogenesis is the way to enable MS prevention, early treatment, and the development of therapies that target specific pathophysiological components of the heterogeneous mechanisms of MS, which could alleviate the symptoms and hopefully stop MS. Pertinent to this, we will outline (i) redox processes involved in MS initiation; (ii) the role of reactive species in inflammation; (iii) prooxidative changes responsible for neurodegeneration; and (iv) the potential of antioxidative therapy. Antioxid. Redox Signal. 19, 2286–2334. PMID:23473637

  11. Membrane curvature in cell biology: An integration of molecular mechanisms.

    PubMed

    Jarsch, Iris K; Daste, Frederic; Gallop, Jennifer L

    2016-08-15

    Curving biological membranes establishes the complex architecture of the cell and mediates membrane traffic to control flux through subcellular compartments. Common molecular mechanisms for bending membranes are evident in different cell biological contexts across eukaryotic phyla. These mechanisms can be intrinsic to the membrane bilayer (either the lipid or protein components) or can be brought about by extrinsic factors, including the cytoskeleton. Here, we review examples of membrane curvature generation in animals, fungi, and plants. We showcase the molecular mechanisms involved and how they collaborate and go on to highlight contexts of curvature that are exciting areas of future research. Lessons from how membranes are bent in yeast and mammals give hints as to the molecular mechanisms we expect to see used by plants and protists. PMID:27528656

  12. Molecular mechanisms of intercellular communication: transmembrane signaling

    SciTech Connect

    Bitensky, M.W.; George, J.S.; Siegel, H.N.; McGregor, D.M.

    1982-01-01

    This short discussion of transmembrane signaling depicts a particular class of signaling devices whose functional characteristics may well be representative of broader classes of membrane switches. These multicomponent aggregates are characterized by tight organization of interacting components which function by conformational interactions to provide sensitive, amplified, rapid, and modulated responses. It is clear that the essential role of such switches in cell-cell interactions necessitated their appearance early in the history of the development of multicellular organisms. It also seems clear that once such devices made their appearance, the conformationally interactive moieties were firmly locked into a regulatory relationship. Since modification of interacting components could perturb or interfere with the functional integrity of the whole switch, genetic drift was only permitted at the input and outflow extremes. However, the GTP binding moiety and its interacting protein domains on contiguous portions of the receptor and readout components were highly conserved. The observed stringent evolutionary conservation of the molecular features of these membrane switches thus applies primarily to the central (GTP binding) elements. An extraordinary degree of variation was permitted within the domains of signal recognition and enzymatic output. Thus, time and evolution have adapted the central logic of the regulatory algorithm to serve a great variety of cellular purposes and to recognize a great variety of chemical and physical signals. This is exemplified by the richness of the hormonal and cellular dialogues found in primates such as man. Here the wealth of intercellular communiation can support the composition and performance of symphonies and the study of cellular immunology.

  13. Molecular Mechanisms of Circadian Regulation During Spaceflight

    NASA Technical Reports Server (NTRS)

    Zanello, S. B.; Boyle, R.

    2012-01-01

    The physiology of both vertebrates and invertebrates follows internal rhythms coordinated in phase with the 24-hour daily light cycle. This circadian clock is governed by a central pacemaker, the suprachiasmatic nucleus (SCN) in the brain. However, peripheral circadian clocks or oscillators have been identified in most tissues. How the central and peripheral oscillators are synchronized is still being elucidated. Light is the main environmental cue that entrains the circadian clock. Under the absence of a light stimulus, the clock continues its oscillation in a free-running condition. In general, three functional compartments of the circadian clock are defined. The vertebrate retina contains endogenous clocks that control many aspects of retinal physiology, including retinal sensitivity to light, neurohormone synthesis (melatonin and dopamine), rod disk shedding, signalling pathways and gene expression. Neurons with putative local circadian rhythm generation are found among all the major neuron populations in the mammalian retina. In the mouse, clock genes and function are more localized to the inner retinal and ganglion cell layers. The photoreceptor, however, secrete melatonin which may still serve a an important circadian signal. The reception and transmission of the non-visual photic stimulus resides in a small subpopulation (1-3%) or retinal ganglion cells (RGC) that express the pigment melanopsin (Opn4) and are called intrisically photoreceptive RGC (ipRGC). Melanopsin peak absorption is at 420 nm and all the axons of the ipRGC reach the SCN. A common countermeasure for circadian re-entrainment utilizes blue-green light to entrain the circadian clock and mitigate the risk of fatigue and health and performance decrement due to circadian rhythm disruption. However, an effective countermeasure targeting the photoreceptor system requires that the basic circadian molecular machinery remains intact during spaceflight. We hypothesize that spaceflight may affect ip

  14. Photodynamic therapy: Biophysical mechanisms and molecular responses

    NASA Astrophysics Data System (ADS)

    Mitra, Soumya

    In photodynamic therapy (PDT), photochemical reactions induced by optical activation of sensitizer molecules cause destruction of the target tissue. In this thesis we present results of several related studies, which investigated the influence of photophysical properties and photobleaching mechanisms of sensitizers and oxygen-dependent tissue optical properties on PDT treatment efficacy. The bleaching mechanism of the sensitizer meso-tetra hydroxyphenyl chlorin (mTHPC) is examined indirectly using measurements of photochemical oxygen consumption during PDT irradiation of multicell tumor spheroids. Analysis of the results with a theoretical model of oxygen diffusion that incorporates the effects of sensitizer photobleaching shows that mTHPC is degraded via a singlet-oxygen (1O2)-mediated bleaching process. The analysis allows us to extract photophysical parameters of mTHPC which are used to account for its enhanced clinical photodynamic potency in comparison to that of Photofrin. Evaluation of the spatially-resolved fluorescence in confocal optical sections of intact spheroids during PDT irradiation allows for the direct experimental verification of mTHPC's 1O2-mediated bleaching mechanism. The technique is also used to investigate the complex bleaching kinetics of Photofrin. The results allow us to successfully reconcile apparently contradictory experimental observations and to confirm the predictions of a new theoretical model in which both 1O2 and excited triplet sensitizer molecules are allowed to contribute to photobleaching. Based on studies performed in tissue-simulating erythrocyte phantoms and in a murine tumor model in vivo, we present clinically relevant results which indicate that a shift toward increased hemoglobin-oxygen saturation due to improved tissue oxygenation reduces PDT treatment beam attenuation and may allow for more effective treatment of deeper lesions. Finally, we investigate the induction of the stress protein, heat shock protein 70 (HSP

  15. MOLECULAR TARGETS AND MECHANISMS FOR ETHANOL ACTION IN GLYCINE RECEPTORS

    PubMed Central

    Perkins, Daya I.; Trudell, James R.; Crawford, Daniel K.; Alkana, Ronald L.; Davies, Daryl L.

    2010-01-01

    Glycine receptors (GlyRs) are recognized as the primary mediators of neuronal inhibition in the spinal cord, brain stem and higher brain regions known to be sensitive to ethanol. Building evidence supports the notion that ethanol acting on GlyRs causes at least a subset of its behavioral effects and may be involved in modulating ethanol intake. For over two decades, GlyRs have been studied at the molecular level as targets for ethanol action. Despite the advances in understanding the effects of ethanol in vivo and in vitro, the precise molecular sites and mechanisms of action for ethanol in ligand-gated ion channels in general, and in GlyRs specifically, are just now starting to become understood. The present review focuses on advances in our knowledge produced by using molecular biology, pressure antagonism, electrophysiology and molecular modeling strategies over the last two decades to probe, identify and model the initial molecular sites and mechanisms of ethanol action in GlyRs. The molecular targets on the GlyR are covered on a global perspective, which includes the intracellular, transmembrane and extracellular domains. The latter has received increasing attention in recent years. Recent molecular models of the sites of ethanol action in GlyRs and their implications to our understanding of possible mechanism of ethanol action and novel targets for drug development in GlyRs are discussed. PMID:20399807

  16. Molecular Mechanisms of Renal Ammonia Transport

    PubMed Central

    Weiner, I. David; Hamm, L. Lee

    2015-01-01

    Acid-base homeostasis to a great extent relies on renal ammonia metabolism. In the past several years, seminal studies have generated important new insights into the mechanisms of renal ammonia transport. In particular, the theory that ammonia transport occurs almost exclusively through nonionic NH3 diffusion and NH4+ trapping has given way to a model postulating that a variety of proteins specifically transport NH3 and NH4+ and that this transport is critical for normal ammonia metabolism. Many of these proteins transport primarily H+ or K+ but also transport NH4+. Nonerythroid Rh glycoproteins transport ammonia and may represent critical facilitators of ammonia transport in the kidney. This review discusses the underlying aspects of renal ammonia transport as well as specific proteins with important roles in renal ammonia transport. PMID:17002591

  17. Molecular mechanisms of Escherichia coli pathogenicity.

    PubMed

    Croxen, Matthew A; Finlay, B Brett

    2010-01-01

    Escherichia coli is a remarkable and diverse organism. This normally harmless commensal needs only to acquire a combination of mobile genetic elements to become a highly adapted pathogen capable of causing a range of diseases, from gastroenteritis to extraintestinal infections of the urinary tract, bloodstream and central nervous system. The worldwide burden of these diseases is staggering, with hundreds of millions of people affected annually. Eight E. coli pathovars have been well characterized, and each uses a large arsenal of virulence factors to subvert host cellular functions to potentiate its virulence. In this Review, we focus on the recent advances in our understanding of the different pathogenic mechanisms that are used by various E. coli pathovars and how they cause disease in humans. PMID:19966814

  18. Rectification mechanism in diblock oligomer molecular diodes.

    PubMed

    Oleynik, I I; Kozhushner, M A; Posvyanskii, V S; Yu, L

    2006-03-10

    We investigated a mechanism of rectification in diblock oligomer diode molecules that have recently been synthesized and showed a pronounced asymmetry in the measured I-V spectrum. The observed rectification effect is due to the resonant nature of electron transfer in the system and the localization properties of bound state wave functions of resonant states of the tunneling electron interacting with an asymmetric molecule in an electric field. The asymmetry of the tunneling wave function is enhanced or weakened depending on the polarity of the applied bias. The conceptually new theoretical approach, the Green's function theory of sub-barrier scattering, is able to provide a physically transparent explanation of this rectification effect based on the concept of the bound state spectrum of a tunneling electron. The theory predicts the characteristic features of the I-V spectrum in qualitative agreement with experiment. PMID:16606295

  19. Anemia: Progress in molecular mechanisms and therapy

    PubMed Central

    Sankaran, Vijay G.; Weiss, Mitchell J.

    2015-01-01

    Anemia is a major source of morbidity and mortality worldwide. Here we review recent insights into how red blood cells (RBCs) are produced, the pathogenic mechanisms underlying various forms of anemia, and novel therapies derived from these findings. It is likely that these new insights, mainly arising from basic scientific studies, will contribute immensely to understanding frequently debilitating forms of anemia and the ability to treat affected patients. Major worldwide diseases that may stand to benefit from the new advances include the hemoglobinopathies (β-thalassemia and sickle cell disease), rare genetic disorders of red blood cell production, and anemias associated with chronic kidney disease, inflammation, and cancer. Promising new treatment approaches include drugs that target recently defined pathways in red blood cell production, iron metabolism, and fetal globin gene expression, as well as gene therapies using improved viral vectors and newly developed genome editing technologies. PMID:25742458

  20. Regulation of the MET oncogene: molecular mechanisms.

    PubMed

    Zhang, Jack; Babic, Andy

    2016-04-01

    TheMEToncogene is a predictive biomarker and an attractive therapeutic target for various cancers. Its expression is regulated at multiple layers via various mechanisms. It is subject to epigenetic modifications, i.e. DNA methylation and histone acetylation. Hypomethylation and acetylation of theMETgene have been associated with its high expression in some cancers. Multiple transcription factors including Sp1 and Ets-1 govern its transcription. After its transcription,METmRNA is spliced into multiple species in the nucleus before being transported to the cytoplasm where its translation is modulated by at least 30 microRNAs and translation initiation factors, e.g. eIF4E and eIF4B.METmRNA produces a single chain pro-Met protein of 170kDa which is cleaved into α and β chains. These two chains are bound together through disulfide bonds to form a heterodimer which undergoes either N-linked or O-linked glycosylation in the Golgi apparatus before it is properly localized in the membrane. Upon interactions with its ligand, i.e. hepatocyte growth factor (HGF), the activity of Met kinase is boosted through various phosphorylation mechanisms and the Met signal is relayed to downstream pathways. The phosphorylated Met is then internalized for subsequent degradation or recycle via proteasome, lysosome or endosome pathways. Moreover, the Met expression is subject to autoregulation and activation by other EGFRs and G-protein coupled receptors. Since deregulation of theMETgene leads to cancer and other pathological conditions, a better understanding of theMETregulation is critical for Met-targeted therapeutics. PMID:26905592

  1. Understanding molecular mechanism of higher plant plasticity under abiotic stress.

    PubMed

    Shao, Hong-Bo; Guo, Qing-Jie; Chu, Li-Ye; Zhao, Xi-Ning; Su, Zhong-Liang; Hu, Ya-Chen; Cheng, Jiang-Feng

    2007-01-15

    Higher plants play the most important role in keeping a stable environment on the earth, which regulate global circumstances in many ways in terms of different levels (molecular, individual, community, and so on), but the nature of the mechanism is gene expression and control temporally and spatially at the molecular level. In persistently changing environment, there are many adverse stress conditions such as cold, drought, salinity and UV-B (280-320 mm), which influence plant growth and crop production greatly. Plants differ from animals in many aspects, but the important may be that plants are more easily influenced by environment than animals. Plants have a series of fine mechanisms for responding to environmental changes, which has been established during their long-period evolution and artificial domestication. These mechanisms are involved in many aspects of anatomy, physiology, biochemistry, genetics, development, evolution and molecular biology, in which the adaptive machinery related to molecular biology is the most important. The elucidation of it will extremely and purposefully promote the sustainable utilization of plant resources and make the best use of its current potential under different scales. This molecular mechanism at least include environmental signal recognition (input), signal transduction (many cascade biochemical reactions are involved in this process), signal output, signal responses and phenotype realization, which is a multi-dimensional network system and contain many levels of gene expression and regulation. We will focus on the molecular adaptive machinery of higher plant plasticity under abiotic stresses. PMID:16914294

  2. Adenosine triphosphate hydrolysis mechanism in kinesin studied by combined quantum-mechanical/molecular-mechanical metadynamics simulations.

    PubMed

    McGrath, Matthew J; Kuo, I-F Will; Hayashi, Shigehiko; Takada, Shoji

    2013-06-19

    Kinesin is a molecular motor that hydrolyzes adenosine triphosphate (ATP) and moves along microtubules against load. While motility and atomic structures have been well-characterized for various members of the kinesin family, not much is known about ATP hydrolysis inside the active site. Here, we study ATP hydrolysis mechanisms in the kinesin-5 protein Eg5 by using combined quantum mechanics/molecular mechanics metadynamics simulations. Approximately 200 atoms at the catalytic site are treated by a dispersion-corrected density functional and, in total, 13 metadynamics simulations are performed with their cumulative time reaching ~0.7 ns. Using the converged runs, we compute free energy surfaces and obtain a few hydrolysis pathways. The pathway with the lowest free energy barrier involves a two-water chain and is initiated by the Pγ-Oβ dissociation concerted with approach of the lytic water to PγO3-. This immediately induces a proton transfer from the lytic water to another water, which then gives a proton to the conserved Glu270. Later, the proton is transferred back from Glu270 to HPO(4)2- via another hydrogen-bonded chain. We find that the reaction is favorable when the salt bridge between Glu270 in switch II and Arg234 in switch I is transiently broken, which facilitates the ability of Glu270 to accept a proton. When ATP is placed in the ADP-bound conformation of Eg5, the ATP-Mg moiety is surrounded by many water molecules and Thr107 blocks the water chain, which together make the hydrolysis reaction less favorable. The observed two-water chain mechanisms are rather similar to those suggested in two other motors, myosin and F1-ATPase, raising the possibility of a common mechanism. PMID:23751065

  3. Molecular mechanisms of LRRK2 regulation

    NASA Astrophysics Data System (ADS)

    Webber, Philip Jeffrey

    Non-synonymous mutations in LRRK2 are the most common known cause of familial and sporadic Parkinson's disease (PD). The dominant inheritance of these mutations in familial PD suggests a gain-of-function mechanism. Increased kinase activity observed in the most common PD associated LRRK2 mutation G2019S suggests that kinase activity is central to disease. However, not all mutations associated with disease are reported to alter kinase activity and controversy exists in the literature about the effects of mutations appearing in the GTPase domain on kinase activity. The studies conducted as a part of this work aim to characterize the mechanisms that regulate LRRK2 kinase activity and the effects of mutations on enzymatic activity of LRRK2 protein. LRRK2 is a large protein with multiple predicted functional domains including two enzymatic domains in the same protein, the small ras-like GTPase domain and a serine-threonine protein kinase domain. Previous studies indicate that LRRK2 kinase is dependent on a functional GTPase domain and binding to GTP is required for kinase activity. Recent work detailed in this dissertation indicates a complex and reciprocal relationship between kinase and GTPase domains. LRRK2 kinase activity is dependent on adapting a homo-dimer that is augmented by PD mutations that increase LRRK2 kinase activity. Activated LRRK2 autophosphorylates the GTPase and c-terminus of Ras (COR) domains robustly. Phosphorylation of these domains is required for normal activity, as preventing autophosphorylation of these sites drastically lowers kinase activity and GTP binding while phosphorylation maintains baseline activity while still reducing GTP binding. Furthermore, we have developed antibodies specific to autophosphorylation residues that track with LRRK2 kinase activity in vitro. While no measurable activity was detected from treated LRRK2 in vivo, LRRK2 protein purified from brain tissue treated with inflammatory stimuli such as LPS, which increases

  4. Molecular mechanism for generation of antibody memory

    PubMed Central

    Shivarov, Velizar; Shinkura, Reiko; Doi, Tomomitsu; Begum, Nasim A.; Nagaoka, Hitoshi; Okazaki, Il-Mi; Ito, Satomi; Nonaka, Taichiro; Kinoshita, Kazuo; Honjo, Tasuku

    2008-01-01

    Activation-induced cytidine deaminase (AID) is the essential enzyme inducing the DNA cleavage required for both somatic hypermutation and class switch recombination (CSR) of the immunoglobulin gene. We originally proposed the RNA-editing model for the mechanism of DNA cleavage by AID. We obtained evidence that fulfils three requirements for CSR by this model, namely (i) AID shuttling between nucleus and cytoplasm, (ii) de novo protein synthesis for CSR, and (iii) AID–RNA complex formation. The alternative hypothesis, designated as the DNA-deamination model, assumes that the in vitro DNA deamination activity of AID is representative of its physiological function in vivo. Furthermore, the resulting dU was removed by uracil DNA glycosylase (UNG) to generate a basic site, followed by phosphodiester bond cleavage by AP endonuclease. We critically examined each of these provisional steps. We identified a cluster of mutants (H48A, L49A, R50A and N51A) that had particularly higher CSR activities than expected from their DNA deamination activities. The most striking was the N51A mutant that had no ability to deaminate DNA in vitro but retained approximately 50 per cent of the wild-type level of CSR activity. We also provide further evidence that UNG plays a non-canonical role in CSR, namely in the repair step of the DNA breaks. Taking these results together, we favour the RNA-editing model for the function of AID in CSR. PMID:19022739

  5. Molecular mechanisms of asymmetric RAF dimer activation.

    PubMed

    Jambrina, Pablo G; Bohuszewicz, Olga; Buchete, Nicolae-Viorel; Kolch, Walter; Rosta, Edina

    2014-08-01

    Protein phosphorylation is one of the most common post-translational modifications in cell regulatory mechanisms. Dimerization plays also a crucial role in the kinase activity of many kinases, including RAF, CDK2 (cyclin-dependent kinase 2) and EGFR (epidermal growth factor receptor), with heterodimers often being the most active forms. However, the structural and mechanistic details of how phosphorylation affects the activity of homo- and hetero-dimers are largely unknown. Experimentally, synthesizing protein samples with fully specified and homogeneous phosphorylation states remains a challenge for structural biology and biochemical studies. Typically, multiple changes in phosphorylation lead to activation of the same protein, which makes structural determination methods particularly difficult. It is also not well understood how the occurrence of phosphorylation and dimerization processes synergize to affect kinase activities. In the present article, we review available structural data and discuss how MD simulations can be used to model conformational transitions of RAF kinase dimers, in both their phosphorylated and unphosphorylated forms. PMID:25109958

  6. Molecular mechanisms of dominant expression in porphyria.

    PubMed

    Badminton, M N; Elder, G H

    2005-01-01

    Partial deficiency of enzymes in the haem synthetic pathway gives rise to a group of seven inherited metabolic disorders, the porphyrias. Each deficiency is associated with a characteristic increase in haem precursors that correlates with the symptoms associated with individual porphyrias and allows accurate diagnosis. Two types of clinical presentation occur separately or in combination; acute life-threatening neurovisceral attacks and/or cutaneous symptoms. Five of the porphyrias are low-penetrance autosomal dominant conditions in which clinical expression results from additional factors that act by increasing demand for haem or by causing an additional decrease in enzyme activity or by a combination of these effects. These include both genetic and environmental factors. In familial porphyria cutanea tarda (PCTF), environmental factors that include alcohol, exogenous oestrogens and hepatotropic viruses result in inhibition of hepatic enzyme activity via a mechanism that involves excess iron accumulation. In erythropoietic protoporphyria (EPP), co-inheritance of a functional polymorphism in trans to a null ferrochelatase allele accounts for most clinically overt cases. In the autosomal dominant acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria), acute neurovisceral attacks occur in a minority of those who inherit one of these disorders. Although various exogenous (e.g. drugs, alcohol) and endogenous factors (e.g. hormones) have been identified as provoking acute attacks, these do not provide a full explanation for the low penetrance of these disorders. It seems probable that genetic background influences susceptibility to acute attacks, but the genes that are involved have not yet been identified. PMID:15868463

  7. Molecular mechanisms of translation initiation in eukaryotes

    PubMed Central

    Pestova, Tatyana V.; Kolupaeva, Victoria G.; Lomakin, Ivan B.; Pilipenko, Evgeny V.; Shatsky, Ivan N.; Agol, Vadim I.; Hellen, Christopher U. T.

    2001-01-01

    Translation initiation is a complex process in which initiator tRNA, 40S, and 60S ribosomal subunits are assembled by eukaryotic initiation factors (eIFs) into an 80S ribosome at the initiation codon of mRNA. The cap-binding complex eIF4F and the factors eIF4A and eIF4B are required for binding of 43S complexes (comprising a 40S subunit, eIF2/GTP/Met-tRNAi and eIF3) to the 5′ end of capped mRNA but are not sufficient to promote ribosomal scanning to the initiation codon. eIF1A enhances the ability of eIF1 to dissociate aberrantly assembled complexes from mRNA, and these factors synergistically mediate 48S complex assembly at the initiation codon. Joining of 48S complexes to 60S subunits to form 80S ribosomes requires eIF5B, which has an essential ribosome-dependent GTPase activity and hydrolysis of eIF2-bound GTP induced by eIF5. Initiation on a few mRNAs is cap-independent and occurs instead by internal ribosomal entry. Encephalomyocarditis virus (EMCV) and hepatitis C virus epitomize distinct mechanisms of internal ribosomal entry site (IRES)-mediated initiation. The eIF4A and eIF4G subunits of eIF4F bind immediately upstream of the EMCV initiation codon and promote binding of 43S complexes. EMCV initiation does not involve scanning and does not require eIF1, eIF1A, and the eIF4E subunit of eIF4F. Initiation on some EMCV-like IRESs requires additional noncanonical initiation factors, which alter IRES conformation and promote binding of eIF4A/4G. Initiation on the hepatitis C virus IRES is even simpler: 43S complexes containing only eIF2 and eIF3 bind directly to the initiation codon as a result of specific interaction of the IRES and the 40S subunit. PMID:11416183

  8. Molecular and cellular mechanisms of myocardial stunning.

    PubMed

    Bolli, R; Marbán, E

    1999-04-01

    The past two decades have witnessed an explosive growth of knowledge regarding postischemic myocardial dysfunction or myocardial "stunning." The purpose of this review is to summarize current information regarding the pathophysiology and pathogenesis of this phenomenon. Myocardial stunning should not be regarded as a single entity but rather as a "syndrome" that has been observed in a wide variety of experimental settings, which include the following: 1) stunning after a single, completely reversible episode of regional ischemia in vivo; 2) stunning after multiple, completely reversible episodes of regional ischemia in vivo; 3) stunning after a partly reversible episode of regional ischemia in vivo (subendocardial infarction); 4) stunning after global ischemia in vitro; 5) stunning after global ischemia in vivo; and 6) stunning after exercise-induced ischemia (high-flow ischemia). Whether these settings share a common mechanism is unknown. Although the pathogenesis of myocardial stunning has not been definitively established, the two major hypotheses are that it is caused by the generation of oxygen-derived free radicals (oxyradical hypothesis) and by a transient calcium overload (calcium hypothesis) on reperfusion. The final lesion responsible for the contractile depression appears to be a decreased responsiveness of contractile filaments to calcium. Recent evidence suggests that calcium overload may activate calpains, resulting in selective proteolysis of myofibrils; the time required for resynthesis of damaged proteins would explain in part the delayed recovery of function in stunned myocardium. The oxyradical and calcium hypotheses are not mutually exclusive and are likely to represent different facets of the same pathophysiological cascade. For example, increased free radical formation could cause cellular calcium overload, which would damage the contractile apparatus of the myocytes. Free radical generation could also directly alter contractile filaments in a

  9. Anti-NR2A/B Antibodies and Other Major Molecular Mechanisms in the Pathogenesis of Cognitive Dysfunction in Systemic Lupus Erythematosus

    PubMed Central

    Tay, Sen Hee; Mak, Anselm

    2015-01-01

    Systemic lupus erythematosus (SLE) is an autoimmune disease that affects approximately 1–45.3 per 100,000 people worldwide. Although deaths as a result of active and renal diseases have been substantially declining amongst SLE patients, disease involving the central nervous system (CNS), collectively termed neuropsychiatric systemic lupus erythematosus (NPSLE), remains one of the important causes of death in these patients. Cognitive dysfunction is one of the most common manifestations of NPSLE, which comprises deficits in information-processing speed, attention and executive function, in conjunction with preservation of speech. Albeit a prevalent manifestation of NPSLE, the pathogenetic mechanisms of cognitive dysfunction remain unclear. Recent advances in genetic studies, molecular techniques, neuropathology, neuroimaging and cognitive science have gleaned valuable insights into the pathophysiology of lupus-related cognitive dysfunction. In recent years, a role for autoantibodies, molecular and cellular mechanisms in cognitive dysfunction, has been emerging, challenging our previous concept of the brain as an immune privileged site. This review will focus on the potential pathogenic factors involved in NPSLE, including anti-N-methyl-d-aspartate receptor subunit NR2A/B (anti-NR2A/B) antibodies, matrix metalloproteinase-9, neutrophil extracellular traps and pro-inflammatory mediators. Better understanding of these mechanistic processes will enhance identification of new therapeutic modalities to halt the progression of cognitive decline in SLE patients. PMID:25955648

  10. Mini-review: Molecular mechanisms of antifouling compounds.

    PubMed

    Qian, Pei-Yuan; Chen, Lianguo; Xu, Ying

    2013-01-01

    Various antifouling (AF) coatings have been developed to protect submerged surfaces by deterring the settlement of the colonizing stages of fouling organisms. A review of the literature shows that effective AF compounds with specific targets are ones often considered non-toxic. Such compounds act variously on ion channels, quorum sensing systems, neurotransmitters, production/release of adhesive, and specific enzymes that regulate energy production or primary metabolism. In contrast, AF compounds with general targets may or may not act through toxic mechanisms. These compounds affect a variety of biological activities including algal photosynthesis, energy production, stress responses, genotoxic damage, immunosuppressed protein expression, oxidation, neurotransmission, surface chemistry, the formation of biofilms, and adhesive production/release. Among all the targets, adhesive production/release is the most common, possibly due to a more extensive research effort in this area. Overall, the specific molecular targets and the molecular mechanisms of most AF compounds have not been identified. Thus, the information available is insufficient to draw firm conclusions about the types of molecular targets to be used as sensitive biomarkers for future design and screening of compounds with AF potential. In this review, the relevant advantages and disadvantages of the molecular tools available for studying the molecular targets of AF compounds are highlighted briefly and the molecular mechanisms of the AF compounds, which are largely a source of speculation in the literature, are discussed. PMID:23574197

  11. Molecular and Physiological Mechanisms of Membrane Receptor Systems Functioning

    PubMed Central

    Severin, E.S.; Savvateeva, M.V.

    2011-01-01

    Molecular physiology is a new interdisciplinary field of knowledge that looks into how complicated biological systems function. The living cell is a relatively simple, but at the same time very sophisticated biological system. After the sequencing of the human genome, molecular physiology has endeavored to investigate the systems of cellular interactions at a completely new level based on knowledge of the spatial organization and functions of receptors, their ligands, and protein-protein interactions. In recent years, the achievements in molecular physiology have centered on the study of sensor reception mechanisms and intercellular data transfer, as well as the immune system physiology, amongst other processes. PMID:22649671

  12. Cardiac Embryology and Molecular Mechanisms of Congenital Heart Disease: A Primer for Anesthesiologists.

    PubMed

    Kloesel, Benjamin; DiNardo, James A; Body, Simon C

    2016-09-01

    Congenital heart disease is diagnosed in 0.4% to 5% of live births and presents unique challenges to the pediatric anesthesiologist. Furthermore, advances in surgical management have led to improved survival of those patients, and many adult anesthesiologists now frequently take care of adolescents and adults who have previously undergone surgery to correct or palliate congenital heart lesions. Knowledge of abnormal heart development on the molecular and genetic level extends and improves the anesthesiologist's understanding of congenital heart disease. In this article, we aim to review current knowledge pertaining to genetic alterations and their cellular effects that are involved in the formation of congenital heart defects. Given that congenital heart disease can currently only occasionally be traced to a single genetic mutation, we highlight some of the difficulties that researchers face when trying to identify specific steps in the pathogenetic development of heart lesions. PMID:27541719

  13. Molecular Mimicry as a Mechanism of Autoimmune Disease

    PubMed Central

    Cusick, Matthew F.; Libbey, Jane E.; Fujinami, Robert S.

    2012-01-01

    A variety of mechanisms have been suggested as the means by which infections can initiate and/or exacerbate autoimmune diseases. One mechanism is molecular mimicry, where a foreign antigen shares sequence or structural similarities with self-antigens. Molecular mimicry has typically been characterized on an antibody or T cell level. However, structural relatedness between pathogen and self does not account for T cell activation in a number of autoimmune diseases. A proposed mechanism that could have been misinterpreted for molecular mimicry is the expression of dual T cell receptors (TCR) on a single T cell. These T cells have dual reactivity to both foreign and self-antigens leaving the host vulnerable to foreign insults capable of triggering an autoimmune response. In this review, we briefly discuss what is known about molecular mimicry followed by a discussion of the current understanding of dual TCRs. Finally, we discuss three mechanisms, including molecular mimicry, dual TCRs and chimeric TCRs, by which dual reactivity of the T cell may play a role in autoimmune diseases. PMID:22095454

  14. Reaction Mechanism of Mycobacterium Tuberculosis Glutamine Synthetase Using Quantum Mechanics/Molecular Mechanics Calculations.

    PubMed

    Moreira, Cátia; Ramos, Maria J; Fernandes, Pedro Alexandrino

    2016-06-27

    This paper is devoted to the understanding of the reaction mechanism of mycobacterium tuberculosis glutamine synthetase (mtGS) with atomic detail, using computational quantum mechanics/molecular mechanics (QM/MM) methods at the ONIOM M06-D3/6-311++G(2d,2p):ff99SB//B3LYP/6-31G(d):ff99SB level of theory. The complete reaction undergoes a three-step mechanism: the spontaneous transfer of phosphate from ATP to glutamate upon ammonium binding (ammonium quickly loses a proton to Asp54), the attack of ammonia on phosphorylated glutamate (yielding protonated glutamine), and the deprotonation of glutamine by the leaving phosphate. This exothermic reaction has an activation free energy of 21.5 kcal mol(-1) , which is consistent with that described for Escherichia coli glutamine synthetase (15-17 kcal mol(-1) ). The participating active site residues have been identified and their role and energy contributions clarified. This study provides an insightful atomic description of the biosynthetic reaction that takes place in this enzyme, opening doors for more accurate studies for developing new anti-tuberculosis therapies. PMID:27225077

  15. Physiological and molecular biochemical mechanisms of bile formation

    PubMed Central

    Reshetnyak, Vasiliy Ivanovich

    2013-01-01

    This review considers the physiological and molecular biochemical mechanisms of bile formation. The composition of bile and structure of a bile canaliculus, biosynthesis and conjugation of bile acids, bile phospholipids, formation of bile micellar structures, and enterohepatic circulation of bile acids are described. In general, the review focuses on the molecular physiology of the transporting systems of the hepatocyte sinusoidal and apical membranes. Knowledge of physiological and biochemical basis of bile formation has implications for understanding the mechanisms of development of pathological processes, associated with diseases of the liver and biliary tract. PMID:24259965

  16. Alpha-Synuclein in Parkinson's Disease: From Pathogenetic Dysfunction to Potential Clinical Application

    PubMed Central

    2016-01-01

    Parkinson's disease is a neurodegenerative disease/synucleinopathy that develops slowly; however, there is no efficient method of early diagnosis, nor is there a cure. Progressive dopaminergic neuronal cell loss in the substantia nigra pars compacta and widespread aggregation of the α-synuclein protein (encoded by the SNCA gene) in the form of Lewy bodies and Lewy neurites are the neuropathological hallmarks of Parkinson's disease. The SNCA gene has undergone gene duplications, triplications, and point mutations. However, the specific mechanism of α-synuclein in Parkinson's disease remains obscure. Recent research showed that various α-synuclein oligomers, pathological aggregation, and propagation appear to be harmful in certain areas in Parkinson's disease patients. This review summarizes our current knowledge of the pathogenetic dysfunction of α-synuclein associated with Parkinson's disease and highlights current approaches that seek to develop this protein as a possible diagnostic biomarker and therapeutic target. PMID:27610264

  17. Pathogenetic Importance and Therapeutic Implications of NF-κB in Lymphoid Malignancies

    PubMed Central

    Lim, Kian-Huat; Yang, Yibin; Staudt, Louis M.

    2014-01-01

    Summary Derangement of the nuclear factor κB (NF-κB) pathway initiates and/or sustains many types of human cancer. B-cell malignancies are particularly affected by oncogenic mutations, translocations, and copy number alterations affecting key components the NF-κB pathway, most likely owing to the pervasive role of this pathway in normal B cells. These genetic aberrations cause tumors to be ‘addicted’ to NF-κB, which can be exploited therapeutically. Since each subtype of lymphoid cancer utilizes different mechanisms to activate NF-κB, several different therapeutic strategies are needed to address this pathogenetic heterogeneity. Fortunately, a number of drugs that block signaling cascades leading to NF-κB are in early phase clinical trials, several of which are already showing activity in lymphoid malignancies. PMID:22435566

  18. A coordinated molecular 'fishing' mechanism in heterodimeric kinesin.

    PubMed

    Hou, Ruizheng; Wang, Zhisong

    2010-01-01

    Kar3 is a kinesin motor that facilitates chromosome segregation during cell division. Unlike many members of the kinesin superfamily, Kar3 forms a heterodimer with non-motor protein Vik1 or Cik1 in vivo. The heterodimers show ATP-driven minus-end directed motility along a microtubule (MT) lattice, and also serve as depolymerase at the MT ends. The molecular mechanisms behind this dual functionality remain mysterious. Here, a molecular mechanical model for the Kar3/Vik1 heterodimer based on structural, kinetic and motility data reveals a long-range chemomechanical transmission mechanism that resembles a familiar fishing tactic. By this molecular 'fishing', ATP-binding to Kar3 dissociates catalytically inactive Vik1 off MT to facilitate minus-end sliding of the dimer on the MT lattice. When the dimer binds the frayed ends of MT, the fishing channels ATP hydrolysis energy into MT depolymerization by a mechanochemical effect. The molecular fishing thus provides a unified mechanistic ground for Kar3's dual functionality. The fishing-promoted depolymerization differs from the depolymerase mechanisms found in homodimeric kinesins. The fishing also enables intermolecular coordination with a chemomechanical coupling feature different from the paradigmatic pattern of homodimeric motors. This study rationalizes some puzzling experimental observation, and suggests new experiments for further elucidation of the fishing mechanism. PMID:20720285

  19. Antigenic variation: Molecular and genetic mechanisms of relapsing disease

    SciTech Connect

    Cruse, J.M.; Lewis, R.E.

    1987-01-01

    This book contains 10 chapters. They are: Contemporary Concepts of Antigenic Variation; Antigenic Variation in the Influenza Viruses; Mechanisms of Escape of Visna Lentiviruses from Immunological Control; A Review of Antigenic Variation by the Equine Infectious Anemia Virus; Biologic and Molecular Variations in AIDS Retrovirus Isolates; Rabies Virus Infection: Genetic Mutations and the Impact on Viral Pathogenicity and Immunity; Immunobiology of Relapsing Fever; Antigenic Variation in African Trypanosomes; Antigenic Variation and Antigenic Diversity in Malaria; and Mechanisms of Immune Evasion in Schistosomiasis.

  20. Resveratrol and Calcium Signaling: Molecular Mechanisms and Clinical Relevance

    PubMed Central

    McCalley, Audrey E.; Kaja, Simon; Payne, Andrew J.; Koulen, Peter

    2014-01-01

    Resveratrol is a naturally occurring compound contributing to cellular defense mechanisms in plants. Its use as a nutritional component and/or supplement in a number of diseases, disorders, and syndromes such as chronic diseases of the central nervous system, cancer, inflammatory diseases, diabetes, and cardiovascular diseases has prompted great interest in the underlying molecular mechanisms of action. The present review focuses on resveratrol, specifically its isomer trans-resveratrol, and its effects on intracellular calcium signaling mechanisms. As resveratrol's mechanisms of action are likely pleiotropic, its effects and interactions with key signaling proteins controlling cellular calcium homeostasis are reviewed and discussed. The clinical relevance of resveratrol's actions on excitable cells, transformed or cancer cells, immune cells and retinal pigment epithelial cells are contrasted with a review of the molecular mechanisms affecting calcium signaling proteins on the plasma membrane, cytoplasm, endoplasmic reticulum, and mitochondria. The present review emphasizes the correlation between molecular mechanisms of action that have recently been identified for resveratrol and their clinical implications. PMID:24905603

  1. Molecular mechanism of bacterial type 1 and P pili assembly.

    PubMed

    Busch, Andreas; Phan, Gilles; Waksman, Gabriel

    2015-03-01

    The formation of adhesive surface structures called pili or fimbriae ('bacterial hair') is an important contributor towards bacterial pathogenicity and persistence. To fight often chronic or recurrent bacterial infections such as urinary tract infections, it is necessary to understand the molecular mechanism of the nanomachines assembling such pili. Here, we focus on the so far best-known pilus assembly machinery: the chaperone-usher pathway producing the type 1 and P pili, and highlight the most recently acquired structural knowledge. First, we describe the subunits' structure and the molecular role of the periplasmic chaperone. Second, we focus on the outer-membrane usher structure and the catalytic mechanism of usher-mediated pilus biogenesis. Finally, we describe how the detailed understanding of the chaperone-usher pathway at a molecular level has paved the way for the design of a new generation of bacterial inhibitors called 'pilicides'. PMID:25624519

  2. Mechanically Induced Trapping of Molecular Interactions and Its Applications.

    PubMed

    Garcia-Cordero, Jose L; Maerkl, Sebastian J

    2016-06-01

    Measuring binding affinities and association/dissociation rates of molecular interactions is important for a quantitative understanding of cellular mechanisms. Many low-throughput methods have been developed throughout the years to obtain these parameters. Acquiring data with higher accuracy and throughput is, however, necessary to characterize complex biological networks. Here, we provide an overview of a high-throughput microfluidic method based on mechanically induced trapping of molecular interactions (MITOMI). MITOMI can be used to obtain affinity constants and kinetic rates of hundreds of protein-ligand interactions in parallel. It has been used in dozens of studies to measure binding affinities of transcription factors, map protein interaction networks, identify pharmacological inhibitors, and perform high-throughput, low-cost molecular diagnostics. This article covers the technological aspects of MITOMI and its applications. PMID:25805850

  3. Resolving the molecular mechanism of cadherin catch bond formation

    NASA Astrophysics Data System (ADS)

    Manibog, Kristine; Li, Hui; Rakshit, Sabyasachi; Sivasankar, Sanjeevi

    2014-06-01

    Classical cadherin Ca2+-dependent cell-cell adhesion proteins play key roles in embryogenesis and in maintaining tissue integrity. Cadherins mediate robust adhesion by binding in multiple conformations. One of these adhesive states, called an X-dimer, forms catch bonds that strengthen and become longer lived in the presence of mechanical force. Here we use single-molecule force-clamp spectroscopy with an atomic force microscope along with molecular dynamics and steered molecular dynamics simulations to resolve the molecular mechanisms underlying catch bond formation and the role of Ca2+ ions in this process. Our data suggest that tensile force bends the cadherin extracellular region such that they form long-lived, force-induced hydrogen bonds that lock X-dimers into tighter contact. When Ca2+ concentration is decreased, fewer de novo hydrogen bonds are formed and catch bond formation is eliminated.

  4. Mechanical tuning of conductance and thermopower in helicene molecular junctions.

    PubMed

    Vacek, Jaroslav; Chocholoušová, Jana Vacek; Stará, Irena G; Starý, Ivo; Dubi, Yonatan

    2015-05-21

    Helicenes are inherently chiral polyaromatic molecules composed of all-ortho fused benzene rings possessing a spring-like structure. Here, using a combination of density functional theory and tight-binding calculations, it is demonstrated that controlling the length of the helicene molecule by mechanically stretching or compressing the molecular junction can dramatically change the electronic properties of the helicene, leading to a tunable switching behavior of the conductance and thermopower of the junction with on/off ratios of several orders of magnitude. Furthermore, control over the helicene length and number of rings is shown to lead to more than an order of magnitude increase in the thermopower and thermoelectric figure-of-merit over typical molecular junctions, presenting new possibilities of making efficient thermoelectric molecular devices. The physical origin of the strong dependence of the transport properties of the junction is investigated, and found to be related to a shift in the position of the molecular orbitals. PMID:25905658

  5. Molecular Mechanisms of Bone 18F-NaF Deposition

    PubMed Central

    Czernin, Johannes; Satyamurthy, Nagichettiar; Schiepers, Christiaan

    2011-01-01

    There is renewed interest in 18F-NaF bone imaging with PET or PET/CT. The current brief discussion focuses on the molecular mechanisms of 18F-NaF deposition in bone and presents model-based approaches to quantifying bone perfusion and metabolism in the context of preclinical and clinical applications of bone imaging with PET. PMID:21078790

  6. Conformational analyses of periplanone analogs by molecular mechanics calculations.

    PubMed

    Shimazaki, K; Mori, M; Okada, K; Chuman, T; Goto, H; Osawa, E; Sakakibara, K; Hirota, M

    1991-04-01

    Conformational parameters of pheromonally active analogs (1 and 2) of periplanones, the sex pheromones of the American cockroach, were investigated by molecular mechanics calculations. They existed in several conformers with small energy differences. These results were supported by NMR analysis. The structural features of the conformers of the analogs were compared with X-ray structures of periplanones. PMID:24258922

  7. Catalytic mechanism of RNA backbone cleavage by ribonuclease H from quantum mechanics/molecular mechanics simulations.

    PubMed

    Rosta, Edina; Nowotny, Marcin; Yang, Wei; Hummer, Gerhard

    2011-06-15

    We use quantum mechanics/molecular mechanics simulations to study the cleavage of the ribonucleic acid (RNA) backbone catalyzed by ribonuclease H. This protein is a prototypical member of a large family of enzymes that use two-metal catalysis to process nucleic acids. By combining Hamiltonian replica exchange with a finite-temperature string method, we calculate the free energy surface underlying the RNA-cleavage reaction and characterize its mechanism. We find that the reaction proceeds in two steps. In a first step, catalyzed primarily by magnesium ion A and its ligands, a water molecule attacks the scissile phosphate. Consistent with thiol-substitution experiments, a water proton is transferred to the downstream phosphate group. The transient phosphorane formed as a result of this nucleophilic attack decays by breaking the bond between the phosphate and the ribose oxygen. In the resulting intermediate, the dissociated but unprotonated leaving group forms an alkoxide coordinated to magnesium ion B. In a second step, the reaction is completed by protonation of the leaving group, with a neutral Asp132 as a likely proton donor. The overall reaction barrier of ∼15 kcal mol(-1), encountered in the first step, together with the cost of protonating Asp132, is consistent with the slow measured rate of ∼1-100/min. The two-step mechanism is also consistent with the bell-shaped pH dependence of the reaction rate. The nonmonotonic relative motion of the magnesium ions along the reaction pathway agrees with X-ray crystal structures. Proton-transfer reactions and changes in the metal ion coordination emerge as central factors in the RNA-cleavage reaction. PMID:21539371

  8. Total Proteome Analysis Identifies Migration Defects as a Major Pathogenetic Factor in Immunoglobulin Heavy Chain Variable Region (IGHV)-unmutated Chronic Lymphocytic Leukemia*

    PubMed Central

    Eagle, Gina L.; Zhuang, Jianguo; Jenkins, Rosalind E.; Till, Kathleen J.; Jithesh, Puthen V.; Lin, Ke; Johnson, Gillian G.; Oates, Melanie; Park, Kevin; Kitteringham, Neil R.; Pettitt, Andrew R.

    2015-01-01

    The mutational status of the immunoglobulin heavy chain variable region defines two clinically distinct forms of chronic lymphocytic leukemia (CLL) known as mutated (M-CLL) and unmutated (UM-CLL). To elucidate the molecular mechanisms underlying the adverse clinical outcome associated with UM-CLL, total proteomes from nine UM-CLL and nine M-CLL samples were analyzed by isobaric tags for relative and absolute quantification (iTRAQ)-based mass spectrometry. Based on the expression of 3521 identified proteins, principal component analysis separated CLL samples into two groups corresponding to immunoglobulin heavy chain variable region mutational status. Computational analysis showed that 43 cell migration/adhesion pathways were significantly enriched by 39 differentially expressed proteins, 35 of which were expressed at significantly lower levels in UM-CLL samples. Furthermore, UM-CLL cells underexpressed proteins associated with cytoskeletal remodeling and overexpressed proteins associated with transcriptional and translational activity. Taken together, our findings indicate that UM-CLL cells are less migratory and more adhesive than M-CLL cells, resulting in their retention in lymph nodes, where they are exposed to proliferative stimuli. In keeping with this hypothesis, analysis of an extended cohort of 120 CLL patients revealed a strong and specific association between UM-CLL and lymphadenopathy. Our study illustrates the potential of total proteome analysis to elucidate pathogenetic mechanisms in cancer. PMID:25645933

  9. Total proteome analysis identifies migration defects as a major pathogenetic factor in immunoglobulin heavy chain variable region (IGHV)-unmutated chronic lymphocytic leukemia.

    PubMed

    Eagle, Gina L; Zhuang, Jianguo; Jenkins, Rosalind E; Till, Kathleen J; Jithesh, Puthen V; Lin, Ke; Johnson, Gillian G; Oates, Melanie; Park, Kevin; Kitteringham, Neil R; Pettitt, Andrew R

    2015-04-01

    The mutational status of the immunoglobulin heavy chain variable region defines two clinically distinct forms of chronic lymphocytic leukemia (CLL) known as mutated (M-CLL) and unmutated (UM-CLL). To elucidate the molecular mechanisms underlying the adverse clinical outcome associated with UM-CLL, total proteomes from nine UM-CLL and nine M-CLL samples were analyzed by isobaric tags for relative and absolute quantification (iTRAQ)-based mass spectrometry. Based on the expression of 3521 identified proteins, principal component analysis separated CLL samples into two groups corresponding to immunoglobulin heavy chain variable region mutational status. Computational analysis showed that 43 cell migration/adhesion pathways were significantly enriched by 39 differentially expressed proteins, 35 of which were expressed at significantly lower levels in UM-CLL samples. Furthermore, UM-CLL cells underexpressed proteins associated with cytoskeletal remodeling and overexpressed proteins associated with transcriptional and translational activity. Taken together, our findings indicate that UM-CLL cells are less migratory and more adhesive than M-CLL cells, resulting in their retention in lymph nodes, where they are exposed to proliferative stimuli. In keeping with this hypothesis, analysis of an extended cohort of 120 CLL patients revealed a strong and specific association between UM-CLL and lymphadenopathy. Our study illustrates the potential of total proteome analysis to elucidate pathogenetic mechanisms in cancer. PMID:25645933

  10. Investigation of deformation mechanisms of staggered nanocomposites using molecular dynamics

    NASA Astrophysics Data System (ADS)

    Mathiazhagan, S.; Anup, S.

    2016-08-01

    Biological materials with nanostructure of regularly or stair-wise staggered arrangements of hard platelets reinforced in a soft protein matrix have superior mechanical properties. Applications of these nanostructures to ceramic matrix composites could enhance their toughness. Using molecular dynamics simulations, mechanical behaviour of the bio-inspired nanocomposites is studied. Regularly staggered model shows better flow behaviour compared to stair-wise staggered model due to the symmetrical crack propagation along the interface. Though higher stiffness and strength are obtained for stair-wise staggered models, rapid crack propagation reduces the toughness. Arresting this crack propagation could lead to superior mechanical properties in stair-wise staggered models.

  11. Novel molecular mechanisms and regeneration therapy for heart failure.

    PubMed

    Oka, Toru; Morita, Hiroyuki; Komuro, Issei

    2016-03-01

    Heart failure (HF) is one of the leading causes of mortality in the world. Various molecular mechanisms have been proposed for HF, but its precise mechanisms are still largely unknown. In this review, summarizing the "President's Distinguished Lecture Award" of XX World Congress of International Society for Heart Research 2010 in Kyoto, Japan, we introduce recent our studies on HF, including 1) p53-induced suppression of Hif-1-induced angiogenesis as a novel mechanism of HF, 2) angiogenesis as a potential therapeutic strategy for HF, and 3) IGFBP-4 as a novel factor for cardiomyogenesis by inhibiting canonical Wnt signaling. PMID:26829118

  12. Molecular mechanics methods for individual carbon nanotubes and nanotube assemblies

    NASA Astrophysics Data System (ADS)

    Eberhardt, Oliver; Wallmersperger, Thomas

    2015-04-01

    Since many years, carbon nanotubes (CNTs) have been considered for a wide range of applications due to their outstanding mechanical properties. CNTs are tubular structures, showing a graphene like hexagonal lattice. Our interest in the calculation of the mechanical properties is motivated by several applications which demand the knowledge of the material behavior. One application in which the knowledge of the material behavior is vital is the CNT based fiber. Due to the excellent stiffness and strength of the individual CNTs, these fibers are expected to be a promising successor for state of the art carbon fibers. However, the mechanical properties of the fibers fall back behind the properties of individual CNTs. It is assumed that this gap in the properties is a result of the van-der-Waals interactions of the individual CNTs within the fiber. In order to understand the mechanical behavior of the fibers we apply a molecular mechanics approach. The mechanical properties of the individual CNTs are investigated by using a modified structural molecular mechanics approach. This is done by calculating the properties of a truss-beam element framework representing the CNT with the help of a chemical force field. Furthermore, we also investigate the interactions of CNTs arranged in basic CNT assemblies, mimicking the ones in a simple CNT fiber. We consider the van-der-Waals interactions in the structure and calculate the potential surface of the CNT assemblies.

  13. Molecular mechanisms of peritoneal dissemination in gastric cancer

    PubMed Central

    Kanda, Mitsuro; Kodera, Yasuhiro

    2016-01-01

    Peritoneal dissemination represents a devastating form of gastric cancer (GC) progression with a dismal prognosis. There is no effective therapy for this condition. The 5-year survival rate of patients with peritoneal dissemination is 2%, even including patients with only microscopic free cancer cells without macroscopic peritoneal nodules. The mechanism of peritoneal dissemination of GC involves several steps: detachment of cancer cells from the primary tumor, survival in the free abdominal cavity, attachment to the distant peritoneum, invasion into the subperitoneal space and proliferation with angiogenesis. These steps are not mutually exclusive, and combinations of different molecular mechanisms can occur in each process of peritoneal dissemination. A comprehensive understanding of the molecular events involved in peritoneal dissemination is important and should be systematically pursued. It is crucial to identify novel strategies for the prevention of this condition and for identification of markers of prognosis and the development of molecular-targeted therapies. In this review, we provide an overview of recently published articles addressing the molecular mechanisms of peritoneal dissemination of GC to provide an update on what is currently known in this field and to propose novel promising candidates for use in diagnosis and as therapeutic targets. PMID:27570420

  14. Molecular mechanisms of peritoneal dissemination in gastric cancer.

    PubMed

    Kanda, Mitsuro; Kodera, Yasuhiro

    2016-08-14

    Peritoneal dissemination represents a devastating form of gastric cancer (GC) progression with a dismal prognosis. There is no effective therapy for this condition. The 5-year survival rate of patients with peritoneal dissemination is 2%, even including patients with only microscopic free cancer cells without macroscopic peritoneal nodules. The mechanism of peritoneal dissemination of GC involves several steps: detachment of cancer cells from the primary tumor, survival in the free abdominal cavity, attachment to the distant peritoneum, invasion into the subperitoneal space and proliferation with angiogenesis. These steps are not mutually exclusive, and combinations of different molecular mechanisms can occur in each process of peritoneal dissemination. A comprehensive understanding of the molecular events involved in peritoneal dissemination is important and should be systematically pursued. It is crucial to identify novel strategies for the prevention of this condition and for identification of markers of prognosis and the development of molecular-targeted therapies. In this review, we provide an overview of recently published articles addressing the molecular mechanisms of peritoneal dissemination of GC to provide an update on what is currently known in this field and to propose novel promising candidates for use in diagnosis and as therapeutic targets. PMID:27570420

  15. Quantum Mechanical/Molecular Mechanical Studies on Spectral Tuning Mechanisms of Visual Pigments and Other Photoactive Proteins†

    PubMed Central

    Altun, Ahmet; Yokoyama, Shozo; Morokuma, Keiji

    2008-01-01

    The protein environments surrounding the retinal tune electronic absorption maximum from 350 to 630 nm. Hybrid quantum mechanical/molecular mechanical (QM/MM) methods can be used in calculating excitation energies of retinal in its native protein environments and in studying the molecular basis of spectral tuning. We hereby review recent QM/MM results on the phototransduction of bovine rhodopsin, bacteriorhodopsin, sensory rhodopsin II, nonretinal photoactive yellow protein and their mutants. PMID:18331400

  16. Autoantibodies to intracellular antigens: generation and pathogenetic role.

    PubMed

    Racanelli, Vito; Prete, Marcella; Musaraj, Gerta; Dammacco, Franco; Perosa, Federico

    2011-06-01

    Autoantibodies to intracellular antigens form a large family of immunoglobulins directed to a variety of ubiquitously expressed intracellular molecules, including numerous enzymes, some ribonucleoproteins and double-stranded DNA. These anti-self antibodies have been found to be selectively expressed in sera of patients with several systemic (non-organ-specific) autoimmune diseases, such as systemic sclerosis (SSc), SLE, mixed connective tissue disease, Sjögren's syndrome and idiopathic myopathies. Despite their important diagnostic and prognostic value and their utility in assessing disease activity, little is known about the molecular mechanisms involved in their generation and role in autoimmune diseases nor is it known why particular autoantibodies are preferentially expressed in certain diseases. Here, we review the different lines of research which are presently being conducted to understand how these autoantibodies are generated (e.g. through apoptotic body formation, molecular mimicry and other mechanisms) and how they encounter antigen in order to cause an autoimmune disease. The recently reported mechanism of intracellular immunity mediated by Ro52 (or tripartite motif containing 21, TRIM21) in a cellular model of adenovirus infection is opening new perspectives for studying the effects of autoantibodies once they get inside cells. PMID:21397735

  17. Electronic structure and conformation of polymers from cluster molecular orbital and molecular mechanics calculations: Polyimide

    SciTech Connect

    Kafafi, S.A. ); LaFemina, J.P. ); Nauss, J.L. )

    1990-11-21

    Full geometry optimizations using molecular mechanics and the quantum chemical AM1 method have been carried out to determine the minimum energy conformation of pyromellitic dianhydride-oxydianiline polyimide (PMDA-ODA PI). The phenyl-imide twist angle for this compound was determined to be {approximately}30. These computations also provided a quantitative determination of the energy gap (7 eV), electron affinity ({minus}2 eV), and ionization potential (8.97 eV). Computations on the PMDA-ODA PI radical anion provided an estimate of the hopping barrier for an electron to hop from one chain to another (3.2 eV), the mechanism believed responsible for photoconduction. Moreover, the use of qualitative molecular orbital theory (QMOT) arguments provided an interpretation of these results in a simple molecular orbital framework.

  18. Molecular Mechanisms of the Formation and Progression of Intracranial Aneurysms

    PubMed Central

    KATAOKA, Hiroharu

    2015-01-01

    Until recently, only a little was understood about molecular mechanisms of the development of an intracranial aneurysm (IA). Recent advancements over the last decade in the field of genetics and molecular biology have provided us a wide variety of evidences supporting the notion that chronic inflammation is closely associated with the pathogenesis of IA development. In the field of genetics, large-scale Genome-wide association studies (GWAS) has identified some IA susceptible loci and genes related to cell cycle and endothelial function. Researches in molecular biology using human samples and animal models have revealed the common pathway of the initiation, progression, and rupture of IAs. IA formation begins with endothelial dysfunction followed by pathological remodeling with degenerative changes of vascular walls. Medical treatments inhibiting inflammatory cascades in IA development are likely to prevent IA progression and rupture. Statins and aspirin are expected to suppress IA progression by their anti-inflammatory effects. Decoy oligodeoxynucleotides (ODNs) inhibiting inflammatory transcription factors such as nuclear factor kappa-B (NF-κB) and Ets-1 are the other promising choice of the prevention of IA development. Further clarification of molecular mechanisms of the formation and progression of IAs will shed light to the pathogenesis of IA development and provide insight into novel diagnostic and therapeutic strategies for IAs. PMID:25761423

  19. Molecular Mechanisms of Chromium in Alleviating Insulin Resistance

    PubMed Central

    Hua, Yinan; Clark, Suzanne; Ren, Jun; Sreejayan, Nair

    2011-01-01

    Type 2 diabetes is often associated with obesity, dyslipidemia, and cardiovascular anomalies and is a major health problem approaching global epidemic proportions. Insulin resistance, a prediabetic condition, precedes the onset of frank type 2 diabetes and offers potential avenues for early intervention to treat the disease. Although lifestyle modifications and exercise can reduce the incidence of diabetes, compliance has proved to be difficult, warranting pharmacological interventions. However, most of the currently available drugs that improve insulin sensitivity have adverse effects. Therefore, attractive strategies to alleviate insulin resistance include dietary supplements. One such supplement is chromium, which has been shown reduce insulin resistance in some, but not all, studies. Furthermore, the molecular mechanisms of chromium in alleviating insulin resistance remain elusive. This review examines emerging reports on the effect of chromium, as well as molecular and cellular mechanisms by which chromium may provide beneficial effects in alleviating insulin resistance. PMID:22423897

  20. [Molecular mechanisms of the plague pathogenic agent interaction with invertebrates].

    PubMed

    Kutyrev, V V; Eroshenko, G A; Popov, N V; Vidiaeva, N A; Konnov, N P

    2009-01-01

    Microbe Russian Anti-Plague Research Institute, Saratov, Russia The literature data and experimental results of the authors on the molecular basis of plague agent interaction with invertebrates are discussed. The details of the plague agent life cycle, its genome organization, and molecular genetic mechanisms of its survival in flea vector and on the nematode cuticule are discussed. The experimental data about the ability to form biofilms at abiotic and biotic surfaces in the Yersinia pestis strains of the main and non-main subspecies are presented. Mechanisms of horizontal and vertical transmission of plague agent are considered. The suggestion about participation of the new member in the complex parasitic biocenosis (nematode, vector parasite) is put forward. PMID:20050160

  1. Cellular and Molecular Mechanisms of Arrhythmia by Oxidative Stress

    PubMed Central

    Sovari, Ali A.

    2016-01-01

    Current therapies for arrhythmia using ion channel blockade, catheter ablation, or an implantable cardioverter defibrillator have limitations, and it is important to search for new antiarrhythmic therapeutic targets. Both atrial fibrillation and heart failure, a condition with increased arrhythmic risk, are associated with excess amount of reactive oxygen species (ROS). There are several possible ways for ROS to induce arrhythmia. ROS can cause focal activity and reentry. ROS alter multiple cardiac ionic currents. ROS promote cardiac fibrosis and impair gap junction function, resulting in reduced myocyte coupling and facilitation of reentry. In order to design effective antioxidant drugs for treatment of arrhythmia, it is essential to explore the molecular mechanisms by which ROS exert these arrhythmic effects. Activation of Ca2+/CaM-dependent kinase II, c-Src tyrosine kinase, protein kinase C, and abnormal splicing of cardiac sodium channels are among the recently discovered molecular mechanisms of ROS-induced arrhythmia. PMID:26981310

  2. Potential Molecular and Cellular Mechanism of Psychotropic Drugs

    PubMed Central

    Seo, Myoung Suk; Scarr, Elizabeth; Lai, Chi-Yu

    2014-01-01

    Psychiatric disorders are among the most debilitating of all medical illnesses. Whilst there are drugs that can be used to treat these disorders, they give sub-optimal recovery in many people and a significant number of individuals do not respond to any treatments and remain treatment resistant. Surprisingly, the mechanism by which psychotropic drugs cause their therapeutic benefits remain unknown but likely involves the underlying molecular pathways affected by the drugs. Hence, in this review, we have focused on recent findings on the molecular mechanism affected by antipsychotic, mood stabilizing and antidepressant drugs at the levels of epigenetics, intracellular signalling cascades and microRNAs. We posit that understanding these important interactions will result in a better understanding of how these drugs act which in turn may aid in considering how to develop drugs with better efficacy or increased therapeutic reach. PMID:25191500

  3. Derivation of a Molecular Mechanics Force Field for Cholesterol

    SciTech Connect

    Cournia, Zoe; Vaiana, Andrea C.; Smith, Jeremy C.; Ullmann, G. Matthias M.

    2004-01-01

    As a necessary step toward realistic cholesterol:biomembrane simulations, we have derived CHARMM molecular mechanics force-field parameters for cholesterol. For the parametrization we use an automated method that involves fitting the molecular mechanics potential to both vibrational frequencies and eigenvector projections derived from quantum chemical calculations. Results for another polycyclic molecule, rhodamine 6G, are also given. The usefulness of the method is thus demonstrated by the use of reference data from two molecules at different levels of theory. The frequency-matching plots for both cholesterol and rhodamine 6G show overall agreement between the CHARMM and quantum chemical normal modes, with frequency matching for both molecules within the error range found in previous benchmark studies.

  4. Polycystic liver diseases: advanced insights into the molecular mechanisms

    PubMed Central

    Perugorria, Maria J.; Masyuk, Tatyana V.; Marin, Jose J.; Marzioni, Marco; Bujanda, Luis; LaRusso, Nicholas F.; Banales, Jesus M.

    2015-01-01

    Polycystic liver diseases are genetic disorders characterized by progressive bile duct dilatation and/or cyst development. The large volume of hepatic cysts causes different symptoms and complications such as abdominal distension, local pressure with back pain, hypertension, gastro-oesophageal reflux and dyspnea as well as bleeding, infection and rupture of the cysts. Current therapeutic strategies are based on surgical procedures and pharmacological management, which partially prevent or ameliorate the disease. However, as these treatments only show short-term and/or modest beneficial effects, liver transplantation is the only definitive therapy. Therefore, interest in understanding the molecular mechanisms involved in disease pathogenesis is increasing so that new targets for therapy can be identified. In this Review, the genetic mechanisms underlying polycystic liver diseases and the most relevant molecular pathways of hepatic cystogenesis are discussed. Moreover, the main clinical and preclinical studies are highlighted and future directions in basic as well as clinical research are indicated. PMID:25266109

  5. New Insights Into Molecular Mechanisms of Diabetic Kidney Disease

    PubMed Central

    Badal, Shawn S.; Danesh, Farhad R.

    2014-01-01

    Diabetic kidney disease remains a major microvascular complication of diabetes and the most common cause of chronic kidney failure requiring dialysis in the United States. Medical advances over the past century have substantially improved the management of diabetes mellitus and thereby have increased patient survival. However, current standards of care reduce but do not eliminate the risk of diabetic kidney disease, and further studies are warranted to define new strategies for reducing the risk of diabetic kidney disease. In this review, we highlight some of the novel and established molecular mechanisms that contribute to the development of the disease and its outcomes. In particular, we discuss recent advances in our understanding of the molecular mechanisms implicated in the pathogenesis and progression of diabetic kidney disease, with special emphasis on the mitochondrial oxidative stress and microRNA targets. Additionally, candidate genes associated with susceptibility to diabetic kidney disease and alterations in various cytokines, chemokines, and growth factors are addressed briefly. PMID:24461730

  6. The strawberry plant defense mechanism: a molecular review.

    PubMed

    Amil-Ruiz, Francisco; Blanco-Portales, Rosario; Muñoz-Blanco, Juan; Caballero, José L

    2011-11-01

    Strawberry, a small fruit crop of great importance throughout the world, has been considered a model plant system for Rosaceae, and is susceptible to a large variety of phytopathogenic organisms. Most components and mechanisms of the strawberry defense network remain poorly understood. However, from current knowledge, it seems clear that the ability of a strawberry plant to respond efficiently to pathogens relies first on the physiological status of injured tissue (pre-formed mechanisms of defense) and secondly on the general ability to recognize and identify the invaders by surface plant receptors, followed by a broad range of induced mechanisms, which include cell wall reinforcement, production of reactive oxygen species, phytoalexin generation and pathogenesis-related protein accumulation. Dissection of these physiological responses at a molecular level will provide valuable information to improve future breeding strategies for new strawberry varieties and to engineer strawberry plants for durable and broad-spectrum disease resistance. In turn, this will lead to a reduction in use of chemicals and in environmental risks. Advances in the understanding of the molecular interplay between plant (mainly those considered model systems) and various classes of microbial pathogens have been made in the last two decades. However, major progress in the genetics and molecular biology of strawberry is still needed to uncover fully the way in which this elaborate plant innate immune system works. These fundamental insights will provide a conceptual framework for rational human intervention through new strawberry research approaches. In this review, we will provide a comprehensive overview and discuss recent advances in molecular research on strawberry defense mechanisms against pathogens. PMID:21984602

  7. Underlying molecular and cellular mechanisms in childhood irritable bowel syndrome.

    PubMed

    Chumpitazi, Bruno P; Shulman, Robert J

    2016-12-01

    Irritable bowel syndrome (IBS) affects a large number of children throughout the world. The symptom expression of IBS is heterogeneous, and several factors which may be interrelated within the IBS biopsychosocial model play a role. These factors include visceral hyperalgesia, intestinal permeability, gut microbiota, psychosocial distress, gut inflammation, bile acids, food intolerance, colonic bacterial fermentation, and genetics. The molecular and cellular mechanisms of these factors are being actively investigated. In this mini-review, we present updates of these mechanisms and, where possible, relate the findings to childhood IBS. Mechanistic elucidation may lead to the identification of biomarkers as well as personalized childhood IBS therapies. PMID:26883355

  8. Mechanisms of ventricular arrhythmias: from molecular fluctuations to electrical turbulence.

    PubMed

    Qu, Zhilin; Weiss, James N

    2015-01-01

    Ventricular arrhythmias have complex causes and mechanisms. Despite extensive investigation involving many clinical, experimental, and computational studies, effective biological therapeutics are still very limited. In this article, we review our current understanding of the mechanisms of ventricular arrhythmias by summarizing the state of knowledge spanning from the molecular scale to electrical wave behavior at the tissue and organ scales and how the complex nonlinear interactions integrate into the dynamics of arrhythmias in the heart. We discuss the challenges that we face in synthesizing these dynamics to develop safe and effective novel therapeutic approaches. PMID:25340965

  9. Mechanisms of Ventricular Arrhythmias: From Molecular Fluctuations to Electrical Turbulence

    PubMed Central

    Qu, Zhilin; Weiss, James N.

    2015-01-01

    Ventricular arrhythmias have complex causes and mechanisms. Despite extensive investigation involving many clinical, experimental, and computational studies, effective biological therapeutics are still very limited. In this article, we review our current understanding of the mechanisms of ventricular arrhythmias by summarizing the state of knowledge spanning from the molecular scale to electrical wave behavior at the tissue and organ scales and how the complex nonlinear interactions integrate into the dynamics of arrhythmias in the heart. We discuss the challenges that we face in synthesizing these dynamics to develop safe and effective novel therapeutic approaches. PMID:25340965

  10. Molecular mechanisms for vascular complications of targeted cancer therapies.

    PubMed

    Gopal, Srila; Miller, Kenneth B; Jaffe, Iris Z

    2016-10-01

    Molecularly targeted anti-cancer therapies have revolutionized cancer treatment by improving both quality of life and survival in cancer patients. However, many of these drugs are associated with cardiovascular toxicities that are sometimes dose-limiting. Moreover, the long-term cardiovascular consequences of these drugs, some of which are used chronically, are not yet known. Although the scope and mechanisms of the cardiac toxicities are better defined, the mechanisms for vascular toxicities are only beginning to be elucidated. This review summarizes what is known about the vascular adverse events associated with three classes of novel anti-cancer therapies: vascular endothelial growth factor (VEGF) inhibitors, breakpoint cluster-Abelson (BCR-ABL) kinase inhibitors used to treat chronic myelogenous leukaemia (CML) and immunomodulatory agents (IMiDs) used in myeloma therapeutics. Three of the best described vascular toxicities are reviewed including hypertension, increased risk of acute cardiovascular ischaemic events and arteriovenous thrombosis. The available data regarding the mechanism by which each therapy causes vascular complication are summarized. When data are limited, potential mechanisms are inferred from the known effects of inhibiting each target on vascular cell function and disease. Enhanced understanding of the molecular mechanisms of vascular side effects of targeted cancer therapy is necessary to effectively manage cancer patients and to design safer targeted cancer therapies for the future. PMID:27612952

  11. Molecular mechanisms and proposed targets for selected anticancer gold compounds.

    PubMed

    Casini, Angela; Messori, Luigi

    2011-01-01

    Nowadays, gold compounds constitute a family of very promising experimental agents for cancer treatment. Indeed, several gold(I) and gold(III) compounds were shown to manifest outstanding antiproliferative properties in vitro against selected human tumor cell lines and some of them performed remarkably well even in tumor models in vivo. Notably, the peculiar chemical properties of the gold centre impart innovative pharmacological profiles to gold-based metallodrugs most likely in relation to novel molecular mechanisms. The precise mechanisms through which cytotoxic gold compounds produce their biological effects are still largely unknown. Within this frame, the major aim of this review is to define the possible modes of action and the most probable biomolecular targets for a few representative gold compounds on which extensive biochemical and cellular data have been gathered. In particular, we will focus on auranofin and analogues, on gold(III) porphyrins and gold(III) dithiocarbamates. For these three families markedly distinct molecular mechanisms were recently invoked: a direct mitochondrial mechanism involving thioredoxin reductase inhibition in the case of the gold(I) complexes, the influence on some apoptotic proteins--i.e. MAPKs and Bcl-2--for gold(III) porphyrins, and the proteasome inhibition for gold(III) dithiocarbamates. In a few cases the distinct mechanisms may overlap. The general perspectives for the development of new gold compounds as effective anticancer agents with innovative modes of action are critically discussed. PMID:22039866

  12. Molecular Mechanisms of Treg-Mediated T Cell Suppression

    PubMed Central

    Schmidt, Angelika; Oberle, Nina; Krammer, Peter H.

    2012-01-01

    CD4+CD25highFoxp3+ regulatory T cells (Tregs) can suppress other immune cells and, thus, are critical mediators of peripheral self-tolerance. On the one hand, Tregs avert autoimmune disease and allergies. On the other hand, Tregs can prevent immune reactions against tumors and pathogens. Despite the importance of Tregs, the molecular mechanisms of suppression remain incompletely understood and controversial. Proliferation and cytokine production of CD4+CD25− conventional T cells (Tcons) can be inhibited directly by Tregs. In addition, Tregs can indirectly suppress Tcon activation via inhibition of the stimulatory capacity of antigen presenting cells. Direct suppression of Tcons by Tregs can involve immunosuppressive soluble factors or cell contact. Different mechanisms of suppression have been described, so far with no consensus on one universal mechanism. Controversies might be explained by the fact that different mechanisms may operate depending on the site of the immune reaction, on the type and activation state of the suppressed target cell as well as on the Treg activation status. Further, inhibition of T cell effector function can occur independently of suppression of proliferation. In this review, we summarize the described molecular mechanisms of suppression with a particular focus on suppression of Tcons and rapid suppression of T cell receptor-induced calcium (Ca2+), NFAT, and NF-κB signaling in Tcons by Tregs. PMID:22566933

  13. Cardiovascular effects of cocaine: cellular, ionic and molecular mechanisms.

    PubMed

    Turillazzi, E; Bello, S; Neri, M; Pomara, C; Riezzo, I; Fineschi, V

    2012-01-01

    Cocaine is a widely abused drug responsible for the majority of deaths ascribed to drug overdose. Many mechanisms have been proposed in order to explain the various cocaine associated cardiovascular complications. Conventionally, cocaine cardiotoxicity has been thought to be mediated indirectly through its sympathomimetic effect, i.e., by inhibiting the reuptake and thus increasing the levels of neuronal catecholamines at work on adrenoceptors. Increased oxidative stress, reactive oxygen species, and cocaine-induced apoptosis in the heart muscle have suggested a new way to understand the cardiotoxic effects of cocaine. More recent studies have led the attention to the interaction of cocaine and some metabolites with cardiac sodium, calcium and potassium channels. The current paper is aimed to investigate the molecular mechanisms of cocaine cardiotoxicity which have a specific clinical and forensic interest. From a clinical point of view the full knowledge of the exact mechanisms by which cocaine exerts cardio - vascular damage is essential to identify potential therapeutic targets and improve novel strategies for cocaine related cardiovascular diseases. From a forensic point of view, it is to be underlined that cocaine use is often associated to sudden death in young, otherwise healthy individuals. While such events are widely reported, the relationship between cardiac morphological alterations and molecular/cellular mechanisms is still controversial. In conclusion, the study of cocaine cardiovascular toxicity needs a strict collaboration between clinicians and pathologists which may be very effective in further dissecting the mechanisms underlying cocaine cardiotoxicity and understanding the cardiac cocaine connection. PMID:22856657

  14. Genomic and molecular mechanisms for efficient biodegradation of aromatic dye.

    PubMed

    Sun, Su; Xie, Shangxian; Chen, Hu; Cheng, Yanbing; Shi, Yan; Qin, Xing; Dai, Susie Y; Zhang, Xiaoyu; Yuan, Joshua S

    2016-01-25

    Understanding the molecular mechanisms for aromatic compound degradation is crucial for the development of effective bioremediation strategies. We report the discovery of a novel phenomenon for improved degradation of Direct Red 5B azo dye by Irpex lacteus CD2 with lignin as a co-substrate. Transcriptomics analysis was performed to elucidate the molecular mechanisms of aromatic degradation in white rot fungus by comparing dye, lignin, and dye/lignin combined treatments. A full spectrum of lignin degradation peroxidases, oxidases, radical producing enzymes, and other relevant components were up-regulated under DR5B and lignin treatments. Lignin induced genes complemented the DR5B induced genes to provide essential enzymes and redox conditions for aromatic compound degradation. The transcriptomics analysis was further verified by manganese peroxidase (MnP) protein over-expression, as revealed by proteomics, dye decolorization assay by purified MnP and increased hydroxyl radical levels, as indicated by an iron reducing activity assay. Overall, the molecular and genomic mechanisms indicated that effective aromatic polymer degradation requires synergistic enzymes and radical-mediated oxidative reactions to form an effective network of chemical processes. This study will help to guide the development of effective bioremediation and biomass degradation strategies. PMID:26476316

  15. [Progress in the molecular genetic mechanism of gonadoblastoma].

    PubMed

    Lili, Yu; Wanru, Dong; Minghui, Chen; Xiangyang, Kong

    2015-11-01

    Gonadoblastoma (GB), a rare in situ germ cell tumor derived from sex cord and germ cells, is closely associated with gonadal dysgenesis. About 80% of GB individuals exhibit 46, XY female phenotype while the others are 45, XY and 46, XX with disorders of sex development. Moreover, 35% of GB can eventually develop into malignant tumors, such as seminoma and dysgerminoma tumors. The molecular genetic mechanism of GB remains to be fully uncovered due to phenotypic and genetic heterogeneity. Increasing studies show that the formation of GB is closely related to genes regulating sexual differentiation and determination (e.g., SRY, WT1, SOX9, Foxl2, TSPY, etc), and is affected by the interaction of genetic and epigenetic regulation. Here we describe the clinical and pathological features, diagnosis and treatment of GB, and also summarize the molecular genetic and epigenetic mechanisms underlying the gonadal abnormalities that lead to GB. We analyze and construct the common gene regulatory networks related to the development of GB, and describe some obstacles and deficiencies in current studies to provide innovative perspectives on further studying the pathological and molecular mechanisms of GB. PMID:26582524

  16. Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

    PubMed Central

    Ahmad, Saif; Bhatia, Kanchan; Kannan, Annapoorna; Gangwani, Laxman

    2016-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. SMA is primarily characterized by degeneration of the spinal motor neurons that leads to skeletal muscle atrophy followed by symmetric limb paralysis, respiratory failure, and death. In humans, mutation of the Survival Motor Neuron 1 (SMN1) gene shifts the load of expression of SMN protein to the SMN2 gene that produces low levels of full-length SMN protein because of alternative splicing, which are sufficient for embryonic development and survival but result in SMA. The molecular mechanisms of the (a) regulation of SMN gene expression and (b) degeneration of motor neurons caused by low levels of SMN are unclear. However, some progress has been made in recent years that have provided new insights into understanding of the cellular and molecular basis of SMA pathogenesis. In this review, we have briefly summarized recent advances toward understanding of the molecular mechanisms of regulation of SMN levels and signaling mechanisms that mediate neurodegeneration in SMA. PMID:27042141

  17. Molecular structure and elastic properties of thermotropic liquid crystals: Integrated molecular dynamics—Statistical mechanical theory vs molecular field approach

    NASA Astrophysics Data System (ADS)

    Capar, M. Ilk; Nar, A.; Ferrarini, A.; Frezza, E.; Greco, C.; Zakharov, A. V.; Vakulenko, A. A.

    2013-03-01

    The connection between the molecular structure of liquid crystals and their elastic properties, which control the director deformations relevant for electro-optic applications, remains a challenging objective for theories and computations. Here, we compare two methods that have been proposed to this purpose, both characterized by a detailed molecular level description. One is an integrated molecular dynamics-statistical mechanical approach, where the bulk elastic constants of nematics are calculated from the direct correlation function (DCFs) and the single molecule orientational distribution function [D. A. McQuarrie, Statistical Mechanics (Harper & Row, New York, 1973)]. The latter is obtained from atomistic molecular dynamics trajectories, together with the radial distribution function, from which the DCF is then determined by solving the Ornstein-Zernike equation. The other approach is based on a molecular field theory, where the potential of mean torque experienced by a mesogen in the liquid crystal phase is parameterized according to its molecular surface. In this case, the calculation of elastic constants is combined with the Monte Carlo sampling of single molecule conformations. Using these different approaches, but the same description, at the level of molecular geometry and torsional potentials, we have investigated the elastic properties of the nematic phase of two typical mesogens, 4'-n-pentyloxy-4-cyanobiphenyl and 4'-n-heptyloxy-4-cyanobiphenyl. Both methods yield K3(bend) >K1 (splay) >K2 (twist), although there are some discrepancies in the average elastic constants and in their anisotropy. These are interpreted in terms of the different approximations and the different ways of accounting for the structural properties of molecules in the two approaches. In general, the results point to the role of the molecular shape, which is modulated by the conformational freedom and cannot be fully accounted for by a single descriptor such as the aspect ratio.

  18. Molecular structure and elastic properties of thermotropic liquid crystals: integrated molecular dynamics--statistical mechanical theory vs molecular field approach.

    PubMed

    Ilk Capar, M; Nar, A; Ferrarini, A; Frezza, E; Greco, C; Zakharov, A V; Vakulenko, A A

    2013-03-21

    The connection between the molecular structure of liquid crystals and their elastic properties, which control the director deformations relevant for electro-optic applications, remains a challenging objective for theories and computations. Here, we compare two methods that have been proposed to this purpose, both characterized by a detailed molecular level description. One is an integrated molecular dynamics-statistical mechanical approach, where the bulk elastic constants of nematics are calculated from the direct correlation function (DCFs) and the single molecule orientational distribution function [D. A. McQuarrie, Statistical Mechanics (Harper & Row, New York, 1973)]. The latter is obtained from atomistic molecular dynamics trajectories, together with the radial distribution function, from which the DCF is then determined by solving the Ornstein-Zernike equation. The other approach is based on a molecular field theory, where the potential of mean torque experienced by a mesogen in the liquid crystal phase is parameterized according to its molecular surface. In this case, the calculation of elastic constants is combined with the Monte Carlo sampling of single molecule conformations. Using these different approaches, but the same description, at the level of molecular geometry and torsional potentials, we have investigated the elastic properties of the nematic phase of two typical mesogens, 4'-n-pentyloxy-4-cyanobiphenyl and 4'-n-heptyloxy-4-cyanobiphenyl. Both methods yield K3(bend) >K1 (splay) >K2 (twist), although there are some discrepancies in the average elastic constants and in their anisotropy. These are interpreted in terms of the different approximations and the different ways of accounting for the structural properties of molecules in the two approaches. In general, the results point to the role of the molecular shape, which is modulated by the conformational freedom and cannot be fully accounted for by a single descriptor such as the aspect ratio

  19. Nanostructure and molecular mechanics of spider dragline silk protein assemblies

    PubMed Central

    Keten, Sinan; Buehler, Markus J.

    2010-01-01

    Spider silk is a self-assembling biopolymer that outperforms most known materials in terms of its mechanical performance, despite its underlying weak chemical bonding based on H-bonds. While experimental studies have shown that the molecular structure of silk proteins has a direct influence on the stiffness, toughness and failure strength of silk, no molecular-level analysis of the nanostructure and associated mechanical properties of silk assemblies have been reported. Here, we report atomic-level structures of MaSp1 and MaSp2 proteins from the Nephila clavipes spider dragline silk sequence, obtained using replica exchange molecular dynamics, and subject these structures to mechanical loading for a detailed nanomechanical analysis. The structural analysis reveals that poly-alanine regions in silk predominantly form distinct and orderly beta-sheet crystal domains, while disorderly regions are formed by glycine-rich repeats that consist of 31-helix type structures and beta-turns. Our structural predictions are validated against experimental data based on dihedral angle pair calculations presented in Ramachandran plots, alpha-carbon atomic distances, as well as secondary structure content. Mechanical shearing simulations on selected structures illustrate that the nanoscale behaviour of silk protein assemblies is controlled by the distinctly different secondary structure content and hydrogen bonding in the crystalline and semi-amorphous regions. Both structural and mechanical characterization results show excellent agreement with available experimental evidence. Our findings set the stage for extensive atomistic investigations of silk, which may contribute towards an improved understanding of the source of the strength and toughness of this biological superfibre. PMID:20519206

  20. Ultra High Molecular Weight Polyethylene: Mechanics, Morphology, and Clinical Behavior

    PubMed Central

    Sobieraj, MC; Rimnac, CM

    2013-01-01

    Ultra high molecular weight polyethylene (UHMWPE) is a semicrystalline polymer that has been used for over four decades as a bearing surface in total joint replacements. The mechanical properties and wear properties of UHMWPE are of interest with respect to the in vivo performance of UHMWPE joint replacement components. The mechanical properties of the polymer are dependent on both its crystalline and amorphous phases. Altering either phase (i.e., changing overall crystallinity, crystalline morphology, or crosslinking the amorphous phase) can affect the mechanical behavior of the material. There is also evidence that the morphology of UHMWPE, and, hence, its mechanical properties evolve with loading. UHMWPE has also been shown to be susceptible to oxidative degradation following gamma radiation sterilization with subsequent loss of mechanical properties. Contemporary UHMWPE sterilization methods have been developed to reduce or eliminate oxidative degradation. Also, crosslinking of UHMWPE has been pursued to improve the wear resistance of UHMWPE joint components. The 1st generation of highly crosslinked UHMWPEs have resulted in clinically reduced wear; however, the mechanical properties of these materials, such as ductility and fracture toughness, are reduced when compared to the virgin material. Therefore, a 2nd generation of highly crosslinked UHMWPEs are being introduced to preserve the wear resistance of the 1st generation while also seeking to provide oxidative stability and improved mechanical properties. PMID:19627849

  1. Linking traits based on their shared molecular mechanisms

    PubMed Central

    Oren, Yael; Nachshon, Aharon; Frishberg, Amit; Wilentzik, Roni; Gat-Viks, Irit

    2015-01-01

    There is growing recognition that co-morbidity and co-occurrence of disease traits are often determined by shared genetic and molecular mechanisms. In most cases, however, the specific mechanisms that lead to such trait–trait relationships are yet unknown. Here we present an analysis of a broad spectrum of behavioral and physiological traits together with gene-expression measurements across genetically diverse mouse strains. We develop an unbiased methodology that constructs potentially overlapping groups of traits and resolves their underlying combination of genetic loci and molecular mechanisms. For example, our method predicts that genetic variation in the Klf7 gene may influence gene transcripts in bone marrow-derived myeloid cells, which in turn affect 17 behavioral traits following morphine injection; this predicted effect of Klf7 is consistent with an in vitro perturbation of Klf7 in bone marrow cells. Our analysis demonstrates the utility of studying hidden causative mechanisms that lead to relationships between complex traits. DOI: http://dx.doi.org/10.7554/eLife.04346.001 PMID:25781485

  2. Hyperthermophilic Enzymes: Sources, Uses, and Molecular Mechanisms for Thermostability

    PubMed Central

    Vieille, Claire; Zeikus, Gregory J.

    2001-01-01

    Enzymes synthesized by hyperthermophiles (bacteria and archaea with optimal growth temperatures of >80°C), also called hyperthermophilic enzymes, are typically thermostable (i.e., resistant to irreversible inactivation at high temperatures) and are optimally active at high temperatures. These enzymes share the same catalytic mechanisms with their mesophilic counterparts. When cloned and expressed in mesophilic hosts, hyperthermophilic enzymes usually retain their thermal properties, indicating that these properties are genetically encoded. Sequence alignments, amino acid content comparisons, crystal structure comparisons, and mutagenesis experiments indicate that hyperthermophilic enzymes are, indeed, very similar to their mesophilic homologues. No single mechanism is responsible for the remarkable stability of hyperthermophilic enzymes. Increased thermostability must be found, instead, in a small number of highly specific alterations that often do not obey any obvious traffic rules. After briefly discussing the diversity of hyperthermophilic organisms, this review concentrates on the remarkable thermostability of their enzymes. The biochemical and molecular properties of hyperthermophilic enzymes are described. Mechanisms responsible for protein inactivation are reviewed. The molecular mechanisms involved in protein thermostabilization are discussed, including ion pairs, hydrogen bonds, hydrophobic interactions, disulfide bridges, packing, decrease of the entropy of unfolding, and intersubunit interactions. Finally, current uses and potential applications of thermophilic and hyperthermophilic enzymes as research reagents and as catalysts for industrial processes are described. PMID:11238984

  3. Molecular Mechanism of Active Zone Organization at Vertebrate Neuromuscular Junctions

    PubMed Central

    Nishimune, Hiroshi

    2013-01-01

    Organization of presynaptic active zones is essential for development, plasticity, and pathology of the nervous system. Recent studies indicate a trans-synaptic molecular mechanism that organizes the active zones by connecting the pre- and the postsynaptic specialization. The presynaptic component of this trans-synaptic mechanism is comprised of cytosolic active zone proteins bound to the cytosolic domains of voltage-dependent calcium channels (P/Q-, N-, and L-type) on the presynaptic membrane. The postsynaptic component of this mechanism is the synapse organizer (laminin β2) that is expressed by the postsynaptic cell and accumulates specifically on top of the postsynaptic specialization. The pre- and the postsynaptic components interact directly between the extracellular domains of calcium channels and laminin β2 to anchor the presynaptic protein complex in front of the postsynaptic specialization. Hence, the presynaptic calcium channel functions as a scaffolding protein for active zone organization and as an ion-conducting channel for synaptic transmission. In contrast to the requirement of calcium influx for synaptic transmission, the formation of the active zone does not require the calcium influx through the calcium channels. Importantly, the active zones of adult synapses are not stable structures and require maintenance for their integrity. Furthermore, aging or diseases of the central and peripheral nervous system impair the active zones. This review will focus on the molecular mechanisms that organize the presynaptic active zones and summarize recent findings at the neuromuscular junctions and other synapses. PMID:22135013

  4. Molecular mechanisms of coronavirus RNA capping and methylation.

    PubMed

    Chen, Yu; Guo, Deyin

    2016-02-01

    The 5'-cap structures of eukaryotic mRNAs are important for RNA stability, pre-mRNA splicing, mRNA export, and protein translation. Many viruses have evolved mechanisms for generating their own cap structures with methylation at the N7 position of the capped guanine and the ribose 2'-Oposition of the first nucleotide, which help viral RNAs escape recognition by the host innate immune system. The RNA genomes of coronavirus were identified to have 5'-caps in the early 1980s. However, for decades the RNA capping mechanisms of coronaviruses remained unknown. Since 2003, the outbreak of severe acute respiratory syndrome coronavirus has drawn increased attention and stimulated numerous studies on the molecular virology of coronaviruses. Here, we review the current understanding of the mechanisms adopted by coronaviruses to produce the 5'-cap structure and methylation modification of viral genomic RNAs. PMID:26847650

  5. MOLECULAR MECHANISM OF URANIUM REDUCTION BY CLOSTRIDIA AND ITS MANIPULATION.

    SciTech Connect

    FRANCIS, A.J.; GAO, W.; CHIDAMBARAM, D.; DODGE, C.J.

    2006-11-16

    This research addresses the need for detailed studies of the enzymatic mechanisms for reduction of radionuclides and/or metals by fermentative microorganisms. The overall objective of this research is to elucidate systematically the molecular mechanisms involved in the reduction of uranium by Clostridia. We propose to (1) determine the role of hydrogenases in uranium reduction, (2) purify the enzymes involved in uranium reduction, (3) determine the mechanisms of reduction, e.g., one or two electron transfer reactions, and (4) elucidate the genetic control of the enzymes and cellular factors involved in uranium reduction. This is a collaborative study between BNL and Stanford University involving expertise in biomolecular science, biochemistry, microbiology, and electrochemistry.

  6. Molecular Mechanism of Uranium Reduction by Clostridia and its Manipulation

    SciTech Connect

    A. J. Francis; W. Gao, D. Chidambaram; C.J. Dodge

    2006-06-01

    This research addresses the need for detailed studies of the enzymatic mechanisms for reduction of radionuclides and/or metals by fermentative microorganisms. The overall objective of this research is to elucidate systematically the molecular mechanisms involved in the reduction of uranium by Clostridia. We propose to (1) determine the role of hydrogenases in uranium reduction, (22) purify the enzymes involved in uranium reduction, (3) determine the mechanisms of reduction, e.g., one or two electron transfer reactions, and (4) elucidate the genetic control of the enzymes and cellular factors involved in uranium reduction. This is a collaborative study between BNL and Stanford University involving expertise in biomolecular science, biochemistry, microbiology, and electrochemistry.

  7. Molecular mechanisms of drug resistance and its reversal in cancer.

    PubMed

    Kartal-Yandim, Melis; Adan-Gokbulut, Aysun; Baran, Yusuf

    2016-08-01

    Chemotherapy is the main strategy for the treatment of cancer. However, the main problem limiting the success of chemotherapy is the development of multidrug resistance. The resistance can be intrinsic or acquired. The resistance phenotype is associated with the tumor cells that gain a cross-resistance to a large range of drugs that are structurally and functionally different. Multidrug resistance arises via many unrelated mechanisms, such as overexpression of energy-dependent efflux proteins, decrease in uptake of the agents, increase or alteration in drug targets, modification of cell cycle checkpoints, inactivation of the agents, compartmentalization of the agents, inhibition of apoptosis and aberrant bioactive sphingolipid metabolism. Exact elucidation of resistance mechanisms and molecular and biochemical approaches to overcome multidrug resistance have been a major goal in cancer research. This review comprises the mechanisms guiding multidrug resistance in cancer chemotherapy and also touches on approaches for reversing the resistance. PMID:25757878

  8. Physiological, Molecular and Genetic Mechanisms of Long-Term Habituation

    SciTech Connect

    Calin-Jageman, Robert J

    2009-09-12

    Work funded on this grant has explored the mechanisms of long-term habituation, a ubiquitous form of learning that plays a key role in basic cognitive functioning. Specifically, behavioral, physiological, and molecular mechanisms of habituation have been explored using a simple model system, the tail-elicited siphon-withdrawal reflex (T-SWR) in the marine mollusk Aplysia californica. Substantial progress has been made on the first and third aims, providing some fundamental insights into the mechanisms by which memories are stored. We have characterized the physiological correlates of short- and long-term habituation. We found that short-term habituation is accompanied by a robust sensory adaptation, whereas long-term habituation is accompanied by alterations in sensory and interneuron synaptic efficacy. Thus, our data indicates memories can be shifted between different sites in a neural network as they are consolidated from short to long term. At the molecular level, we have accomplished microarray analysis comparing gene expression in both habituated and control ganglia. We have identified a network of putatively regulated transcripts that seems particularly targeted towards synaptic changes (e.g. SNAP25, calmodulin) . We are now beginning additional work to confirm regulation of these transcripts and build a more detailed understanding of the cascade of molecular events leading to the permanent storage of long-term memories. On the third aim, we have fostered a nascent neuroscience program via a variety of successful initiatives. We have funded over 11 undergraduate neuroscience scholars, several of whom have been recognized at national and regional levels for their research. We have also conducted a pioneering summer research program for community college students which is helping enhance access of underrepresented groups to life science careers. Despite minimal progress on the second aim, this project has provided a) novel insight into the network mechanisms by

  9. Molecular mechanisms of cisplatin cytotoxicity in acute promyelocytic leukemia cells

    PubMed Central

    Kumar, Sanjay; Tchounwou, Paul B.

    2015-01-01

    Cis-diamminedichloroplatinum (II) (cisplatin) is a widely used anti-tumor drug for the treatment of a broad range of human malignancies with successful therapeutic outcomes for head and neck, ovarian, and testicular cancers. It has been found to inhibit cell cycle progression and to induce oxidative stress and apoptosis in acute promyelocytic leukemia (APL) cells. However, its molecular mechanisms of cytotoxic action are poorly understood. We hypothesized that cisplatin induces cytotoxicity through DNA adduct formation, oxidative stress, transcriptional factors (p53 and AP-1), cell cycle regulation, stress signaling and apoptosis in APL cells. We used the APL cell line as a model, and applied a variety of molecular tools to elucidate the cytototoxic mode of action of cisplatin. We found that cisplatin inhibited cell proliferation by a cytotoxicity, characterized by DNA damage and modulation of oxidative stress. Cisplatin also activated p53 and phosphorylated activator protein (AP-1) component, c-Jun at serine (63, 73) residue simultaneously leading to cell cycle arrest through stimulation of p21 and down regulation of cyclins and cyclin dependent kinases in APL cell lines. It strongly activated the intrinsic pathway of apoptosis through alteration of the mitochondrial membrane potential, release of cytochrome C, and up-regulation of caspase 3 activity. It also down regulated the p38MAPK pathway. Overall, this study highlights the molecular mechanisms that underline cisplatin toxicity to APL cells, and provides insights into selection of novel targets and/or design of therapeutic agents to treat APL. PMID:26486083

  10. Molecular mechanisms of mutagenesis determined by the recombinant DNA technology

    SciTech Connect

    Lee, W.R.

    1985-01-01

    A study of the alteration of the DNA in the mutant gene can determine mechanisms of mutation by distinguishing between mutations induced by transition, transversion, frameshifts of a single base and deletions involving many base pairs. The association of a specific pattern of response with a mutagen will permit detecting mutants induced by the mutagen with a reduced background by removing mutations induced by other mechanisms from the pool of potential mutants. From analyses of studies that have been conducted, it is quite apparent that there are substantial differences among mutagens in their modes of action. Of 31 x-ray induced mutants, 20 were large deletions while only 3 showed normal Southern blots. Only one mutant produced a sub-unit polypeptide of normal molecular weight and charge in the in vivo test whereas in vitro synthesis produced a second one. In contrast, nine of thirteen EMS induced mutants produced cross-reacting proteins with sub-unit polypeptide molecular weights equivalent to wild type. Two of three ENU induced mutants recently analyzed in our laboratory produced protein with sub-unit polypeptide molecular weight and electrical charge similar to the wild type stock in which the mutants were induced. One ENU induced mutation is a large deletion. 21 refs., 1 fig.