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Sample records for molecular pathogenetic mechanisms

  1. [Radiation-induced genomic instability: phenomenon, molecular mechanisms, pathogenetic significance].

    PubMed

    Mazurik, V K; Mikhaĭlov, V F

    2001-01-01

    The recent data on the radiation-induced genome instability as a special state of progeny of cells irradiated in vitro as well as after a whole body exposure to ionizing radiation, that make these cells considerably different from normal, unirradiated cells, were considered. This state presents a number of cytogenetical, molecular-biological, cytological and biochemical manifestations untypical for normal cells. The state is controlled by the mechanisms of regulation of checkpoints of cell cycle, and apoptosis, that is under gene p53 control. The proof has been found that this state transfers from irradiated maternal cells to their surviving progeny by the epigenetical mechanisms and would exist until the cells restore the original state of response on the DNA damage. From the point of view of the genome instability conception, that considers the chromatine rearrangement as the adaptive-evolution mechanism of adaptation of the species to changeable environmental conditions, the radiation-induced genome instability may be considered as transition of irradiated progeny to the state of read these to adaptation changes with two alternative pathways. The first leads to adaptation to enviromental conditions and restoring of normal cell functions. The second presents the cell transition into the transformed state with remain genome instability and with increase of tumour growth probability.

  2. Molecular pathogenetic mechanisms and new therapeutic perspectives in anthracycline-induced cardiomyopathy

    PubMed Central

    2009-01-01

    Anthracyclines are among the most powerful drugs for the treatment of oncologic diseases both in childhood and in adulthood. Nevertheless, their major antineoplastic efficacy can be seriously impaired by collateral toxic cardiac effects causing cardiomyopathy with chronic heart failure that is refractory to conventional medical therapy. This article reports possible subcellular molecular alterations of anthracycline-induced cardiomyopathy (reactive oxygen species formation, apoptosis, inflammatory signalling, altered expression of cardiomyocytes specific genes, etc) and indicates some new therapeutic perspectives resulting from a better understanding of the molecular pathogenetic mechanisms. PMID:19930562

  3. Molecular pathogenetic mechanisms and new therapeutic perspectives in anthracycline-induced cardiomyopathy.

    PubMed

    Distefano, Giuseppe

    2009-11-20

    Anthracyclines are among the most powerful drugs for the treatment of oncologic diseases both in childhood and in adulthood. Nevertheless, their major antineoplastic efficacy can be seriously impaired by collateral toxic cardiac effects causing cardiomyopathy with chronic heart failure that is refractory to conventional medical therapy.This article reports possible subcellular molecular alterations of anthracycline-induced cardiomyopathy (reactive oxygen species formation, apoptosis, inflammatory signalling, altered expression of cardiomyocytes specific genes, etc) and indicates some new therapeutic perspectives resulting from a better understanding of the molecular pathogenetic mechanisms.

  4. Pathogenetic mechanisms in gastric cancer

    PubMed Central

    Shi, Jing; Qu, Yi-Ping; Hou, Peng

    2014-01-01

    Gastric cancer (GC) is a major public health issue as the fourth most common cancer and the second leading cause of cancer-related death. Recent advances have improved our understanding of its molecular pathogenesis, as best exemplified by elucidating the fundamental role of several major signaling pathways and related molecular derangements. Central to these mechanisms are the genetic and epigenetic alterations in these signaling pathways, such as gene mutations, copy number variants, aberrant gene methylation and histone modification, nucleosome positioning, and microRNAs. Some of these genetic/epigenetic alterations represent effective diagnostic and prognostic biomarkers and therapeutic targets for GC. This information has now opened unprecedented opportunities for better understanding of the molecular mechanisms of gastric carcinogenesis and the development of novel therapeutic strategies for this cancer. The pathogenetic mechanisms of GC are the focus of this review. PMID:25320518

  5. Pathogenetic mechanisms of coronary ectasia.

    PubMed

    Antoniadis, Antonios P; Chatzizisis, Yiannis S; Giannoglou, George D

    2008-11-28

    Coronary ectasia is defined as local or generalized aneurysmal dilatation of the coronary arteries. The present review summarizes the molecular, cellular and vascular mechanisms which are involved in the pathobiology of coronary ectasia. Coronary ectasia likely represents an exaggerated form of expansive vascular remodeling (i.e. excessive expansive remodeling) in response to atherosclerotic plaque growth. Enzymatic degradation of the extracellular matrix of the media is the major pathophysiologic process that leads to ectasia. Atherosclerotic lesions within ectatic regions of the coronary arteries appear to be highly inflamed high-risk plaques with proclivity to rupture. Better understanding of the pathogenetic processes involved in coronary ectasia is anticipated that will provide a further insight into the clinical significance and natural history of this entity, and may also have direct clinical implications in the management and follow-up strategy of this condition.

  6. Pathogenetic mechanisms of focal cortical dysplasia.

    PubMed

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

    2014-07-01

    Focal cortical dysplasias (FCDs) constitute a prevalent cause of intractable epilepsy in children, and is one of the leading conditions requiring epilepsy surgery. Despite recent advances in 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. A systematic review of the literature regarding the histologic, molecular, and electrophysiologic aspects of FCDs was conducted. Disruption of the mammalian target of rapamycin (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. Encouraging progress has been achieved on the molecular and electrophysiologic 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. Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.

  7. 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

  8. 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

  9. [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.

  10. [Gastroesophageal reflux and asthma--pathogenetic mechanisms and treatment].

    PubMed

    Gabriela, Jimborean; Ianosi, Edith Simona; Aberle, Emese; Comes, Alexandra

    2012-01-01

    Gastroesophageal reflux and bronchial asthma are frequently encountered comorbidities that maintain an ambivalent relationship, generating a vicious circle where gastroesophageal reflux increases asthmatic symptoms or precipitates bronchial asthma and asthma can trigger or worsen gastroesophageal reflux disease. Pathogenetic mechanisms of these interrelation are imperfectly understood, despite intense concerns of specialists in both areas. There have been incriminated: eso-bronchial constrictor vagal mediated reflexes, bronchial hyperreactivity, neurogenic inflammation induced by hydrochloric acid penetration in the oesofagus, airways hydrochloric acid microaspiration with asthmatic trigger effects, increased bronchial resistance or increased immune response to antigens. Bronchial obstruction and some antiasthmatic medication can decrease lower esophageal sphincter pressure and thus triggering or aggravating gastroesophageal reflux. The diagnosis of the gastroesophageal reflux in asthmatics involves a careful clinical exam, digestive functional test (up to 24 hours monitoring esophageal pH) and esogastroscopy. Gastroesophageal reflux treatment in asthmatic patients claims elimination of both disease risk factors, diet, proton-pump inhibitors.

  11. 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

  12. 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

  13. Novel pathogenetic mechanisms and structural adaptations in ischemic mitral regurgitation.

    PubMed

    Silbiger, Jeffrey J

    2013-10-01

    Ischemic mitral regurgitation (MR) is a common complication of myocardial infarction thought to result from leaflet tethering caused by displacement of the papillary muscles that occurs as the left ventricle remodels. The author explores the possibility that left atrial remodeling may also play a role in the pathogenesis of ischemic MR, through a novel mechanism: atriogenic leaflet tethering. When ischemic MR is hemodynamically significant, the left ventricle compensates by dilating to preserve forward output using the Starling mechanism. Left ventricular dilatation, however, worsens MR by increasing the mitral valve regurgitant orifice, leading to a vicious cycle in which MR begets more MR. The author proposes that several structural adaptations play a role in reducing ischemic MR. In contrast to the compensatory effects of left ventricular enlargement, these may reduce, rather than increase, its severity. The suggested adaptations involve the mitral valve leaflets, the papillary muscles, the mitral annulus, and the left ventricular false tendons. This review describes the potential role each may play in reducing ischemic MR. Therapies that exploit these adaptations are also discussed.

  14. Motor neuron 'bistability'. A pathogenetic mechanism for cramps and myokymia.

    PubMed

    Baldissera, F; Cavallari, P; Dworzak, F

    1994-10-01

    In three patients suffering from chronic muscle cramps, spasms and myokymia, these involuntary contractions were triggered in the triceps surae, quadriceps, flexor carpi radialis or flexor digitorum by means of single or short-train stimulation of homonymous Ia afferents, elicited by electrical means or tendon taps. In some cases cramp was induced by the first afferent volleys; more often, however, continued stimulation produced stepwise recruitment of motor units (whose rhythmic firing was visible as myokymia in the muscle) until cramp developed. Cramps and myokymic discharges could usually be terminated by a single maximal stimulus to the motor axons (producing antidromic invasion and Renshaw inhibition of the motor neurons), or by short trains of volleys in inhibitory pathways from the skin. The fact that it was possible to induce myokymia and cramps by brief synaptic excitation and terminate them by antidromic invasion or synaptic inhibition, suggests that the mechanism generating these disturbances is intrinsic to alpha-motor neuron somata. Similar on-off switching of self-sustained motor discharges has been observed in the decerebrate cat and is known to depend on 'bistability' of the motor neuron membrane. We propose that a similar mechanism is responsible for discharges that produce cramp.

  15. [Myocardial dysfunction in sepsis--definition and pathogenetic mechanisms].

    PubMed

    Muriová, K; Maláska, J; Otevrel, F; Slezák, M; Kratochvíl, M; Sevík, P

    2010-03-01

    Sepsis is considered to be the major cause of morbidity and mortality of patients hospitalised in intensive care. It's defined as a systemic inflammatory response of organism to infection. Incidence of myocardial dysfunction in studies with severe sepsis patients is up to two thirds of patients. Cardiac dysfunction shows a continuum from isolated and mild diastolic dysfunction to combined severe diastolic and systolic failure of both ventricles mimicking even cardiogenic shock in some patients. Typical features of septic myocardial dysfunction (SMD) are decrease in ejection fraction (EF) with dilatation ofventricles, e.g. increase in end-diastolic volume (EDV). Reversibility of myocardial dysfunction during a period from 7 to 10 days in survivors is other typical manifestation of SMD. Hence, one can speculate that development of such a type ofSMD as a temporary protective compensatory mechanism could be advantageous for of an individual patient. A large body ofevidence about mechanisms ofSMD was described; endothelial dysfunction with consequent microcirculatory and mitochondrial dysfunction and role of circulating factors are considered to be the most important.

  16. [Understanding the pathogenetic mechanisms of SIRS and sepsis and development of innovative therapies of sepsis].

    PubMed

    Aikawa, Naoki; Fujishima, Seitaro

    2004-12-01

    The concept of systemic inflammatory response syndrome (SIRS) was introduced in 1992 to define and objectively diagnose sepsis. Over the last decade, the definition of sepsis has been used for inclusion criteria of multicenter trials to develop innovative therapies of sepsis. With the recent understanding of the pathogenetic mechanisms of sepsis, many drugs have been tested, but only two drugs (activated protein C and neutrophil-elastase inhibitor) have been approved for clinical use in sepsis or SIRS. Further understanding of basic pathophysiology of SIRS and sepsis holds promise to develop a new therapeutic strategy to improve survival of patients with SIRS and sepsis.

  17. 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.

  18. 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

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

    PubMed

    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.

  20. Postprandial Dysmetabolism and Oxidative Stress in Type 2 Diabetes: Pathogenetic Mechanisms and Therapeutic Strategies.

    PubMed

    Sottero, Barbara; Gargiulo, Simona; Russo, Isabella; Barale, Cristina; Poli, Giuseppe; Cavalot, Franco

    2015-09-01

    Postprandial dysmetabolism in type 2 diabetes (T2D) is known to impact the progression and evolution of this complex disease process. However, the underlying pathogenetic mechanisms still require full elucidation to provide guidance for disease prevention and treatment. This review focuses on the marked redox changes and inflammatory stimuli provoked by the spike in blood glucose and lipids in T2D individuals after meals. All the causes of exacerbated postprandial oxidative stress in T2D were analyzed, also considering the consequence of enhanced inflammation on vascular damage. Based on this in-depth analysis, current strategies of prevention and pharmacologic management of T2D were critically reexamined with particular emphasis on their potential redox-related rationale.

  1. CALCIFIC AORTIC VALVE DISEASE: PART 1 – MOLECULAR PATHOGENETIC ASPECTS, HEMODYNAMICS AND ADAPTIVE FEEDBACKS

    PubMed Central

    Pasipoularides, Ares

    2016-01-01

    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

  2. A New Theory to Explain the Underlying Pathogenetic Mechanism of Sudden Infant Death Syndrome

    PubMed Central

    Lavezzi, Anna Maria

    2015-01-01

    The author, on the basis of numerous studies on the neuropathology of SIDS, performed on a very wide set of cases, first highlights the neuronal centers of the human brainstem involved in breathing control in perinatal life, with the pontine Kölliker–Fuse nucleus (KFN) as main coordinator. What emerges from this analysis is that the prenatal respiratory movements differ from those post-natally in two respects: (1) they are episodic, only aimed at the lung development and (2) they are abolished by hypoxia, not being of vital importance in utero, mainly to limit the consumption of oxygen. Then, as this fetal inhibitory reflex represents an important defense expedient, the author proposes a new original interpretation of the pathogenetic mechanism leading to SIDS. Infants, in a critical moment of the autonomic control development, in hypoxic conditions could awaken the reflex left over from fetal life and arrest breathing, as he did in similar situations in prenatal life, rather than promote the hyperventilation usually occurring to restore the normal concentration of oxygen. This behaviour obviously leads to a fatal outcome. This hypothesis is supported by immunohistochemical results showing in high percentage of SIDS victims, and not in age-matched infant controls, neurochemical alterations of the Kölliker–Fuse neurons, potentially indicative of their inactivation. The new explanation of SIDS blames a sort of auto-inhibition of the KFN functionality, wrongly arisen with the same protective purpose to preserve the life in utero, as trigger of the sudden infant death. PMID:26539157

  3. Ocular delayed hypersensitivity: a pathogenetic mechanism of chlamydial-conjunctivitis in guinea pigs.

    PubMed Central

    Watkins, N G; Hadlow, W J; Moos, A B; Caldwell, H D

    1986-01-01

    We used a naturally occurring, Chlamydia psittaci-caused eye disease in guinea pigs, guinea pig inclusion conjunctivitis, as an animal model to understand both the immune response and the pathogenesis of chlamydial eye infections. When instilled into the conjunctival sac of guinea pigs that had been previously infected and were immune, viable chlamydiae or a Triton X-100-soluble extract of them produced a short-lived (12-48 hr) eye disease indistinguishable clinically and histologically from that observed during primary chlamydial eye infection. The clinical and histologic findings were consistent with those of ocular delayed hypersensitivity. Ocular delayed hypersensitivity was induced by primary chlamydial infection at mucosal sites other than conjunctival, such as vaginal and intestinal. Preliminary characterization of the hypersensitivity allergen shows that it is heat sensitive and common to the genus Chlamydia. The allergen is apparently not surface-exposed on chlamydiae and requires viable but not replicating organisms for activity. Our observation should be useful in understanding pathogenetic mechanisms of Chlamydia trachomatis-caused infections in humans, in particular those that produce chronic inflammatory diseases, such as blinding trachoma and urogenital diseases. Images PMID:3463978

  4. 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

  5. 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

  6. Alexia with agraphia due to the left posterior inferior temporal lobe lesion--neuropsychological analysis and its pathogenetic mechanisms.

    PubMed

    Kawahata, N; Nagata, K; Shishido, F

    1988-03-01

    We report three cases of alexia with agraphia due to the left posterior inferior temporal lesions. In Case 1, the reading disability was more prominent in the use of Kana than in the use of Kanji, which is similar to previously reported cases of alexia with agraphia due to angular gyrus lesion. In Cases 2 and 3, by contrast, the reading disability was more prominent in the use of Kanji than in the use of Kana. In spontaneous writing and dictation, the disability was more pronounced in the use of Kanji compared with the use of Kana. In each of the three cases, the CT scan and positron emission tomography showed a localized lesion in the lower part of the left posterior temporal lobe. A typical form of an alexia with agraphia could be caused not only by the left angular lesion but also by the left posterior inferior temporal lesion. We discuss the neuropsychological analysis and pathogenetic mechanisms of alexia with agraphia due to the left posterior inferior temporal lesion in the comparison of alexia with agraphia caused by the left angular lesion.

  7. 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

    2016-05-03

    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.

  8. Insulin resistance and cancer risk: an overview of the pathogenetic mechanisms.

    PubMed

    Arcidiacono, Biagio; Iiritano, Stefania; Nocera, Aurora; Possidente, Katiuscia; Nevolo, Maria T; Ventura, Valeria; Foti, Daniela; Chiefari, Eusebio; Brunetti, Antonio

    2012-01-01

    Insulin resistance is common in individuals with obesity or type 2 diabetes (T2D), in which circulating insulin levels are frequently increased. Recent epidemiological and clinical evidence points to a link between insulin resistance and cancer. The mechanisms for this association are unknown, but hyperinsulinaemia (a hallmark of insulin resistance) and the increase in bioavailable insulin-like growth factor I (IGF-I) appear to have a role in tumor initiation and progression in insulin-resistant patients. Insulin and IGF-I inhibit the hepatic synthesis of sex-hormone binding globulin (SHBG), whereas both hormones stimulate the ovarian synthesis of sex steroids, whose effects, in breast epithelium and endometrium, can promote cellular proliferation and inhibit apoptosis. Furthermore, an increased risk of cancer among insulin-resistant patients can be due to overproduction of reactive oxygen species (ROS) that can damage DNA contributing to mutagenesis and carcinogenesis. On the other hand, it is possible that the abundance of inflammatory cells in adipose tissue of obese and diabetic patients may promote systemic inflammation which can result in a protumorigenic environment. Here, we summarize recent progress on insulin resistance and cancer, focusing on various implicated mechanisms that have been described recently, and discuss how these mechanisms may contribute to cancer initiation and progression.

  9. Role of zinc and copper ions in the pathogenetic mechanisms of Alzheimer's and Parkinson's diseases.

    PubMed

    Stelmashook, E V; Isaev, N K; Genrikhs, E E; Amelkina, G A; Khaspekov, L G; Skrebitsky, V G; Illarioshkin, S N

    2014-05-01

    Disbalance of zinc (Zn2+) and copper (Cu2+) ions in the central nervous system is involved in the pathogenesis of numerous neurodegenerative disorders such as multisystem atrophy, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Wilson-Konovalov disease, Alzheimer's disease, and Parkinson's disease. Among these, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most frequent age-related neurodegenerative pathologies with disorders in Zn2+ and Cu2+ homeostasis playing a pivotal role in the mechanisms of pathogenesis. In this review we generalized and systematized current literature data concerning this problem. The interactions of Zn2+ and Cu2+ with amyloid precursor protein (APP), β-amyloid (Abeta), tau-protein, metallothioneins, and GSK3β are considered, as well as the role of these interactions in the generation of free radicals in AD and PD. Analysis of the literature suggests that the main factors of AD and PD pathogenesis (oxidative stress, structural disorders and aggregation of proteins, mitochondrial dysfunction, energy deficiency) that initiate a cascade of events resulting finally in the dysfunction of neuronal networks are mediated by the disbalance of Zn2+ and Cu2+.

  10. Gene mutation in microRNA target sites of CFTR gene: a novel pathogenetic mechanism in cystic fibrosis?

    PubMed

    Amato, Felice; Seia, Manuela; Giordano, Sonia; Elce, Ausilia; Zarrilli, Federica; Castaldo, Giuseppe; Tomaiuolo, Rossella

    2013-01-01

    Cystic fibrosis (CF) is the most frequent lethal genetic disorder among Caucasians. It depends on alterations of a chloride channel expressed by most epithelial cells and encoded by CFTR gene. Also using scanning techniques to analyze the whole coding regions of CFTR gene, mutations are not identified in up to 10% of CF alleles, and such figure increases in CFTR-related disorders (CFTR-RD). Other gene regions may be the site of causing-disease mutations. We searched for genetic variants in the 1500 bp of CFTR 3' untranslated region, typical target of microRNA (miRNA) posttranscriptional gene regulation, in either CF patients with the F508del homozygous genotype and different clinical expression (n = 20), CF (n = 32) and CFTR-RD (n = 43) patients with one or none mutation after CFTR scanning and in controls (n = 50). We identified three SNPs, one of which, the c.*1043A>C, was located in a region predicted to bind miR-433 and miR-509-3p. Such mutation was peculiar of a CFTR-RD patient that had Congenital Bilateral Absence of Vas Deferens (CBAVD), diffuse bronchiectasis, a borderline sweat chloride test and the heterozygous severe F508del mutation on the other allele. The expression analysis demonstrated that the c.*1043A>C increases the affinity for miR-509-3p and slightly decreases that for the miR-433. Both miRNAs cause in vitro a reduced expression of CFTR protein. Thus, the c.*1043A>C may act as a mild CFTR mutation enhancing the affinity for inhibitory miRNAs as a novel pathogenetic mechanism in CF.

  11. Genetic Alterations of the Retinoblastoma-Related Gene RB2/p130 Identify Different Pathogenetic Mechanisms in and among Burkitt’s Lymphoma Subtypes

    PubMed Central

    Cinti, Caterina; Leoncini, Lorenzo; Nyongo, Aggrey; Ferrari, Filomena; Lazzi, Stefano; Bellan, Cristiana; Vatti, Rosella; Zamparelli, Alessandra; Cevenini, Gabriele; osi, Gian Marco T; Claudio, Pier Paolo; Maraldi, Nadir M.; Tosi, Piero; Giordano, Antonio

    2000-01-01

    Alterations of cell cycle-associated genes probably contribute to the pathogenesis of Burkitt’s Lymphoma (BL), in addition to c-myc translocation. Mutations disrupting the nuclear localization signal of the retinoblastoma-related gene RB2/p130 have been documented recently in BL cell lines and primary tumors. Given the importance of the RB2/p130 gene in controlling cell growth, mutations of this gene may result in uncontrolled cell proliferation. We tested the expression and genomic organization of the RB2/p130 gene in relation to the proliferative features of a series of BL samples collected from the endemic and sporadic regions, regardless of whether the samples were acquired immune deficiency syndrome (AIDS)-related. The expression of the Rb2/p130, p107, and cell proliferation-related proteins (cyclin A and B) was determined by immunohistochemistry. The structures of exons 19 through 22 of the RB2/p130 gene, encoding for the B domain and C terminus, were analyzed by polymerase chain reaction (PCR) analysis and single-strand conformation polymorphism (SSCP) technique. The direct PCR products were sequenced to identify the actual mutations. Our results suggest that BL is composed of a mixture of molecular types with distinct genetic and phenotypic patterns, probably resulting from different pathogenetic mechanisms. In endemic BL, the RB2/p130 gene is mutated in most of the cases, and the protein is restricted to the cytoplasm. In AIDS-related BL, high levels of nuclear expression of the wild-type pRb2/p130, p107, and cell proliferation-related proteins were detected. This finding is in line with the molecular mechanisms observed in virus-linked oncogenesis. Sporadic BLs were mainly characterized by the low nuclear values of the wild-type pRb2/p130 and, conversely, the high values of p107. The increased cell proliferation due to different alterations of cell growth control by Rb-related proteins may be the first step in lymphomagenesis, during which additional

  12. Molecular phylogenetic and pathogenetic characterization of Fusarium solani species complex (FSSC), the cause of dry rot on potato in Iran.

    PubMed

    Chehri, Khosrow; Ghasempour, Hamid Reza; Karimi, Naser

    2014-01-01

    Members of Fusarium solani species complex (FSSC) are common pathogens of potato, causing dry rot in the west of Iran which involved Hamedan, Kermanshah, Eilam and Kurdistan provinces. Therefore, the objectives in this study were to isolate and identify disease-causing FSSC from infected potato tubers based on the morphological and molecular characteristics. Forty-five isolates of Fusarium were obtained from potato tubers collected from the wet market in different regions of the west of Iran and identified as FSSC through morphological characters. All of the isolates were evaluated for their pathogenicity on healthy potato tubers in the planthouse. The tubers rot symptoms were observed on the 21st day after inoculation of Fusarium isolates on the tubers tested. In the tubers inoculation tests, lesion sizes were quite variable; therefore, the measurement was done to compare the depth and width of lesion expansion among the isolates. Based on the sequence data from translation elongation factor (EF-lα) gene and internal transcript spacer (ITS) regions analysis, all of the selected FSSC isolates were divided into two major groups. This is the first report on molecular identification of FSSC strains isolated from potato tubers in Iran and Fusarium falciforme was reported for the first time in Iran.

  13. Impairment of Energy-Dependent Processes in the Muscle Tissue as a Pathogenetic Mechanism of Statin-Induced Myopathy.

    PubMed

    Mikashinovich, Z I; Belousova, E S; Sarkisyan, O G

    2017-02-01

    Administration of simvastatin was followed by a decrease in activities of superoxide dismutase and cytochrome oxidase in rat mitochondria, which attested to dysfunction of the respiratory chain. The decrease in total ATPase and Ca(2+)-ATPase activities in muscle tissue homogenates reflected impaired transport of active cations essential for muscle contraction. We conclude that abnormal relationships in the system of energy synthetic and energy-dependent processes in myocytes serve as the molecular basis for the formation of statin-induced degenerative changes.

  14. Molecular mechanisms in gliomagenesis.

    PubMed

    Hulleman, Esther; Helin, Kristian

    2005-01-01

    Glioma, and in particular high-grade astrocytoma termed glioblastoma multiforme (GBM), is the most common primary tumor of the brain. Primarily because of its diffuse nature, there is no effective treatment for GBM, and relatively little is known about the processes by which it develops. Therefore, in order to design novel therapies and treatments for GBM, research has recently intensified to identify the cellular and molecular mechanisms leading to GBM formation. Modeling of astrocytomas by genetic manipulation of mice suggests that deregulation of the pathways that control gliogenesis during normal brain development, such as the differentiation of neural stem cells (NSCs) into astrocytes, might contribute to GBM formation. These pathways include growth factor-induced signal transduction routes and processes that control cell cycle progression, such as the p16-CDK4-RB and the ARF-MDM2-p53 pathways. The expression of several of the components of these signaling cascades has been found altered in GBM, and recent data indicate that combinations of mutations in these pathways may contribute to GBM formation, although the exact mechanisms are still to be uncovered. Use of novel techniques including large-scale genomics and proteomics in combination with relevant mouse models will most likely provide novel insights into the molecular mechanisms underlying glioma formation and will hopefully lead to development of treatment modalities for GBM.

  15. Molecular mechanisms of etoposide

    PubMed Central

    Montecucco, Alessandra; Zanetta, Francesca; Biamonti, Giuseppe

    2015-01-01

    Etoposide derives from podophyllotoxin, a toxin found in the American Mayapple. It was first synthesized in 1966 and approved for cancer therapy in 1983 by the U.S. Food and Drug Administration (Hande, 1998[25]). Starting from 1980s several studies demonstrated that etoposide targets DNA topoisomerase II activities thus leading to the production of DNA breaks and eliciting a response that affects several aspects of cell metabolisms. In this review we will focus on molecular mechanisms that account for the biological effect of etoposide. PMID:26600742

  16. Understanding molecular structure from molecular mechanics.

    PubMed

    Allinger, Norman L

    2011-04-01

    Molecular mechanics gives us a well known model of molecular structure. It is less widely recognized that valence bond theory gives us structures which offer a direct interpretation of molecular mechanics formulations and parameters. The electronic effects well-known in physical organic chemistry can be directly interpreted in terms of valence bond structures, and hence quantitatively calculated and understood. The basic theory is outlined in this paper, and examples of the effects, and their interpretation in illustrative examples is presented.

  17. Cisplatin nephrotoxicity: molecular mechanisms

    PubMed Central

    Hanigan, Marie H.; Devarajan, Prasad

    2007-01-01

    Summary Cisplatin is one of the most widely used chemotherapeutic agents for the treatment of several human malignancies. The efficacy of cisplatin is dose dependent, but the significant risk of nephrotoxicity frequently hinders the use of higher doses to maximize its antineoplastic effects. Several advances in our understanding of the biochemical and molecular mechanisms underlying cisplatin nephrotoxicity have recently emerged, and are reviewed in this article. Evidence is presented for distinct mechanisms of cisplatin toxicity in actively dividing tumor cells versus the normally quiescent renal proximal tubular epithelial cells. The unexpected role of gamma-glutamyl transpeptidase in cisplatin nephrotoxicity is elucidated. Recent studies demonstrating the ability of proximal tubular cells to metabolize cisplatin to a nephrotoxin are reviewed. The evidence for apoptosis as a major mechanism underlying cisplatin-induced renal cell injury is presented, along with the data exploring the role of specific intracellular pathways that may mediate the programmed cell death. The information gleaned from this review may provide critical clues to novel therapeutic interventions aimed at minimizing cisplatin-induced nephrotoxicity while enhancing its antineoplastic efficacy. PMID:18185852

  18. Molecular mechanisms in cardiomyopathy.

    PubMed

    Dadson, Keith; Hauck, Ludger; Billia, Filio

    2017-07-01

    Cardiomyopathies represent a heterogeneous group of diseases that negatively affect heart function. Primary cardiomyopathies specifically target the myocardium, and may arise from genetic [hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), mitochondrial cardiomyopathy] or genetic and acquired [dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM)] etiology. Modern genomics has identified mutations that are common in these populations, while in vitro and in vivo experimentation with these mutations have provided invaluable insight into the molecular mechanisms native to these diseases. For example, increased myosin heavy chain (MHC) binding and ATP utilization lead to the hypercontractile sarcomere in HCM, while abnormal protein-protein interaction and impaired Ca(2+) flux underlie the relaxed sarcomere of DCM. Furthermore, expanded access to genetic testing has facilitated identification of potential risk factors that appear through inheritance and manifest sometimes only in the advanced stages of the disease. In this review, we discuss the genetic and molecular abnormalities unique to and shared between these primary cardiomyopathies and discuss some of the important advances made using more traditional basic science experimentation. © 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  19. Hodgkin/Reed-Sternberg cells and Hodgkin's disease in patients with B-cell chronic lymphocytic leukaemia: an immunohistological, molecular and clinical study of four cases suggesting a heterogeneous pathogenetic background.

    PubMed

    Pescarmona, E; Pignoloni, P; Mauro, F R; Cerretti, R; Anselmo, A P; Mandelli, F; Baroni, C D

    2000-08-01

    We report the immunohistological, molecular and clinical findings in four patients affected by B-cell chronic lymphocytic leukaemia (CLL) who developed "Richter's syndrome with Hodgkin's disease (HD) features" or "CLL with Hodgkin's transformation", all characterised by the presence of typical Hodgkin/Reed-Sternberg (H/RS) cells in lymph node biopsies. In three cases the nodal involvement by CLL was demonstrated both by the presence of a predominant background of CD5/CD19/CD23+ small lymphocytes and an IgH monoclonal rearrangement revealed by PCR analysis. Conversely, in the remaining case there was neither immunohistological nor molecular evidence of lymph node involvement by CLL. In all four cases H/RS cells were Epstein-Barr virus (EBV) latent membrane protein (LMP-1) positive. These findings suggest that the presence of H/RS cells in the first three patients, who had CLL/HD nodal involvement, might be related to transformation or clonal evolution of CLL cells in H/RS cells, which is in keeping with use of the term "CLL with Hodgkin's transformation". In the fourth case a de novo HD may be postulated, representing a second malignancy presumably not clonally related to CLL. In all cases a key pathogenetic role of EBV is suggested by the expression of LMP-1 in H/RS cells. Our findings indicate that the presence of typical H/RS cells in lymph node biopsies in CLL patients may reflect a heterogeneous pathogenetic background. The different clinico-pathologic settings should be taken into consideration because of their possible implications for patients' treatment and prognosis.

  20. Molecular Mechanisms of Preeclampsia

    PubMed Central

    Hod, Tammy; Cerdeira, Ana Sofia; Karumanchi, S. Ananth

    2015-01-01

    Preeclampsia is a pregnancy-specific disease characterized by new onset hypertension and proteinuria after 20 wk of gestation. It is a leading cause of maternal and fetal morbidity and mortality worldwide. Exciting discoveries in the last decade have contributed to a better understanding of the molecular basis of this disease. Epidemiological, experimental, and therapeutic studies from several laboratories have provided compelling evidence that an antiangiogenic state owing to alterations in circulating angiogenic factors leads to preeclampsia. In this review, we highlight the role of key circulating antiangiogenic factors as pathogenic biomarkers and in the development of novel therapies for preeclampsia. PMID:26292986

  1. Molecular mechanisms of carcinogenesis

    SciTech Connect

    Hall, E.J.

    1997-03-01

    The possibility that chromosomal changes are responsible for neoplasia was proposed in the early years of this century. A combination of improved cytogenetics and the advent of recombinant technology has settled the issue. As recently as 20 years ago, however, the genetic and molecular basis of familiar predisposition to cancer were a mystery, and it is only in the last few years that light has been shed on a few specific types of malignancies. As the genetic basis of human cancer had been documented, a number of genes have been identified as functioning either as oncogenes which act in a dominant fashion to promote tumor growth when mutated, or as tumor suppressor genes which act in a recessive fashion.

  2. Molecular Mechanisms of Parturition

    PubMed Central

    1997-01-01

    The initial signal for triggering human parturition might be fetal but of trophoblastic origin. Concomitantly, this placental signal would have as its target not only the uterus but also the fetus by activating its hypothalamo-pituitary-adrenocortical axis. The latter would represent a second fetal signal which, at the fetomaternal interface, would amplify and define in time the mechanisms responsible for the onset of labor, implying changes in the myometrial and cervical extracellular matrix associated with the accession of the contractile phenotype for myometrial cells. At each phase of these processes in the utero-feto-placental system, the nature of these signals remains to be identified. Is there a single substance, or rather, and more likely, a combination of several? We appear to be in the presence of dynamic systems of a neuro-immuno-hormonal type which are difficult to describe. Nevertheless, steroid hormones appear to coordinate their successive equilibriums until they become irreversible. Such irreversibility constitutes the essential sign of parturition. PMID:18476161

  3. Molecular Mechanisms of Neuronal Responsivity.

    DTIC Science & Technology

    1987-07-10

    O-A187 061 MOLECULAR MECHANISMS OF NEURONAL RESPONSIVITY(U) / VERMONT UNIV BURLINGTON COIL OF MEDICINE V EHRLICH 7 UwKL7RS1S1 IS1 JUL 87 RFOSR-TR-87...The grant was awarded to support the organization of a scientific conference entitled: "Molecular Mechanisms of Neuronal Responsivity." This...from the University of New York, on: "Synaptic Transmission and Neuronal Integration." It should be mentioned that this presentation emerged as a most

  4. [The new pathogenetic treatment of cervical dystonia: rationale, methods, outcomes].

    PubMed

    Naryshkin, A G; Preobrazhenskaia, I G; Timofeev, I S; Filimonov, V N; Sheliakin, A M

    2000-01-01

    The paper presents data obtained from studies of the impact of the otolithic apparatus of the inner ear on the degree of symptoms of cervical dystonia. The findings make it possible to substantiate a pathogenetic treatment of this disease, which involves intratimpanal unilateral injection of the vestibulotoxic antibiotic streptomycin. The results achieved and the mechanisms of the therapeutical effect observed are discussed.

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

    PubMed

    Lillicrap, David

    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.

  6. Molecular Mechanism of Water Evaporation.

    PubMed

    Nagata, Yuki; Usui, Kota; Bonn, Mischa

    2015-12-04

    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.

  7. 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.

  8. [Molecular mechanisms of bone calcification].

    PubMed

    Hoshi, Kazuto; Ozawa, Hidehiro

    2003-04-01

    Bone matrix consists mainly of hydroxyapatite and organics. The latter include various substances which interact with minerals. Osteoblasts secrete these organic substances and control crystal formation and growth of hydroxyapatite. The authors discuss the molecular mechanisms of calcification by focusing on the mineral/organic interaction.

  9. Molecular mechanisms of neurite extension.

    PubMed Central

    Valtorta, F; Leoni, C

    1999-01-01

    The extension of neurites is a major task of developing neurons, requiring a significant metabolic effort to sustain the increase in molecular synthesis necessary for plasma membrane expansion. In addition, neurite extension involves changes in the subsets of expressed proteins and reorganization of the cytomatrix. These phenomena are driven by environmental cues which activate signal transduction processes as well as by the intrinsic genetic program of the cell. The present review summarizes some of the most recent progress made in the elucidation of the molecular mechanisms underlying these processes. PMID:10212488

  10. 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

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

    PubMed

    Pivonello, Claudia; De Martino, Maria Cristina; Negri, Mariarosaria; Cuomo, Gaia; Cariati, Federica; Izzo, Francesco; Colao, Annamaria; Pivonello, Rosario

    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.

  12. 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

  13. Molecular mechanisms of dendrite morphogenesis

    PubMed Central

    Arikkath, Jyothi

    2012-01-01

    Dendrites are key integrators of synaptic information in neurons and play vital roles in neuronal plasticity. Hence, it is necessary that dendrite arborization is precisely controlled and coordinated with synaptic activity to ensure appropriate functional neural network integrity. In the past several years, it has become increasingly clear that several cell intrinsic and extrinsic mechanisms contribute to dendritic arborization. In this review, we will discuss some of the molecular mechanisms that regulate dendrite morphogenesis, particularly in cortical and hippocampal pyramidal neurons and some of the implications of aberrant dendritic morphology for human disease. Finally, we will discuss the current challenges and future directions in the field. PMID:23293584

  14. 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

  15. 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

  16. Molecular mechanisms of antibiotic resistance.

    PubMed

    Wright, Gerard D

    2011-04-14

    Over the past decade, resistance to antibiotics has emerged as a crisis of global proportion. Microbes resistant to many and even all clinically approved antibiotics are increasingly common and easily spread across continents. At the same time there are fewer new antibiotic drugs coming to market. We are reaching a point where we are no longer able to confidently treat a growing number of bacterial infections. The molecular mechanisms of drug resistance provide the essential knowledge on new drug development and clinical use. These mechanisms include enzyme catalyzed antibiotic modifications, bypass of antibiotic targets and active efflux of drugs from the cell. Understanding the chemical rationale and underpinnings of resistance is an essential component of our response to this clinical challenge.

  17. 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

  18. Anticancer Molecular Mechanisms of Resveratrol.

    PubMed

    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.

  19. 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

  20. Molecular mechanisms of renal aging.

    PubMed

    Schmitt, Roland; Melk, Anette

    2017-09-01

    Epidemiologic, clinical, and molecular evidence suggest that aging is a major contributor to the increasing incidence of acute kidney injury and chronic kidney disease. The aging kidney undergoes complex changes that predispose to renal pathology. The underlying molecular mechanisms could be the target of therapeutic strategies in the future. Here, we summarize recent insight into cellular and molecular processes that have been shown to contribute to the renal aging phenotype.The main clinical finding of renal aging is the decrease in glomerular filtration rate, and its structural correlate is the loss of functioning nephrons. Mechanistically, this has been linked to different processes, such as podocyte hypertrophy, glomerulosclerosis, tubular atrophy, and gradual microvascular rarefaction. Renal functional recovery after an episode of acute kidney injury is significantly worse in elderly patients. This decreased regenerative potential, which is a hallmark of the aging process, may be caused by cellular senescence. Accumulation of senescent cells could explain insufficient repair and functional loss, a view that has been strengthened by recent studies showing that removal of senescent cells results in attenuation of renal aging. Other potential mechanisms are alterations in autophagy as an important component of a disturbed renal stress response and functional differences in the inflammatory system. Promising therapeutic measures to counteract these age-related problems include mimetics of caloric restriction, pharmacologic renin-angiotensin-aldosterone system inhibition, and novel strategies of senotherapy with the goal of reducing the number of senescent cells to decrease aging-related disease in the kidney. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  1. Vitiligo: pathogenetic hypotheses and targets for current therapies.

    PubMed

    Guerra, Liliana; Dellambra, Elena; Brescia, Serena; Raskovic, Desanka

    2010-06-01

    Vitiligo is a multifactorial disorder characterized by the appearance of white maculae that may spread over the entire body skin. Depigmentation arises from the loss of functioning melanocytes. Non segmental vitiligo (NSV) is the most common form of the disease: it is usually progressive and may be associated with familiarity and autoimmunity. Segmental vitiligo (SV) frequently stabilizes few years after its onset. Vitiligo etiology involves multiple pathogenetic factors, most of them working in concert. Impaired antioxidative defences lead to accumulation of reactive oxygen species (ROS), which affect melanocytes. Mitochondrial membrane lipid peroxidation may participate to ROS overproduction. A temporal sequence may connect oxidative stress and autoimmunity. Overall, a genetic predisposition renders vitiligo melanocytes more susceptible to precipitating factors than normal healthy melanocytes. The definition of isolated or superimposed manifestations of polygenic skin disorders has been proposed for SV and SV-NSV association. Keratinocytes and melanocytes are both affected and apoptosis, ageing or melanocythorragy are the ultimate effects of the complex deregulation in vitiligo skin. Pathogenetic therapies mainly act by inducing immunosuppression and stimulation of melanocyte proliferation and migration. Here the most popular hypotheses for the pathogenesis of vitiligo are summarized. Fundamental cellular, biochemical and molecular alterations accounting for melanocyte destruction in vitiligo are also described. Last, pathogenetic approaches in the treatment of such a complex disease are discussed, with particular consideration on the cellular and molecular targets of the current therapies.

  2. Molecular Mechanisms of Anthracycline Activity

    NASA Astrophysics Data System (ADS)

    Beretta, Giovanni Luca; Zunino, Franco

    On the basis of evidence that anthracyclines are DNA intercalating agents and DNA is the primary target, a large number of analogs and related intercalators have been developed. However, doxorubicin and closely related anthracyclines still remain among the most effective antitumor agents. Multiple mechanisms have been proposed to explain their efficacy. They include inhibition of DNA-dependent functions, free radical formation, and membrane interactions. The primary mechanism of action is now ascribed to drug interference with the function of DNA topoisomerase II. The stabilization of the topoisomerase-mediated cleavable complex results in a specific type of DNA damage (i.e., double-strand protein-associated DNA breaks). The drug-stabilized cleavable complex is a potentially reversible molecular event and its persistence, as a consequence of strong DNA binding, may be recognized as an apoptotic stimulus. Indirect evidence supports the notion that the bioreductive processes of the quinone moiety generating the semiquinone radical with concomitant production of reactive oxygen species may contribute to the drug effects. The cellular defense mechanisms and response to genotoxic/cytotoxic stress appear to be critical determinants of the tumor sensitivity to anthracyclines.

  3. [Wobenzym in the combined pathogenetic therapy of chronic urethrogenic prostatitis].

    PubMed

    Martynenko, A V

    1998-08-01

    The paper addresses the issues of pathogenetic therapy of uretrogenous prostatitis, its key features being as follows: 1) association with pancreatic pathology; 2) the presence of noninfectious agent; 3) autoimmune character. The proposed treatment scheme includes wobenzyme, a polyenzymic drug preparation, capable of exerting positive effects in the treatment of the pathology in question, which fact bears relation to intimate mechanisms of evolution of chronic urethrogenous prostatitis.

  4. Molecular mechanisms of maculopapular exanthema.

    PubMed

    Fernández, Tahia D; Canto, Gabriela; Blanca, Miguel

    2009-06-01

    Maculopapular exanthema is a common cutaneous manifestation of many diseases produced by several agents able to activate the immune system, the most common of which are drugs and viruses. In spite of its high frequency, knowledge of the molecular mechanisms involved remains scarce. The cytokine patterns in maculopapular exanthema have a Th1 or Th0 pattern, according to whether the reaction is induced by a drug or a virus, respectively. Additionally, the involvement of CD4 T-lymphocytes with cytotoxic capabilities has been shown in the former. Different chemokines and their receptors are also involved in skin homing, such as CCL20, CCL27, CXCL9 or CXCL10, and oxidative stress can help exacerbate the symptoms. These findings may be very important for the diagnostic evaluation of these entities and for the development of new tools for diagnosis and treatment.

  5. 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.

  6. Molecular mechanisms of cryptococcal meningitis.

    PubMed

    Liu, Tong-Bao; Perlin, David S; Xue, Chaoyang

    2012-01-01

    Fungal meningitis is a serious disease caused by a fungal infection of the central nervous system (CNS) mostly in individuals with immune system deficiencies. Fungal meningitis is often fatal without proper treatment, and the mortality rate remains unacceptably high even with antifungal drug interventions. Currently, cryptococcal meningitis is the most common fungal meningitis in HIV-1/AIDS, and its disease mechanism has been extensively studied. The key steps for fungi to infect brain and cause meningitis after establishment of local infection are the dissemination of fungal cells to the bloodstream and invasion through the blood brain barrier to reach the CNS. In this review, we use cryptococcal CNS infection as an example to describe the current molecular understanding of fungal meningitis, including the establishment of the infection, dissemination, and brain invasion. Host and microbial factors that contribute to these infection steps are also discussed.

  7. Molecular mechanisms of RNA interference.

    PubMed

    Wilson, Ross C; Doudna, Jennifer A

    2013-01-01

    Small RNA molecules regulate eukaryotic gene expression during development and in response to stresses including viral infection. Specialized ribonucleases and RNA-binding proteins govern the production and action of small regulatory RNAs. After initial processing in the nucleus by Drosha, precursor microRNAs (pre-miRNAs) are transported to the cytoplasm, where Dicer cleavage generates mature microRNAs (miRNAs) and short interfering RNAs (siRNAs). These double-stranded products assemble with Argonaute proteins such that one strand is preferentially selected and used to guide sequence-specific silencing of complementary target mRNAs by endonucleolytic cleavage or translational repression. Molecular structures of Dicer and Argonaute proteins, and of RNA-bound complexes, have offered exciting insights into the mechanisms operating at the heart of RNA-silencing pathways.

  8. Molecular Mechanisms of Antisense Oligonucleotides.

    PubMed

    Crooke, Stanley T

    2017-04-01

    In 1987, when I became interested in the notion of antisense technology, I returned to my roots in RNA biochemistry and began work to understand how oligonucleotides behave in biological systems. Since 1989, my research has focused primarily on this topic, although I have been involved in most areas of research in antisense technology. I believe that the art of excellent science is to frame large important questions that are perhaps not immediately answerable with existing knowledge and methods, and then conceive a long-term (multiyear) research strategy that begins by answering the most pressing answerable questions on the path to the long-term goals. Then, a step-by-step research pathway that will address the strategic questions posed must be implemented, adjusting the plan as new things are learned. This is the approach we have taken at Ionis. Obviously, to create antisense technology, we have had to address a wide array of strategic questions, for example, the medicinal chemistry of oligonucleotides, manufacturing and analytical methods, pharmacokinetics and toxicology, as well as questions about the molecular pharmacology of antisense oligonucleotides (ASOs). Each of these endeavors has consumed nearly three decades of scientific effort, is still very much a work-in-progress, and has resulted in hundreds of publications. As a recipient of the Lifetime Achievement Award 2016 granted by the Oligonucleotide Therapeutic Society, in this note, my goal is to summarize the contributions of my group to the efforts to understand the molecular mechanisms of ASOs.

  9. Molecular Mechanisms of Antisense Oligonucleotides

    PubMed Central

    2017-01-01

    In 1987, when I became interested in the notion of antisense technology, I returned to my roots in RNA biochemistry and began work to understand how oligonucleotides behave in biological systems. Since 1989, my research has focused primarily on this topic, although I have been involved in most areas of research in antisense technology. I believe that the art of excellent science is to frame large important questions that are perhaps not immediately answerable with existing knowledge and methods, and then conceive a long-term (multiyear) research strategy that begins by answering the most pressing answerable questions on the path to the long-term goals. Then, a step-by-step research pathway that will address the strategic questions posed must be implemented, adjusting the plan as new things are learned. This is the approach we have taken at Ionis. Obviously, to create antisense technology, we have had to address a wide array of strategic questions, for example, the medicinal chemistry of oligonucleotides, manufacturing and analytical methods, pharmacokinetics and toxicology, as well as questions about the molecular pharmacology of antisense oligonucleotides (ASOs). Each of these endeavors has consumed nearly three decades of scientific effort, is still very much a work-in-progress, and has resulted in hundreds of publications. As a recipient of the Lifetime Achievement Award 2016 granted by the Oligonucleotide Therapeutic Society, in this note, my goal is to summarize the contributions of my group to the efforts to understand the molecular mechanisms of ASOs. PMID:28080221

  10. Cancer chemoprevention - selected molecular mechanisms.

    PubMed

    Walczak, Katarzyna; Marciniak, Sebastian; Rajtar, Grażyna

    2017-03-02

    The effect of diet on cancer formation and prevention of carcinogenesis has attracted considerable attention for years and is the subject of several studies. Some components of the daily diet, such as resveratrol, curcumin, genistein, gingerol, can significantly reduce the risk of cancer or affect the rate of tumor progression. Cancer chemoprevention assumes the use of natural or synthetic biologically active substances in order to prevent, inhibit or reverse the progression of cancer. There are many biologically active compounds in several natural products, i.e. garlic, ginger, soy, curcuma, tomatoes, cruciferous plants or green tea. Their chemopreventive activity is based on the inhibition of processes underlying carcinogenesis (inflammation, transformation and proliferation), but also affects the final phase of carcinogenesis - angiogenesis and metastasis. Despite the relatively low toxicity of chemopreventive agents, their molecular targets often coincide with the objectives of the currently used cancer therapies. The widespread use of chemopreventive agents may contribute to reduction of the rate of cancer incidence, and increase the effectiveness of conventional cancer therapies. In the present study, selected molecular mechanisms of the chemopreventive activity have been discussed, especially their involvement in the regulation of signal transduction, cell cycle regulation, apoptosis, metastasis and angiogenesis. The role of chemopreventive agents in the inflammatory process, the metabolism of xenobiotics and multidrug resistance has been also characterized.

  11. 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.

  12. A potential pathogenetic mechanism for multiple endocrine neoplasia type 2 syndromes involves ret-induced impairment of terminal differentiation of neuroepithelial cells.

    PubMed Central

    Califano, D; D'Alessio, A; Colucci-D'Amato, G L; De Vita, G; Monaco, C; Santelli, G; Di Fiore, P P; Vecchio, G; Fusco, A; Santoro, M; de Franciscis, V

    1996-01-01

    Germ-line missense mutations of the receptor-like tyrosine kinase ret are the causative genetic event of the multiple endocrine neoplasia (MEN) type 2A and type 2B syndromes and of the familial medullary thyroid carcinoma. We have used the rat pheochromocytoma cell line, PC12, as a model system to investigate the mechanism or mechanisms by which expression of activated ret alleles contributes to the neoplastic phenotype in neuroendocrine cells. Here we show that stable expression of ret mutants (MEN2A and MEN2B alleles) in PC12 cells causes a dramatic conversion from a round to a flat morphology, accompanied by the induction of genes belonging to the early as well as the delayed response to nerve growth factor. However, in the transfected PC12 cells, the continuous expression of neuronal specific genes is not associated with the suppression of cell proliferation. Furthermore, expression of ret mutants renders PC12 cells unresponsive to nerve growth factor-induced inhibition of proliferation. These results suggest that induction of an aberrant pattern of differentiation, accompanied by unresponsiveness to growth-inhibitory physiological signals, may be part of the mechanism of action of activated ret alleles in the pathogenesis of neuroendocrine tumors associated with MEN2 syndromes. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 6 PMID:8755580

  13. Molecular mechanisms of penile erection.

    PubMed

    Mas, Manuel

    2010-10-01

    The penis physiological states of flaccidity or erection, result from the contraction or relaxation, respectively, of smooth muscle cells in the corpora cavernosa (CSMCs). They result from the interaction of various inter and intracellular molecular signaling pathways. During the more usual state of flaccidity seems to predominate a tonic sympathetic activity, releasing noradrenaline (NA) and other agonists that generate contractile signals in the CSMCs, with the likely cooperation of endothelium-derived messengers. Through activation of membrane receptors in the CSMCs they raise the intracellular messengers inositol triphosphate (IP3) and diacylglycerol (DAG). This results in a transient increase in cytosolic calcium concentration [Ca2+]i that starts the contractile response which is further sustained by the parallel agonist-induced activation of a "calcium sensitizing" mechanism involving the RhoA/Rho-kinase pathway. Overexpression of the latter might contribute to several vascular disorders as hypertension, vasospasm or erectile dysfunction. On sexual stimulation the cavernous nerves release nitric oxide (NO) that starts the erectile response. They also release acetylcholine that stimulates the endothelium to generate a more sustained release of NO. NO diffuses into CSMCs and increases their intracellular levels of cyclic guanosin monophosphate (cGMP) which decreases [Ca2+]i and deactivates the calcium sensitizing mechanism, thus relaxing CSMCs. This main physiological pathway for CSMCs relaxation is helped by the cyclic adenosin monophosphate (cAMP) pathway activated by various intercellular messengers from neural or paracrine sources, including prostaglandins E (PGE). Different phosphodiesterase enzymes (PDEs) inactivate the cyclic nucleotides thereby limiting their erectogenic action. Indeed the pharmacological inhibition of PDEs, especially the cGMP-specific PDE5, greatly enhances the erectile responses. There are crosstalk mechanisms between the cGMP and c

  14. Molecular toxicity mechanism of nanosilver.

    PubMed

    McShan, Danielle; Ray, Paresh C; Yu, Hongtao

    2014-03-01

    Silver is an ancient antibiotic that has found many new uses due to its unique properties on the nanoscale. Due to its presence in many consumer products, the toxicity of nanosilver has become a hot topic. This review summarizes recent advances, particularly the molecular mechanism of nanosilver toxicity. The surface of nanosilver can easily be oxidized by O(2) and other molecules in the environmental and biological systems leading to the release of Ag(+), a known toxic ion. Therefore, nanosilver toxicity is closely related to the release of Ag(+). In fact, it is difficult to determine what portion of the toxicity is from the nano-form and what is from the ionic form. The surface oxidation rate is closely related to the nanosilver surface coating, coexisting molecules, especially thiol-containing compounds, lighting conditions, and the interaction of nanosilver with nucleic acids, lipid molecules, and proteins in a biological system. Nanosilver has been shown to penetrate the cell and become internalized. Thus, nanosilver often acts as a source of Ag(+) inside the cell. One of the main mechanisms of toxicity is that it causes oxidative stress through the generation of reactive oxygen species and causes damage to cellular components including DNA damage, activation of antioxidant enzymes, depletion of antioxidant molecules (e.g., glutathione), binding and disabling of proteins, and damage to the cell membrane. Several major questions remain to be answered: (1) the toxic contribution from the ionic form versus the nano-form; (2) key enzymes and signaling pathways responsible for the toxicity; and (3) effect of coexisting molecules on the toxicity and its relationship to surface coating.

  15. [Molecular mechanisms of antibody synthesis].

    PubMed

    Bartram, C R; Kleihauer, E

    1984-10-01

    Antibodies or immunoglobulins play a central part in the immune system. The basic unit of an antibody is composed of two identical light and two identical heavy chains; each chain contains two functionally and structurally distinct regions: an amino-terminal variable or antigen-binding site, and a carboxy-terminal constant region responsible for immunological effector functions. Thanks to recombinant DNA technology the paradox of a limited number of genes and a virtually unlimited capacity to generate specific antibodies has now been resolved at least in outline. Immunoglobulin chains are encoded in multiple gene segments of three unlinked gene families scattered along chromosomes 2 (kappa light chain), 14 (heavy chain) and 22 (lambda light chain). During B-cell differentiation these genes are assembled by somatic recombination mechanisms to form active genes. The enormous diversity generated by means of DNA rearrangements is supplemented by mutations somatically introduced into variable region sequences. The medical impact of these discoveries will be substantial. Possible applications include identification of B-cell precursors lacking conventional markes, a molecular classification of lymphomas and a precise distinction between monoclonal and polyclonal lymphoproliferative disorders.

  16. 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

  17. Molecular mechanisms of drug addiction.

    PubMed

    Nestler, Eric J

    2004-01-01

    Regulation of gene expression is one mechanism by which drugs of abuse can induce relatively long-lasting changes in the brain to cause a state of addiction. Here, we focus on two transcription factors, CREB (cAMP response element binding protein) and DeltaFosB, which contribute to drug-induced changes in gene expression. Both are activated in the nucleus accumbens, a major brain reward region, but mediate different aspects of the addicted state. CREB mediates a form of tolerance and dependence, which dampens an individual's sensitivity to subsequent drug exposure and contributes to a negative emotional state during early phases of withdrawal. In contrast, DeltaFosB mediates a state of relatively prolonged sensitization to drug exposure and may contribute to the increased drive and motivation for drug, which is a core symptom of addictive disorders. A major goal of current research is to identify the many target genes through which CREB and DeltaFosB mediate these behavioral states. In addition, future work needs to understand how CREB and DeltaFosB, acting in concert with numerous other drug-induced molecular changes in nucleus accumbens and many other brain regions, interact with one another to produce the complex behavioral phenotype that defines addiction.

  18. Molecular mechanisms of synaptic plasticity and memory.

    PubMed

    Elgersma, Y; Silva, A J

    1999-04-01

    To unravel the molecular and cellular bases of learning and memory is one of the most ambitious goals of modern science. The progress of recent years has not only brought us closer to understanding the molecular mechanisms underlying stable, long-lasting changes in synaptic strength, but it has also provided further evidence that these mechanisms are required for memory formation.

  19. Anencephaly: MRI findings and pathogenetic theories.

    PubMed

    Calzolari, Ferdinando; Gambi, Beatrice; Garani, Giampaolo; Tamisari, Lalla

    2004-12-01

    We describe the MRI appearances of an anencephalic newborn who survived for 13 h; particularities of this case are male gender and the absence of other associated malformations. Moreover, we discuss the pathogenetic theories of anencephaly, correlating MRI findings with embryological data. An exencephaly-anencephaly sequence due to amnion rupture is hypothesized.

  20. 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

  1. Molecular Mechanisms of Nitroarene Degradation

    DTIC Science & Technology

    2002-09-17

    nitrobenzene with the concomitant formation of catechol . The analogous enzyme system in Pseudomonas JS42 oxidizes 2-nitrotoluene to 3-methylcatechol and...2NTDO) system from Pseudomonas JS42. The enzymes catalyzing the initial oxidations of nitrobenzene and 2-nitrotoluene belong to a family of...color and the native molecular weight (35,000) showed that the active enzyme was a monomer. The N-terminal sequence of the recombinant reductase was

  2. Molecular Mechanisms and Apoptosis in Pdt

    NASA Astrophysics Data System (ADS)

    Krammer, Barbara; Verwanger, Thomas

    2010-04-01

    Photodynamic Therapy (PDT) is a successful new therapy for malignant and non-malignant diseases. It is based on the activation of a photosensitizing dye by visible light in the target tissue, followed by production of cytotoxic substances. The article gives a short overview on the field of PDT with main focus on molecular mechanisms and apoptosis. It includes photodynamic principles, clinical application and procedures, biological effects, molecular mechanisms of damage processing and apoptosis.

  3. Mechanisms of Multiphoton Dissociation of Molecular Ions.

    DTIC Science & Technology

    1981-04-30

    dissociation energy and are thus re- Thus, some small fraction of all ions produced in our moved from the beam by unimolecular decomposition. source probably...AD-A099 121 SRI INTERNATIONAL MENLO PARK CA F/6 7/5 MECHANISMS OF MULTIPHOTON DISSOCIATION OF MOLECULAR IONS, U) APR 81 M J COGGIOLA. J R PETERSON, P...Final Report MECHANISMS OF MULTIPHOTON DISSOCIATION OF MOLECULAR IONS By: Michael J. Coggiola, Project Leader James R. Peterson, Project Supervisor

  4. Molecular mechanisms of antibiotic resistance.

    PubMed

    Blair, Jessica M A; Webber, Mark A; Baylay, Alison J; Ogbolu, David O; Piddock, Laura J V

    2015-01-01

    Antibiotic-resistant bacteria that are difficult or impossible to treat are becoming increasingly common and are causing a global health crisis. Antibiotic resistance is encoded by several genes, many of which can transfer between bacteria. New resistance mechanisms are constantly being described, and new genes and vectors of transmission are identified on a regular basis. This article reviews recent advances in our understanding of the mechanisms by which bacteria are either intrinsically resistant or acquire resistance to antibiotics, including the prevention of access to drug targets, changes in the structure and protection of antibiotic targets and the direct modification or inactivation of antibiotics.

  5. 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.

  6. Molecular mechanisms of cancer pain.

    PubMed

    Mantyh, Patrick W; Clohisy, Denis R; Koltzenburg, Martin; Hunt, Steve P

    2002-03-01

    Pain is the most disruptive influence on the quality of life of cancer patients. Although significant advances are being made in cancer treatment and diagnosis, the basic neurobiology of cancer pain is poorly understood. New insights into these mechanisms are now arising from animal models, and have the potential to fundamentally change the way that cancer pain is controlled.

  7. Molecular Mechanisms of Bone Metastasis.

    PubMed

    Weidle, Ulrich H; Birzele, Fabian; Kollmorgen, Gwendlyn; Rüger, Rüdiger

    2016-01-01

    Metastasis of breast and prostate cancer as well as multiple myeloma to the bones represents a significant medical problem. We herein discuss the molecular basis of the creation of pre-metastatic niches, the process of bone metastasis and the phenomenon of tumor dormancy in the bone marrow as well as its regulation. We describe the identification and validation of genes mediating bone metastasis by use of pre-clinical models of bone metastasis. Additionally, we discuss the role of small integrin binding N-linked glycoproteins (SIBLINGS), the chemokine/chemokine receptor CXCL12/CXCR4 pathway and the role of micro RNAs (miRNAs) as mediators of bone metastasis. Finally, we summarize clinical achievements for the treatment of bone metastases.

  8. 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

  9. Molecular mechanisms underlying the Arabidopsis circadian clock.

    PubMed

    Nakamichi, Norihito

    2011-10-01

    A wide range of biological processes exhibit circadian rhythm, enabling plants to adapt to the environmental day-night cycle. This rhythm is generated by the so-called 'circadian clock'. Although a number of genetic approaches have identified >25 clock-associated genes involved in the Arabidopsis clock mechanism, the molecular functions of a large part of these genes are not known. Recent comprehensive studies have revealed the molecular functions of several key clock-associated proteins. This progress has provided mechanistic insights into how key clock-associated proteins are integrated, and may help in understanding the essence of the clock's molecular mechanisms.

  10. 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

  11. Molecular mechanisms in neurologic disorders.

    PubMed

    Cunniff, C

    2001-09-01

    Although many pediatric neurologic disorders, such as epilepsy and mental retardation, are the result of a combination of genetic and environmental factors, many others are the result of mutations of single genes. Most of these single gene traits are inherited in autosomal dominant, autosomal recessive, or X-linked fashion. The diversity of mutations that are responsible for these diseases produces variability in phenotypic expression. However, there are other important features of many neurologic disorders that cannot be explained by standard models of mendelian inheritance. This review focuses on recently described mechanisms, such as genomic imprinting, germline mosaicism, mitochondrial inheritance, and triplet repeat expansion. The diagnostic evaluation, prognostic significance, and recurrence risk for specific neurogenetic disorders is correlated with these underlying disease mechanisms.

  12. 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

  13. 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. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Molecular mechanisms of appetite regulation.

    PubMed

    Yu, Ji Hee; Kim, Min-Seon

    2012-12-01

    The prevalence of obesity has been rapidly increasing worldwide over the last several decades and has become a major health problem in developed countries. The brain, especially the hypothalamus, plays a key role in the control of food intake by sensing metabolic signals from peripheral organs and modulating feeding behaviors. To accomplish these important roles, the hypothalamus communicates with other brain areas such as the brainstem and reward-related limbic pathways. The adipocyte-derived hormone leptin and pancreatic β-cell-derived insulin inform adiposity to the hypothalamus. Gut hormones such as cholecystokinin, peptide YY, pancreatic polypeptide, glucagon-like peptide 1, and oxyntomodulin transfer satiety signals to the brain and ghrelin relays hunger signals. The endocannabinoid system and nutrients are also involved in the physiological regulation of food intake. In this article, we briefly review physiological mechanisms of appetite regulation.

  15. Molecular mechanisms of Ebola pathogenesis.

    PubMed

    Rivera, Andrea; Messaoudi, Ilhem

    2016-11-01

    Ebola viruses (EBOVs) and Marburg viruses (MARVs) are among the deadliest human viruses, as highlighted by the recent and widespread Ebola virus outbreak in West Africa, which was the largest and longest epidemic of Ebola virus disease (EVD) in history, resulting in significant loss of life and disruptions across multiple continents. Although the number of cases has nearly reached its nadir, a recent cluster of 5 cases in Guinea on March 17, 2016, has extended the enhanced surveillance period to June 15, 2016. New, enhanced 90-d surveillance windows replaced the 42-d surveillance window to ensure the rapid detection of new cases that may arise from a missed transmission chain, reintroduction from an animal reservoir, or more important, reemergence of the virus that has persisted in an EVD survivor. In this review, we summarize our current understanding of EBOV pathogenesis, describe vaccine and therapeutic candidates in clinical trials, and discuss mechanisms of viral persistence and long-term health sequelae for EVD survivors. © Society for Leukocyte Biology.

  16. Molecular mechanisms and regulation of iron transport.

    PubMed

    Chung, Jayong; Wessling-Resnick, Marianne

    2003-04-01

    Iron homeostasis is primarily maintained through regulation of its transport. This review summarizes recent discoveries in the field of iron transport that have shed light on the molecular mechanisms of dietary iron uptake, pathways for iron efflux to and between peripheral tissues, proteins implicated in organellar transport of iron (particularly the mitochondrion), and novel regulators that have been proposed to control iron assimilation. The transport of both transferrin-bound and nontransferrin-bound iron to peripheral tissues is discussed. Finally, the regulation of iron transport is also considered at the molecular level, with posttranscriptional, transcriptional, and posttranslational control mechanisms being reviewed.

  17. Modelling the molecular mechanisms of aging

    PubMed Central

    Mc Auley, Mark T.; Guimera, Alvaro Martinez; Hodgson, David; Mcdonald, Neil; Mooney, Kathleen M.; Morgan, Amy E.

    2017-01-01

    The aging process is driven at the cellular level by random molecular damage that slowly accumulates with age. Although cells possess mechanisms to repair or remove damage, they are not 100% efficient and their efficiency declines with age. There are many molecular mechanisms involved and exogenous factors such as stress also contribute to the aging process. The complexity of the aging process has stimulated the use of computational modelling in order to increase our understanding of the system, test hypotheses and make testable predictions. As many different mechanisms are involved, a wide range of models have been developed. This paper gives an overview of the types of models that have been developed, the range of tools used, modelling standards and discusses many specific examples of models that have been grouped according to the main mechanisms that they address. We conclude by discussing the opportunities and challenges for future modelling in this field. PMID:28096317

  18. Pathogenesis and Molecular Mechanisms of Zika Virus.

    PubMed

    Nayak, Shriddha; Lei, Jun; Pekosz, Andrew; Klein, Sabra; Burd, Irina

    2016-09-01

    Zika virus (ZIKV) is one of the most important emerging viruses of 2016. A developing outbreak in the Americas has demonstrated an association between the virus and serious clinical manifestations, such as Guillain-Barré syndrome in adults and congenital malformations in infants born to infected mothers. Pathogenesis and mechanisms of neurologic or immune disease by ZIKV have not been clearly delineated. However, several pathways have been described to explain viral involvement in brain and immune system as well as other organ systems such as eye, skin, and male and female reproductive tracts. ZIKV activates toll-like receptor 3 and several pathways have been described to explain the mechanisms at a molecular level. The mechanism of microcephaly has been more difficult to demonstrate experimentally, likely due to the multifactorial and complex nature of the phenotype. This article provides an overview of existing literature on ZIKV pathogenicity and possible molecular mechanisms of disease as outlined to date.

  19. Modelling the molecular mechanisms of aging.

    PubMed

    Mc Auley, Mark T; Guimera, Alvaro Martinez; Hodgson, David; Mcdonald, Neil; Mooney, Kathleen M; Morgan, Amy E; Proctor, Carole J

    2017-02-28

    The aging process is driven at the cellular level by random molecular damage that slowly accumulates with age. Although cells possess mechanisms to repair or remove damage, they are not 100% efficient and their efficiency declines with age. There are many molecular mechanisms involved and exogenous factors such as stress also contribute to the aging process. The complexity of the aging process has stimulated the use of computational modelling in order to increase our understanding of the system, test hypotheses and make testable predictions. As many different mechanisms are involved, a wide range of models have been developed. This paper gives an overview of the types of models that have been developed, the range of tools used, modelling standards and discusses many specific examples of models that have been grouped according to the main mechanisms that they address. We conclude by discussing the opportunities and challenges for future modelling in this field.

  20. Molecular Mechanisms of Bladder Outlet Obstruction in Transgenic Male Mice Overexpressing Aromatase (Cyp19a1)

    PubMed Central

    Lin, Wei; Rahman, Nafis A.; Lin, Jian; Zhang, Hua; Gou, Kemian; Yu, Wanpeng; Zhu, Dahai; Li, Ning; Huhtaniemi, Ilpo; Li, Xiangdong

    2011-01-01

    We investigated the etiology and molecular mechanisms of bladder outlet obstruction (BOO). Transgenic (Tg) male mice overexpressing aromatase (Cyp19a1) under the ubiquitin C promoter in the estrogen-susceptible C57Bl/6J genetic background (AROM+/6J) developed inguinal hernia by 2 months and severe BOO by 9 to 10 months, with 100% penetrance. These mice gradually developed uremia, renal failure, renal retention, and finally died. The BOO bladders were threefold larger than in age-matched wild-type (WT) males and were filled with urine on necropsy. Hypotrophic smooth muscle cells formed the thin detrusor urinae muscle, and collagen III accumulation contributed to the reduced compliance of the bladder. p-AKT and ERα expression were up-regulated and Pten expression was down-regulated in the BOO bladder urothelium. Expression of only ERα in the intradetrusor fibroblasts suggests a specific role of this estrogen receptor form in urothelial proliferation. Inactivation of Pten, which in turn activated the p-AKT pathway, was strictly related to the activation of the ERα pathway in the BOO bladders. Human relevance for these findings was provided by increased expression of p-AKT, PCNA, and ERα and decreased expression of PTEN in severe human BOO samples, compared with subnormal to mild samples. These findings clarify the involvement of estrogen excess and/or imbalance of the androgen/estrogen ratio in the molecular pathogenetic mechanisms of BOO and provide a novel lead into potential treatment strategies for BOO. PMID:21356374

  1. Molecular Mechanisms of Failure in Polymer Nanocomposites

    NASA Astrophysics Data System (ADS)

    Gersappe, Dilip

    2002-07-01

    Molecular dynamics simulations of polymers reinforced with nanoscopic filler particles reveal the mechanisms by which nanofillers improve the toughness of the material. We find that the mobility of the nanofiller particle, rather than its surface area, controls its ability to dissipate energy. Our results show similarities between the toughening mechanisms observed in polymer nanocomposites and those postulated for biological structural materials such as spider silk and abalone adhesive.

  2. General Anesthetics and Molecular Mechanisms of Unconsciousness

    PubMed Central

    Forman, Stuart A.; Chin, Victor A.

    2013-01-01

    General anesthetic agents are unique in clinical medicine, because they are the only drugs used to produce unconsciousness as a therapeutic goal. In contrast to older hypotheses that assumed all general anesthetics produce their central nervous system effects through a common mechanism, we outline evidence that general anesthesia represents a number of distinct pharmacological effects that are likely mediated by different neural circuits, and perhaps via different molecular targets. Within the context of this neurobiological framework, we review recent molecular pharmacological and transgenic animal studies. These studies reveal that different groups of general anesthetics, which can be discerned based on their clinical features, produce unconsciousness via distinct molecular targets and therefore via distinct mechanisms. We further postulate that different types of general anesthetics selectively disrupt different critical steps (perhaps in different neuronal circuits) in the processing of sensory information and memory that results in consciousness. PMID:18617817

  3. Disease resistance: Molecular mechanisms and biotechnological applications

    USDA-ARS?s Scientific Manuscript database

    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 ...

  4. Mechanisms and economy of molecular machines

    NASA Astrophysics Data System (ADS)

    Klumpp, Stefan

    2012-11-01

    Cells contain millions of biomolecules that function as molecular machines. This paper reviews aspects of the mechanisms of these machines (alternative pathways and cooperativity) as well as the economic principles of their use in cells. The focus is on the machines that process the genetic information, in particular RNA polymerases.

  5. Mechanical transduction mechanisms of RecA-like molecular motors.

    PubMed

    Liao, Jung-Chi

    2011-12-01

    A majority of ATP-dependent molecular motors are RecA-like proteins, performing diverse functions in biology. These RecA-like molecular motors consist of a highly conserved core containing the ATP-binding site. Here I examined how ATP binding within this core is coupled to the conformational changes of different RecA-like molecular motors. Conserved hydrogen bond networks and conformational changes revealed two major mechanical transduction mechanisms: (1) intra-domain conformational changes and (2) inter-domain conformational changes. The intra-domain mechanism has a significant hydrogen bond rearrangement within the domain containing the P-loop, causing relative motion between two parts of the protein. The inter-domain mechanism exhibits little conformational change in the P-loop domain. Instead, the major conformational change is observed between the P-loop domain and an adjacent domain or subunit containing the arginine finger. These differences in the mechanical transduction mechanisms may link to the underlying energy surface governing a Brownian ratchet or a power stroke.

  6. [Cellular and molecular mechanisms of memory].

    PubMed

    Laroche, Serge

    2010-01-01

    A defining characteristic of the brain is its remarkable capacity to undergo activity-dependent functional and morphological remodelling via mechanisms of plasticity that form the basis of our capacity to encode and retain memories. Today, it is generally accepted that one key neurobiological mechanism underlying the formation of memories reside in activity-driven modifications of synaptic strength and structural remodelling of neural networks activated during learning. The discovery and detailed report of the phenomenon generally known as long-term potentiation, a long-lasting activity-dependent form of synaptic strengthening, opened a new chapter in the study of the neurobiological substrate of memory in the vertebrate brain, and this form of synaptic plasticity has now become the dominant model in the search for the cellular bases of learning and memory. To date, the key events in the cellular and molecular mechanisms underlying synaptic plasticity and memory formation are starting to be identified. They require the activation of specific receptors and of several molecular cascades to convert extracellular signals into persistent functional changes in neuronal connectivity. Accumulating evidence suggests that the rapid activation of neuronal gene programs is a key mechanism underlying the enduring modification of neural networks required for the laying down of memory. The recent developments in the search for the cellular and molecular mechanisms of memory storage are reviewed.

  7. [Neonatal hyperbilirubinemia and molecular mechanisms of jaundice].

    PubMed

    Jirsa, M; Sticová, E

    2013-07-01

    The introductory summarises the classical path of heme degradation and classification of jaundice. Subsequently, a description of neonatal types of jaundice is given, known as Crigler Najjar, Gilberts, DubinJohnson and Rotor syndromes, emphasising the explanation of the molecular mechanisms of these metabolic disorders. Special attention is given to a recently discovered molecular mechanism of the Rotor syndrome. The mechanism is based on the inability of the liver to retrospectively uptake the conjugated bilirubin fraction primarily excreted into the blood, not bile. A reduced ability of the liver to uptake the conjugated bilirubin contributes to the development of hyperbilirubinemia in common disorders of the liver and bile ducts and to the toxicity of xenobiotics and drugs using transport proteins for conjugated bilirubin.

  8. Teratogenic effects of thalidomide: molecular mechanisms.

    PubMed

    Ito, Takumi; Ando, Hideki; Handa, Hiroshi

    2011-05-01

    Fifty years ago, prescription of the sedative thalidomide caused a worldwide epidemic of multiple birth defects. The drug is now used in the treatment of leprosy and multiple myeloma. However, its use is limited due to its potent teratogenic activity. The mechanism by which thalidomide causes limb malformations and other developmental defects is a long-standing question. Multiple hypotheses exist to explain the molecular mechanism of thalidomide action. Among them, theories involving oxidative stress and anti-angiogenesis have been widely supported. Nevertheless, until recently, the direct target of thalidomide remained elusive. We identified a thalidomide-binding protein, cereblon (CRBN), as a primary target for thalidomide teratogenicity. Our data suggest that thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting its ubiquitin ligase activity. In this review, we summarize the biology of thalidomide, focusing on the molecular mechanisms of its teratogenic effects. In addition, we discuss the questions still to be addressed.

  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. 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.

  11. 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.

  12. Geochemical Reaction Mechanism Discovery from Molecular Simulation

    DOE PAGES

    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

  13. 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

  14. 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

  15. Molecular mechanisms and clinical applications of angiogenesis

    PubMed Central

    Carmeliet, Peter; Jain, Rakesh K.

    2014-01-01

    Blood vessels deliver oxygen and nutrients to every part of the body, but also nourish diseases such as cancer. Over the past decade, our understanding of the molecular mechanisms of angiogenesis (blood vessel growth) has increased at an explosive rate and has led to the approval of anti-angiogenic drugs for cancer and eye diseases. So far, hundreds of thousands of patients have benefited from blockers of the angiogenic protein vascular endothelial growth factor, but limited efficacy and resistance remain outstanding problems. Recent preclinical and clinical studies have shown new molecular targets and principles, which may provide avenues for improving the therapeutic benefit from anti-angiogenic strategies. PMID:21593862

  16. Molecular mechanisms for proton transport in membranes.

    PubMed Central

    Nagle, J F; Morowitz, H J

    1978-01-01

    Likely mechanisms for proton transport through biomembranes are explored. The fundamental structural element is assumed to be continuous chains of hydrogen bonds formed from the protein side groups, and a molecular example is presented. From studies in ice, such chains are predicted to have low impedance and can function as proton wires. In addition, conformational changes in the protein may be linked to the proton conduction. If this possibility is allowed, a simple proton pump can be described that can be reversed into a molecular motor driven by an electrochemical potential across the membrane. PMID:272644

  17. Molecular Mechanisms of Neuroplasticity: An Expanding Universe.

    PubMed

    Gulyaeva, N V

    2017-03-01

    Biochemical processes in synapses and other neuronal compartments underlie neuroplasticity (functional and structural alterations in the brain enabling adaptation to the environment, learning, memory, as well as rehabilitation after brain injury). This basic molecular level of brain plasticity covers numerous specific proteins (enzymes, receptors, structural proteins, etc.) participating in many coordinated and interacting signal and metabolic processes, their modulation forming a molecular basis for brain plasticity. The articles in this issue are focused on different "hot points" in the research area of biochemical mechanisms supporting neuroplasticity.

  18. Kava hepatotoxicity: pathogenetic aspects and prospective considerations.

    PubMed

    Teschke, Rolf

    2010-10-01

    Kava hepatotoxicity is a well-defined herb-induced liver injury, caused by the use of commercial anxyolytic ethanolic and acetonic kava extracts, and of traditional recreational aqueous kava extracts. The aim of this review is to elucidate possible pathogenetic factors for the development of kava-induced liver injury, considering also confounding variables. In patients with liver disease in a causal relation to kava ± comedication, confounding factors include non-adherence to therapy recommendations and comedication consisting of synthetic and herbal drugs and dietary supplements including herbal ones and herbs-kava mixtures. Various possible pathogenetic factors have to be discussed and comprise metabolic interactions with exogenous compounds at the hepatic microsomal cytochrome P450 level; genetic enzyme deficiencies; toxic constituents and metabolites derived from the kava extract including impurities and adulterations; cyclooxygenase inhibition; P-glycoprotein alterations; hepatic glutathione depletion; solvents and solubilizers of the extracts; and kava raw material of poor quality. In particular, inappropriate kava plant parts and unsuitable kava cultivars may have been used sometimes for manufacturing the kava extracts instead of the rhizome of a noble cultivar of the kava plant (Piper methysticum G. Forster). In conclusion, kava hepatotoxicity occurred independently of the extraction medium used for the kava extracts and may primarily be attributed to daily overdose, prolonged treatment and to a few kava extract batches of poor quality; by improving kava quality and adherence to therapy recommendation under avoidance of comedication, liver injury by kava should be a preventable disease, at least to a major extent.

  19. Diuretics as pathogenetic treatment for heart failure

    PubMed Central

    Guglin, Maya

    2011-01-01

    Increased intracardiac filling pressure or congestion causes symptoms and leads to hospital admissions in patients with heart failure, regardless of their systolic function. A history of hospital admission, in turn, predicts further hospitalizations and morbidity, and a higher number of hospitalizations determine higher mortality. Congestion is therefore the driving force of the natural history of heart failure. Congestion is the syndrome shared by heart failure with preserved and reduced systolic function. These two conditions have almost identical morbidity, mortality, and survival because the outcomes are driven by congestion. A small difference in favor of heart failure with preserved systolic function comes from decreased ejection fraction and left ventricular remodeling which is only present in heart failure with decreased systolic function. The magnitude of this difference reflects the contribution of decreased systolic function and ventricular remodeling to the progression of heart failure. The only treatment available for congestion is fluid removal via diuretics, ultrafiltration, or dialysis. It is the only treatment that works equally well for heart failure with reduced and preserved systolic function because it affects congestion, the main pathogenetic feature of the disease. Diuretics are pathogenetic therapy for heart failure. PMID:21403798

  20. The molecular mechanism of plant gravitropism.

    PubMed

    Di, Wu; Linzhou, Huang; Jin, Gao; Yonghong, Wang

    2016-07-20

    Gravity is an important environmental factor that regulates plant growth and morphogenesis. In response to gravity stimulus, plants can set the optimum angle between the organs and the gravity vector. Plant gravitropism is divided into four sequential steps, including gravity perception, signal transduction, asymmetrical distribution of auxin, and organ curvature. In recent years, large numbers of mutants with defective gravitropism have been identified and genes involved in the regulation of gravitropism have been functionally characterized. In particular, progress has been achieved on elucidating the molecular mechanisms of gravity perception and asymmetrical distribution of auxin. As one of the most important strategies for plant to adapt environmental changes, gravitropism is also involved in the regulation of rice plant architecture and grain yield through modulating rice tiller angle. Therefore, the investigation of plant gravitropism not only contributes to decipher the regulatory mechanisms of plant growth and development, but also helps to guide the genetic improvement of crop architecture. However, the molecular mechanisms and regulatory network of gravitropism remain to be elusive. In this review, we focus on recent progress on elucidating molecular mechanisms underlying gravitropism and its involvement in regulating rice tiller angle, which is an important agronomic trait that determines rice plant architecture and thus grain yields.

  1. Regulation of renal potassium secretion: molecular mechanisms.

    PubMed

    Welling, Paul A

    2013-05-01

    A new understanding of renal potassium balance has emerged as the molecular underpinnings of potassium secretion have become illuminated, highlighting the key roles of apical potassium channels, renal outer medullary potassium channel (ROMK) and Big Potassium (BK), in the aldosterone-sensitive distal nephron and collecting duct. These channels act as the final-regulated components of the renal potassium secretory machinery. Their activity, number, and driving forces are precisely modulated to ensure potassium excretion matches dietary potassium intake. Recent identification of the underlying regulatory mechanisms at the molecular level provides a new appreciation of the physiology and reveals a molecular insight to explain the paradoxic actions of aldosterone on potassium secretion. Here, we review the current state of knowledge in the field.

  2. From mTOR to cognition: molecular and cellular mechanisms of cognitive impairments in tuberous sclerosis

    PubMed Central

    Ehninger, D.; de Vries, P. J.; Silva, A. J.

    2010-01-01

    Background Tuberous sclerosis (TSC) is a multi-system disorder caused by heterozygous mutations in the TSC1 or TSC2 gene and is often associated with neuropsychiatric symptoms, including intellectual disability, specific neuropsychological deficits, autism, other behavioural disorders and epilepsy. Method Here, we review evidence from animal models of TSC for the role of specific molecular and cellular processes in the pathogenesis of cognitive, developmental and epilepsy-related manifestations seen in the disorder. Results Recent evidence shows that, in animal models, disinhibited mTOR (mammalian target of rapamycin) signalling substantially contributes to neuropsychiatric phenotypes, including cognitive deficits and seizures. We discuss potential pathogenetic mechanisms involved in the cognitive phenotypes of TSC and present implications regarding mTOR inhibitor-based treatments for TSC-related neuropsychiatric features. Conclusions Results suggest that reversing the underlying molecular deficits of TSC with rapamycin or other mTOR inhibitors could result in clinically significant improvements of cognitive function and neurological symptoms, even if treatments are started in adulthood. PMID:19694899

  3. Pathogenetic determinants in Kawasaki disease: the haematological point of view.

    PubMed

    Del Principe, Domenico; Pietraforte, Donatella; Gambardella, Lucrezia; Marchesi, Alessandra; Tarissi de Jacobis, Isabella; Villani, Alberto; Malorni, Walter; Straface, Elisabetta

    2017-04-01

    Kawasaki disease is a multisystemic vasculitis that can result in coronary artery lesions. It predominantly affects young children and is characterized by prolonged fever, diffuse mucosal inflammation, indurative oedema of the hands and feet, a polymorphous skin rash and non-suppurative lymphadenopathy. Coronary artery involvement is the most important complication of Kawasaki disease and may cause significant coronary stenosis resulting in ischemic heart disease. The introduction of intravenous immunoglobulin decreases the incidence of coronary artery lesions to less than 5%. The etiopathogenesis of this disease remains unclear. Several lines of evidence suggest that an interplay between a microbial infection and a genetic predisposition could take place in the development of the disease. In this review, we summarize the state of the art of pathogenetic mechanisms of Kawasaki disease underscoring the relevance of haematological features as a novel field of investigation.

  4. Molecular mechanism for the umami taste synergism

    PubMed Central

    Zhang, Feng; Klebansky, Boris; Fine, Richard M.; Xu, Hong; Pronin, Alexey; Liu, Haitian; Tachdjian, Catherine; Li, Xiaodong

    2008-01-01

    Umami is one of the 5 basic taste qualities. The umami taste of L-glutamate can be drastically enhanced by 5′ ribonucleotides and the synergy is a hallmark of this taste quality. The umami taste receptor is a heteromeric complex of 2 class C G-protein-coupled receptors, T1R1 and T1R3. Here we elucidate the molecular mechanism of the synergy using chimeric T1R receptors, site-directed mutagenesis, and molecular modeling. We propose a cooperative ligand-binding model involving the Venus flytrap domain of T1R1, where L-glutamate binds close to the hinge region, and 5′ ribonucleotides bind to an adjacent site close to the opening of the flytrap to further stabilize the closed conformation. This unique mechanism may apply to other class C G-protein-coupled receptors. PMID:19104071

  5. Molecular mechanisms of UV-induced apoptosis.

    PubMed

    Kulms, D; Schwarz, T

    2000-10-01

    Sunburn cells, single standing cells with typical morphologic features occurring in UV-exposed skin, have been recognized as keratinocytes undergoing apoptosis following UV irradiation. Induction of apoptosis following UV exposure appears to be a protective mechanism, getting rid off severely damaged cells that bear the risk of malignant transformation. UV-mediated apoptosis is a highly complex process in which different molecular pathways are involved. These include DNA damage, activation of the tumor suppressor gene p53, triggering of cell death receptors either directly by UV or by autocrine release of death ligands, mitochondrial damage and cytochrome C release. Detailed knowledge about the interplay between these pathways will increase our understanding of photocarcinogenesis. This review briefly discusses recent findings concerning the molecular mechanisms underlying UV-induced apoptosis.

  6. Molecular mechanism of the sweet taste enhancers

    PubMed Central

    Zhang, Feng; Klebansky, Boris; Fine, Richard M.; Liu, Haitian; Xu, Hong; Servant, Guy; Zoller, Mark; Tachdjian, Catherine; Li, Xiaodong

    2010-01-01

    Positive allosteric modulators of the human sweet taste receptor have been developed as a new way of reducing dietary sugar intake. Besides their potential health benefit, the sweet taste enhancers are also valuable tool molecules to study the general mechanism of positive allosteric modulations of T1R taste receptors. Using chimeric receptors, mutagenesis, and molecular modeling, we reveal how these sweet enhancers work at the molecular level. Our data argue that the sweet enhancers follow a similar mechanism as the natural umami taste enhancer molecules. Whereas the sweeteners bind to the hinge region and induce the closure of the Venus flytrap domain of T1R2, the enhancers bind close to the opening and further stabilize the closed and active conformation of the receptor. PMID:20173095

  7. Molecular mechanism of the sweet taste enhancers.

    PubMed

    Zhang, Feng; Klebansky, Boris; Fine, Richard M; Liu, Haitian; Xu, Hong; Servant, Guy; Zoller, Mark; Tachdjian, Catherine; Li, Xiaodong

    2010-03-09

    Positive allosteric modulators of the human sweet taste receptor have been developed as a new way of reducing dietary sugar intake. Besides their potential health benefit, the sweet taste enhancers are also valuable tool molecules to study the general mechanism of positive allosteric modulations of T1R taste receptors. Using chimeric receptors, mutagenesis, and molecular modeling, we reveal how these sweet enhancers work at the molecular level. Our data argue that the sweet enhancers follow a similar mechanism as the natural umami taste enhancer molecules. Whereas the sweeteners bind to the hinge region and induce the closure of the Venus flytrap domain of T1R2, the enhancers bind close to the opening and further stabilize the closed and active conformation of the receptor.

  8. Molecular mechanism for the umami taste synergism.

    PubMed

    Zhang, Feng; Klebansky, Boris; Fine, Richard M; Xu, Hong; Pronin, Alexey; Liu, Haitian; Tachdjian, Catherine; Li, Xiaodong

    2008-12-30

    Umami is one of the 5 basic taste qualities. The umami taste of L-glutamate can be drastically enhanced by 5' ribonucleotides and the synergy is a hallmark of this taste quality. The umami taste receptor is a heteromeric complex of 2 class C G-protein-coupled receptors, T1R1 and T1R3. Here we elucidate the molecular mechanism of the synergy using chimeric T1R receptors, site-directed mutagenesis, and molecular modeling. We propose a cooperative ligand-binding model involving the Venus flytrap domain of T1R1, where L-glutamate binds close to the hinge region, and 5' ribonucleotides bind to an adjacent site close to the opening of the flytrap to further stabilize the closed conformation. This unique mechanism may apply to other class C G-protein-coupled receptors.

  9. 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.

  10. 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.

  11. 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.

  12. Cellular and Molecular Mechanisms of Pain

    PubMed Central

    Basbaum, Allan I.; Bautista, Diana M.; Scherrer, Grégory; Julius, David

    2009-01-01

    The nervous system detects and interprets a wide range of thermal and mechanical stimuli as well as environmental and endogenous chemical irritants. When intense, these stimuli generate acute pain, and in the setting of persistent injury, both peripheral and central nervous system components of the pain transmission pathway exhibit tremendous plasticity, enhancing pain signals and producing hypersensitivity. When plasticity facilitates protective reflexes, it can be beneficial, but when the changes persist, a chronic pain condition may result. Genetic, electrophysiological, and pharmacological studies are elucidating the molecular mechanisms that underlie detection, coding, and modulation of noxious stimuli that generate pain. PMID:19837031

  13. MOLECULAR MECHANISMS OF FEAR LEARNING AND MEMORY

    PubMed Central

    Johansen, Joshua P.; Cain, Christopher K.; Ostroff, Linnaea E.; LeDoux, Joseph E.

    2011-01-01

    Pavlovian fear conditioning is a useful behavioral paradigm for exploring the molecular mechanisms of learning and memory because a well-defined response to a specific environmental stimulus is produced through associative learning processes. Synaptic plasticity in the lateral nucleus of the amygdala (LA) underlies this form of associative learning. Here we summarize the molecular mechanisms that contribute to this synaptic plasticity in the context of auditory fear conditioning, the form of fear conditioning best understood at the molecular level. We discuss the neurotransmitter systems and signaling cascades that contribute to three phases of auditory fear conditioning: acquisition, consolidation, and reconsolidation. These studies suggest that multiple intracellular signaling pathways, including those triggered by activation of Hebbian processes and neuromodulatory receptors, interact to produce neural plasticity in the LA and behavioral fear conditioning. Together, this research illustrates the power of fear conditioning as a model system for characterizing the mechanisms of learning and memory in mammals, and potentially for understanding fear related disorders, such as PTSD and phobias. PMID:22036561

  14. Molecular Mechanisms of Right Ventricular Failure

    PubMed Central

    Reddy, Sushma; Bernstein, Daniel

    2015-01-01

    An abundance of data has provided insight into the mechanisms underlying the development of left ventricular (LV) hypertrophy and its progression to LV failure. In contrast, there is minimal data on the adaptation of the right ventricle (RV) to pressure and volume overload and the transition to RV failure. This is a critical clinical question, as the RV is uniquely at risk in many patients with repaired or palliated congenital heart disease and in those with pulmonary hypertension. Standard heart failure therapies have failed to improve function or survival in these patients, suggesting a divergence in the molecular mechanisms of RV vs. LV failure. Although, on the cellular level, the remodeling responses of the RV and LV to pressure overload are largely similar, there are several key differences: the stressed RV is more susceptible to oxidative stress, has a reduced angiogenic response, and is more likely to activate cell death pathways than the stressed LV. Together, these differences could explain the more rapid progression of the RV to failure vs. the LV. This review will highlight known molecular differences between the RV and LV responses to hemodynamic stress, the unique stressors on the RV associated with congenital heart disease, and the need to better understand these molecular mechanisms if we are to develop RV-specific heart failure therapeutics. PMID:26527692

  15. [Cellular and molecular mechanisms of memory].

    PubMed

    Laroche, S

    2001-01-01

    There has been nearly a century of interest in the idea that information is encoded in the brain as specific spatio-temporal patterns of activity in distributed networks and stored as changes in the efficacy of synaptic connections on neurons that are activated during learning. The discovery and detailed report of the phenomenon generally known as long-term potentiation opened a new chapter in the study of synaptic plasticity in the vertebrate brain, and this form of synaptic plasticity has now become the dominant model in the search for the cellular bases of learning and memory. To date, the key events in the cellular and molecular mechanisms underlying synaptic plasticity are starting to be identified. They require the activation of specific receptors and of several molecular cascades to convert extracellular signals into persistent functional changes in neuronal connectivity. Accumulating evidence suggests that the rapid activation of the genetic machinery is a key mechanism underlying the enduring modification of neural networks required for the laying down of memory. The recent developments in the search for the cellular and molecular mechanisms of memory storage are reviewed.

  16. Molecular mechanisms of optic axon guidance

    NASA Astrophysics Data System (ADS)

    Inatani, Masaru

    2005-12-01

    Axon guidance is one of the critical processes during vertebrate central nervous system (CNS) development. The optic nerve, which contains the axons of retinal ganglion cells, has been used as a powerful model to elucidate some of the mechanisms underlying axon guidance because it is easily manipulated experimentally, and its function is well understood. Recent molecular biology studies have revealed that numerous guidance molecules control the development of the visual pathway. This review introduces the molecular mechanisms involved in each critical step during optic axon guidance. Axonal projections to the optic disc are thought to depend on adhesion molecules and inhibitory extracellular matrices such as chondroitin sulfate. The formation of the head of the optic nerve and the optic chiasm require ligand-receptor interactions between netrin-1 and the deleted in colorectal cancer receptor, and Slit proteins and Robo receptors, respectively. The gradient distributions of ephrin ligands and Eph receptors are essential for correct ipsilateral projections at the optic chiasm and the topographic mapping of axons in the superior colliculus/optic tectum. The precise gradient is regulated by transcription factors determining the retinal dorso-ventral and nasal-temporal polarities. Moreover, the axon guidance activities by Slit and semaphorin 5A require the existence of heparan sulfate, which binds to numerous guidance molecules. Recent discoveries about the molecular mechanisms underlying optic nerve guidance will facilitate progress in CNS developmental biology and axon-regeneration therapy.

  17. 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.

  18. 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

  19. Gene fusions in soft tissue tumors: Recurrent and overlapping pathogenetic themes.

    PubMed

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

    2016-04-01

    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. © 2015 Wiley Periodicals, Inc.

  20. Molecular mechanisms for protein-encoded inheritance.

    PubMed

    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

    2009-09-01

    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.

  1. Molecular mechanisms of chemoresistance in gastric cancer

    PubMed Central

    Shi, Wen-Jia; Gao, Jin-Bo

    2016-01-01

    Gastric cancer is the fourth most common cancer and the second leading cause of cancer deaths worldwide. Chemotherapy is one of the major treatments for gastric cancer, but drug resistance limits the effectiveness of chemotherapy, which results in treatment failure. Resistance to chemotherapy can be present intrinsically before the administration of chemotherapy or it can develop during chemotherapy. The mechanisms of chemotherapy resistance in gastric cancer are complex and multifactorial. A variety of factors have been demonstrated to be involved in chemoresistance, including the reduced intracellular concentrations of drugs, alterations in drug targets, the dysregulation of cell survival and death signaling pathways, and interactions between cancer cells and the tumor microenvironment. This review focuses on the molecular mechanisms of chemoresistance in gastric cancer and on recent studies that have sought to overcome the underlying mechanisms of chemoresistance. PMID:27672425

  2. 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.

  3. Identifying Cellular and Molecular Mechanisms for Magnetosensation

    PubMed Central

    Clites, Benjamin L.; Pierce, Jonathan T.

    2017-01-01

    Diverse animals ranging from worms and insects to birds and turtles perf orm impressive journeys using the magnetic field of the earth as a cue. Although major cellular and molecular mechanisms for sensing mechanical and chemical cues have been elucidated over the past three decades, the mechanisms that animals use to sense magnetic fields remain largely mysterious. Here we survey progress on the search for magnetosensory neurons and magnetosensitive molecules important for animal behaviors. Emphasis is placed on magnetosensation in insects and birds, as well as on the magnetosensitive neuron pair AFD in the nematode Caenorhabditis elegans. We also review conventional criteria used to define animal magnetoreceptors and suggest how approaches used to identify receptors for other sensory modalities may be adapted for magnetoreceptors. Finally, we discuss prospects for under-utilized and novel approaches to identify the elusive magnetoreceptors in animals. PMID:28772099

  4. Molecular model with quantum mechanical bonding information.

    PubMed

    Bohórquez, Hugo J; Boyd, Russell J; Matta, Chérif F

    2011-11-17

    The molecular structure can be defined quantum mechanically thanks to the theory of atoms in molecules. Here, we report a new molecular model that reflects quantum mechanical properties of the chemical bonds. This graphical representation of molecules is based on the topology of the electron density at the critical points. The eigenvalues of the Hessian are used for depicting the critical points three-dimensionally. The bond path linking two atoms has a thickness that is proportional to the electron density at the bond critical point. The nuclei are represented according to the experimentally determined atomic radii. The resulting molecular structures are similar to the traditional ball and stick ones, with the difference that in this model each object included in the plot provides topological information about the atoms and bonding interactions. As a result, the character and intensity of any given interatomic interaction can be identified by visual inspection, including the noncovalent ones. Because similar bonding interactions have similar plots, this tool permits the visualization of chemical bond transferability, revealing the presence of functional groups in large molecules.

  5. 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

  6. Measuring the mechanical properties of molecular conformers

    NASA Astrophysics Data System (ADS)

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

    2015-09-01

    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.

  7. 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.

  8. 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.

  9. Measuring the mechanical properties of molecular conformers.

    PubMed

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

    2015-09-21

    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.

  10. Molecular Mechanisms Involved in Schwann Cell Plasticity

    PubMed Central

    Boerboom, Angélique; Dion, Valérie; Chariot, Alain; Franzen, Rachelle

    2017-01-01

    Schwann cell incredible plasticity is a hallmark of the utmost importance following nerve damage or in demyelinating neuropathies. After injury, Schwann cells undergo dedifferentiation before redifferentiating to promote nerve regeneration and complete functional recovery. This review updates and discusses the molecular mechanisms involved in the negative regulation of myelination as well as in the reprogramming of Schwann cells taking place early following nerve lesion to support repair. Significant advance has been made on signaling pathways and molecular components that regulate SC regenerative properties. These include for instance transcriptional regulators such as c-Jun or Notch, the MAPK and the Nrg1/ErbB2/3 pathways. This comprehensive overview ends with some therapeutical applications targeting factors that control Schwann cell plasticity and highlights the need to carefully modulate and balance this capacity to drive nerve repair. PMID:28261057

  11. [Molecular mechanism of idiopathic basal ganglia calcification].

    PubMed

    Wang, Cheng; Xu, Xuan; Li, Lulu; Wang, Tao; Zhang, Min; Shen, Lu; Tang, Beisha; Liu, Jingyu

    2015-08-01

    Idiopathic basal ganglia calcification (IBGC), also known as Fahr’s disease, is an inheritable neurodegenerative syndrome characterized by mineral deposits in the basal ganglia and other brain regions. Patients with IBGC are often accompanied with movement disorders, cognitive impairment as well as psychiatric abnormalities. So far, no therapeutic drug has been developed for the treatment of IBGC. Recently, genetic studies have identified several genes associated with IBGC, including SLC20A2, PDGFRB, PDGFB, ISG15 and XPR1. Loss-of-function mutations in these genes have been associated with disturbance in phosphate homeostasis in brain regions, the dysfunction of blood-brain barrier as well as enhanced IFN-α/β immunity. In this review, we summarize the latest research progress in the studies on molecular genetics of IBGC, and discuss the molecular mechanisms underlying the pathophysiology of mutations of different genes.

  12. Molecular mechanism of Endosulfan action in mammals.

    PubMed

    Sebastian, Robin; Raghavan, Sathees C

    2017-03-01

    Endosulfan is a broad-spectrum organochlorine pesticide, speculated to be detrimental to human health in areas of active exposure. However, the molecular insights to its mechanism of action remain poorly understood. In two recent studies, our group investigated the physiological and molecular aspects of endosulfan action using in vitro, ex vivo and in vivo analyses. The results showed that apart from reducing fertility levels in male animals, Endosulfan induced DNA damage that triggers compromised DNA damage response leading to undesirable processing of broken DNA ends. In this review, pesticide use especially of Endosulfan in the Indian scenario is summarized and the importance of our findings, especially the rationalized use of pesticides in the future, is emphasized.

  13. Modeling molecular mechanisms in the axon

    NASA Astrophysics Data System (ADS)

    de Rooij, R.; Miller, K. E.; Kuhl, E.

    2017-03-01

    Axons are living systems that display highly dynamic changes in stiffness, viscosity, and internal stress. However, the mechanistic origin of these phenomenological properties remains elusive. Here we establish a computational mechanics model that interprets cellular-level characteristics as emergent properties from molecular-level events. We create an axon model of discrete microtubules, which are connected to neighboring microtubules via discrete crosslinking mechanisms that obey a set of simple rules. We explore two types of mechanisms: passive and active crosslinking. Our passive and active simulations suggest that the stiffness and viscosity of the axon increase linearly with the crosslink density, and that both are highly sensitive to the crosslink detachment and reattachment times. Our model explains how active crosslinking with dynein motors generates internal stresses and actively drives axon elongation. We anticipate that our model will allow us to probe a wide variety of molecular phenomena—both in isolation and in interaction—to explore emergent cellular-level features under physiological and pathological conditions.

  14. Modeling molecular mechanisms in the axon

    NASA Astrophysics Data System (ADS)

    de Rooij, R.; Miller, K. E.; Kuhl, E.

    2016-12-01

    Axons are living systems that display highly dynamic changes in stiffness, viscosity, and internal stress. However, the mechanistic origin of these phenomenological properties remains elusive. Here we establish a computational mechanics model that interprets cellular-level characteristics as emergent properties from molecular-level events. We create an axon model of discrete microtubules, which are connected to neighboring microtubules via discrete crosslinking mechanisms that obey a set of simple rules. We explore two types of mechanisms: passive and active crosslinking. Our passive and active simulations suggest that the stiffness and viscosity of the axon increase linearly with the crosslink density, and that both are highly sensitive to the crosslink detachment and reattachment times. Our model explains how active crosslinking with dynein motors generates internal stresses and actively drives axon elongation. We anticipate that our model will allow us to probe a wide variety of molecular phenomena—both in isolation and in interaction—to explore emergent cellular-level features under physiological and pathological conditions.

  15. 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

  16. Pitfall in quantum mechanical/molecular mechanical molecular dynamics simulation of small solutes in solution.

    PubMed

    Hu, Hao; Liu, Haiyan

    2013-05-30

    Developments in computing hardware and algorithms have made direct molecular dynamics simulation with the combined quantum mechanical/molecular mechanical methods affordable for small solute molecules in solution, in which much improved accuracy can be obtained via the quantum mechanical treatment of the solute molecule and even sometimes water molecules in the first solvation shell. However, unlike the conventional molecular mechanical simulations of large molecules, e.g., proteins, in solutions, special care must be taken in the technical details of the simulation, including the thermostat of the solute/solvent system, so that the conformational space of the solute molecules can be properly sampled. We show here that the common setup for classical molecular mechanical molecular dynamics simulations, such as the Berendsen or single Nose-Hoover thermostat, and/or rigid water models could lead to pathological sampling of the solutes' conformation. In the extreme example of a methanol molecule in aqueous solution, improper and sluggish setups could generate two peaks in the distribution of the O-H bond length. We discuss the factors responsible for this somewhat unexpected result and evoke a simple and ancient technical fix-up to resolve this problem.

  17. Molecular mechanisms of metal hyperaccumulation in plants.

    PubMed

    Verbruggen, Nathalie; Hermans, Christian; Schat, Henk

    2009-03-01

    Metal hyperaccumulator plants accumulate and detoxify extraordinarily high concentrations of metal ions in their shoots. Metal hyperaccumulation is a fascinating phenomenon, which has interested scientists for over a century. Hyperaccumulators constitute an exceptional biological material for understanding mechanisms regulating plant metal homeostasis as well as plant adaptation to extreme metallic environments.Our understanding of metal hyperaccumulation physiology has recently increased as a result of the development of molecular tools. This review presents key aspects of our current understanding of plant metal – in particular cadmium (Cd),nickel (Ni) and zinc (Zn) – hyperaccumulation.

  18. Quantum Mechanical Studies of Molecular Hyperpolarizabilities.

    DTIC Science & Technology

    1980-04-30

    exponent , reflects the screening of an electron in a given orbital by the interior electrons in the atom or molecule. In practice, when studying...Basis sets have evolved over the years in molecular quantum mechanics until sets of orbital exponents for the different atoms composing the molecule have...and R. P. Hurst , J. Chem. Phys. 46, 2356 (1967); S. P. LickmannI and J. W. Moskowitz, J. Chem. Phys. 54, 3622 7T971). 26. T. H. Dunning, J. Chem. Phys

  19. Molecular Mechanisms of Inner Ear Development

    PubMed Central

    Wu, Doris K.; Kelley, Matthew W.

    2012-01-01

    The inner ear is a structurally complex vertebrate organ built to encode sound, motion, and orientation in space. Given its complexity, it is not surprising that inner ear dysfunction is a relatively common consequence of human genetic mutation. Studies in model organisms suggest that many genes currently known to be associated with human hearing impairment are active during embryogenesis. Hence, the study of inner ear development provides a rich context for understanding the functions of genes implicated in hearing loss. This chapter focuses on molecular mechanisms of inner ear development derived from studies of model organisms. PMID:22855724

  20. Molecular mechanisms of head and neck cancer.

    PubMed

    Deshpande, Amit M; Wong, David T

    2008-05-01

    Despite advances in understanding the underlying genetics, squamous cell carcinoma of the head and neck (SCCHN) remains a major health risk and one of the leading causes of mortality in the world. Current standards of treatment have significantly improved long-term survival rates of patients, but second tumors and metastases still remain the most frequent cause of high mortality in SCCHN patients. A better understanding of the underlying genetic mechanisms of SCCHN tumorigenesis will help in developing better diagnostics and, hence, better cures. In this article we will briefly outline the current state of diagnostics and treatment and our understanding of the molecular causes of SCCHN.

  1. Molecular mechanisms of astrocyte-induced synaptogenesis.

    PubMed

    Baldwin, Katherine T; Eroglu, Cagla

    2017-08-01

    Astrocytes are morphologically complex cells that perform a wide variety of critical functions in the brain. As a structurally and functionally integrated component of the synapse, astrocytes secrete proteins, lipids, and small molecules that bind neuronal receptors to promote synaptogenesis and regulate synaptic connectivity. Additionally, astrocytes are key players in circuit formation, instructing the formation of synapses between distinct classes of neurons. This review highlights recent publications on the topic of astrocyte-mediated synaptogenesis, with a focus on the molecular mechanisms through which astrocytes orchestrate the formation of synaptic circuits. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Molecular mechanics of silk nanostructures under varied mechanical loading.

    PubMed

    Bratzel, Graham; Buehler, Markus J

    2012-06-01

    Spider dragline silk is a self-assembling tunable protein composite fiber that rivals many engineering fibers in tensile strength, extensibility, and toughness, making it one of the most versatile biocompatible materials and most inviting for synthetic mimicry. While experimental studies have shown that the peptide sequence and molecular structure of silk have a direct influence on the stiffness, toughness, and failure strength of silk, few molecular-level analyses of the nanostructure of silk assemblies, in particular, under variations of genetic sequences have been reported. In this study, atomistic-level structures of wildtype as well as modified MaSp1 protein from the Nephila clavipes spider dragline silk sequences, obtained using an in silico approach based on replica exchange molecular dynamics and explicit water molecular dynamics, are subjected to simulated nanomechanical testing using different force-control loading conditions including stretch, pull-out, and peel. The authors have explored the effects of the poly-alanine length of the N. clavipes MaSp1 peptide sequence and identify differences in nanomechanical loading conditions on the behavior of a unit cell of 15 strands with 840-990 total residues used to represent a cross-linking β-sheet crystal node in the network within a fibril of the dragline silk thread. The specific loading condition used, representing concepts derived from the protein network connectivity at larger scales, have a significant effect on the mechanical behavior. Our analysis incorporates stretching, pull-out, and peel testing to connect biochemical features to mechanical behavior. The method used in this study could find broad applications in de novo design of silk-like tunable materials for an array of applications.

  3. Protein mechanics: how force regulates molecular function.

    PubMed

    Seifert, Christian; Gräter, Frauke

    2013-10-01

    Regulation of proteins is ubiquitous and vital for any organism. Protein activity can be altered chemically, by covalent modifications or non-covalent binding of co-factors. Mechanical forces are emerging as an additional way of regulating proteins, by inducing a conformational change or by partial unfolding. We review some advances in experimental and theoretical techniques to study protein allostery driven by mechanical forces, as opposed to the more conventional ligand driven allostery. In this respect, we discuss recent single molecule pulling experiments as they have substantially augmented our view on the protein allostery by mechanical signals in recent years. Finally, we present a computational analysis technique, Force Distribution Analysis, that we developed to reveal allosteric pathways in proteins. Any kind of external perturbation, being it ligand binding or mechanical stretching, can be viewed as an external force acting on the macromolecule, rendering force-based experimental or computational techniques, a very general approach to the mechanics involved in protein allostery. This unifying view might aid to decipher how complex allosteric protein machineries are regulated on the single molecular level. Copyright © 2013 Elsevier B.V. All rights reserved.

  4. Simulation with quantum mechanics/molecular mechanics for drug discovery.

    PubMed

    Barbault, Florent; Maurel, François

    2015-10-01

    Biological macromolecules, such as proteins or nucleic acids, are (still) molecules and thus they follow the same chemical rules that any simple molecule follows, even if their size generally renders accurate studies unhelpful. However, in the context of drug discovery, a detailed analysis of ligand association is required for understanding or predicting their interactions and hybrid quantum mechanics/molecular mechanics (QM/MM) computations are relevant tools to help elucidate this process. In this review, the authors explore the use of QM/MM for drug discovery. After a brief description of the molecular mechanics (MM) technique, the authors describe the subtractive and additive techniques for QM/MM computations. The authors then present several application cases in topics involved in drug discovery. QM/MM have been widely employed during the last decades to study chemical processes such as enzyme-inhibitor interactions. However, despite the enthusiasm around this area, plain MM simulations may be more meaningful than QM/MM. To obtain reliable results, the authors suggest fixing several keystone parameters according to the underlying chemistry of each studied system.

  5. Simulation with quantum mechanics/molecular mechanics for drug discovery.

    PubMed

    Barbault, Florent; Maurel, François

    2015-08-08

    Biological macromolecules, such as proteins or nucleic acids, are (still) molecules and thus they follow the same chemical rules that any simple molecule follows, even if their size generally renders accurate studies unhelpful. However, in the context of drug discovery, a detailed analysis of ligand association is required for understanding or predicting their interactions and hybrid quantum mechanics/molecular mechanics (QM/MM) computations are relevant tools to help elucidate this process. Areas covered: In this review, the authors explore the use of QM/MM for drug discovery. After a brief description of the molecular mechanics (MM) technique, the authors describe the subtractive and additive techniques for QM/MM computations. The authors then present several application cases in topics involved in drug discovery. Expert opinion: QM/MM have been widely employed during the last decades to study chemical processes such as enzyme-inhibitor interactions. However, despite the enthusiasm around this area, plain MM simulations may be more meaningful than QM/MM. To obtain reliable results, the authors suggest fixing several keystone parameters according to the underlying chemistry of each studied system.

  6. Molecular mechanics of tropocollagen-hydroxyapatite biomaterials

    NASA Astrophysics Data System (ADS)

    Dubey, Devendra Kumar

    Hard biomaterials such as bone, dentin, and nacre show remarkable mechanical performance and serve as inspiration for development of next generation of composite materials with high strength and toughness. Such materials have primarily an organic phase (e.g. tropocollagen (TC) or chitin) and a mineral phase (e.g. hydroxyapatite (HAP) or aragonite) arranged in a staggered arrangement at nanoscopic length scales. Interfacial interactions between the organic phases and the mineral phases and structural effects arising due to the staggered and hierarchical arrangements are identified to be the two most important determinants for high mechanical performance of such biomaterials. Effects of these determinants in such biomaterials are further intertwined with factors such as loading configuration, chemical environment, mineral crystal shape, and residue sequences in polymer chains. Atomistic modeling is a desired approach to investigate such sub nanoscale issues as experimental techniques for investigations at such small scale are still in nascent stage. For this purpose, explicit three dimensional (3D) molecular dynamics (MD) and ab initio MD simulations of quasi-static mechanical deformations of idealized Tropocollagen-Hydroxyapatite (TC-HAP) biomaterials with distinct interfacial arrangements and different loading configurations are performed. Focus is on developing insights into the molecular level mechanics of TC-HAP biomaterials at fundamental lengthscale with emphasis on interface phenomenon. Idealized TC-HAP atomistic models are analyzed for their mechanical strength and fracture failure behavior from the viewpoint of interfacial interactions between TC and HAP and associated molecular mechanisms. In particular, study focuses on developing an understanding of factors such as role of interfacial structural arrangement, hierarchical structure design, influence of water, effect of changes in HAP crystal shape, and mutations in TC molecule on the mechanical strength

  7. Multiscale Quantum Mechanics/Molecular Mechanics Simulations with Neural Networks.

    PubMed

    Shen, Lin; Wu, Jingheng; Yang, Weitao

    2016-10-11

    Molecular dynamics simulation with multiscale quantum mechanics/molecular mechanics (QM/MM) methods is a very powerful tool for understanding the mechanism of chemical and biological processes in solution or enzymes. However, its computational cost can be too high for many biochemical systems because of the large number of ab initio QM calculations. Semiempirical QM/MM simulations have much higher efficiency. Its accuracy can be improved with a correction to reach the ab initio QM/MM level. The computational cost on the ab initio calculation for the correction determines the efficiency. In this paper we developed a neural network method for QM/MM calculation as an extension of the neural-network representation reported by Behler and Parrinello. With this approach, the potential energy of any configuration along the reaction path for a given QM/MM system can be predicted at the ab initio QM/MM level based on the semiempirical QM/MM simulations. We further applied this method to three reactions in water to calculate the free energy changes. The free-energy profile obtained from the semiempirical QM/MM simulation is corrected to the ab initio QM/MM level with the potential energies predicted with the constructed neural network. The results are in excellent accordance with the reference data that are obtained from the ab initio QM/MM molecular dynamics simulation or corrected with direct ab initio QM/MM potential energies. Compared with the correction using direct ab initio QM/MM potential energies, our method shows a speed-up of 1 or 2 orders of magnitude. It demonstrates that the neural network method combined with the semiempirical QM/MM calculation can be an efficient and reliable strategy for chemical reaction simulations.

  8. Molecular mechanisms of glucocorticoid receptor signaling.

    PubMed

    Labeur, Marta; Holsboer, Florian

    2010-01-01

    This review highlights the most recent findings on the molecular mechanisms of the glucocorticoid receptor (GR). Most effects of glucocorticoids are mediated by the intracellular GR which is present in almost every tissue and controls transcriptional activation via direct and indirect mechanisms. Nevertheless the glu-cocorticoid responses are tissue -and gene- specific. GR associates selectively with corticosteroid ligands produced in the adrenal gland in response to changes of humoral homeostasis. Ligand interaction with GR promotes either GR binding to genomic glucocorticoid response elements, in turn modulating gene transcription, or interaction of GR monomers with other transcription factors activated by other signalling pathways leading to transrepression. The GR regulates a broad spectrum of physiological functions, including cell differentiation, metabolism and inflammatory responses. Thus, disruption or dysregulation of GR function will result in severe impairments in the maintenance of homeostasis and the control of adaptation to stress.

  9. [Molecular genetic mechanism of the kidney cancer].

    PubMed

    Nakaigawa, N; Yao, M; Kishida, T; Kubota, Y

    2001-01-01

    The oncogenic mechanisms of renal cell carcinoma(RCC) are becoming elucidated with recent advances in molecular biology. von Hipple-Lindau disease(VHL) tumor suppressor gene is mutated and inactivated frequently in clear cell type RCCs. The VHL protein forms a complex which shows a ubiquitin ligase activity. The lost of the ubiquitin ligase activity of VHL protein may be a key step for clear cell tumorigenesis. Papillary renal cell carcinomas are caused by activating mutation in the tyrosine kinase domain of the MET gene. This tumorigenic pathway is regulated by c-Src. Immunogene therapies have been started for the patients with advanced RCC. The information based on microarray and Serial Analysis of Gene Expression(SAGE) will provide novel diagnosis and therapy which focus on the tumorigenic mechanism of RCC in the near future.

  10. 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.

  11. Molecular mechanisms of phase change in locusts.

    PubMed

    Wang, Xianhui; Kang, Le

    2014-01-01

    Phase change in locusts is an ideal model for studying the genetic architectures and regulatory mechanisms associated with phenotypic plasticity. The recent development of genomic and metabolomic tools and resources has furthered our understanding of the molecular basis of phase change in locusts. Thousands of phase-related genes and metabolites have been highlighted using large-scale expressed sequence tags, microarrays, high-throughput transcriptomic sequences, or metabolomic approaches. However, only several key factors, including genes, metabolites, and pathways, have a critical role in phase transition in locusts. For example, CSP (chemosensory protein) and takeout genes, the dopamine pathway, protein kinase A, and carnitines were found to be involved in the regulation of behavioral phase change and gram-negative bacteria-binding proteins in prophylaxical disease resistance of gregarious locusts. Epigenetic mechanisms including small noncoding RNAs and DNA methylation have been implicated. We review these new advances in the molecular basis of phase change in locusts and present some challenges that need to be addressed.

  12. Understanding the molecular mechanisms of reprogramming

    SciTech Connect

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

    2016-05-06

    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. - Highlights: • Pioneer transcription factor activity underlies the initial steps of iPSC generation. • Reprogramming can occur by cis- and/or trans- reprogramming events. • Cis-reprogramming implies remodeling of the chromatin for enabling TF accessibility. • Trans-reprogramming encompasses direct binding of Tfs to their target gene promoters.

  13. 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

  14. Cellular and molecular mechanisms of dental nociception.

    PubMed

    Chung, G; Jung, S J; Oh, S B

    2013-11-01

    Due, in part, to the unique structure of the tooth, dental pain is initiated via distinct mechanisms. Here we review recent advances in our understanding of inflammatory tooth pain and discuss 3 hypotheses proposed to explain dentinal hypersensitivity: The first hypothesis, supported by functional expression of temperature-sensitive transient receptor potential channels, emphasizes the direct transduction of noxious temperatures by dental primary afferent neurons. The second hypothesis, known as hydrodynamic theory, attributes dental pain to fluid movement within dentinal tubules, and we discuss several candidate cellular mechanical transducers for the detection of fluid movement. The third hypothesis focuses on the potential sensory function of odontoblasts in the detection of thermal or mechanical stimuli, and we discuss the accumulating evidence that supports their excitability. We also briefly update on a novel strategy for local nociceptive anesthesia via nociceptive transducer molecules in dental primary afferents with the potential to specifically silence pain fibers during dental treatment. Further understanding of the molecular mechanisms of dental pain would greatly enhance the development of therapeutics that target dental pain.

  15. 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

  16. Quantum mechanics/molecular mechanics dual Hamiltonian free energy perturbation.

    PubMed

    Polyak, Iakov; Benighaus, Tobias; Boulanger, Eliot; Thiel, Walter

    2013-08-14

    The dual Hamiltonian free energy perturbation (DH-FEP) method is designed for accurate and efficient evaluation of the free energy profile of chemical reactions in quantum mechanical/molecular mechanical (QM/MM) calculations. In contrast to existing QM/MM FEP variants, the QM region is not kept frozen during sampling, but all degrees of freedom except for the reaction coordinate are sampled. In the DH-FEP scheme, the sampling is done by semiempirical QM/MM molecular dynamics (MD), while the perturbation energy differences are evaluated from high-level QM/MM single-point calculations at regular intervals, skipping a pre-defined number of MD sampling steps. After validating our method using an analytic model potential with an exactly known solution, we report a QM/MM DH-FEP study of the enzymatic reaction catalyzed by chorismate mutase. We suggest guidelines for QM/MM DH-FEP calculations and default values for the required computational parameters. In the case of chorismate mutase, we apply the DH-FEP approach in combination with a single one-dimensional reaction coordinate and with a two-dimensional collective coordinate (two individual distances), with superior results for the latter choice.

  17. Quantum mechanics/molecular mechanics dual Hamiltonian free energy perturbation

    NASA Astrophysics Data System (ADS)

    Polyak, Iakov; Benighaus, Tobias; Boulanger, Eliot; Thiel, Walter

    2013-08-01

    The dual Hamiltonian free energy perturbation (DH-FEP) method is designed for accurate and efficient evaluation of the free energy profile of chemical reactions in quantum mechanical/molecular mechanical (QM/MM) calculations. In contrast to existing QM/MM FEP variants, the QM region is not kept frozen during sampling, but all degrees of freedom except for the reaction coordinate are sampled. In the DH-FEP scheme, the sampling is done by semiempirical QM/MM molecular dynamics (MD), while the perturbation energy differences are evaluated from high-level QM/MM single-point calculations at regular intervals, skipping a pre-defined number of MD sampling steps. After validating our method using an analytic model potential with an exactly known solution, we report a QM/MM DH-FEP study of the enzymatic reaction catalyzed by chorismate mutase. We suggest guidelines for QM/MM DH-FEP calculations and default values for the required computational parameters. In the case of chorismate mutase, we apply the DH-FEP approach in combination with a single one-dimensional reaction coordinate and with a two-dimensional collective coordinate (two individual distances), with superior results for the latter choice.

  18. 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

  19. Molecular Mechanisms of Placebo Responses In Humans

    PubMed Central

    Peciña, Marta; Zubieta, Jon-Kar

    2014-01-01

    Endogenous opioid and non-opioid mechanisms [e.g. dopamine (DA), endocannabinoids (eCB)] have been implicated in the formation of placebo analgesic effects, with initial reports dating back three-decades. Besides the perspective that placebo effects confound randomized clinical trials (RCTs), the information so far acquired points to neurobiological systems that when activated by positive expectations and maintained through conditioning and reward learning are capable of inducing physiological changes that lead to the experience of analgesia and improvements in emotional state. Molecular neuroimaging techniques with positron emission tomography (PET) and the selective μ-opioid and D2/3 radiotracers [11C]carfentanil and [11C]raclopride have significantly contributed to our understanding of the neurobiological systems involved in the formation of placebo effects. This line of research has described neural and neurotransmitter networks implicated in placebo responses and provided the technical tools to examine inter-individual differences in the function of placebo responsive mechanisms, and potential surrogates (biomarkers). As a consequence, the formation of biological placebo effects is now being linked to the concept of resiliency mechanisms, partially determined by genetic factors, and uncovered by the cognitive emotional integration of the expectations created by the therapeutic environment and its maintenance through learning mechanisms. Further work needs to extend this research into clinical conditions where the rates of placebo responses are high and its neurobiological mechanisms have been largely unexplored (e.g. mood and anxiety disorders, persistent pain syndromes, or even Parkinson Disease and multiple sclerosis). The delineation of these processes within and across diseases would point to biological targets that have not been contemplated in traditional drug development. PMID:25510510

  20. Vibrational spectrum at a water surface: a hybrid quantum mechanics/molecular mechanics molecular dynamics approach.

    PubMed

    Ishiyama, Tatsuya; Takahashi, Hideaki; Morita, Akihiro

    2012-03-28

    A hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulation is applied to the calculation of surface orientational structure and vibrational spectrum (second-order nonlinear susceptibility) at the vapor/water interface for the first time. The surface orientational structure of the QM water molecules is consistent with the previous MD studies, and the calculated susceptibility reproduces the experimentally reported one, supporting the previous results using the classical force field MD simulation. The present QM/MM MD simulation also demonstrates that the positive sign of the imaginary part of the second-order nonlinear susceptibility at the lower hydrogen bonding OH frequency region originates not from individual molecular orientational structure, but from cooperative electronic structure through the hydrogen bonding network.

  1. Molecular Mechanisms of DNA Replication Checkpoint Activation

    PubMed Central

    Recolin, Bénédicte; van der Laan, Siem; Tsanov, Nikolay; Maiorano, Domenico

    2014-01-01

    The major challenge of the cell cycle is to deliver an intact, and fully duplicated, genetic material to the daughter cells. To this end, progression of DNA synthesis is monitored by a feedback mechanism known as replication checkpoint that is untimely linked to DNA replication. This signaling pathway ensures coordination of DNA synthesis with cell cycle progression. Failure to activate this checkpoint in response to perturbation of DNA synthesis (replication stress) results in forced cell division leading to chromosome fragmentation, aneuploidy, and genomic instability. In this review, we will describe current knowledge of the molecular determinants of the DNA replication checkpoint in eukaryotic cells and discuss a model of activation of this signaling pathway crucial for maintenance of genomic stability. PMID:24705291

  2. Molecular mechanisms for enhanced DNA vaccine immunogenicity

    PubMed Central

    Li, Lei; Petrovsky, Nikolai

    2016-01-01

    Summary In the two decades since their initial discovery, DNA vaccines technologies have come a long way. Unfortunately, when applied to human subjects inadequate immunogenicity is still the biggest challenge for practical DNA vaccine use. Many different strategies have been tested in preclinical models to address this problem, including novel plasmid vectors and codon optimization to enhance antigen expression, new gene transfection systems or electroporation to increase delivery efficiency, protein or live virus vector boosting regimens to maximise immune stimulation, and formulation of DNA vaccines with traditional or molecular adjuvants. Better understanding of the mechanisms of action of DNA vaccines has also enabled better use of the intrinsic host response to DNA to improve vaccine immunogenicity. This review summarizes recent advances in DNA vaccine technologies and related intracellular events and how these might impact on future directions of DNA vaccine development. PMID:26707950

  3. Molecular Mechanisms of Midfacial Developmental Defects

    PubMed Central

    Suzuki, Akiko; Sangani, Dhruvee R.; Ansari, Afreen; Iwata, Junichi

    2015-01-01

    The morphogenesis of midfacial processes requires the coordination of a variety of cellular functions of both mesenchymal and epithelial cells to develop complex structures. Any failure or delay in midfacial development as well as any abnormal fusion of the medial and lateral nasal and maxillary prominences will result in developmental defects in the midface with a varying degree of severity, including cleft, hypoplasia, and midline expansion. In spite of the advances in human genome sequencing technology, the causes of nearly 70 percent of all birth defects, which include midfacial development defects, remain unknown. Recent studies in animal models have highlighted the importance of specific signaling cascades and genetic-environmental interactions in the development of the midfacial region. This review will summarize the current understanding of the morphogenetic processes and molecular mechanisms underlying midfacial birth defects based on mouse models with midfacial developmental abnormalities. PMID:26562615

  4. Molecular mechanics calculations on muscarinic agonists

    NASA Astrophysics Data System (ADS)

    Kooijman, Huub; Kanters, Jan A.; Kroon, Jan

    1990-10-01

    Molecular mechanics calculations have been performed on the conformation freedom with respect to the torsion angles OCCN and COCC of acetylcholine, α( R-methylacetylcholine,β( S)-methylacetylcholine, α( R),β( S)-diemthylacetylcholine and muscarine, in order to obtain information about the active conformation and its interaction with the muscarinic cholinergic receptor. Muscarine has a rather flexible ring system, which makes modelling of the receptor site on the active conformation of this particular ligand a difficult problem. A common minimum for these compounds was found at {+ gauche,anti}), which is identified with the active conformation. However, OCCN angles of up to 120° can be accommodated in the receptor site. The reduced cholinergic activity of the α-methyl derivatives is probably caused by unfavourable interactions between the α-methyl group and the receptor site. The apparent contradictory high activity of the 2-acetyloxycyclopropylammonium ion can be explained by the distorted geometry of α substitution.

  5. Molecular and cellular mechanisms of heterotopic ossification.

    PubMed

    Ramirez, Diana M; Ramirez, Melissa R; Reginato, Anthony M; Medici, Damian

    2014-10-01

    Heterotopic ossification (HO) is a debilitating condition in which cartilage and bone forms in soft tissues such as muscle, tendon, and ligament causing immobility. This process is induced by inflammation associated with traumatic injury. In an extremely rare genetic disorder called fibrodysplasia ossificans progessiva (FOP), a combination of inflammation associated with minor soft tissue injuries and a hereditary genetic mutation causes massive HO that progressively worsens throughout the patients' lifetime leading to the formation of an ectopic skeleton. An activating mutation in the BMP type I receptor ALK2 has been shown to contribute to the heterotopic lesions in FOP patients, yet recent studies have shown that other events are required to stimulate HO including activation of sensory neurons, mast cell degranulation, lymphocyte infiltration, skeletal myocyte cell death, and endothelial-mesenchymal transition (EndMT). In this review, we discuss the recent evidence and mechanistic data that describe the cellular and molecular mechanisms that give rise to heterotopic bone.

  6. Molecular and cellular mechanisms of heterotopic ossification

    PubMed Central

    Ramirez, Diana M.; Ramirez, Melissa R.; Reginato, Anthony M.; Medici, Damian

    2015-01-01

    Summary Heterotopic ossification (HO) is a debilitating condition in which cartilage and bone forms in soft tissues such as muscle, tendon, and ligament causing immobility. This process is induced by inflammation associated with traumatic injury. In an extremely rare genetic disorder called fibrodysplasia ossificans progessiva (FOP), a combination of inflammation associated with minor soft tissue injuries and a hereditary genetic mutation causes massive HO that progressively worsens throughout the patients’ lifetime leading to the formation of an ectopic skeleton. An activating mutation in the BMP type I receptor ALK2 has been shown to contribute to the heterotopic lesions in FOP patients, yet recent studies have shown that other events are required to stimulate HO including activation of sensory neurons, mast cell degranulation, lymphocyte infiltration, skeletal myocyte cell death, and endothelial-mesenchymal transition (EndMT). In this review, we discuss the recent evidence and mechanistic data that describe the cellular and molecular mechanisms that give rise to heterotopic bone. PMID:24796520

  7. Sarcopenia: monitoring, molecular mechanisms, and physical intervention.

    PubMed

    Zembroń-Łacny, A; Dziubek, W; Rogowski, Ł; Skorupka, E; Dąbrowska, G

    2014-01-01

    According to European Working Group on Sarcopenia in Older People (EWGSOP) sarcopenia includes both a loss of muscle strength and a decline in functional quality in addition to the loss of muscle protein mass. In order to develop strategies to prevent and treat sarcopenia, the risk factors and causes of sarcopenia must be identified. Age-related muscle loss is characterized by the contribution of multiple factors, and there is growing evidence for a prominent role of low-grade chronic inflammation in sarcopenia. The elderly who are less physically active are more likely to have lower skeletal muscle mass and strength and are at increased risk of developing sarcopenia. Resistance training added to aerobic exercise or high-intensity interval training promote numerous changes in skeletal muscle, many of which may help to prevent or reverse sarcopenia. In this review, we provided current information on definition and monitoring, molecular mechanisms, and physical intervention to counteract sarcopenia.

  8. Molecular mechanisms of insulin resistance in diabetes.

    PubMed

    Soumaya, Kouidhi

    2012-01-01

    Molecular components of impaired insulin signaling pathway have emerged with growing interest to understand how the environment and genetic susceptibility combine to cause defects in this fundamental pathway that lead to insulin resistance. When insulin resistance is combined with beta-cell defects in glucose-stimulated insulin secretion, impaired glucose tolerance, hyperglycemia, or Type 2 diabetes can result. The most common underlying cause is obesity, although primary insulin resistance in normal-weight individuals is also possible. The adipose tissue releases free fatty acids that contribute to insulin resistance and also acts as a relevant endocrine organ producing mediators (adipokines) that can modulate insulin signalling. This chapter deals with the core elements promoting, insulin resistance, associated with impaired insulin signalling pathway and adipocyte dysfunction. A detailed understanding of these basic pathophysiological mechanisms is critical for the development of novel therapeutic strategies to treat diabetes.

  9. Molecular mechanisms for enhanced DNA vaccine immunogenicity.

    PubMed

    Li, Lei; Petrovsky, Nikolai

    2016-01-01

    In the two decades since their initial discovery, DNA vaccines technologies have come a long way. Unfortunately, when applied to human subjects inadequate immunogenicity is still the biggest challenge for practical DNA vaccine use. Many different strategies have been tested in preclinical models to address this problem, including novel plasmid vectors and codon optimization to enhance antigen expression, new gene transfection systems or electroporation to increase delivery efficiency, protein or live virus vector boosting regimens to maximise immune stimulation, and formulation of DNA vaccines with traditional or molecular adjuvants. Better understanding of the mechanisms of action of DNA vaccines has also enabled better use of the intrinsic host response to DNA to improve vaccine immunogenicity. This review summarizes recent advances in DNA vaccine technologies and related intracellular events and how these might impact on future directions of DNA vaccine development.

  10. 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

  11. Molecular mechanisms of pancreatitis: current opinion.

    PubMed

    Vonlaufen, Alain; Wilson, Jeremy S; Apte, Minoti V

    2008-09-01

    Pancreatitis (necroinflammation of the pancreas) has both acute and chronic manifestations. Gallstones are the major cause of acute pancreatitis, whereas alcohol is associated with acute as well as chronic forms of the disease. Cases of true idiopathic pancreatitis are steadily diminishing as more genetic causes of the disease are discovered. The pathogenesis of acute pancreatitis has been extensively investigated over the past four decades; the general current consensus is that the injury is initiated within pancreatic acinar cells subsequent to premature intracellular activation of digestive enzymes. Repeated attacks of acute pancreatitis have the potential to evolve into chronic disease characterized by fibrosis and loss of pancreatic function. Our knowledge of the process of scarring has advanced considerably with the isolation and study of pancreatic stellate cells, now established as the key cells in pancreatic fibrogenesis. The present review summarizes recent developments in the field particularly with respect to the progress made in unraveling the molecular mechanisms of acute and chronic pancreatic injury secondary to gallstones, alcohol and genetic factors. It is anticipated that continued research in the area will lead to the identification and characterization of molecular pathways that may be therapeutically targeted to prevent/inhibit the initiation and progression of the disease.

  12. Molecular Mechanisms Governing IL-24 Gene Expression

    PubMed Central

    Sahoo, Anupama

    2012-01-01

    Interleukin-24 (IL-24) belongs to the IL-10 family of cytokines and is well known for its tumor suppressor activity. This cytokine is released by both immune and nonimmune cells and acts on non-hematopoietic tissues such as skin, lung and reproductive tissues. Apart from its ubiquitous tumor suppressor function, IL-24 is also known to be involved in the immunopathology of autoimmune diseases like psoriasis and rheumatoid arthritis. Although the cellular sources and functions of IL-24 are being increasingly investigated, the molecular mechanisms of IL-24 gene expression at the levels of signal transduction, epigenetics and transcription factor binding are still unclear. Understanding the specific molecular events that regulate the production of IL-24 will help to answer the remaining questions that are important for the design of new strategies of immune intervention involving IL-24. Herein, we briefly review the signaling pathways and transcription factors that facilitate, induce, or repress production of this cytokine along with the cellular sources and functions of IL-24. PMID:22536164

  13. [EBOLA HEMORRHAGIC FEVER: DIAGNOSTICS, ETIOTROPIC AND PATHOGENETIC THERAPY, PREVENTION].

    PubMed

    Zhdanov, K V; Zakharenko, S M; Kovalenko, A N; Semenov, A V; Fisun, A Ya

    2015-01-01

    The data on diagnostics, etiotropic and pathogenetic therapy, prevention of Ebola hemorrhagic fever are presented including diagnostic algorithms for different clinical situations. Fundamentals of pathogenetic therapy are described. Various groups of medications used for antiviral therapy of conditions caused by Ebola virus are characterized. Experimental drugs at different stages of clinical studies are considered along with candidate vaccines being developed for the prevention of the disease.

  14. Exact and Optimal Quantum Mechanics/Molecular Mechanics Boundaries.

    PubMed

    Sun, Qiming; Chan, Garnet Kin-Lic

    2014-09-09

    Motivated by recent work in density matrix embedding theory, we define exact link orbitals that capture all quantum mechanical (QM) effects across arbitrary quantum mechanics/molecular mechanics (QM/MM) boundaries. Exact link orbitals are rigorously defined from the full QM solution, and their number is equal to the number of orbitals in the primary QM region. Truncating the exact set yields a smaller set of link orbitals optimal with respect to reproducing the primary region density matrix. We use the optimal link orbitals to obtain insight into the limits of QM/MM boundary treatments. We further analyze the popular general hybrid orbital (GHO) QM/MM boundary across a test suite of molecules. We find that GHOs are often good proxies for the most important optimal link orbital, although there is little detailed correlation between the detailed GHO composition and optimal link orbital valence weights. The optimal theory shows that anions and cations cannot be described by a single link orbital. However, expanding to include the second most important optimal link orbital in the boundary recovers an accurate description. The second optimal link orbital takes the chemically intuitive form of a donor or acceptor orbital for charge redistribution, suggesting that optimal link orbitals can be used as interpretative tools for electron transfer. We further find that two optimal link orbitals are also sufficient for boundaries that cut across double bonds. Finally, we suggest how to construct "approximately" optimal link orbitals for practical QM/MM calculations.

  15. Pathogenetic insights from the treatment of rheumatoid arthritis.

    PubMed

    McInnes, Iain B; Schett, Georg

    2017-06-10

    Rheumatoid arthritis is a chronic autoimmune disease that causes progressive articular damage, functional loss, and comorbidity. The development of effective biologics and small-molecule kinase inhibitors in the past two decades has substantially improved clinical outcomes. Just as understanding of pathogenesis has led in large part to the development of drugs, so have mode-of-action studies of these specific immune-targeted agents revealed which immune pathways drive articular inflammation and related comorbidities. Cytokine inhibitors have definitively proven a critical role for tumour necrosis factor α and interleukin 6 in disease pathogenesis and possibly also for granulocyte-macrophage colony-stimulating factor. More recently, clinical trials with Janus kinase (JAK) inhibitors have shown that cytokine receptors that signal through the JAK/STAT signalling pathway are important for disease, informing the pathogenetic function of additional cytokines (such as the interferons). Finally, successful use of costimulatory blockade and B-cell depletion in the clinic has revealed that the adaptive immune response and the downstream events initiated by these cells participate directly in synovial inflammation. Taken together, it becomes apparent that understanding the effects of specific immune interventions can elucidate definitive molecular or cellular nodes that are essential to maintain complex inflammatory networks that subserve diseases like rheumatoid arthritis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. The molecular mechanisms of oesophageal cancer.

    PubMed

    McCabe, M L; Dlamini, Z

    2005-07-01

    Apoptosis is a process of programmed cell death, which is as essential as cell growth, for the maintenance of homeostasis. When these processes loose integration such as cancer, then uncontrolled cell growth occurs. Cancer of the oesophagus ranks as the ninth most common malignancy in the world, and recent evidence shows that its incidence is increasing. Prognosis of this disease is poor, with an overall 5-year survival rate of less than 10%. Unraveling the mechanisms or developing animal models for oesophageal carcinoma have thus far not been successful. It is believed that oesophageal cancer has an intricate molecular mechanism of evading apoptosis by the down-regulation of Bax, up-regulation of Bcl-2, Bcl-xl and Survivin, mutation of p53 and alteration in Fas expression. A great deal of research has been performed in order to determine the key genes that initiate and promote the growth of oesophageal cancer. This review focuses on apoptosis and candidate genes linked to the development of oesophageal cancer, which it is hoped may provide diagnostic and therapeutic tools, and potential therapeutic strategies for the management of this carcinoma.

  17. Quantum mechanics/molecular mechanics restrained electrostatic potential fitting.

    PubMed

    Burger, Steven K; Schofield, Jeremy; Ayers, Paul W

    2013-12-05

    We present a quantum mechanics/molecular mechanics (QM/MM) method to evaluate the partial charges of amino acid residues for use in MM potentials based on their protein environment. For each residue of interest, the nearby residues are included in the QM system while the rest of the protein is treated at the MM level of theory. After a short structural optimization, the partial charges of the central residue are fit to the electrostatic potential using the restrained electrostatic potential (RESP) method. The resulting charges and electrostatic potential account for the individual environment of the residue, although they lack the transferable nature of library partial charges. To evaluate the quality of the QM/MM RESP charges, thermodynamic integration is used to measure the pKa shift of the aspartic acid residues in three different proteins, turkey egg lysozyme, beta-cryptogein, and Thioredoxin. Compared to the AMBER ff99SB library values, the QM/MM RESP charges show better agreement between the calculated and experimental pK(a) values for almost all of the residues considered.

  18. Multiresolution molecular mechanics: Implementation and efficiency

    NASA Astrophysics Data System (ADS)

    Biyikli, Emre; To, Albert C.

    2017-01-01

    Atomistic/continuum coupling methods combine accurate atomistic methods and efficient continuum methods to simulate the behavior of highly ordered crystalline systems. Coupled methods utilize the advantages of both approaches to simulate systems at a lower computational cost, while retaining the accuracy associated with atomistic methods. Many concurrent atomistic/continuum coupling methods have been proposed in the past; however, their true computational efficiency has not been demonstrated. The present work presents an efficient implementation of a concurrent coupling method called the Multiresolution Molecular Mechanics (MMM) for serial, parallel, and adaptive analysis. First, we present the features of the software implemented along with the associated technologies. The scalability of the software implementation is demonstrated, and the competing effects of multiscale modeling and parallelization are discussed. Then, the algorithms contributing to the efficiency of the software are presented. These include algorithms for eliminating latent ghost atoms from calculations and measurement-based dynamic balancing of parallel workload. The efficiency improvements made by these algorithms are demonstrated by benchmark tests. The efficiency of the software is found to be on par with LAMMPS, a state-of-the-art Molecular Dynamics (MD) simulation code, when performing full atomistic simulations. Speed-up of the MMM method is shown to be directly proportional to the reduction of the number of the atoms visited in force computation. Finally, an adaptive MMM analysis on a nanoindentation problem, containing over a million atoms, is performed, yielding an improvement of 6.3-8.5 times in efficiency, over the full atomistic MD method. For the first time, the efficiency of a concurrent atomistic/continuum coupling method is comprehensively investigated and demonstrated.

  19. Multiresolution molecular mechanics: Implementation and efficiency

    SciTech Connect

    Biyikli, Emre; To, Albert C.

    2017-01-01

    Atomistic/continuum coupling methods combine accurate atomistic methods and efficient continuum methods to simulate the behavior of highly ordered crystalline systems. Coupled methods utilize the advantages of both approaches to simulate systems at a lower computational cost, while retaining the accuracy associated with atomistic methods. Many concurrent atomistic/continuum coupling methods have been proposed in the past; however, their true computational efficiency has not been demonstrated. The present work presents an efficient implementation of a concurrent coupling method called the Multiresolution Molecular Mechanics (MMM) for serial, parallel, and adaptive analysis. First, we present the features of the software implemented along with the associated technologies. The scalability of the software implementation is demonstrated, and the competing effects of multiscale modeling and parallelization are discussed. Then, the algorithms contributing to the efficiency of the software are presented. These include algorithms for eliminating latent ghost atoms from calculations and measurement-based dynamic balancing of parallel workload. The efficiency improvements made by these algorithms are demonstrated by benchmark tests. The efficiency of the software is found to be on par with LAMMPS, a state-of-the-art Molecular Dynamics (MD) simulation code, when performing full atomistic simulations. Speed-up of the MMM method is shown to be directly proportional to the reduction of the number of the atoms visited in force computation. Finally, an adaptive MMM analysis on a nanoindentation problem, containing over a million atoms, is performed, yielding an improvement of 6.3–8.5 times in efficiency, over the full atomistic MD method. For the first time, the efficiency of a concurrent atomistic/continuum coupling method is comprehensively investigated and demonstrated.

  20. Molecular mechanisms regulating CD13-mediated adhesion

    PubMed Central

    Ghosh, Mallika; Gerber, Claire; Rahman, M Mamunur; Vernier, Kaitlyn M; Pereira, Flavia E; Subramani, Jaganathan; Caromile, Leslie A; Shapiro, Linda H

    2014-01-01

    CD13/Aminopeptidase N is a transmembrane metalloproteinase that is expressed in many tissues where it regulates various cellular functions. In inflammation, CD13 is expressed on myeloid cells, is up-regulated on endothelial cells at sites of inflammation and mediates monocyte/endothelial adhesion by homotypic interactions. In animal models the lack of CD13 alters the profiles of infiltrating inflammatory cells at sites of ischaemic injury. Here, we found that CD13 expression is enriched specifically on the pro-inflammatory subset of monocytes, suggesting that CD13 may regulate trafficking and function of specific subsets of immune cells. To further dissect the mechanisms regulating CD13-dependent trafficking we used the murine model of thioglycollate-induced sterile peritonitis. Peritoneal monocytes, macrophages and dendritic cells were significantly decreased in inflammatory exudates from global CD13KO animals when compared with wild-type controls. Furthermore, adoptive transfer of wild-type and CD13KO primary myeloid cells, or wild-type myeloid cells pre-treated with CD13-blocking antibodies into thioglycollate-challenged wild-type recipients demonstrated fewer CD13KO or treated cells in the lavage, suggesting that CD13 expression confers a competitive advantage in trafficking. Similarly, both wild-type and CD13KO cells were reduced in infiltrates in CD13KO recipients, confirming that both monocytic and endothelial CD13 contribute to trafficking. Finally, murine monocyte cell lines expressing mouse/human chimeric CD13 molecules demonstrated that the C-terminal domain of the protein mediates CD13 adhesion. Therefore, this work verifies that the altered inflammatory trafficking in CD13KO mice is the result of aberrant myeloid cell subset trafficking and further defines the molecular mechanisms underlying this regulation. PMID:24627994

  1. [Ontogenetic clock: molecular-genetic mechanism].

    PubMed

    Pisaruk, A V

    2010-01-01

    Proposed is a hypothesis of the mechanism providing for the cell to count out the time of life and to change (according to the set program) the expression of chromosomal genes in order to control ontogenesis ("ontogenetic clock"). This mechanism represents an autonomous molecular-genetic oscillator, which memorizes the number of cycles of own oscillations through cutting the terminal tau-segment of chrono-DNA using special restrictase. The latter is formed at this segment out of two sub-units (proteins) in each cycle of oscillator operation. These proteins are alternately synthesized on ribosomes, since each inhibits the synthesis of the other, thus ensuring successive binding of restrictase sub-units at the terminal segment of chrono-DNA and its single section in one cycle. In addition, each of these proteins is a repressor of own gene and activator of the gene of the other protein, thus ensuring efficiency and reliability of oscillator operation. The design of oscillator of ontogenetic clock is similar to that of circadian oscillator, but its frequency is not synchronized with the nature's physical rhythms and depends on body temperature. Therefore, it is physical rather than biological time that is measured. The chrono-DNA consists of short repetitive sequences of nucleotides (tau-segments) and temporal (regulatory) genes inserted over specified number of these segments. The shortening of chrono-DNA leads to uncovering the next gene and to its destruction by exonuclease. As a result, the synthesis of activator (repressor) stops and the expression of some chromosomal genes changes, initiating the next stage of ontogenesis.

  2. 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.

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

    DOE PAGES

    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

  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.

    PubMed

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

    2014-12-01

    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; and 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 NN heterolytic bond cleavage (kd~10(7) 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 three NONOates that have been investigated are subject to additional acid catalysis that occurs through di-protonation of the [NN(O)NO](-) group. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Molluscum-like cutaneous cryptococcosis: a histopathological and pathogenetic appraisal.

    PubMed

    Ramdial, Pratistadevi K; Calonje, Eduardo; Sing, Yetish; Chotey, Nivesh A; Aboobaker, Jamila

    2008-11-01

    Molluscum-like cutaneous cryptococcosis (MLCC) is characterized by hypopigmented or skin-colored papules with central umbilication. The histomorphological nuances of Cryptococcus neoformans infection that effect mimicry of molluscum contagiosum are undocumented. This histopathological study was undertaken to assess the histopathological characteristics of MLCC and to determine potential evolutionary pathogenetic mechanisms and significance. A 5-year retrospective re-appraisal of cutaneous cryptococcosis biopsies with a clinical molluscum-like appearance. All 26 specimens with a molluscum-like appearance showed a dome-shaped architecture with central invagination and dermal C. neoformans of varying size and shape, with capsular fragmentation; 20 biopsies had a paucireactive appearance and 6 combined granulomatous and paucireactive foci. Twenty, two and four biopsies showed transepidermal, transfollicular and combined transepidermal and transfollicular elimination (TFE) of fungi, necrobiotic collagen and debris through the central invagination, respectively. Subepithelial neutrophils and collagen necrobiosis were identified in 8 and 14 cases each, respectively. Varying sized and shaped yeasts, capsules of varying width, capsular fragmentation and collagen necrobiosis were ultrastructurally confirmed. Transepithelial and TFE of C. neoformans, necrobiotic collagen, inflammatory cells and cellular debris account for the morphological attributes of MLCC. The eliminatory process is a potential public health hazard, serving as a vehicle for C. neoformans transfer to the exterior.

  7. Cellular and molecular mechanisms of intestinal fibrosis

    PubMed Central

    Speca, Silvia; Giusti, Ilaria; Rieder, Florian; Latella, Giovanni

    2012-01-01

    Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in several different enteropathies, including inflammatory bowel disease. It develops through complex cell, extracellular matrix, cytokine and growth factor interactions. Distinct cell types are involved in intestinal fibrosis, such as resident mesenchymal cells (fibroblasts, myofibroblasts and smooth muscle cells) but also ECM-producing cells derived from epithelial and endothelial cells (through a process termed epithelial- and endothelial-mesenchymal transition), stellate cells, pericytes, local or bone marrow-derived stem cells. The most important soluble factors that regulate the activation of these cells include cytokines, chemokines, growth factors, components of the renin-angiotensin system, angiogenic factors, peroxisome proliferator-activated receptors, mammalian target of rapamycin, and products of oxidative stress. It soon becomes clear that although inflammation is responsible for triggering the onset of the fibrotic process, it only plays a minor role in the progression of this condition, as fibrosis may advance in a self-perpetuating fashion. Definition of the cellular and molecular mechanisms involved in intestinal fibrosis may provide the key to developing new therapeutic approaches. PMID:22851857

  8. Molecular mechanisms controlling legume autoregulation of nodulation

    PubMed Central

    Reid, Dugald E.; Ferguson, Brett J.; Hayashi, Satomi; Lin, Yu-Hsiang; Gresshoff, Peter M.

    2011-01-01

    Background High input costs and environmental pressures to reduce nitrogen use in agriculture have increased the competitive advantage of legume crops. The symbiotic relationship that legumes form with nitrogen-fixing soil bacteria in root nodules is central to this advantage. Scope Understanding how legume plants maintain control of nodulation to balance the nitrogen gains with their energy needs and developmental costs will assist in increasing their productivity and relative advantage. For this reason, the regulation of nodulation has been extensively studied since the first mutants exhibiting increased nodulation were isolated almost three decades ago. Conclusions Nodulation is regulated primarily via a systemic mechanism known as the autoregulation of nodulation (AON), which is controlled by a CLAVATA1-like receptor kinase. Multiple components sharing homology with the CLAVATA signalling pathway that maintains control of the shoot apical meristem in arabidopsis have now been identified in AON. This includes the recent identification of several CLE peptides capable of activating nodule inhibition responses, a low molecular weight shoot signal and a role for CLAVATA2 in AON. Efforts are now being focused on directly identifying the interactions of these components and to identify the form that long-distance transport molecules take. PMID:21856632

  9. Molecular mechanisms controlling legume autoregulation of nodulation.

    PubMed

    Reid, Dugald E; Ferguson, Brett J; Hayashi, Satomi; Lin, Yu-Hsiang; Gresshoff, Peter M

    2011-10-01

    High input costs and environmental pressures to reduce nitrogen use in agriculture have increased the competitive advantage of legume crops. The symbiotic relationship that legumes form with nitrogen-fixing soil bacteria in root nodules is central to this advantage. Understanding how legume plants maintain control of nodulation to balance the nitrogen gains with their energy needs and developmental costs will assist in increasing their productivity and relative advantage. For this reason, the regulation of nodulation has been extensively studied since the first mutants exhibiting increased nodulation were isolated almost three decades ago. Nodulation is regulated primarily via a systemic mechanism known as the autoregulation of nodulation (AON), which is controlled by a CLAVATA1-like receptor kinase. Multiple components sharing homology with the CLAVATA signalling pathway that maintains control of the shoot apical meristem in arabidopsis have now been identified in AON. This includes the recent identification of several CLE peptides capable of activating nodule inhibition responses, a low molecular weight shoot signal and a role for CLAVATA2 in AON. Efforts are now being focused on directly identifying the interactions of these components and to identify the form that long-distance transport molecules take.

  10. Molecular mechanisms of cadmium induced mutagenicity.

    PubMed

    Filipic, M; Fatur, T; Vudrag, M

    2006-02-01

    Cadmium is a human carcinogen of worldwide concern because it accumulates in the environment due to its extremely long half-life. Its compounds are classified as human carcinogens by several regulatory agencies. Cadmium affects cell proliferation, differentiation, apoptosis and other cellular activities and can cause numerous molecular lesions that would be relevant to carcinogenesis. For a long time cadmium has been considered as a non-genotoxic carcinogen, as it is only weakly mutagenic in bacterial and mammalian cell test systems. Recently, we presented evidence that when assayed in a test system, in which both intragenic and multilocus mutations can be detected, cadmium acts as a strong mutagen which induces predominantly multilocus deletions. In this review, we discuss two mechanisms that play an important role in cadmium mutagenicity: (i) induction of reactive oxygen species (ROS); and (ii) inhibition of DNA repair. Experimental evidence suggests that cadmium at low, for environmental exposure relevant concentrations, induces mutations by inducing oxidative DNA damage and that it decreases genetic stability by inhibiting the repair of endogenous and exogenous DNA lesions, which in turn increase the probability of mutations and consequently cancer initiation by this metal.

  11. Molecular mechanisms of failure in polymer nanocomposites

    NASA Astrophysics Data System (ADS)

    Gersappe, Dilip

    2003-03-01

    With the emergence of synthetic methods that can produce nanometer sized fillers, resulting in an enormous increase of surface area, polymers reinforced with nanoscale particles should offer the possibility of vastly improved properties. However, experimental evidence suggests that the paradigms that have been used for conventional filled composites cannot account for the behavior of nanocomposites. We examine the role that spherical nanofillers play on the rheology and the strength of the nanocomposite by using Molecular Dynamics simulations. We find that the enhancement of properties in nanocomposites is a result of the equivalence of time scales for motion for the polymer and the filler. We show that the mobility of the nanofiller, rather than its surface area, is key to the performance of the nanocomposite and that this mobility is a complex function of the size of the filler, the attraction between the polymer and the filler, and the thermodynamic state of the matrix. Our results show similarities between the toughening mechanisms in polymer nanocomposites and those postulated for naturally occurring biological materials which also contain nanoscaled assemblies, such as spider silk and abalone adhesive.

  12. 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

  13. Molecular mechanisms of asymmetric division in oocytes.

    PubMed

    Sun, Shao-Chen; Kim, Nam-Hyung

    2013-08-01

    In contrast to symmetric division in mitosis, mammalian oocyte maturation is characterized by asymmetric cell division that produces a large egg and a small polar body. The asymmetry results from oocyte polarization, which includes spindle positioning, migration, and cortical reorganization, and this process is critical for fertilization and the retention of maternal components for early embryo development. Although actin dynamics are involved in this process, the molecular mechanism underlying this remained unclear until the use of confocal microscopy and live cell imaging became widespread in recent years. Information obtained through a PubMed database search of all articles published in English between 2000 and 2012 that included the phrases "oocyte, actin, spindle migration," "oocyte, actin, polar body," or "oocyte, actin, asymmetric division" was reviewed. The actin nucleation factor actin-related protein 2/3 complex and its nucleation-promoting factors, formins and Spire, and regulators such as small GTPases, partitioning-defective/protein kinase C, Fyn, microRNAs, cis-Golgi apparatus components, myosin/myosin light-chain kinase, spindle stability regulators, and spindle assembly checkpoint regulators, play critical roles in asymmetric cell division in oocytes. This review summarizes recent findings on these actin-related regulators in mammalian oocyte asymmetric division and outlines a complete signaling pathway.

  14. Molecular mechanisms underlying chemical liver injury

    PubMed Central

    Gu, Xinsheng; Manautou, Jose E.

    2013-01-01

    The liver is necessary for survival. Its strategic localisation, blood flow and prominent role in the metabolism of xenobiotics render this organ particularly susceptible to injury by chemicals to which we are ubiquitously exposed. The pathogenesis of most chemical-induced liver injuries is initiated by the metabolic conversion of chemicals into reactive intermediate species, such as electrophilic compounds or free radicals, which can potentially alter the structure and function of cellular macromolecules. Many reactive intermediate species can produce oxidative stress, which can be equally detrimental to the cell. When protective defences are overwhelmed by excess toxicant insult, the effects of reactive intermediate species lead to deregulation of cell signalling pathways and dysfunction of biomolecules, leading to failure of target organelles and eventual cell death. A myriad of genetic factors determine the susceptibility of specific individuals to chemical-induced liver injury. Environmental factors, lifestyle choices and pre-existing pathological conditions also have roles in the pathogenesis of chemical liver injury. Research aimed at elucidating the molecular mechanism of the pathogenesis of chemical-induced liver diseases is fundamental for preventing or devising new modalities of treatment for liver injury by chemicals. PMID:22306029

  15. Spiers Memorial Lecture. Molecular mechanics and molecular electronics.

    PubMed

    Beckman, Robert; Beverly, Kris; Boukai, Akram; Bunimovich, Yuri; Choi, Jang Wook; DeIonno, Erica; Green, Johnny; Johnston-Halperin, Ezekiel; Luo, Yi; Sheriff, Bonnie; Stoddart, Fraser; Heath, James R

    2006-01-01

    We describe our research into building integrated molecular electronics circuitry for a diverse set of functions, and with a focus on the fundamental scientific issues that surround this project. In particular, we discuss experiments aimed at understanding the function of bistable rotaxane molecular electronic switches by correlating the switching kinetics and ground state thermodynamic properties of those switches in various environments, ranging from the solution phase to a Langmuir monolayer of the switching molecules sandwiched between two electrodes. We discuss various devices, low bit-density memory circuits, and ultra-high density memory circuits that utilize the electrochemical switching characteristics of these molecules in conjunction with novel patterning methods. We also discuss interconnect schemes that are capable of bridging the micrometre to submicrometre length scales of conventional patterning approaches to the near-molecular length scales of the ultra-dense memory circuits. Finally, we discuss some of the challenges associated with fabricated ultra-dense molecular electronic integrated circuits.

  16. Molecular mechanics models for tetracycline analogs.

    PubMed

    Aleksandrov, Alexey; Simonson, Thomas

    2009-01-30

    Tetracyclines (Tcs) are an important family of antibiotics that bind to the ribosome and several proteins. To model Tc interactions with protein and RNA, we have developed a molecular mechanics force field for 12 tetracyclines, consistent with the CHARMM force field. We considered each Tc variant in its zwitterionic tautomer, with and without a bound Mg(2+). We used structures from the Cambridge Crystallographic Data Base to identify the conformations likely to be present in solution and in biomolecular complexes. A conformational search by simulated annealing was undertaken, using the MM3 force field, for tetracycline, anhydrotetracycline, doxycycline, and tigecycline. Resulting, low-energy structures were optimized with an ab initio method. We found that Tc and its analogs all adopt an extended conformation in the zwitterionic tautomer and a twisted one in the neutral tautomer, and the zwitterionic-extended state is the most stable in solution. Intermolecular force field parameters were derived from a standard supermolecule approach: we considered the ab initio energies and geometries of a water molecule interacting with each Tc analog at several different positions. The final, rms deviation between the ab initio and force field energies, averaged over all forms, was 0.35 kcal/mol. Intramolecular parameters were adopted from either the standard CHARMM force field, the ab initio structure, or the earlier, plain Tc force field. The model reproduces the ab initio geometry and flexibility of each Tc. As tests, we describe MD and free energy simulations of a solvated complex between three Tcs and the Tet repressor protein. (c) 2008 Wiley Periodicals, Inc.

  17. Molecular Mechanisms of Iron Oxyhydroxide Biomineralization

    NASA Astrophysics Data System (ADS)

    Chan, C. S.; Fakra, S.; de Stasio, G.; Banfield, J. F.

    2003-12-01

    Neutrophilic iron-oxidizing microbes such as Gallionella and PV-1 (Emerson and Moyer, 1997) extrude polymers that become encrusted with iron oxides. Little is known about the identity of these polymers, their biological function and the roles they play in mineralization. To this end, we are investigating iron oxidizers in natural terrestrial iron-rich microbial mat communities, culturing and characterizing them in the laboratory and performing abiotic synthesis experiments based on the natural mineralization processes. Our sampling site is in a flooded former lead-zinc mine in Tennyson, WI, which is host to thick reddish-orange microbial mats. Scanning and transmission electron microscopy studies show that the mat is composed of iron oxide-covered stalks and sheaths (like those formed by Gallionella and Leptothrix spp.), as well as tangled masses of mineralized filaments. There is evidence of polymer influence on mineral phase and morphology in the form of extremely thin (few-unit cell wide), microns-long akaganeite (β -FeOOH) crystals at the center of these mineralized filaments. We are using synchrotron-based X-ray spectromicroscopy (PEEM-photoelectron emisson microscopy and STXM-scanning transmission X-ray microscopy), which has the ability to give chemical information on heterogenous samples at high spatial resolutions. Both PEEM and STXM show that these filaments contain polysaccharides, which are likely templating the akaganeite formation. Initial iron oxide synthesis experiments using model microbial polysaccharides support this hypothesis. Further synthesis and characterization by X-ray absorption and infrared spectroscopy methods is being performed in order to elucidate the molecular mechanisms of mineral nucleation and growth.

  18. [Molecular mechanisms underlying thermosensation in mammals].

    PubMed

    Sokabe, Takaaki; Tominaga, Makoto

    2009-07-01

    Sensing environmental temperature is one of the most important fundamental functions of the living things on the earth. Recently, it has been revealed that several members of the TRP ion channel super family are activated by temperature changes. A number of reports clearly demonstrate that thermal activation of these thermosensitive TRP channels contributes to various temperature-dependent responses in vivo, such as thermosensation, thermotaxis, and the regulation of cellular/tissue functions at physiological body temperature. Nine TRP channels have been reported to respond to a physiological range of temperatures in mammals. TRPV1 and TRPV2 expressed in nociceptive neurons are activated by heat (> 43 degrees C and > 52 degrees C, respectively), and TRPV1-null mice show defects in sensing noxious heat. TRPV3 and TRPV4 are predominantly expressed in skin keratinocytes rather than in sensory neurons, and the gene knock-out of each channel causes abnormal thermotaxis in vivo. TRPM8, which senses cold temperatures (< 27 degrees C), is expressed in nociceptive and non-nociceptive neurons and its loss impairs cold sensitivity. TRPA1 is expressed in nociceptive neurons and acts as a sensor for various harmful stimuli, whereas its responsiveness to noxious cold stimuli is controversial even after the analysis of mice lacking the channel. Other thermoTRPs, TRPM2, TRPM4, and TRPM5 are not expressed in sensory neurons, and are reportedly involved in several functions at physiological body temperatures including insulin secretion, taste sensation, and immune response. In this review, I summarize the molecular mechanisms of thermosensation in mammals by focusing on thermosensitive TRP channels.

  19. 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.

  20. 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 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; and 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.

  1. 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…

  2. Molecular Mechanisms of Par-4-Induced Apoptosis in Prostate Cancer

    DTIC Science & Technology

    2007-05-01

    Sambrook J, Fritsch EF, Maniatis T. (1989). Molecular Cloning : A Laboratory Manual (Cold Spring Harbor, New York: Cold Spring Harbor Laboratory...AD_________________ Award Number: W81XWH-05-1-0622 TITLE: Molecular Mechanisms of Par-4-Induced...SUBTITLE 5a. CONTRACT NUMBER Molecular Mechanisms of Par-4-Induced Apoptosis in Prostate Cancer 5b. GRANT NUMBER W81XWH-05-1-0622 5c. PROGRAM

  3. Identification of disease comorbidity through hidden molecular mechanisms

    PubMed Central

    Ko, Younhee; Cho, Minah; Lee, Jin-Sung; Kim, Jaebum

    2016-01-01

    Despite multiple diseases co-occur, their underlying common molecular mechanisms remain elusive. Identification of comorbid diseases by considering the interactions between molecular components is a key to understand the underlying disease mechanisms. Here, we developed a novel approach utilizing both common disease-causing genes and underlying molecular pathways to identify comorbid diseases. Our approach enables the analysis of common pathologies shared by comorbid diseases through molecular interaction networks. We found that the integration of direct genetic sharing and indirect high-level molecular associations revealed significantly strong consistency with known comorbid diseases. In addition, neoplasm-related diseases showed high comorbidity patterns within themselves as well as with other diseases, indicating severe complications. This study demonstrated that molecular pathway information could be used to discover disease comorbidity and hidden biological mechanism to understand pathogenesis and provide new insight on disease pathology. PMID:27991583

  4. 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.

  5. Quantum Mechanics/Molecular Mechanics Study of the Sialyltransferase Reaction Mechanism.

    PubMed

    Hamada, Yojiro; Kanematsu, Yusuke; Tachikawa, Masanori

    2016-10-11

    The sialyltransferase is an enzyme that transfers the sialic acid moiety from cytidine 5'-monophospho-N-acetyl-neuraminic acid (CMP-NeuAc) to the terminal position of glycans. To elucidate the catalytic mechanism of sialyltransferase, we explored the potential energy surface along the sialic acid transfer reaction coordinates by the hybrid quantum mechanics/molecular mechanics method on the basis of the crystal structure of sialyltransferase CstII. Our calculation demonstrated that CstII employed an SN1-like reaction mechanism via the formation of a short-lived oxocarbenium ion intermediate. The computational barrier height was 19.5 kcal/mol, which reasonably corresponded with the experimental reaction rate. We also found that two tyrosine residues (Tyr156 and Tyr162) played a vital role in stabilizing the intermediate and the transition states by quantum mechanical interaction with CMP.

  6. Cell and molecular mechanics of biological materials

    NASA Astrophysics Data System (ADS)

    Bao, G.; Suresh, S.

    2003-11-01

    Living cells can sense mechanical forces and convert them into biological responses. Similarly, biological and biochemical signals are known to influence the abilities of cells to sense, generate and bear mechanical forces. Studies into the mechanics of single cells, subcellular components and biological molecules have rapidly evolved during the past decade with significant implications for biotechnology and human health. This progress has been facilitated by new capabilities for measuring forces and displacements with piconewton and nanometre resolutions, respectively, and by improvements in bio-imaging. Details of mechanical, chemical and biological interactions in cells remain elusive. However, the mechanical deformation of proteins and nucleic acids may provide key insights for understanding the changes in cellular structure, response and function under force, and offer new opportunities for the diagnosis and treatment of disease. This review discusses some basic features of the deformation of single cells and biomolecules, and examines opportunities for further research.

  7. Molecular and cellular mechanisms of dendritic morphogenesis

    PubMed Central

    Gao, Fen-Biao

    2008-01-01

    Summary Dendrites exhibit unique cell-type specific branching patterns and targeting specificity that are critically important for neuronal function and connectivity. Recent evidence indicates that highly complex transcriptional regulatory networks dictate various aspects of dendritic outgrowth, branching, and routing. In addition to other intrinsic molecular pathways such as membrane protein trafficking, interactions between neighboring dendritic branches also contribute to the final specification of dendritic morphology. Nonredundant coverage by dendrites of same type of neurons, known as tiling, requires the actions of the Tricornered/Furry (Sax-1/Sax-2) signaling pathway. However, the dendrites of a neuron do not cross over each other, a process called self-avoidance that is mediated by Down’s syndrome cell adhesion molecule (Dscam). Those exciting findings have enhanced significantly our understanding of dendritic morphogenesis and revealed the magnitude of complexity in the underlying molecular regulatory networks. PMID:17933513

  8. Molecular Mechanism of Cyclodextrin Mediated Cholesterol Extraction

    PubMed Central

    López, Cesar A.; de Vries, Alex H.; Marrink, Siewert J.

    2011-01-01

    The depletion of cholesterol from membranes, mediated by β-cyclodextrin (β-CD) is well known and documented, but the molecular details of this process are largely unknown. Using molecular dynamics simulations, we have been able to study the CD mediated extraction of cholesterol from model membranes, in particular from a pure cholesterol monolayer, at atomic resolution. Our results show that efficient cholesterol extraction depends on the structural distribution of the CDs on the surface of the monolayer. With a suitably oriented dimer, cholesterol is extracted spontaneously on a nanosecond time scale. Additional free energy calculations reveal that the CDs have a strong affinity to bind to the membrane surface, and, by doing so, destabilize the local packing of cholesterol molecules making their extraction favorable. Our results have implications for the interpretation of experimental measurements, and may help in the rational design of efficient CD based nano-carriers. PMID:21455285

  9. 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.

  10. Glioblastoma: pathology, molecular mechanisms and markers.

    PubMed

    Aldape, Kenneth; Zadeh, Gelareh; Mansouri, Sheila; Reifenberger, Guido; von Deimling, Andreas

    2015-06-01

    Recent advances in genomic technology have led to a better understanding of key molecular alterations that underlie glioblastoma (GBM). The current WHO-based classification of GBM is mainly based on histologic features of the tumor, which frequently do not reflect the molecular differences that describe the diversity in the biology of these lesions. The current WHO definition of GBM relies on the presence of high-grade astrocytic neoplasm with the presence of either microvascular proliferation and/or tumor necrosis. High-throughput analyses have identified molecular subtypes and have led to progress in more accurate classification of GBM. These findings, in turn, would result in development of more effective patient stratification, targeted therapeutics, and prediction of patient outcome. While consensus has not been reached on the precise nature and means to sub-classify GBM, it is clear that IDH-mutant GBMs are clearly distinct from GBMs without IDH1/2 mutation with respect to molecular and clinical features, including prognosis. In addition, recent findings in pediatric GBMs regarding mutations in the histone H3F3A gene suggest that these tumors may represent a 3rd major category of GBM, separate from adult primary (IDH1/2 wt), and secondary (IDH1/2 mut) GBMs. In this review, we describe major clinically relevant genetic and epigenetic abnormalities in GBM-such as mutations in IDH1/2, EGFR, PDGFRA, and NF1 genes-altered methylation of MGMT gene promoter, and mutations in hTERT promoter. These markers may be incorporated into a more refined classification system and applied in more accurate clinical decision-making process. In addition, we focus on current understanding of the biologic heterogeneity and classification of GBM and highlight some of the molecular signatures and alterations that characterize GBMs as histologically defined. We raise the question whether IDH-wild type high grade astrocytomas without microvascular proliferation or necrosis might best be

  11. Mechanism of Spontaneous Oscillation Emerging from Collective Molecular Motors

    NASA Astrophysics Data System (ADS)

    Shimamoto, Yuta; Ishiwata, Shin'ichi

    2008-04-01

    Biological systems include a large number and various kinds of molecular machines. Individual molecular machines work stochastically, while the systems constructed of the ensembles of these machines exhibit dynamically-ordered phenomena, rather than a simple sum of individual parts. Here we focus on the spontaneous oscillatory contraction (SPOC) observed in the contractile system of muscle. From the mechanical measurements in the precursor state of SPOC, we discuss how the functions of individual molecular motors are autonomously regulated in the contractile system.

  12. 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)

  13. 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

  14. 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

  15. Etiologies and molecular mechanisms of communication disorders

    PubMed Central

    Smith, Shelley D.; Grigorenko, Elena; Willcutt, Erik; Pennington, Bruce F.; Olson, Richard K.; DeFries, John C.

    2010-01-01

    Quantitative behavioral genetic studies have made it clear that communication disorders such as reading disability (RD), language impairment (LI), and autism spectrum disorders (ASD) follow some basic principles: 1) Complex disorders have complex causes, in that each clinical disorder is influenced by a number of separate genes; and 2) at least some behaviorally related disorders are influenced by the same genes. Recent advances in molecular and statistical methods have confirmed these principles and are now leading to an understanding of the genes that may be involved in these disorders and how their disruption may affect the development of the brain. The prospect is that the genes involved in these disorders will define a network of interacting neurologic functions, and that perturbations of different elements of this network will produce susceptibilities for different disorders. Such knowledge would clarify the underlying deficits in these disorders and could lead to revised diagnostic conceptions. These goals are still in the future, however. Identifying the individual genes in such a network is painstaking, and there have been seemingly contradictory studies along the way. Improvements in study design and additional functional analysis of genes is gradually clarifying many of these issues. When combined with careful phenotypic studies, molecular genetic studies have the potential to refine the clinical definitions of communication disorders and influence their remediation. PMID:20814255

  16. Etiologies and molecular mechanisms of communication disorders.

    PubMed

    Smith, Shelley D; Grigorenko, Elena; Willcutt, Erik; Pennington, Bruce F; Olson, Richard K; DeFries, John C

    2010-09-01

    Quantitative behavioral genetic studies have made it clear that communication disorders such as reading disability, language impairment, and autism spectrum disorders follow some basic principles: (1) complex disorders have complex causes, in which each clinical disorder is influenced by a number of separate genes; and (2) at least some behaviorally related disorders are influenced by the same genes. Recent advances in molecular and statistical methods have confirmed these principles and are now leading to an understanding of the genes that may be involved in these disorders and how their disruption may affect the development of the brain. The prospect is that the genes involved in these disorders will define a network of interacting neurologic functions and that perturbations of different elements of this network will produce susceptibilities for different disorders. Such knowledge would clarify the underlying deficits in these disorders and could lead to revised diagnostic conceptions. However, these goals are still in the future. Identifying the individual genes in such a network is painstaking, and there have been seemingly contradictory studies along the way. Improvements in study design and additional functional analysis of genes are gradually clarifying many of these issues. When combined with careful phenotypic studies, molecular genetic studies have the potential to refine the clinical definitions of communication disorders and influence their remediation.

  17. [Molecular biology and immunopathogenetic mechanisms of sepsis].

    PubMed

    Průcha, M

    2009-01-01

    Sepsis, the systemic inflammatory response to infection, causes high mortality in patients in non-coronary units of intensive care. The most important characteristic of sepsis is the interaction between two subjects, the macro and the microorganism, associated with the dysfunction of innate and adaptive immunity. Sepsis is understood more as a dynamic syndrome characterized by many phenomenona which are often antagonistic. The inflammation, characterizing sepsis, does not act as a primary physiological compensatory mechanism and rather oscillates between the phase of hyperinflammatory response and anergy or immunoparalysis. The elucidation of the pathogenesis of sepsis is linked to the understanding of immunopathogenetic mechanisms, which characterize the interaction between the macro and microorganisms.

  18. 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

  19. 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.

  20. 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)

  1. Molecular Mechanisms of Action of BPA.

    PubMed

    Acconcia, Filippo; Pallottini, Valentina; Marino, Maria

    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.

  2. 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)

  3. 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

  4. Molecular mechanisms of polyploidy and hybrid vigor.

    PubMed

    Chen, Z Jeffrey

    2010-02-01

    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, which could lead to better use and exploitation of the increased biomass and yield in hybrids and allopolyploids for food, feed, and biofuels.

  5. 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

  6. Molecular mechanisms of synaptic remodeling in alcoholism.

    PubMed

    Kyzar, Evan J; Pandey, Subhash C

    2015-08-05

    Alcohol use and alcohol addiction represent dysfunctional brain circuits resulting from neuroadaptive changes during protracted alcohol exposure and its withdrawal. Alcohol exerts a potent effect on synaptic plasticity and dendritic spine formation in specific brain regions, providing a neuroanatomical substrate for the pathophysiology of alcoholism. Epigenetics has recently emerged as a critical regulator of gene expression and synaptic plasticity-related events in the brain. Alcohol exposure and withdrawal induce changes in crucial epigenetic processes in the emotional brain circuitry (amygdala) that may be relevant to the negative affective state defined as the "dark side" of addiction. Here, we review the literature concerning synaptic plasticity and epigenetics, with a particular focus on molecular events related to dendritic remodeling during alcohol abuse and alcoholism. Targeting epigenetic processes that modulate synaptic plasticity may yield novel treatments for alcoholism. Published by Elsevier Ireland Ltd.

  7. Molecular mechanics modeling of azobenzene-based photoswitches.

    PubMed

    Duchstein, Patrick; Neiss, Christian; Görling, Andreas; Zahn, Dirk

    2012-06-01

    We present an extension of the generalized amber force field to allow the modeling of azobenzenes by means of classical molecular mechanics. TD-DFT calculations were employed to derive different interaction models for 4-hydroxy-4'-methyl-azobenzene, including the ground (S(0)) and S(1) excited state. For both states, partial charges and the -N = N- torsion potentials were characterized. On this basis, we pave the way to large-scale model simulations involving azobenzene molecular switches. Using the example of an isolated molecule, the mechanics of cyclic switching processes are demonstrated by classical molecular dynamics simulations.

  8. 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.

  9. Molecular and biochemical mechanisms of preterm labour.

    PubMed

    Mohan, Aarthi R; Loudon, Jenifer A; Bennett, Phillip R

    2004-12-01

    Parturition involves the synchronization of myometrial activity and structural changes of the cervix, leading to regular co-ordinated uterine contractions and cervical dilatation and effacement. The biochemical events involved in parturition resemble an inflammatory reaction, with growing evidence pointing to a crucial role for pro-inflammatory cytokines and prostaglandins in labour. There is accumulating evidence that there are common mediators involved in the regulation of 'labour-associated proteins', and that, in each case, an increase or decrease in gene expression mediates changes in their concentration. It is possible, therefore, that targeting these common mediators may represent newer strategies for the prevention of preterm labour. Our aim is to review the mechanical and biochemical mechanisms that may be involved in the processes of term and preterm labour. Specifically, we will consider the regulation of some of the 'labour-associated proteins', chemotactic cytokines, prostaglandins and enzymes of the prostaglandin biosynthetic pathway and the oxytocin receptor.

  10. 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

  11. 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.

  12. Pathogenetic substantiation of extracorporeal detoxication in surgery.

    PubMed

    Ender, L A; Lekhtman, A M; Lobakov, A I

    1990-01-01

    The report is based on the results of treatment of 116 patients with severe purulent-destructive abdominal cavity diseases and 320 patients with liver failure due to bile ducts obturation. Along with surgical operations, methods of organism extracorporeal detoxication-haemosorption, exchange plasmapheresis, autoblood ultraviolet irradiation--were used in all patients either in isolation or in combination with each other. Toxical metabolites concentration, blood integral toxicity, peptids with mean molecular weight concentration, liver profile enzimes activity, lipid metabolism indices, general and liver haemodynamics and electroencephalogram were studied. On the basis of correlations between indices obtained by the method of extreme grouping factors-syndromes were formed, and then in accordance with a special program summary evaluation of detoxication was calculated in marks. A drop in lethality by 28.3% was ensured, as well as a drop in postoperatyonal liver failure by 51.4%.

  13. Cellular and molecular mechanisms of muscle atrophy

    PubMed Central

    Bonaldo, Paolo; Sandri, Marco

    2013-01-01

    Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are activated, and contractile proteins and organelles are removed, resulting in the shrinkage of muscle fibers. Excessive loss of muscle mass is associated with poor prognosis in several diseases, including myopathies and muscular dystrophies, as well as in systemic disorders such as cancer, diabetes, sepsis and heart failure. Muscle loss also occurs during aging. In this paper, we review the key mechanisms that regulate the turnover of contractile proteins and organelles in muscle tissue, and discuss how impairments in these mechanisms can contribute to muscle atrophy. We also discuss how protein synthesis and degradation are coordinately regulated by signaling pathways that are influenced by mechanical stress, physical activity, and the availability of nutrients and growth factors. Understanding how these pathways regulate muscle mass will provide new therapeutic targets for the prevention and treatment of muscle atrophy in metabolic and neuromuscular diseases. PMID:23268536

  14. 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.

  15. Fibromyalgia--from syndrome to disease. Overview of pathogenetic mechanisms.

    PubMed

    Henriksson, Karl G

    2003-05-01

    According to the classification criteria proposed by the American College of Rheumatology, fibromyalgia is a long-standing multifocal pain condition combined with generalised allodynia/hyperalgesia. It is the generalised allodynia/hyperalgesia that distinguishes fibromyalgia from other conditions with chronic musculoskeletal pain. Central sensitisation of nociceptive neurons in the dorsal horn due to activation of N-methyl-D-aspartic acid receptors and disinhibition of pain due to deficient function of the descending inhibitory system are probable pathogenic factors for allodynia/hyperalgesia. Furthermore, chronic pain is a chronic emotional and physical stressor. Chronic stress and chronic sleep disturbance are not specific for fibromyalgia but could be the causes of symptoms like fatigue, cognitive difficulties and other stress-related symptoms. They may also cause neuroendocrinological and immunological aberrations.

  16. Shaken baby syndrome: pathogenetic mechanism, clinical features and preventive aspects.

    PubMed

    Vitale, A; Vicedomini, D; Vega, G R; Greco, N; Messi, G

    2012-12-01

    The shaken baby syndrome (SBS) is an extremely serious form of child abuse and a leading cause of death and disability in childhood. The syndrome usually occurs in infants younger than 1 year when a parent or a care-giver tries to stop the baby from crying by vigorous manual shaking. The repetitive oscillations with rotational acceleration of the head can result in injuries of both vascular and neuronal structures. The most frequent injuries associated with SBS include encephalopathy, retinal hemorrhages, and subdural hemorrhage. Fractures of the vertebrae, long bones, and ribs may also be associated with the syndrome. Victims of abuse have various presenting signs and symptoms ranging from irritability, decreased responsiveness and lethargy to convulsions, and death. Diagnosis is often difficult because usually parents or caregivers not tell the truth about what has happened to their child and because usually there is no external evidence of trauma. However, the syndrome might be suspected if the information provided are vague or changing and when the child presents with retinal hemorrhages, subdural hematoma, or fractures that cannot be explained by accidental trauma or other medical conditions. Of infants who are victims of SBS, approximately 15% to 38% die and 30% are at risk of long-term neurologic sequelae, including cognitive and behavioural disturbances, motor and visual deficits, learning deficits and epilepsy. Parents and caregivers must be warned about the dangers of shaking infants.

  17. Pathogenetic mechanisms of fetal akinesia deformation sequence and oligohydramnios sequence.

    PubMed

    Rodríguez, J I; Palacios, J

    1991-09-01

    This article briefly reviews the participation of fetal compression, muscular weakness, and fetal akinesia in the genesis of the anomalies found in fetal akinesia deformation sequence (FADS) and oligohydramnios sequence (OS). Both sequences share phenotypic manifestations, such as arthrogryposis, short umbilical cord, and lung hypoplasia, in relation to decreased intrauterine fetal motility. Other characteristic manifestations found in OS, such as Potter face, and redundant skin, are produced by fetal compression. On the other hand, growth retardation, craniofacial anomalies, micrognathia, long bone hypoplasia, and polyhydramnios found in FADS could be related to intrauterine muscular weakness.

  18. Regulatory and pathogenetic mechanisms of autoantibodies in SLE.

    PubMed

    Radic, Marko; Herrmann, Martin; van der Vlag, Johan; Rekvig, Ole Petter

    2011-08-01

    In the 53 years since the discovery of anti-DNA autoantibodies in lupus [1, 2, 3] , recalcitrant questions have been pondered and possible answers have been debated. The discovery of anti-DNA autoantibodies presented many puzzles: How is immunological tolerance to native B-form DNA broken? What elicits characteristic systemic lupus erythematosus (SLE) autoantibodies? Which of the diverse anti-nuclear reactivities are pathogenic? What is the role of autoantibodies in the clinical presentation of disease? How do genetic predisposition and environmental triggers contribute to SLE? These questions were brought into focus by Professor David Stollar in an introductory presentation to an intense, three-day meeting set among the rugged and inspiring scenery of the Norwegian arctic coastline (the Scientific Program is included as supplemental File 1). Other participants presented and discussed topics directed to understanding the origin and clinico-pathological impact of autoantibodies to chromatin and phospholipid antigens. In the following, several aspects of the workshop are discussed.

  19. 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

  20. Ultraviolet radiation and skin cancer: molecular mechanisms.

    PubMed

    Hussein, Mahmoud R

    2005-03-01

    Every living organism on the surface of the earth is exposed to the ultraviolet (UV) fraction of the sunlight. This electromagnetic energy has both life-giving and life-endangering effects. UV radiation can damage DNA and thus mutagenize several genes involved in the development of the skin cancer. The presence of typical signature of UV-induced mutations on these genes indicates that the ultraviolet-B part of sunlight is responsible for the evolution of cutaneous carcinogenesis. During this process, variable alterations of the oncogenic, tumor-suppressive, and cell-cycle control signaling pathways occur. These pathways include (a) mutated PTCH (in the mitogenic Sonic Hedgehog pathway) and mutated p53 tumor-suppressor gene in basal cell carcinomas, (b) an activated mitogenic ras pathway and mutated p53 in squamous cell carcinomas, and (c) an activated ras pathway, inactive p16, and p53 tumor suppressors in melanomas. This review presents background information about the skin optics, UV radiation, and molecular events involved in photocarcinogenesis.

  1. Dissecting the Molecular Mechanisms of Electrotactic Effects

    PubMed Central

    Bonazzi, Daria; Minc, Nicolas

    2014-01-01

    Significance: Steady electric fields (EFs) surround cells and tissues in vivo and may regulate cellular behavior during development, wound healing, or tissue regeneration. Application of exogenous EFs of similar magnitude as those found in vivo can direct migration, growth, and division in most cell types, ranging from bacteria to mammalian cells. These EF effects have therapeutic potential, for instance, in accelerating wound healing or improving nerve repair. EFs are thought to signal through the plasma membrane to locally activate or recruit components of the cytoskeleton and the polarity machinery. How EFs might function to steer polarity is, however, poorly understood at a molecular level. Recent Advances: Here, we review recent work introducing genetically tractable systems, such as yeast and Dictyostelium cells, that begin to identify proteins and pathways involved in this response both at the level of ion transport at the membrane and at the level of cytoskeleton regulation. Critical Issues: These studies highlight the complexity of these EF effects and bring important novel views on core polarity regulation. Future Directions: Future work pursuing initial screening in model organisms should generate broad mechanistic understanding of electrotactic effects. PMID:24761354

  2. Molecular mechanisms of male germ cell differentiation.

    PubMed

    Hecht, N B

    1998-07-01

    During spermatogenesis, diploid stem cells differentiate, undergo meiosis, and transform into haploid spermatozoa. As this precisely timed series of events proceeds, chromosomal ploidy is reduced and the nucleosomes of the chromatin are replaced by a transcriptionally quiescent protamine-containing nucleus. The premature termination of transcription during the haploid phase of spermatogenesis necessitates an especially prominent role for posttranscriptional regulation in the temporal and spatial expression of many testis-specific proteins and isozymes. In this review article, discussion will focus on novel mechanisms regulating gene expression in mammalian male germ cells from genome to protein.

  3. 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

  4. Molecular mechanisms of chromosomal rearrangement in fungi.

    PubMed

    Fierro, F; Martín, J F

    1999-01-01

    Both sexual and asexual fungi undergo chromosomal rearrangements, which are the main cause of karyotype variability among the populations. Different recombination processes can produce chromosomal reorganizations, both during mitosis and meiosis, but other mechanisms operate to limit the extent of the rearrangements; some of these mechanisms, such as the RIP (repeat-induced point mutations) of Neurospora crassa, have been well established for sexual fungi. In laboratory strains, treatments such as mutation and transformation enhance the appearance of chromosomal rearrangements. Different DNA sequences present in fungal genomes are able to promote these reorganizations; some of these sequences are involved in well-regulated processes (e.g., site-specific recombination) but most of them act simply as substrates for recombination events leading to DNA rearrangements. In Penicillium chrysogenum we have found that short specific DNA sequences are involved in tandem reiterations leading to amplification of the cluster of the penicillin biosynthesis genes. In some cases, specific chromosomal rearrangements have been associated with particular phenotypes (as occurs in adaptive-like mutants of Candida albicans and Candida stellatoidea), and they may play a role in genetic variability for environmental adaptation.

  5. 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

  6. 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.

  7. [Pathogenetic and therapeutic aspects of secondary anorexia].

    PubMed

    Laviano, A; Cascino, A; Muscaritoli, M; Rossi Fanelli, F

    2000-01-01

    Anorexia is an often underrated symptom in the clinical management of patients suffering from chronic diseases. Moreover, the anorexia accompanying chronic diseases (secondary anorexia) is often confused with anorexia nervosa, a typically neuropsychiatric disorder involving completely different pathogenic mechanisms and therapeutic strategies. Secondary anorexia is one of the main factors responsible for the development of malnutrition, which in turn negatively affects patient morbidity and mortality. Different mechanisms have been proposed to explain the pathogenesis of secondary anorexia. However, consistent experimental and clinical evidence seems to point to hypothalamic serotonergic system hyperactivity as a preeminent cause; this hyperactivity appears to be triggered by enhanced brain availability of tryptophan, the aminoacid precursor of serotonin. The hyperactive hypothalamic serotonergic system might also represent the final effector where different regulatory and modulating pathways, including cytokines, converge. The involvement of tryptophan and the hypothalamic serotonergic system is further supported by the effectiveness of a therapeutic strategy, based on the inhibition of tryptophan entry into the brain, in increasing the food intake of anorectic patients. Although these results represent an encouraging approach to the treatment of secondary anorexia, with possible beneficial effects on the nutritional status of patients, they need to be validated in larger trials.

  8. 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.

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

    PubMed Central

    Daste, Frederic

    2016-01-01

    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

  10. [Molecular mechanisms of skeletal muscle hypertrophy].

    PubMed

    Astratenkova, I V; Rogozkin, V A

    2014-06-01

    Enzymes Akt, AMPK, mTOR, S6K and PGC-1a coactivator take part in skeletal muscles in the regulation of synthesis of proteins. The expression of these proteins is regulated by growth factors, hormones, nutrients, mechanical loading and leads to an increase in muscle mass and skeletal muscle hypertrophy. The review presents the results of studies published in the past four years, which expand knowledge on the effects of various factors on protein synthesis in skeletal muscle. The attention is focused on the achievements that reveal and clarify the signaling pathways involved in the regulation of protein synthesis in skeletal muscle. The central place is taken by mTOR enzyme which controls and regulates the main stages of the cascade of reactions of muscle proteins providing synthesis in the conditions of human life. coactivator PGC-1a.

  11. 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.

  12. Cellular and molecular mechanisms coordinating pancreas development.

    PubMed

    Bastidas-Ponce, Aimée; Scheibner, Katharina; Lickert, Heiko; Bakhti, Mostafa

    2017-08-15

    The pancreas is an endoderm-derived glandular organ that participates in the regulation of systemic glucose metabolism and food digestion through the function of its endocrine and exocrine compartments, respectively. While intensive research has explored the signaling pathways and transcriptional programs that govern pancreas development, much remains to be discovered regarding the cellular processes that orchestrate pancreas morphogenesis. Here, we discuss the developmental mechanisms and principles that are known to underlie pancreas development, from induction and lineage formation to morphogenesis and organogenesis. Elucidating such principles will help to identify novel candidate disease genes and unravel the pathogenesis of pancreas-related diseases, such as diabetes, pancreatitis and cancer. © 2017. Published by The Company of Biologists Ltd.

  13. 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

  14. Anemia: progress in molecular mechanisms and therapies.

    PubMed

    Sankaran, Vijay G; Weiss, Mitchell J

    2015-03-01

    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 both the understanding of frequently debilitating forms of anemia and the ability to treat affected patients. Major worldwide diseases that are likely to benefit from new advances include the hemoglobinopathies (β-thalassemia and sickle cell disease); rare genetic disorders of RBC production; and anemias associated with chronic kidney disease, inflammation, and cancer. Promising new approaches to treatment include drugs that target recently defined pathways in RBC production, iron metabolism, and fetal globin-family gene expression, as well as gene therapies that use improved viral vectors and newly developed genome editing technologies.

  15. Flavonoids health benefits and their molecular mechanism.

    PubMed

    Xiao, Z-P; Peng, Z-Y; Peng, M-J; Yan, W-B; Ouyang, Y-Z; Zhu, H-L

    2011-02-01

    Flavonoids are a group of polyphenolic compounds, diverse in chemical structure and characteristics, found ubiquitously in plants. Until now, more than 9000 different flavonoid compounds were described in plants, where they play important biological roles by affecting several developmental processes. There has been increasing interest in the research of flavonoids from dietary sources, due to growing evidence of the versatile health benefits of flavonoids including anti-inflammatory, antioxidant, antiproliferative and anticancer activity, freeradical scavenging capacity, antihypertensive effects, coronary heart disease prevention and anti-human immunodeficiency virus functions. This paper reviews the current advances in flavonoids in food with emphasis on mechanism aspects on the basis of the published literature, which may provide some guidance for researchers in further investigations and for industries in developing practical health agents.

  16. [Molecular mechanism for feeding and food preference regulation].

    PubMed

    Minokoshi, Yasuhiko

    2016-03-01

    Feeding behavior is regulated by homeostatic and hedonic mechanisms. NPY/AgRP neurons in the arcuate hypothalamus are involved in the homeostatic regulation, and dopaminergic neurons in the ventral tegmental area regulating the nucleus of accumbens are involved in the hedonic regulation, respectively. Food preference also appears to be regulated by both homeostatic and hedonic mechanisms. However, molecular mechanism for food preference regulation remains elusive and further studies are necessary.

  17. 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

  18. 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.

  19. [Molecular genetic and epigenetic mechanisms of hepatocarcinogenesis].

    PubMed

    Xue, Kai-Xian

    2005-06-01

    Hepatocellular carcinoma (HCC) is a major type of primary liver cancer and one of the most frequent human malignant neoplasms. Common risk factors of human HCC include chronic hepatitis virus (HBV and HCV) infection, dietary aflatoxin B1 (AFB1) ingestion, chronic alcohol abuse, and cirrhosis associated with genetic liver diseases. Hepatocarcinogenesis is the result of interaction between hereditary and environmental factors. Inheritance determines individual susceptibility to cancer; environment determines which susceptible individuals express cancer. Studies of genetic and epigenetic mechanisms of hepatocarcinogenesis showed that HCC development is a complex polygene and multipathway process; the activation of proto-oncogenes and the inactivation of tumor suppressor genes induced by genetic and epigenetic alterations are core biological processes of hepatocarcinogenesis; RB1, p53, and Wnt pathways are commonly affected in HCCs of different etiologies, which may reflect common pathologic sequence of HCC: chronic liver injury, cirrhosis, atypical hyperplastic nodules, and HCC of early stages. Hepatitis virus infection-associated HCCs have frequent alterations in RB1 pathway, including methylation of p16INK4a and RB1 genes and amplification of Cyclin D1. AFB1 exposure-associated HCCs have frequent alterations in p53 pathway; the G-->T mutation of p53 gene at codon 249 has been identified as a genetic hallmark of HCC caused by AFB1. Alcoholism-associated HCCs have frequent alterations in both RB1 and p53 pathways. The roles of some important genes related to cell apoptosis, DNA repair, drug metabolism, and tumor metastasis in hepatocarcinogenesis had been discussed.

  20. Molecular mechanisms of ultraviolet radiation carcinogenesis.

    PubMed

    Ananthaswamy, H N; Pierceall, W E

    1990-12-01

    UV radiation is a potent DNA damaging agent and a known inducer of skin cancer in experimental animals. There is excellent scientific evidence to indicate that most non-melanoma human skin cancers are induced by repeated exposure to sunlight. UV radiation is unique in that it induces DNA damage that differs from the lesions induced by any other carcinogen. The prevalence of skin cancer on sun-exposed body sites in individuals with the inherited disorder XP suggests that defective repair of UV-induced DNA damage can lead to cancer induction. Carcinogenesis in the skin, as elsewhere, is a multistep process in which a series of genetic and epigenetic events leads to the emergence of a clone of cells that have escaped normal growth control mechanisms. The principal candidates that are involved in these events are oncogenes and tumor suppressor genes. Oncogenes display a positive effect on transformation, whereas tumor suppressor genes have an essentially negative effect, blocking transformation. Activated ras oncogenes have been identified in human skin cancers. In most cases, the mutations in the ras oncogenes have been localized to pyrimidine-rich sequences, which indicates that these sites are probably the targets for UV-induced DNA damage and subsequent mutation and transformation. The finding that activation of ras oncogenes in benign and self-regressing keratoacanthomas in both humans and in animals indicates that they play a role in the early stages of carcinogenesis (Corominas et al., 1989; Kumar et al., 1990). Since cancers do not arise immediately after exposure to physical or chemical carcinogens, ras oncogenes must remain latent for long periods of time. Tumor growth and progression into the more malignant stages may require additional events involving activation of other oncogenes or deletion of growth suppressor genes. In addition, amplification of proto-oncogenes or other genes may also be involved in tumor induction or progression. In contrast to the

  1. 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.

  2. Recent Advances in Molecular Mechanisms of Abdominal Aortic Aneurysm Formation

    PubMed Central

    Annambhotla, Suman; Bourgeois, Sebastian; Wang, Xinwen; Lin, Peter H.; Yao, Qizhi; Chen, Changyi

    2010-01-01

    Abdominal Aortic Aneurysm (AAA) is an increasingly common clinical condition with fatal implications. It is associated with advanced age, male gender, cigarette smoking, atherosclerosis, hypertension, and genetic predisposition. Although significant evidence has emerged in the last decade, the molecular mechanisms of AAA formation remains poorly understood. Currently, the treatment for AAA remains primarily surgical with the lone innovation of endovascular therapy. With advance in the human genome, understanding precisely which molecules and genes mediate AAA development and blocking their activity at the molecular level could lead to important new discoveries and therapies. This review summarizes recent updates in molecular mechanisms of AAA formation including animal models, autoimmune components, infection, key molecules and cytokines, mechanical forces, genetics and pharmacotherapy. This review will be helpful to those who want to recognize the newest endeavors within the field and identify possible lines of investigation in AAA. PMID:18259804

  3. Graph-drawing algorithms geometries versus molecular mechanics in fullereness

    NASA Astrophysics Data System (ADS)

    Kaufman, M.; Pisanski, T.; Lukman, D.; Borštnik, B.; Graovac, A.

    1996-09-01

    The algorithms of Kamada-Kawai (KK) and Fruchterman-Reingold (FR) have been recently generalized (Pisanski et al., Croat. Chem. Acta 68 (1995) 283) in order to draw molecular graphs in three-dimensional space. The quality of KK and FR geometries is studied here by comparing them with the molecular mechanics (MM) and the adjacency matrix eigenvectors (AME) algorithm geometries. In order to compare different layouts of the same molecule, an appropriate method has been developed. Its application to a series of experimentally detected fullerenes indicates that the KK, FR and AME algorithms are able to reproduce plausible molecular geometries.

  4. Principles of cellular-molecular mechanisms underlying neuron functions.

    PubMed

    Ratushnyak, Alexander S; Zapara, Tatiana A

    2009-12-01

    In the present work, it was experimentally shown that a neuron in vitro was capable of responding in a manner similar to habituation, Pavlov's reflex and avoidance of the reinforcements. The locality of plastic property modifications and molecular morphology, as well as the connection between functional activity and cytoskeleton have been revealed. A hypothesis is formulated that the neuron is a molecular system which may exercise the control, forecast, recognition, and classification. The basic principles of the molecular mechanisms of the responses underlying integrative activity, learning and memory at the neuronal level are discussed.

  5. Molecular deformation mechanisms of the wood cell wall material.

    PubMed

    Jin, Kai; Qin, Zhao; Buehler, Markus J

    2015-02-01

    Wood is a biological material with outstanding mechanical properties resulting from its hierarchical structure across different scales. Although earlier work has shown that the cellular structure of wood is a key factor that renders it excellent mechanical properties at light weight, the mechanical properties of the wood cell wall material itself still needs to be understood comprehensively. The wood cell wall material features a fiber reinforced composite structure, where cellulose fibrils act as stiff fibers, and hemicellulose and lignin molecules act as soft matrix. The angle between the fiber direction and the loading direction has been found to be the key factor controlling the mechanical properties. However, how the interactions between theses constitutive molecules contribute to the overall properties is still unclear, although the shearing between fibers has been proposed as a primary deformation mechanism. Here we report a molecular model of the wood cell wall material with atomistic resolution, used to assess the mechanical behavior under shear loading in order to understand the deformation mechanisms at the molecular level. The model includes an explicit description of cellulose crystals, hemicellulose, as well as lignin molecules arranged in a layered nanocomposite. The results obtained using this model show that the wood cell wall material under shear loading deforms in an elastic and then plastic manner. The plastic regime can be divided into two parts according to the different deformation mechanisms: yielding of the matrix and sliding of matrix along the cellulose surface. Our molecular dynamics study provides insights of the mechanical behavior of wood cell wall material at the molecular level, and paves a way for the multi-scale understanding of the mechanical properties of wood.

  6. 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

  7. Common molecular mechanisms in explicit and implicit memory.

    PubMed

    Barco, Angel; Bailey, Craig H; Kandel, Eric R

    2006-06-01

    Cellular and molecular studies of both implicit and explicit memory suggest that experience-dependent modulation of synaptic strength and structure is a fundamental mechanism by which these memories are encoded and stored within the brain. In this review, we focus on recent advances in our understanding of two types of memory storage: (i) sensitization in Aplysia, a simple form of implicit memory, and (ii) formation of explicit spatial memories in the mouse hippocampus. These two processes share common molecular mechanisms that have been highly conserved through evolution.

  8. [Progress in researches of molecular mechanism of schistosome cercariae infection].

    PubMed

    Du, Xiaofeng; Ju, Chuan; Hu, Wei

    2013-12-01

    Schistosome cercariae must penetrate skin as an initial step to successfully infect the final host. Proteolytic enzymes secreted from the acetabular glands of cercariae contribute significantly to the invasion process. Nowadays, the researches of molecular mechanism of schistosome infection mainly focus on the cercarial secretions including serine protease and cysteine protease. Previous researches already showed that Schistosoma mansoni penetrates the skin mainly depend on cercarial elastease secreted by cercariae while Schistosoma japonicum penetrates the skin chiefly by cathepsin B2. The illustration of molecular mechanism of schistosome cecariae infection will accelerate the identification of novel vaccines and drug targets.

  9. Quantum mechanical/molecular mechanical study on the mechanism of the enzymatic Baeyer-Villiger reaction.

    PubMed

    Polyak, Iakov; Reetz, Manfred T; Thiel, Walter

    2012-02-08

    We report a combined quantum mechanical/molecular mechanical (QM/MM) study on the mechanism of the enzymatic Baeyer-Villiger reaction catalyzed by cyclohexanone monooxygenase (CHMO). In QM/MM geometry optimizations and reaction path calculations, density functional theory (B3LYP/TZVP) is used to describe the QM region consisting of the substrate (cyclohexanone), the isoalloxazine ring of C4a-peroxyflavin, the side chain of Arg-329, and the nicotinamide ring and the adjacent ribose of NADP(+), while the remainder of the enzyme is represented by the CHARMM force field. QM/MM molecular dynamics simulations and free energy calculations at the semiempirical OM3/CHARMM level employ the same QM/MM partitioning. According to the QM/MM calculations, the enzyme-reactant complex contains an anionic deprotonated C4a-peroxyflavin that is stabilized by strong hydrogen bonds with the Arg-329 residue and the NADP(+) cofactor. The CHMO-catalyzed reaction proceeds via a Criegee intermediate having pronounced anionic character. The initial addition reaction has to overcome an energy barrier of about 9 kcal/mol. The formed Criegee intermediate occupies a shallow minimum on the QM/MM potential energy surface and can undergo fragmentation to the lactone product by surmounting a second energy barrier of about 7 kcal/mol. The transition state for the latter migration step is the highest point on the QM/MM energy profile. Gas-phase reoptimizations of the QM region lead to higher barriers and confirm the crucial role of the Arg-329 residue and the NADP(+) cofactor for the catalytic efficiency of CHMO. QM/MM calculations for the CHMO-catalyzed oxidation of 4-methylcyclohexanone reproduce and rationalize the experimentally observed (S)-enantioselectivity for this substrate, which is governed by the conformational preferences of the corresponding Criegee intermediate and the subsequent transition state for the migration step.

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

    NASA Astrophysics Data System (ADS)

    Hou, Ruizheng; Wang, Zhisong

    2010-09-01

    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 deploymerization 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.

  11. Molecular mechanisms controlling the cell cycle in embryonic stem cells.

    PubMed

    Abdelalim, Essam M

    2013-12-01

    Embryonic stem (ES) cells are originated from the inner cell mass of a blastocyst stage embryo. They can proliferate indefinitely, maintain an undifferentiated state (self-renewal), and differentiate into any cell type (pluripotency). ES cells have an unusual cell cycle structure, consists mainly of S phase cells, a short G1 phase and absence of G1/S checkpoint. Cell division and cell cycle progression are controlled by mechanisms ensuring the accurate transmission of genetic information from generation to generation. Therefore, control of cell cycle is a complicated process, involving several signaling pathways. Although great progress has been made on the molecular mechanisms involved in the regulation of ES cell cycle, many regulatory mechanisms remain unknown. This review summarizes the current knowledge about the molecular mechanisms regulating the cell cycle of ES cells and describes the relationship existing between cell cycle progression and the self-renewal.

  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.

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

    PubMed

    Tay, Sen Hee; Mak, Anselm

    2015-05-06

    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.

  14. 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.

  15. Combination of metformin with chemotherapeutic drugs via different molecular mechanisms.

    PubMed

    Peng, Mei; Darko, Kwame Oteng; Tao, Ting; Huang, Yanjun; Su, Qiongli; He, Caimei; Yin, Tao; Liu, Zhaoqian; Yang, Xiaoping

    2017-03-01

    Metformin, a widely prescribed drug for treating type II diabetes, is one of the most extensively recognized metabolic modulators which has shown an important anti-cancer property. However, fairly amount of clinical trials on its single administration have not demonstrated a convincing efficiency yet. Thus, recent studies tend to combine metformin with clinical commonly used chemotherapeutic drugs to decrease their toxicity and attenuate their tumor resistance. These strategies have displayed promising clinical benefits. Interestingly, metformin experiences a diversity of molecular mechanisms when it combines different chemotherapeutic drugs. For example, AMPK/mTOR signaling pathway activation plays a major role when it combines with hormone modulating drugs. In contrast, suppression of HIF-1, p-gp and MRP1 protein expression is its main mechanism when metformin combines with anti-metabolites. Furthermore, when combining of metformin with antibiotics, inhibition of oxidative stress and inflammatory signaling pathway becomes a novel pharmaceutical mechanism for its cardio-protective effect. Induction of apoptotic mitochondria and nucleus could be the major player for the synergistic effect of its combination with cisplatin. In contrast, down-regulation of lipoprotein or cholesterol synthesis might be the undefined molecular base when metformin combines with taxane. Thus, deep exploration of molecular mechanisms of metformin with these different drugs is critical to understand its synergistic effect and help for personalized administration. In this mini-review, detailed molecular mechanisms of these combinations are discussed and summarized. This work will promote better understanding of molecular mechanisms of metformin and provide precise targets to identify specific patient groups to achieve satisfactory treatment efficacy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Combined quantum mechanical/molecular mechanics modeling for large organometallic and metallobiochemical systems

    NASA Astrophysics Data System (ADS)

    Leong, Max Kangchien

    A method of combined quantum mechanics/molecular mechanics has been developed to model larger organometallic and metallobiochemical systems where neither quantum mechanics nor molecular mechanics, applied separately, can solve the problem. An electronically transparent interface, which allows charge transfers between the quantum and classical fragments, is devised and realized by employing a special iterative procedure of double (intrafragment and interfragment) self-consistent calculations. The combined QM/MM scheme was successfully applied to model iron picket-fence porphyrin, vitamin B12, aquocobalamin, and vitamin B12 coenzyme molecules.

  17. Resolving the molecular mechanism of cadherin catch bond formation

    SciTech Connect

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

    2014-06-02

    Classical cadherin Ca(2+)-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 Ca(2+) 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 Ca(2+) concentration is decreased, fewer de novo hydrogen bonds are formed and catch bond formation is eliminated

  18. The molecular mechanisms of hemodialysis vascular access failure

    PubMed Central

    Franzoni, Marco; Misra, Sanjay

    2016-01-01

    The arteriovenous fistula has been used for more than 50 years to provide vascular access for patients undergoing hemodialysis. More than 1.5 million patients worldwide have end stage renal disease and this population will continue to grow. The arteriovenous fistula is the preferred vascular access for patients, but its patency rate at 1 year is only 60%. The majority of arteriovenous fistulas fail because of intimal hyperplasia. In recent years, there have been many studies investigating the molecular mechanisms responsible for intimal hyperplasia and subsequent thrombosis. These studies have identified common pathways including inflammation, uremia, hypoxia, sheer stress, and increased thrombogenicity. These cellular mechanisms lead to increased proliferation, migration, and eventually stenosis. These pathways work synergistically through shared molecular messengers. In this review, we will examine the literature concerning the molecular basis of hemodialysis vascular access malfunction. PMID:26806833

  19. 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

  20. Brief homeopathic pathogenetic experimentation: a unique educational tool in Brazil.

    PubMed

    Teixeira, Marcus Zulian

    2009-09-01

    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.

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

    NASA Astrophysics Data System (ADS)

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

    2015-05-01

    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.

  2. A Molecular Mechanics Study of Monensin B Ion Selectivity.

    DTIC Science & Technology

    well known knot theorist working with Jon Simon under the math part of the ONR stereochemical topology project. 2) The 5-rung THYME diol-ditosylate has...trefoil knot, which will posses 100 atoms in the ring. 3) The first molecular mechanics studies on the THYME system have been accomplished. 4) Preliminary

  3. Mechanistic insights into Mg2+-independent prenylation by CloQ from classical molecular mechanics and hybrid quantum mechanics/molecular mechanics molecular dynamics simulations.

    PubMed

    Bayse, Craig A; Merz, Kenneth M

    2014-08-05

    Understanding the mechanism of prenyltransferases is important to the design of engineered proteins capable of synthesizing derivatives of naturally occurring therapeutic agents. CloQ is a Mg(2+)-independent aromatic prenyltransferase (APTase) that transfers a dimethylallyl group to 4-hydroxyphenylpyruvate in the biosynthetic pathway for clorobiocin. APTases consist of a common ABBA fold that defines a β-barrel containing the reaction cavity. Positively charged basic residues line the inside of the β-barrel of CloQ to activate the pyrophosphate leaving group to replace the function of the Mg(2+) cofactor in other APTases. Classical molecular dynamics simulations of CloQ, its E281G and F68S mutants, and the related NovQ were used to explore the binding of the 4-hydroxyphenylpyruvate (4HPP) and dimethylallyl diphosphate substrates in the reactive cavity and the role of various conserved residues. Hybrid quantum mechanics/molecular mechanics potential of mean force (PMF) calculations show that the effect of the replacement of the Mg(2+) cofactor with basic residues yields a similar activation barrier for prenylation to Mg(2+)-dependent APTases like NphB. The topology of the binding pocket for 4HPP is important for selective prenylation at the ortho position of the ring. Methylation at this position alters the conformation of the substrate for O-prenylation at the phenol group. Further, a two-dimensional PMF scan shows that a "reverse" prenylation product may be a possible target for protein engineering.

  4. 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.

  5. Molecular mechanisms underlying the fetal programming of adult disease.

    PubMed

    Vo, Thin; Hardy, Daniel B

    2012-08-01

    Adverse events in utero can be critical in determining quality of life and overall health. It is estimated that up to 50 % of metabolic syndrome diseases can be linked to an adverse fetal environment. However, the mechanisms linking impaired fetal development to these adult diseases remain elusive. This review uncovers some of the molecular mechanisms underlying how normal physiology may be impaired in fetal and postnatal life due to maternal insults in pregnancy. By understanding the mechanisms, which include epigenetic, transcriptional, endoplasmic reticulum (ER) stress, and reactive oxygen species (ROS), we also highlight how intervention in fetal and neonatal life may be able to prevent these diseases long-term.

  6. 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.

  7. A Molecular Mechanics Analysis of Molecular Recognition by Cyclodextrin Mimics of Alpha-Chymotrypsin

    DTIC Science & Technology

    1989-05-26

    Recognition By Cyclodextrin Mimics of Alpha-Chymotrypsin i by C.A. Venanzi. P.M. Canzius, Z. Zhang, and J.D. Bunce LT IC To Be Published in CLECTE JUN 0 51...Clasification) A Molecular Mechanics Analysis of Molecular Recognition By Cyclodextrin Mimics of Alpha-Chymotrypsin. 12. PERSONAL AUTHOR(S) C.A. Venanzil... CYCLODEXTRIN MIMICS OF 0( -CHYMOTRYPSIN Carol A. Venanzi1 , Preston M. Canzius, Zhifeng Zhang, and Jeffrey D. Bunce Department of Chemical Engineering

  8. Molecular Mechanisms in Mood Regulation Involving the Circadian Clock

    PubMed Central

    Albrecht, Urs

    2017-01-01

    The circadian system coordinates activities and functions in cells and tissues in order to optimize body functions in anticipation to daily changes in the environment. Disruption of the circadian system, due to irregular lifestyle such as rotating shift work, frequent travel across time-zones, or chronic stress, is correlated with several diseases such as obesity, cancer, and neurological disorders. Molecular mechanisms linking the circadian clock with neurological functions have been uncovered suggesting that disruption of the clock may be critically involved in the development of mood disorders. In this mini-review, I will summarize molecular mechanisms in which clock components play a central role for mood regulation. Such mechanisms have been identified in the monoaminergic system, the HPA axis, and neurogenesis. PMID:28223962

  9. Molecular mechanics of mineralized collagen fibrils in bone

    NASA Astrophysics Data System (ADS)

    Nair, Arun K.; Gautieri, Alfonso; Chang, Shu-Wei; Buehler, Markus J.

    2013-04-01

    Bone is a natural composite of collagen protein and the mineral hydroxyapatite. The structure of bone is known to be important to its load-bearing characteristics, but relatively little is known about this structure or the mechanism that govern deformation at the molecular scale. Here we perform full-atomistic calculations of the three-dimensional molecular structure of a mineralized collagen protein matrix to try to better understand its mechanical characteristics under tensile loading at various mineral densities. We find that as the mineral density increases, the tensile modulus of the network increases monotonically and well beyond that of pure collagen fibrils. Our results suggest that the mineral crystals within this network bears up to four times the stress of the collagen fibrils, whereas the collagen is predominantly responsible for the material’s deformation response. These findings reveal the mechanism by which bone is able to achieve superior energy dissipation and fracture resistance characteristics beyond its individual constituents.

  10. Molecular Mechanisms in Mood Regulation Involving the Circadian Clock.

    PubMed

    Albrecht, Urs

    2017-01-01

    The circadian system coordinates activities and functions in cells and tissues in order to optimize body functions in anticipation to daily changes in the environment. Disruption of the circadian system, due to irregular lifestyle such as rotating shift work, frequent travel across time-zones, or chronic stress, is correlated with several diseases such as obesity, cancer, and neurological disorders. Molecular mechanisms linking the circadian clock with neurological functions have been uncovered suggesting that disruption of the clock may be critically involved in the development of mood disorders. In this mini-review, I will summarize molecular mechanisms in which clock components play a central role for mood regulation. Such mechanisms have been identified in the monoaminergic system, the HPA axis, and neurogenesis.

  11. Molecular mechanisms of neuropathological changes in Alzheimer's disease: a review.

    PubMed

    Serý, Omar; Povová, Jana; Míšek, Ivan; Pešák, Lukáš; Janout, Vladimir

    2013-01-01

    More than 100 years after description of Alzheimer's disease (AD), two major pathological processes observed already by Alois Alzheimer, remain as the main explanation of the pathogenesis of Alzheimer's disease. Important molecular interactions leading to AD neuropathology were described in amyloid cascade and in tau protein function. No clinical trials with novel therapies based on amyloid cascade and tau protein hypotheses have been successful. The main aim of recent research is focused on the question what is primary mechanism leading to the molecular development of AD pathology. Promising explanation of triggering mechanism can be seen in vascular pathology that have direct influence on the development of pathological processes typical for Alzheimer disease. Novel insight into a number of cellular signaling mechanisms, as well as mitochondrial function in Alzheimer disease could also bring explanations of initial processes leading to the development of this pathology.

  12. Molecular mechanics of mineralized collagen fibrils in bone

    PubMed Central

    Nair, Arun K.; Gautieri, Alfonso; Chang, Shu-Wei; Buehler, Markus J.

    2013-01-01

    Bone is a natural composite of collagen protein and the mineral hydroxyapatite. The structure of bone is known to be important to its load-bearing characteristics, but relatively little is known about this structure or the mechanism that govern deformation at the molecular scale. Here we perform full-atomistic calculations of the three-dimensional molecular structure of a mineralized collagen protein matrix to try to better understand its mechanical characteristics under tensile loading at various mineral densities. We find that as the mineral density increases, the tensile modulus of the network increases monotonically and well beyond that of pure collagen fibrils. Our results suggest that the mineral crystals within this network bears up to four times the stress of the collagen fibrils, whereas the collagen is predominantly responsible for the material’s deformation response. These findings reveal the mechanism by which bone is able to achieve superior energy dissipation and fracture resistance characteristics beyond its individual constituents. PMID:23591891

  13. Submillisecond Elastic Recoil Reveals Molecular Origins of Fibrin Fiber Mechanics

    PubMed Central

    Hudson, Nathan E.; Ding, Feng; Bucay, Igal; O’Brien, E. Timothy; Gorkun, Oleg V.; Superfine, Richard; Lord, Susan T.; Dokholyan, Nikolay V.; Falvo, Michael R.

    2013-01-01

    Fibrin fibers form the structural scaffold of blood clots. Thus, their mechanical properties are of central importance to understanding hemostasis and thrombotic disease. Recent studies have revealed that fibrin fibers are elastomeric despite their high degree of molecular ordering. These results have inspired a variety of molecular models for fibrin’s elasticity, ranging from reversible protein unfolding to rubber-like elasticity. An important property that has not been explored is the timescale of elastic recoil, a parameter that is critical for fibrin’s mechanical function and places a temporal constraint on molecular models of fiber elasticity. Using high-frame-rate imaging and atomic force microscopy-based nanomanipulation, we measured the recoil dynamics of individual fibrin fibers and found that the recoil was orders of magnitude faster than anticipated from models involving protein refolding. We also performed steered discrete molecular-dynamics simulations to investigate the molecular origins of the observed recoil. Our results point to the unstructured αC regions of the otherwise structured fibrin molecule as being responsible for the elastic recoil of the fibers. PMID:23790375

  14. 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.

  15. 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

  16. Molecular mechanisms involved in mammalian primary sex determination.

    PubMed

    She, Zhen-Yu; Yang, Wan-Xi

    2014-08-01

    Sex determination refers to the developmental decision that directs the bipotential genital ridge to develop as a testis or an ovary. Genetic studies on mice and humans have led to crucial advances in understanding the molecular fundamentals of sex determination and the mutually antagonistic signaling pathway. In this review, we summarize the current molecular mechanisms of sex determination by focusing on the known critical sex determining genes and their related signaling pathways in mammalian vertebrates from mice to humans. We also discuss the underlying delicate balance between testis and ovary sex determination pathways, concentrating on the antagonisms between major sex determining genes.

  17. Dissecting molecular mechanisms in the living brain of dementia patients.

    PubMed

    Barrio, Jorge R; Satyamurthy, Nagichettiar; Huang, Sung-Cheng; Petric, Andrej; Small, Gary W; Kepe, Vladimir

    2009-07-21

    Understanding the molecular mechanisms associated with the development of dementia is essential for designing successful interventions. Dementia, like cancer and cardiovascular disease, requires early detection to potentially arrest or prevent further disease progression. By the time a neurologist begins to manage clinical symptoms, the disease has often damaged the brain significantly. Because successful treatment is the logical goal, detecting the disease when brain damage is still limited is of the essence. The role of chemistry in this discovery process is critical. With the advent of molecular imaging, the understanding of molecular mechanisms in human neurodegenerative diseases has exploded. Traditionally, knowledge of enzyme and neurotransmitter function in humans has been extrapolated from animal studies, but now we can acquire data directly from both healthy and diseased human subjects. In this Account, we describe the use of molecular imaging probes to elucidate the biochemical and cellular bases of dementia (e.g., Alzheimer's disease) and the application of these discoveries to the design of successful therapeutic interventions. Molecular imaging permits observation and evaluation of the basic molecular mechanisms of disease progression in the living brains of patients. 2-Deoxy-2-[(18)F]fluoro-d-glucose is used to assess the effect of Alzheimer's disease progression on neuronal circuits projecting from and to the temporal lobe (one of the earliest metabolic signs of the disease). Recently, we have developed imaging probes for detection of amyloid neuropathology (both tau and beta-amyloid peptide deposits) and neuronal losses. These probes allow us to visualize the development of pathology in the living brain of dementia patients and its consequences, such as losses of critical neurons associated with memory deficits and other neuropsychiatric impairments. Because inflammatory processes are tightly connected to the brain degenerative processes

  18. [Paraneoplastic syndromes: pathogenetic theories, clinical aspects and therapeutic approach].

    PubMed

    Ngonga, Gaelle Flore Ketchandja; Ferrari, Daniela; Lorusso, Lorenzo; Gasparetto, Chiara; Neznama, Eva; D'Abramo, Manuela; Ricevuti, Giovanni

    2005-01-01

    Paraneoplastic syndromes are uncommon diseases with different pathogenesis and clinical manifestations, correlated with neoplasms but not due to the tumor, metastasis or other distant effects. The aim of the present article is to describe the main paraneoplastic syndromes (neurological, endocrine-metabolic, rheumatological, osteo-articular, dermatological, hematological, vascular and nephrological), the associated pathogenetic theories (theory of the common embryonal sketches, theory of reactivation of the information and autoimmune theory) and the most important therapeutic approaches, on the basis of the literature. Experimental works, reviews and clinical observations, in some cases still in progress, regarding the described syndromes, their pathogenesis and their therapeutic approach have been examined. No meta-analyses regarding paraneoplastic syndromes have been published in the literature. The better described pathogenesis is the autoimmune one, characteristic of neurological, nephrologic and some dermatologic syndromes, for which the clinical and laboratory findings have been well supported. The pathogenetic theories associated with the other syndromes have been correlated on the basis of the literature. Paraneoplastic syndromes are important because their identification permits an early diagnosis of tumors and rapid treatment, with a largely improved prognosis and life expectancy for the patient. They often represent the only signal of a silent neoplasm; sometimes they precede the tumor itself. More studies are necessary for a better definition of their clinical aspects and pathogenesis and to delineate standard guidelines for a diagnostic-therapeutic approach to these diseases.

  19. A quantum mechanics/molecular mechanics study on the hydrolysis mechanism of New Delhi metallo-β-lactamase-1.

    PubMed

    Zhu, Kongkai; Lu, Junyan; Liang, Zhongjie; Kong, Xiangqian; Ye, Fei; Jin, Lu; Geng, Heji; Chen, Yong; Zheng, Mingyue; Jiang, Hualiang; Li, Jun-Qian; Luo, Cheng

    2013-03-01

    New Delhi metallo-β-lactamase-1 (NDM-1) has emerged as a major global threat to human health for its rapid rate of dissemination and ability to make pathogenic microbes resistant to almost all known β-lactam antibiotics. In addition, effective NDM-1 inhibitors have not been identified to date. In spite of the plethora of structural and kinetic data available, the accurate molecular characteristics of and details on the enzymatic reaction of NDM-1 hydrolyzing β-lactam antibiotics remain incompletely understood. In this study, a combined computational approach including molecular docking, molecular dynamics simulations and quantum mechanics/molecular mechanics calculations was performed to characterize the catalytic mechanism of meropenem catalyzed by NDM-1. The quantum mechanics/molecular mechanics results indicate that the ionized D124 is beneficial to the cleavage of the C-N bond within the β-lactam ring. Meanwhile, it is energetically favorable to form an intermediate if no water molecule coordinates to Zn2. Moreover, according to the molecular dynamics results, the conserved residue K211 plays a pivotal role in substrate binding and catalysis, which is quite consistent with previous mutagenesis data. Our study provides detailed insights into the catalytic mechanism of NDM-1 hydrolyzing meropenem β-lactam antibiotics and offers clues for the discovery of new antibiotics against NDM-1 positive strains in clinical studies.

  20. A quantum mechanics/molecular mechanics study on the hydrolysis mechanism of New Delhi metallo-β-lactamase-1

    NASA Astrophysics Data System (ADS)

    Zhu, Kongkai; Lu, Junyan; Liang, Zhongjie; Kong, Xiangqian; Ye, Fei; Jin, Lu; Geng, Heji; Chen, Yong; Zheng, Mingyue; Jiang, Hualiang; Li, Jun-Qian; Luo, Cheng

    2013-03-01

    New Delhi metallo-β-lactamase-1 (NDM-1) has emerged as a major global threat to human health for its rapid rate of dissemination and ability to make pathogenic microbes resistant to almost all known β-lactam antibiotics. In addition, effective NDM-1 inhibitors have not been identified to date. In spite of the plethora of structural and kinetic data available, the accurate molecular characteristics of and details on the enzymatic reaction of NDM-1 hydrolyzing β-lactam antibiotics remain incompletely understood. In this study, a combined computational approach including molecular docking, molecular dynamics simulations and quantum mechanics/molecular mechanics calculations was performed to characterize the catalytic mechanism of meropenem catalyzed by NDM-1. The quantum mechanics/molecular mechanics results indicate that the ionized D124 is beneficial to the cleavage of the C-N bond within the β-lactam ring. Meanwhile, it is energetically favorable to form an intermediate if no water molecule coordinates to Zn2. Moreover, according to the molecular dynamics results, the conserved residue K211 plays a pivotal role in substrate binding and catalysis, which is quite consistent with previous mutagenesis data. Our study provides detailed insights into the catalytic mechanism of NDM-1 hydrolyzing meropenem β-lactam antibiotics and offers clues for the discovery of new antibiotics against NDM-1 positive strains in clinical studies.

  1. Atomistic insight into the catalytic mechanism of glycosyltransferases by combined quantum mechanics/molecular mechanics (QM/MM) methods.

    PubMed

    Tvaroška, Igor

    2015-02-11

    Glycosyltransferases catalyze the formation of glycosidic bonds by assisting the transfer of a sugar residue from donors to specific acceptor molecules. Although structural and kinetic data have provided insight into mechanistic strategies employed by these enzymes, molecular modeling studies are essential for the understanding of glycosyltransferase catalyzed reactions at the atomistic level. For such modeling, combined quantum mechanics/molecular mechanics (QM/MM) methods have emerged as crucial. These methods allow the modeling of enzymatic reactions by using quantum mechanical methods for the calculation of the electronic structure of the active site models and treating the remaining enzyme environment by faster molecular mechanics methods. Herein, the application of QM/MM methods to glycosyltransferase catalyzed reactions is reviewed, and the insight from modeling of glycosyl transfer into the mechanisms and transition states structures of both inverting and retaining glycosyltransferases are discussed.

  2. Drug-Target Binding Investigated by Quantum Mechanical/Molecular Mechanical (QM/MM) Methods

    NASA Astrophysics Data System (ADS)

    Rothlisberger, U.; Carloni, P.

    Many important drugs, also used in the clinics, exert their function by binding covalently to their targets. Understanding their action requires quantum mechanical simulations. Here, after briefly reviewing few basic concepts of thermodynamics and kinetics of drug-target binding, we summarize principles and applications of Car-Parrinello quantum mechanics/molecular mechanics (QM/MM) simulations. From this discussion, this approach emerges as a computational methodology particularly well suited to investigate covalent binding in systems of pharmacological relevance.

  3. Inactivation mechanism of glycerol dehydration by diol dehydratase from combined quantum mechanical/molecular mechanical calculations.

    PubMed

    Doitomi, Kazuki; Kamachi, Takashi; Toraya, Tetsuo; Yoshizawa, Kazunari

    2012-11-13

    Inactivation of diol dehydratase during the glycerol dehydration reaction is studied on the basis of quantum mechanical/molecular mechanical calculations. Glycerol is not a chiral compound but contains a prochiral carbon atom. Once it is bound to the active site, the enzyme adopts two binding conformations. One is predominantly responsible for the product-forming reaction (G(R) conformation), and the other primarily contributes to inactivation (G(S) conformation). Reactant radical is converted into a product and byproduct in the product-forming reaction and inactivation, respectively. The OH group migrates from C2 to C1 in the product-forming reaction, whereas the transfer of a hydrogen from the 3-OH group of glycerol to C1 takes place during the inactivation. The activation barrier of the hydrogen transfer does not depend on the substrate-binding conformation. On the other hand, the activation barrier of OH group migration is sensitive to conformation and is 4.5 kcal/mol lower in the G(R) conformation than in the G(S) conformation. In the OH group migration, Glu170 plays a critical role in stabilizing the reactant radical in the G(S) conformation. Moreover, the hydrogen bonding interaction between Ser301 and the 3-OH group of glycerol lowers the activation barrier in G(R)-TS2. As a result, the difference in energy between the hydrogen transfer and the OH group migration is reduced in the G(S) conformation, which shows that the inactivation is favored in the G(S) conformation.

  4. Pathogenetic importance and therapeutic implications of NF-κB in lymphoid malignancies.

    PubMed

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

    2012-03-01

    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.

  5. Pathogenetic model for Tourette syndrome delineates overlap with related neurodevelopmental disorders including Autism.

    PubMed

    Clarke, R A; Lee, S; Eapen, V

    2012-09-04

    Tourette syndrome (TS) is a highly heritable neuropsychiatric disorder characterised by motor and vocal tics. Despite decades of research, the aetiology of TS has remained elusive. Recent successes in gene discovery backed by rapidly advancing genomic technologies have given us new insights into the genetic basis of the disorder, but the growing collection of rare and disparate findings have added confusion and complexity to the attempts to translate these findings into neurobiological mechanisms resulting in symptom genesis. In this review, we explore a previously unrecognised genetic link between TS and a competing series of trans-synaptic complexes (neurexins (NRXNs), neuroligins (NLGNs), leucine-rich repeat transmembrane proteins (LRRTMs), leucine rich repeat neuronals (LRRNs) and cerebellin precursor 2 (CBLN2)) that links it with autism spectrum disorder through neurodevelopmental pathways. The emergent neuropathogenetic model integrates all five genes so far found to be uniquely disrupted in TS into a single pathogenetic chain of events described in context with clinical and research implications.

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

    PubMed

    Xu, Lingjia; Pu, Jiali

    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.

  7. Self-renewal molecular mechanisms of colorectal cancer stem cells

    PubMed Central

    Pan, Tianhui; Xu, Jinghong; Zhu, Yongliang

    2017-01-01

    Colorectal cancer stem cells (CCSCs) represent a small fraction of the colorectal cancer cell population that possess self-renewal and multi-lineage differentiation potential and drive tumorigenicity. Self-renewal is essential for the malignant biological behaviors of colorectal cancer stem cells. While the self-renewal molecular mechanisms of colorectal cancer stem cells are not yet fully understood, the aberrant activation of signaling pathways, such as Wnt, Notch, transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) and Hedgehog-Gli (HH-GLI), specific roles mediated by cell surface markers and micro-environmental factors are involved in the regulation of self-renewal. The elucidation of the molecular mechanisms behind self-renewal may lead to the development of novel targeted interventions for the treatment of colorectal cancer. PMID:27909729

  8. Some Fundamental Molecular Mechanisms of Contractility in Fibrous Macromolecules

    PubMed Central

    Mandelkern, L.

    1967-01-01

    The fundamental molecular mechanisms of contractility and tension development in fibrous macromolecules are developed from the point of view of the principles of polymer physical chemistry. The problem is treated in a general manner to encompass the behavior of all macromolecular systems irrespective of their detailed chemical structure and particular function, if any. Primary attention is given to the contractile process which accompanies the crystal-liquid transition in axially oriented macromolecular systems. The theoretical nature of the process is discussed, and many experimental examples are given from the literature which demonstrate the expected behavior. Experimental attention is focused on the contraction of fibrous proteins, and the same underlying molecular mechanism is shown to be operative for a variety of different systems. PMID:6050598

  9. Molecular mechanisms of sound amplification in the mammalian cochlea.

    PubMed

    Ashmore, J F; Géléoc, G S; Harbott, L

    2000-10-24

    Mammalian hearing depends on the enhanced mechanical properties of the basilar membrane within the cochlear duct. The enhancement arises through the action of outer hair cells that act like force generators within the organ of Corti. Simple considerations show that underlying mechanism of somatic motility depends on local area changes within the lateral membrane of the cell. The molecular basis for this phenomenon is a dense array of particles that are inserted into the basolateral membrane and that are capable of sensing membrane potential field. We show here that outer hair cells selectively take up fructose, at rates high enough to suggest that a sugar transporter may be part of the motor complex. The relation of these findings to a recent candidate for the molecular motor is also discussed.

  10. 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

  11. Molecular mechanisms of acquired resistance to tyrosine kinase targeted therapy

    PubMed Central

    2010-01-01

    In recent years, tyrosine kinases (TKs) have been recognized as central players and regulators of cancer cell proliferation, apoptosis, and angiogenesis, and are therefore considered suitable potential targets for anti-cancer therapies. Several strategies for targeting TKs have been developed, the most successful being monoclonal antibodies and small molecule tyrosine kinase inhibitors. However, increasing evidence of acquired resistance to these drugs has been documented, and extensive preclinical studies are ongoing to try to understand the molecular mechanisms by which cancer cells are able to bypass their inhibitory activity. This review intends to present the most recently identified molecular mechanisms that mediate acquired resistance to tyrosine kinase inhibitors, identified through the use of in vitro models or the analysis of patient samples. The knowledge obtained from these studies will help to design better therapies that prevent and overcome resistance to treatment in cancer patients. PMID:20385023

  12. Separating Mechanical and Chemical Contributions to Molecular-Level Friction

    SciTech Connect

    KIM,HYUN I.; HOUSTON,JACK E.

    2000-08-14

    The authors use force-probe microscopy to study the friction force and the adhesive interaction for molecular monolayer self-assembled on both Au probe tips and substrate surfaces. By systematically varying the chemical nature of the end groups on these monolayers the authors have, for the first time, delineated the mechanical and chemical origins of molecular-level friction. They use chemically inert {double_bond}CH{sub 3} groups on both interracial surfaces to establish the purely mechanical component of the friction and contrast the results with the findings for chemically active {double_bond}COOH end-groups. In addition, by using odd or even numbers of methylene groups in the alkyl backbones of the molecules they are able to determine the levels of inter-film and intra-film hydrogen bonding.

  13. Integrative network analysis reveals molecular mechanisms of blood pressure regulation

    PubMed Central

    Huan, Tianxiao; Meng, Qingying; Saleh, Mohamed A; Norlander, Allison E; Joehanes, Roby; Zhu, Jun; Chen, Brian H; Zhang, Bin; Johnson, Andrew D; Ying, Saixia; Courchesne, Paul; Raghavachari, Nalini; Wang, Richard; Liu, Poching; O'Donnell, Christopher J; Vasan, Ramachandran; Munson, Peter J; Madhur, Meena S; Harrison, David G; Yang, Xia; Levy, Daniel

    2015-01-01

    Genome-wide association studies (GWAS) have identified numerous loci associated with blood pressure (BP). The molecular mechanisms underlying BP regulation, however, remain unclear. We investigated BP-associated molecular mechanisms by integrating BP GWAS with whole blood mRNA expression profiles in 3,679 individuals, using network approaches. BP transcriptomic signatures at the single-gene and the coexpression network module levels were identified. Four coexpression modules were identified as potentially causal based on genetic inference because expression-related SNPs for their corresponding genes demonstrated enrichment for BP GWAS signals. Genes from the four modules were further projected onto predefined molecular interaction networks, revealing key drivers. Gene subnetworks entailing molecular interactions between key drivers and BP-related genes were uncovered. As proof-of-concept, we validated SH2B3, one of the top key drivers, using Sh2b3−/− mice. We found that a significant number of genes predicted to be regulated by SH2B3 in gene networks are perturbed in Sh2b3−/− mice, which demonstrate an exaggerated pressor response to angiotensin II infusion. Our findings may help to identify novel targets for the prevention or treatment of hypertension. PMID:25882670

  14. Molecular mechanisms of desiccation tolerance in resurrection plants.

    PubMed

    Gechev, Tsanko S; Dinakar, Challabathula; Benina, Maria; Toneva, Valentina; Bartels, Dorothea

    2012-10-01

    Resurrection plants are a small but diverse group of land plants characterized by their tolerance to extreme drought or desiccation. They have the unique ability to survive months to years without water, lose most of the free water in their vegetative tissues, fall into anabiosis, and, upon rewatering, quickly regain normal activity. Thus, they are fundamentally different from other drought-surviving plants such as succulents or ephemerals, which cope with drought by maintaining higher steady state water potential or via a short life cycle, respectively. This review describes the unique physiological and molecular adaptations of resurrection plants enabling them to withstand long periods of desiccation. The recent transcriptome analysis of Craterostigma plantagineum and Haberlea rhodopensis under drought, desiccation, and subsequent rehydration revealed common genetic pathways with other desiccation-tolerant species as well as unique genes that might contribute to the outstanding desiccation tolerance of the two resurrection species. While some of the molecular responses appear to be common for both drought stress and desiccation, resurrection plants also possess genes that are highly induced or repressed during desiccation with no apparent sequence homologies to genes of other species. Thus, resurrection plants are potential sources for gene discovery. Further proteome and metabolome analyses of the resurrection plants contributed to a better understanding of molecular mechanisms that are involved in surviving severe water loss. Understanding the cellular mechanisms of desiccation tolerance in this unique group of plants may enable future molecular improvement of drought tolerance in crop plants.

  15. Molecular interaction mechanisms in reverse micellar extraction of microbial transglutaminase.

    PubMed

    Yu, Tingting; Lin, Mingxiang; Wan, Junfen; Cao, Xuejun

    2017-08-18

    Reverse micellar extraction is an efficient and economical alternative for protein purification. In this study, microbial transglutaminase (MTGase) from crude materials was purified using reverse micellar extraction, and the molecular interaction mechanism in reverse micellar extraction of MTGase was explored. By using a molecular simulation study, the interaction mechanism of forward extraction was investigated. The molecular simulation results reveal the interaction of MTGase-water-surfactant is the major driving force for the forward extraction. Further, the effect of ionic strength on molecular interactions in backward extraction was investigated using 1H low-field nuclear magnetic resonance (LF-NMR) and circular dichroism (CD) spectra. In backward extraction, the interactions between water and the other two molecules (MTGase and surfactant molecules) are enhanced while the interactions between target molecules (MTGase) and the other two molecules (water and surfactant molecules) are weakened as the ionic strength increases. Moreover, the effect of size exclusion on backward extraction was also investigated. The results demonstrate size exclusion has limit effect at high ionic strength, and the weakened interaction of MTGase-water-surfactant is the main reason causing the release of the target molecules in backward extraction. This work might provide valuable reference to the MTGase purification and downstream processing. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. How insects survive the cold: molecular mechanisms-a review.

    PubMed

    Clark, Melody S; Worland, M Roger

    2008-11-01

    Insects vary considerably in their ability to survive low temperatures. The tractability of these organisms to experimentation has lead to considerable physiology-based work investigating both the variability between species and the actual mechanisms themselves. This has highlighted a range of strategies including freeze tolerance, freeze avoidance, protective dehydration and rapid cold hardening, which are often associated with the production of specific chemicals such as antifreezes and polyol cryoprotectants. But we are still far from identifying the critical elements behind over-wintering success and how some species can regularly survive temperatures below -20 degrees C. Molecular biology is the most recent tool to be added to the insect physiologist's armoury. With the public availability of the genome sequence of model insects such as Drosophila and the production of custom-made molecular resources, such as EST libraries and microarrays, we are now in a position to start dissecting the molecular mechanisms behind some of these well-characterised physiological responses. This review aims to provide a state-of-the-art snapshot of the molecular work currently being conducted into insect cold tolerance and the very interesting preliminary results from such studies, which provide great promise for the future.

  17. Simulated scaling method for localized enhanced sampling and simultaneous "alchemical" free energy simulations: a general method for molecular mechanical, quantum mechanical, and quantum mechanical/molecular mechanical simulations.

    PubMed

    Li, Hongzhi; Fajer, Mikolai; Yang, Wei

    2007-01-14

    A potential scaling version of simulated tempering is presented to efficiently sample configuration space in a localized region. The present "simulated scaling" method is developed with a Wang-Landau type of updating scheme in order to quickly flatten the distributions in the scaling parameter lambdam space. This proposal is meaningful for a broad range of biophysical problems, in which localized sampling is required. Besides its superior capability and robustness in localized conformational sampling, this simulated scaling method can also naturally lead to efficient "alchemical" free energy predictions when dual-topology alchemical hybrid potential is applied; thereby simultaneously, both of the chemically and conformationally distinct portions of two end point chemical states can be efficiently sampled. As demonstrated in this work, the present method is also feasible for the quantum mechanical and quantum mechanical/molecular mechanical simulations.

  18. Molecular mechanism of interaction between norfloxacin and trypsin studied by molecular spectroscopy and modeling

    NASA Astrophysics Data System (ADS)

    Lu, Yan; Wang, Gongke; Lu, Xiumin; Lv, Juan; Xu, Meihua; Zhang, Weiwei

    2010-01-01

    The molecular mechanism of the binding of norfloxacin (NRF) to trypsin was investigated by fluorescence, synchronous fluorescence and UV-vis absorbance spectroscopy and molecular modeling at physiological conditions. The quenching mechanism and the binding mode were investigated in terms of the association constants and basic thermodynamic parameters. The results of spectroscopic measurements suggested that NRF have a strong ability to quench the intrinsic fluorescence of trypsin through static quenching procedure. Moreover, fluorescence experiments were also performed at different values of pH to elucidate the effect of pH on the binding. The NRF-trypsin complex was stabilized by hydrophobic forces and hydrogen bonding, via tryptophan residue as indicated from the thermodynamic parameters, which was consistent with the results of molecular docking and accessible surface area calculations.

  19. Molecular mechanism of Ca(2+)-catalyzed fusion of phospholipid micelles.

    PubMed

    Tsai, Hui-Hsu Gavin; Juang, Wei-Fu; Chang, Che-Ming; Hou, Tsai-Yi; Lee, Jian-Bin

    2013-11-01

    Although membrane fusion plays key roles in intracellular trafficking, neurotransmitter release, and viral infection, its underlying molecular mechanism and its energy landscape are not well understood. In this study, we employed all-atom molecular dynamics simulations to investigate the fusion mechanism, catalyzed by Ca(2+) ions, of two highly hydrated 1-palmitoyl-2-oleoyl-sn-3-phosphoethanolamine (POPE) micelles. This simulation system mimics the small contact zone between two large vesicles at which the fusion is initiated. Our simulations revealed that Ca(2+) ions are capable of catalyzing the fusion of POPE micelles; in contrast, we did not observe close contact of the two micelles in the presence of only Na(+) or Mg(2+) ions. Determining the free energy landscape of fusion allowed us to characterize the underlying molecular mechanism. The Ca(2+) ions play a key role in catalyzing the micelle fusion in three aspects: creating a more-hydrophobic surface on the micelles, binding two micelles together, and enhancing the formation of the pre-stalk state. In contrast, Na(+) or Mg(2+) ions have relatively limited effects. Effective fusion proceeds through sequential formation of pre-stalk, stalk, hemifused-like, and fused states. The pre-stalk state is the state featuring lipid tails exposed to the inter-micellar space; its formation is the rate-limiting step. The stalk state is the state where a localized hydrophobic core is formed connecting two micelles; its formation occurs in conjunction with water expulsion from the inter-micellar space. This study provides insight into the molecular mechanism of fusion from the points of view of energetics, structure, and dynamics. © 2013 Elsevier B.V. All rights reserved.

  20. Molecular mechanisms of metabolic regulation by insulin in Drosophila.

    PubMed

    Teleman, Aurelio A

    2009-12-14

    The insulin signalling pathway is highly conserved from mammals to Drosophila. Insulin signalling in the fly, as in mammals, regulates a number of physiological functions, including carbohydrate and lipid metabolism, tissue growth and longevity. In the present review, I discuss the molecular mechanisms by which insulin signalling regulates metabolism in Drosophila, comparing and contrasting with the mammalian system. I discuss both the intracellular signalling network, as well as the communication between organs in the fly.

  1. Molecular Transport Mechanisms for Associating and Solvating Penetrant in Polymers

    DTIC Science & Technology

    2007-11-02

    PIB ) at different vapor activities in order to understand complex diffusion mechanisms and probe molecular structures above the glass tranisition. The...the individual diffusion coefficients can be separated and that they are equal to each other for the acetic acid/ PIB system. The values of the...BOH) mixtures in polyisobutylene ( PIB ) was studied at varying mixture compositions. Diffusion coefficients and hydrogen bonding interactions were

  2. Molecular Mechanism of hTERT Function in Mitochondria

    DTIC Science & Technology

    2016-10-20

    Molecular mechanism of hTERT function in mitochondria (x) Material has been given an OPSEC review and it has been determined to be non sensitive and...transcriptase (hTERT) is localized to mitochondria , as well as the nucleus, but details about its biology and function in the organelle remain largely...demonstrate the canonical nuclear RNA [human telomerase RNA (hTR)] is not present in human mitochondria and not required for the mitochondrial

  3. Rattlesnake Neurotoxin Structure, Mechanism of Action, Immunology and Molecular Biology

    DTIC Science & Technology

    1992-09-10

    Aird, S. D., and Kaiser, I. I. (1988) Physiological and immunological properties of small myotoxins from -Zhe venom of the midget faded rattlesnake ...AD-A258 669 AD RATTLESNAKE NEUROTOXIN STRUCTURE, MECHANISM OF ACTION, IMMUNOLOGY AND MOLECULAR BIOLOGY FINAL REPORT D TIC IVAN I. KAISER ELECTE S DEC...u m_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 6 2 7 8 7 A I 6 2 7 8 7 A 8 7 7 I A A [ ~A 3 1 7 8 2 1 (u) Rattlesnake neurotoxin structure

  4. Rattlesnake Neurotoxin Structure, Mechanism of Action, Immunology and Molecular Biology

    DTIC Science & Technology

    1990-09-01

    from the venom of the midget faded . rattlesnake (Crotalus viridis concolor . Toxicon 2&, 319- 323. Rehm, H. and Betz, H. (1982) Binding of B...8217determined. It was shown to have great similarity to the basic subunits of related toxins from the venoms of the South American and midget faded ...AD-A228 003 CONTRACT NO.: DAMD17-89-C-9007 TITLE: RATTLESNAKE NEUROTOXIN STRUCTURE, MECHANISM OF ACTION, IMMUNOLOGY AND MOLECULAR BIOLOGY PRINCIPAL

  5. Unraveling the mechanism of molecular doping in organic semiconductors.

    PubMed

    Mityashin, Alexander; Olivier, Yoann; Van Regemorter, Tanguy; Rolin, Cedric; Verlaak, Stijn; Martinelli, Nicolas G; Beljonne, David; Cornil, Jérôme; Genoe, Jan; Heremans, Paul

    2012-03-22

    The mechanism by which molecular dopants donate free charge carriers to the host organic semiconductor is investigated and is found to be quite different from the one in inorganic semiconductors. In organics, a strong correlation between the doping concentration and its charge donation efficiency is demonstrated. Moreover, there is a threshold doping level below which doping simply has no electrical effect. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Water Exchange Rates and Molecular Mechanism around Aqueous Halide Ions

    SciTech Connect

    Annapureddy, Harsha V.; Dang, Liem X.

    2014-07-17

    Molecular dynamics simulations were performed to systematically study the water-exchange mechanism around aqueous chloride, bromide, and iodide ions. Transition state theory, Grote-Hynes theory, and the reactive flux method were employed to compute water exchange rates. We computed the pressure dependence of rate constants and the corresponding activation volumes to investigate the mechanism of the solvent exchange event. The activation volumes obtained using the transition state theory rate constants are negative for all the three anions, thus indicating an associative mechanism. Contrary to the transition state theory results, activation volumes obtained using rate constants from Grote-Hynes theory and the reactive flux method are positive, thus indicating a dissociative mechanism. The Division of Chemical Sciences, Geosciences, and Biosciences, Office of Basic Energy Sciences (BES), of the U.S. Department of Energy (DOE) funded this work. Battelle operates Pacific Northwest National Laboratory for DOE. The calculations were carried out using computer resources provided by BES.

  7. Kainate receptor trafficking: physiological roles and molecular mechanisms.

    PubMed

    Isaac, John T R; Mellor, Jack; Hurtado, David; Roche, Katherine W

    2004-12-01

    Recently, there has been intense interest in the mechanisms regulating the trafficking and synaptic targeting of kainate receptors in neurons. This topic is still in its infancy when compared with studies of trafficking of other ionotropic glutamate receptors; however, it is already clear that mechanisms exist for subunit- and splice variant-specific trafficking of kainate receptors. There is also enormous diversity of kainate receptor targeting, with the best-studied neurons in this regard being hippocampal CA3 pyramidal neurons and CA1 GABAergic interneurons. This review summarizes the current state of knowledge on this topic, focusing on the molecular mechanisms of kainate receptor trafficking and the potential for these mechanisms to regulate neuronal kainate receptor function.

  8. Mechanical instability of α-quartz: A molecular dynamics study

    NASA Astrophysics Data System (ADS)

    Tse, John S.; Klug, Dennis D.

    1991-12-01

    Pressure-induced amorphization in α-quartz has been investigated using constant-pressure molecular-dynamics calculations with the two-body potential of van Beest, Kramer, and van Santen. Both the static properties and the crystalline-to-amorphous phase transition were very well reproduced. Through an analysis of the elastic moduli, the mechanism for the transformation is shown to be a mechanical instability driven mainly by a cooperative twisting and compression of the helical tetrahedral silicate units with an abrupt decrease in the C12, C23, C13, C14, and C33 elastic moduli.

  9. Molecular Mechanisms Regulating TGF-β-Induced Foxp3 Expression

    PubMed Central

    Xu, Lili; Kitani, Atsushi; Strober, Warren

    2013-01-01

    Molecular mechanisms regulating TGF-β induction of Foxp3 expression and thus induction of iTregs has been the focus of a great deal of study in recent years. It has become clear that this process is influenced by a number of factors as perhaps might be predicted by the fact that there is an overarching need of the immune system to fine-tune response to environmental antigens. In this review we discuss these mechanisms, with the aim of presenting a broad picture of how the various observations fit together to form an integrated regulatory regime. PMID:20404810

  10. Molecular and Cellular Mechanics (Part I): A moderated discussion

    NASA Astrophysics Data System (ADS)

    Corey, David P.; Martin, Pascal

    2015-12-01

    The following is an edited transcript of a recorded discussion session on the topic of "Molecular and Cellular Mechanics". The discussion, moderated by the authors, took place at the 12th International Workshop on the Mechanics of Hearing held at Cape Sounio, Greece, in June 2014. All participants knew that the session was being recorded. In view of both the spontaneous nature of the discussion and the editing, however, this transcript may not represent the considered or final views of the participants, and may not represent a consensus of experts in the field. The reader is advised to consult additional independent publications.

  11. Molecular and Cellular Mechanics (Part II): A moderated discussion

    NASA Astrophysics Data System (ADS)

    Santos-Sacchi, Joseph

    2015-12-01

    The following is an edited transcript of a recorded discussion session on the topic of "Molecular and Cellular Mechanics". The discussion, moderated by the author, took place at the 12th International Workshop on the Mechanics of Hearing held at Cape Sounio, Greece, in June 2014. All participants knew that the session was being recorded. In view of both the spontaneous nature of the discussion and the editing, however, this transcript may not represent the considered or final views of the participants, and may not represent a consensus of experts in the field. The reader is advised to consult additional independent publications.

  12. Molecular mechanisms of heavy metal hyperaccumulation and phytoremediation.

    PubMed

    Yang, Xiaoe; Feng, Ying; He, Zhenli; Stoffella, Peter J

    2005-01-01

    A relatively small group of hyperaccumulator plants is capable of sequestering heavy metals in their shoot tissues at high concentrations. In recent years, major scientific progress has been made in understanding the physiological mechanisms of metal uptake and transport in these plants. However, relatively little is known about the molecular bases of hyperaccumulation. In this paper, current progresses on understanding cellular/molecular mechanisms of metal tolerance/hyperaccumulation by plants are reviewed. The major processes involved in hyperaccumulation of trace metals from the soil to the shoots by hyperaccumulators include: (a) bioactivation of metals in the rhizosphere through root-microbe interaction; (b) enhanced uptake by metal transporters in the plasma membranes; (c) detoxification of metals by distributing to the apoplasts like binding to cell walls and chelation of metals in the cytoplasm with various ligands, such as phytochelatins, metallothioneins, metal-binding proteins; (d) sequestration of metals into the vacuole by tonoplast-located transporters. The growing application of molecular-genetic technologies led to the well understanding of mechanisms of heavy metal tolerance/accumulation in plants, and subsequently many transgenic plants with increased resistance and uptake of heavy metals were developed for the purpose of phytoremediation. Once the rate-limiting steps for uptake, translocation, and detoxification of metals in hyperaccumulating plants are identified, more informed construction of transgenic plants would result in improved applicability of the phytoremediation technology.

  13. [Ethanol tolerance in yeast: molecular mechanisms and genetic engineering].

    PubMed

    Zhang, Qiumei; Zhao, Xinqing; Jiang, Rujiao; Li, Qian; Bai, Fengwu

    2009-04-01

    Improvement of stress tolerance to various adverse environmental conditions (such as toxic products, high temperature) of the industrial microorganisms is important for industrial applications. Ethanol produced by yeast fermentation is inhibitory to both yeast cell growth and metabolisms, and consequently is one of the key stress elements of brewer's yeast. Research on the biochemical and molecular mechanism of the tolerance of yeast can provide basis for breeding of yeast strain with improved ethanol tolerance. In recent years, employing global gene transcriptional analysis and functional analysis, new knowledge on the biochemical and molecular mechanisms of yeast ethanol tolerance has been accumulated, and novel genes and biochemical parameters related to ethanol tolerance have been revealed. Based on these studies, the overexpression and/or disruption of the related genes have successfully resulted in the breeding of new yeast strains with improved ethanol tolerance. This paper reviewed the recent research progress on the molecular mechanism of yeast ethanol tolerance, as well as the genetic engineering manipulations to improve yeast ethanol tolerance. The studies reviewed here not only deepened our knowledge on yeast ethanol tolerance, but also provided basis for more efficient bioconversion for bio-energy production.

  14. Molecular mechanisms of hookworm disease: stealth, virulence, and vaccines.

    PubMed

    Pearson, Mark S; Tribolet, Leon; Cantacessi, Cinzia; Periago, Maria Victoria; Valero, Maria Adela; Valerio, Maria Adela; Jariwala, Amar R; Hotez, Peter; Diemert, David; Loukas, Alex; Bethony, Jeffrey

    2012-07-01

    Hookworms produce a vast repertoire of structurally and functionally diverse molecules that mediate their long-term survival and pathogenesis within a human host. Many of these molecules are secreted by the parasite, after which they interact with critical components of host biology, including processes that are key to host survival. The most important of these interactions is the hookworm's interruption of nutrient acquisition by the host through its ingestion and digestion of host blood. This results in iron deficiency and eventually the microcytic hypochromic anemia or iron deficiency anemia that is the clinical hallmark of hookworm infection. Other molecular mechanisms of hookworm infection cause a systematic suppression of the host immune response to both the parasite and to bystander antigens (eg, vaccines or allergens). This is achieved by a series of molecules that assist the parasite in the stealthy evasion of the host immune response. This review will summarize the current knowledge of the molecular mechanisms used by hookworms to survive for extended periods in the human host (up to 7 years or longer) and examine the pivotal contributions of these molecular mechanisms to chronic hookworm parasitism and host clinical outcomes.

  15. Molecular Mechanism of Isocupressic Acid Supresses MA-10 Cell Steroidogenesis

    PubMed Central

    Tsui, Kuan-Hao; Wang, Jyun-Yuan; Wu, Leang-Shin; Chiu, Chih-Hsien

    2012-01-01

    Consumption of ponderosa pine needles causes late-term abortions in cattle and is a serious poisonous plant problem in foothill and mountain rangelands. Isocupressic acid (IA) is the component of pine needles responsible for the abortifacient effect, its abortifacient effect may be due to inhibition of steroidogenesis. To investigate the more detail molecular mechanism, we used MA-10 cell, which is wild used to investigate molecular mechanism of steroidogenesis, to characterize the molecular mechanisms underlying the actions of IA in more detail. In this report, we focus on the function of IA on important steroidogenic genes, including steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage (P450scc), and 3β-hydroxysteroid dehydrogenase (3β-HSD). We found that IA does not affect enzyme activities of these genes but inhibits transcription of P450scc and translation of StAR and P450scc through attenuating cAMP-PKA signaling. Thus, steroid productions of cells were suppressed. PMID:22666287

  16. Molecular Mechanism of Isocupressic Acid Supresses MA-10 Cell Steroidogenesis.

    PubMed

    Tsui, Kuan-Hao; Wang, Jyun-Yuan; Wu, Leang-Shin; Chiu, Chih-Hsien

    2012-01-01

    Consumption of ponderosa pine needles causes late-term abortions in cattle and is a serious poisonous plant problem in foothill and mountain rangelands. Isocupressic acid (IA) is the component of pine needles responsible for the abortifacient effect, its abortifacient effect may be due to inhibition of steroidogenesis. To investigate the more detail molecular mechanism, we used MA-10 cell, which is wild used to investigate molecular mechanism of steroidogenesis, to characterize the molecular mechanisms underlying the actions of IA in more detail. In this report, we focus on the function of IA on important steroidogenic genes, including steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage (P450scc), and 3β-hydroxysteroid dehydrogenase (3β-HSD). We found that IA does not affect enzyme activities of these genes but inhibits transcription of P450scc and translation of StAR and P450scc through attenuating cAMP-PKA signaling. Thus, steroid productions of cells were suppressed.

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

    PubMed

    Keten, Sinan; Buehler, Markus J

    2010-12-06

    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.

  18. 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

  19. 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.

  20. 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.

  1. 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

  2. [Alzheimer disease: from pathogenetic issues to clinical perspectives].

    PubMed

    Costanza, A; Bouras, C; Kövari, E; Giannakopoulos, P

    2012-09-19

    The aim of this article is a critical review of the main pathogenetic issues debated in Alzheimer disease, with a focus on the clinical perspectives that could derive from. The pertinence of the amyloid cascade hypothesis as a unique and causal explanation of cognitive deterioration is challenged in the light of recent therapeutic failures of clinical trials and increasing role of tau protein in clinical expression. The detection of very early and possibly preclinical stages of the disease emerges as a necessary condition for the efficacy of future amyloid or tau-oriented curative strategies. In this respect, the possibility of finding individual vulnerability markers--in the group of patients with "mild cognitive impairment" or even in cognitively intact subjects--represents a major challenge of the clinical research in this field.

  3. [Beta-endorphin and obesity. Possible pathogenetic implications].

    PubMed

    Giugliano, D; Saccomanno, F; Quatraro, A; Ceriello, A; Torella, R

    1990-01-01

    Several experimental data have documented the ability of both opiates and opioid peptides to stimulate food intake. On the other hand, the plasma beta-endorphin levels found in obese patients are higher than those observed in normal-weight controls, which may have pathogenetic implications. We have investigated the responses of plasma glucose, insulin, C-peptide and glucagon to an infusion of human beta-endorphin in formerly obese subjects who had obtained by dieting the normalization of body weight and in lean controls. The data show that: a) the increased plasma beta-endorphin concentrations found in human obesity are not corrected by normalization of body weight; b) formerly obese subjects behave as obese subjects in their metabolic and hormonal responses to beta-endorphin.

  4. The superspreading mechanism unveiled via molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Theodorakis, Panagiotis; Muller, Erich; Craster, Richard; Matar, Omar

    2014-11-01

    Superspreading, by which aqueous droplets laden with specific surfactants wet hydrophobic substrates, is an unusual and dramatic phenomenon. This is attributed to various factors, e.g., a particular surfactant geometry, Marangoni flow, unique solid-fluid interactions, however, direct evidence for a plausible mechanism for superspreading has not yet been provided. Here, we use molecular dynamics simulations of a coarse-grained model with force fields obtained from the SAFT- γ equation of state to capture the superspreading mechanism of water drops with surfactants on model surfaces. Our simulations highlight and monitor the main features of the molecular behavior that lead to the superspreading mechanism, and reproduce and explain the experimentally-observed characteristic maxima of the spreading rate of the droplet vs. surfactant concentration and wettability. We also present a comparison between superspreading and non-superspreading surfactants underlining the main morphological and energetic characteristics of superspreaders. We believe that this is the first time a plausible superspreading mechanism based on a microscopic description is proposed; this will enable the design of surfactants with enhanced spreading ability specifically tailored for applications. EPSRC Grant Number EP/J010502/1.

  5. 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

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. Modeling and experimental research on a removal mechanism during chemical mechanical polishing at the molecular scale

    NASA Astrophysics Data System (ADS)

    Wei, An; Yongwu, Zhao; Yongguang, Wang

    2010-11-01

    In order to understand the fundamentals of the chemical mechanical polishing (CMP) material removal mechanism, the indentation depth of a slurry particle into a wafer surface is determined using the in situ nanomechanical testing system tribo-indenter by Hysitron. It was found that the removal mechanism in CMP is most probably a molecular scale removal theory. Furthermore, a comprehensive mathematical model was modified and used to pinpoint the effects of wafer/pad relative velocity, which has not been modeled previously. The predicted results based on the current model are shown to be consistent with the published experimental data. Results and analysis may lead to further understanding of the microscopic removal mechanism at the molecular scale in addition to its underlying theoretical foundation.

  12. Molecular Mechanisms of Aging and Immune System Regulation in Drosophila

    PubMed Central

    Eleftherianos, Ioannis; Castillo, Julio Cesar

    2012-01-01

    Aging is a complex process that involves the accumulation of deleterious changes resulting in overall decline in several vital functions, leading to the progressive deterioration in physiological condition of the organism and eventually causing disease and death. The immune system is the most important host-defense mechanism in humans and is also highly conserved in insects. Extensive research in vertebrates has concluded that aging of the immune function results in increased susceptibility to infectious disease and chronic inflammation. Over the years, interest has grown in studying the molecular interaction between aging and the immune response to pathogenic infections. The fruit fly Drosophila melanogaster is an excellent model system for dissecting the genetic and genomic basis of important biological processes, such as aging and the innate immune system, and deciphering parallel mechanisms in vertebrate animals. Here, we review the recent advances in the identification of key players modulating the relationship between molecular aging networks and immune signal transduction pathways in the fly. Understanding the details of the molecular events involved in aging and immune system regulation will potentially lead to the development of strategies for decreasing the impact of age-related diseases, thus improving human health and life span. PMID:22949833

  13. Non Equilibrium Transformations of Molecular Compounds Induced Mechanically

    SciTech Connect

    Descamps, M.; Willart, J. F.; Dudognon, E.

    2006-05-05

    Results clarifying the effects of mechanical milling on molecular solids are shortly reviewed. Special attention has been paid to the temperature of milling with regard to the glass transition temperature of the compounds. It is shown that decreasing the grinding temperature has for incidence to increase the amorphization tendency whereas milling above Tg produces a crystal-to-crystal transformation between polymorphic varieties. These observations contradict the usual proposition that grinding transforms the physical state only by a heating effect which induces a local melting. Equilibrium thermodynamics does not seem to be appropriate for describing the process. The driven alloys concept offers a more rational framework to interpret the effect of the milling temperature. Other results are presented which demonstrate the possibility for grinding to realize low temperature solid state alloying which offers new promising ways to stabilize amorphous molecular solids. In a second part the effect of dehydration of a molecular hydrate is described. It is shown that the rate of the dehydration process is a driving force for this other type of mechanical non equilibrium transformation.

  14. 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.

  15. Discovering novel ligands for understanding molecular mechanism of bacteria chemotaxis

    NASA Astrophysics Data System (ADS)

    Lai, Luhua

    2015-03-01

    In order to understand the molecular mechanism of bacteria chemotaxis, we used a combined experimental and computational approach to discover novel chemoeffector molecules and compare their binding features, as well as the conformational changes they produce. We first used molecular docking to computationally screen a large chemical library and tested binding strengths of the top-ranking molecules for the E. coli chemoreceptor Tar. Chemotactic properties of the binding molecules were then studied using a specially designed microfluidic device. Novel attractant and antagonist molecules were identified that bind directly with the E. coli chemoreceptor Tar. Molecular dynamics simulations showed that attractant and antagonist binding result in distinct conformational changes in Tar. Differences of antagonist and attractant binding suggest that molecules lacking triggering interaction with the receptor behave as antagonist. For Tar, the triggering interaction is mediated by the hydrogen bonds formed between a donor group in the attractant and the main-chain carbonyls in the fourth helix of Tar. This ?bind-and-trigger? mechanism of receptor signaling is verified experimentally by converting an antagonist into an attractant when introducing an NH group into the antagonist compound. Similar conformational changes were also observed in the E. coli Tsr system.

  16. Epidemiological bases and molecular mechanisms linking obesity, diabetes, and cancer.

    PubMed

    Gutiérrez-Salmerón, María; Chocarro-Calvo, Ana; García-Martínez, José Manuel; de la Vieja, Antonio; García-Jiménez, Custodia

    2017-02-01

    The association between diabetes and cancer was hypothesized almost one century ago. Today, a vast number of epidemiological studies support that obese and diabetic populations are more likely to experience tissue-specific cancers, but the underlying molecular mechanisms remain unknown. Obesity, diabetes, and cancer share many hormonal, immune, and metabolic changes that may account for the relationship between diabetes and cancer. In addition, antidiabetic treatments may have an impact on the occurrence and course of some cancers. Moreover, some anticancer treatments may induce diabetes. These observations aroused a great controversy because of the ethical implications and the associated commercial interests. We report an epidemiological update from a mechanistic perspective that suggests the existence of many common and differential individual mechanisms linking obesity and type 1 and 2 diabetes mellitus to certain cancers. The challenge today is to identify the molecular links responsible for this association. Classification of cancers by their molecular signatures may facilitate future mechanistic and epidemiological studies. Copyright © 2016 SEEN. Publicado por Elsevier España, S.L.U. All rights reserved.

  17. Molecular mechanisms of foliar water uptake in a desert tree.

    PubMed

    Yan, Xia; Zhou, Maoxian; Dong, Xicun; Zou, Songbing; Xiao, Honglang; Ma, Xiao-Fei

    2015-11-12

    Water deficits severely affect growth, particularly for the plants in arid and semiarid regions of the world. In addition to precipitation, other subsidiary water, such as dew, fog, clouds and small rain showers, may also be absorbed by leaves in a process known as foliar water uptake. With the severe scarcity of water in desert regions, this process is increasingly becoming a necessity. Studies have reported on physical and physiological processes of foliar water uptake. However, the molecular mechanisms remain less understood. As major channels for water regulation and transport, aquaporins (AQPs) are involved in this process. However, due to the regulatory complexity and functional diversity of AQPs, their molecular mechanism for foliar water uptake remains unclear. In this study, Tamarix ramosissima, a tree species widely distributed in desert regions, was investigated for gene expression patterns of AQPs and for sap flow velocity. Our results suggest that the foliar water uptake of T. ramosissima occurs in natural fields at night when the humidity is over a threshold of 85 %. The diurnal gene expression pattern of AQPs suggests that most AQP gene expressions display a circadian rhythm, and this could affect both photosynthesis and transpiration. At night, the PIP2-1 gene is also upregulated with increased relative air humidity. This gene expression pattern may allow desert plants to regulate foliar water uptake to adapt to extreme drought. This study suggests a molecular basis of foliar water uptake in desert plants. Published by Oxford University Press on behalf of the Annals of Botany Company.

  18. Studies on the molecular mechanisms of seed germination.

    PubMed

    Han, Chao; Yang, Pingfang

    2015-05-01

    Seed germination that begins with imbibition and ends with radicle emergence is the first step for plant growth. Successful germination is not only crucial for seedling establishment but also important for crop yield. After being dispersed from mother plant, seed undergoes continuous desiccation in ecosystem and selects proper environment to trigger germination. Owing to the contribution of transcriptomic, proteomic, and molecular biological studies, molecular aspect of seed germination is elucidated well in Arabidopsis. Recently, more and more proteomic and genetic studies concerning cereal seed germination were performed on rice (Oryza sativa) and barley (Hordeum vulgare), which possess completely different seed structure and domestication background with Arabidopsis. In this review, both the common features and the distinct mechanisms of seed germination are compared among different plant species including Arabidopsis, rice, and maize. These features include morphological changes, cell and its related structure recovery, metabolic activation, hormone behavior, and transcription and translation activation. This review will provide more comprehensive insights into the molecular mechanisms of seed germination.

  19. Molecular mechanisms of the anti-inflammatory functions of interferons

    PubMed Central

    Kovarik, Pavel; Sauer, Ines; Schaljo, Barbara

    2014-01-01

    Interferons are pleiotropic cytokines with important proinflammatory functions required in defence against infections with bacteria, viruses and multicellular parasites. In recent years, fundamental functions of interferons in other processes such as cancer immunosurveillance, immune homeostasis and immunosuppression have been established. In addition, anti-inflammatory roles of interferons are well-documented in several inflammatory disease models in the mouse, most importantly in experimental autoimmune encephalomyelitis that resembles multiple sclerosis in humans. While the beneficial effects of interferons in such disease models are known, the molecular mechanisms remain poorly understood. Only recently a few molecular principles for the anti-inflammatory properties of interferons at the cellular level have been revealed. They include the ability of interferons to reduce the expression of the receptors for the inflammation-related cytokines IL-1 and IL-4, or to increase the expression of the potent anti-inflammatory genes tristetraprolin and Twist. However, the individual contribution of these anti-inflammatory responses to the overall beneficial effects of interferons in inflammatory diseases is still an open question. Also, the reason for the apparently limited number of tissues that are susceptible to the anti-inflammatory functions of interferons remains enigmatic. This review summarizes the present knowledge of the anti-inflammatory effects of interferons, and describes the currently known molecular mechanisms that may help explain the benefits of interferon signalling in several inflammatory diseases. PMID:18086388

  20. Molecular mechanisms of foliar water uptake in a desert tree

    PubMed Central

    Yan, Xia; Zhou, Maoxian; Dong, Xicun; Zou, Songbing; Xiao, Honglang; Ma, Xiao-Fei

    2015-01-01

    Water deficits severely affect growth, particularly for the plants in arid and semiarid regions of the world. In addition to precipitation, other subsidiary water, such as dew, fog, clouds and small rain showers, may also be absorbed by leaves in a process known as foliar water uptake. With the severe scarcity of water in desert regions, this process is increasingly becoming a necessity. Studies have reported on physical and physiological processes of foliar water uptake. However, the molecular mechanisms remain less understood. As major channels for water regulation and transport, aquaporins (AQPs) are involved in this process. However, due to the regulatory complexity and functional diversity of AQPs, their molecular mechanism for foliar water uptake remains unclear. In this study, Tamarix ramosissima, a tree species widely distributed in desert regions, was investigated for gene expression patterns of AQPs and for sap flow velocity. Our results suggest that the foliar water uptake of T. ramosissima occurs in natural fields at night when the humidity is over a threshold of 85 %. The diurnal gene expression pattern of AQPs suggests that most AQP gene expressions display a circadian rhythm, and this could affect both photosynthesis and transpiration. At night, the PIP2-1 gene is also upregulated with increased relative air humidity. This gene expression pattern may allow desert plants to regulate foliar water uptake to adapt to extreme drought. This study suggests a molecular basis of foliar water uptake in desert plants. PMID:26567212

  1. Molecular mechanisms of cognitive dysfunction following traumatic brain injury

    PubMed Central

    Walker, Kendall R.; Tesco, Giuseppina

    2013-01-01

    Traumatic brain injury (TBI) results in significant disability due to cognitive deficits particularly in attention, learning and memory, and higher-order executive functions. The role of TBI in chronic neurodegeneration and the development of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS) and most recently chronic traumatic encephalopathy (CTE) is of particular importance. However, despite significant effort very few therapeutic options exist to prevent or reverse cognitive impairment following TBI. In this review, we present experimental evidence of the known secondary injury mechanisms which contribute to neuronal cell loss, axonal injury, and synaptic dysfunction and hence cognitive impairment both acutely and chronically following TBI. In particular we focus on the mechanisms linking TBI to the development of two forms of dementia: AD and CTE. We provide evidence of potential molecular mechanisms involved in modulating Aβ and Tau following TBI and provide evidence of the role of these mechanisms in AD pathology. Additionally we propose a mechanism by which Aβ generated as a direct result of TBI is capable of exacerbating secondary injury mechanisms thereby establishing a neurotoxic cascade that leads to chronic neurodegeneration. PMID:23847533

  2. Soy isoflavones and prostate cancer: a review of molecular mechanisms.

    PubMed

    Mahmoud, Abeer M; Yang, Wancai; Bosland, Maarten C

    2014-03-01

    Soy isoflavones are dietary components for which an association has been demonstrated with reduced risk of prostate cancer (PCa) in Asian populations. However, the exact mechanism by which these isoflavones may prevent the development or progression of PCa is not completely understood. There are a growing number of animal and in vitro studies that have attempted to elucidate these mechanisms. The predominant and most biologically active isoflavones in soy products, genistein, daidzein, equol, and glycetin, inhibit prostate carcinogenesis in some animal models. Cell-based studies show that soy isoflavones regulate genes that control cell cycle and apoptosis. In this review, we discuss the literature relevant to the molecular events that may account for the benefit of soy isoflavones in PCa prevention or treatment. These reports show that although soy isoflavone-induced growth arrest and apoptosis of PCa cells are plausible mechanisms, other chemo protective mechanisms are also worthy of consideration. These possible mechanisms include antioxidant defense, DNA repair, inhibition of angiogenesis and metastasis, potentiation of radio- and chemotherapeutic agents, and antagonism of estrogen- and androgen-mediated signaling pathways. Moreover, other cells in the cancer milieu, such as the fibroblastic stromal cells, endothelial cells, and immune cells, may be targeted by soy isoflavones, which may contribute to soy-mediated prostate cancer prevention. In this review, these mechanisms are discussed along with considerations about the doses and the preclinical models that have been used.

  3. Soy Isoflavones and Prostate Cancer: A Review of Molecular Mechanisms

    PubMed Central

    Mahmoud, Abeer M.; Yang, Wancai; Bosland, Maarten C.

    2014-01-01

    Soy isoflavones are dietary components for which an association has been demonstrated with reduced risk of prostate cancer (PCa) in Asian populations. However, the exact mechanism by which these isoflavones may prevent the development or progression of PCa is not completely understood. There are a growing number of animal and in vitro studies that have attempted to elucidate these mechanisms. The predominant and most biologically active isoflavones in soy products, genistein, daidzein, equol, and glycetin, inhibit prostate carcinogenesis in some animal models. Cell-based studies show that soy isoflavones regulate genes that control cell cycle and apoptosis. In this review, we discuss the literature relevant to the molecular events that may account for the benefit of soy isoflavones in PCa prevention or treatment. These reports show that although soy isoflavone-induced growth arrest and apoptosis of PCa cells are plausible mechanisms, other chemo protective mechanisms are also worthy of consideration. These possible mechanisms include antioxidant defense, DNA repair, inhibition of angiogenesis and metastasis, potentiation of radio- and chemotherapeutic agents, and antagonism of estrogen- and androgen-mediated signaling pathways. Moreover, other cells in the cancer milieu, such as the fibroblastic stromal cells, endothelial cells, and immune cells, may be targeted by soy isoflavones, which may contribute to soy-mediated prostate cancer prevention. In this review, these mechanisms are discussed along with considerations about the doses and the preclinical models that have been used. PMID:24373791

  4. Combined quantum mechanics/molecular mechanics (QM/MM) methods in computational enzymology.

    PubMed

    van der Kamp, Marc W; Mulholland, Adrian J

    2013-04-23

    Computational enzymology is a rapidly maturing field that is increasingly integral to understanding mechanisms of enzyme-catalyzed reactions and their practical applications. Combined quantum mechanics/molecular mechanics (QM/MM) methods are important in this field. By treating the reacting species with a quantum mechanical method (i.e., a method that calculates the electronic structure of the active site) and including the enzyme environment with simpler molecular mechanical methods, enzyme reactions can be modeled. Here, we review QM/MM methods and their application to enzyme-catalyzed reactions to investigate fundamental and practical problems in enzymology. A range of QM/MM methods is available, from cheaper and more approximate methods, which can be used for molecular dynamics simulations, to highly accurate electronic structure methods. We discuss how modeling of reactions using such methods can provide detailed insight into enzyme mechanisms and illustrate this by reviewing some recent applications. We outline some practical considerations for such simulations. Further, we highlight applications that show how QM/MM methods can contribute to the practical development and application of enzymology, e.g., in the interpretation and prediction of the effects of mutagenesis and in drug and catalyst design.

  5. Molecular Mechanism of Overhauser Dynamic Nuclear Polarization in Insulating Solids.

    PubMed

    Pylaeva, Svetlana; Ivanov, Konstantin L; Baldus, Marc; Sebastiani, Daniel; Elgabarty, Hossam

    2017-05-18

    Dynamic nuclear polarization (DNP), a technique that significantly enhances NMR signals, is experiencing a renaissance owing to enormous methodological developments. In the heart of DNP is a polarization transfer mechanism that endows nuclei with much larger electronic spin polarization. Polarization transfer via the Overhauser effect (OE) is traditionally known to be operative only in liquids and conducting solids. Very recently, surprisingly strong OE-DNP in insulating solids has been reported, with a DNP efficiency that increases with the magnetic field strength. Here we offer an explanation for these perplexing observations using a combination of molecular dynamics and spin dynamics simulations. Our approach elucidates the underlying molecular stochastic motion, provides cross-relaxation rates, explains the observed sign of the NMR enhancement, and estimates the role of nuclear spin diffusion. The presented theoretical description opens the door for rational design of novel polarizing agents for OE-DNP in insulating solids.

  6. Cocoa phytochemicals: recent advances in molecular mechanisms on health.

    PubMed

    Kim, Jiyoung; Kim, Jaekyoon; Shim, Jaesung; Lee, Chang Yong; Lee, Ki Won; Lee, Hyong Joo

    2014-01-01

    Recent reports on cocoa are appealing in that a food commonly consumed for pure pleasure might also bring tangible benefits for human health. Cocoa consumption is correlated with reduced health risks of cardiovascular diseases, hypertension, atherosclerosis, and cancer, and the health-promoting effects of cocoa are mediated by cocoa-driven phytochemicals. Cocoa is rich in procyanidins, theobromine, (-)-epicatechin, catechins, and caffeine. Among the phytochemicals present in consumed cocoa, theobromine is most available in human plasma, followed by caffeine, (-)-epicatechin, catechin, and procyanidins. It has been reported that cocoa phytochemicals specifically modulate or interact with specific molecular targets linked to the pathogenesis of chronic human diseases, including cardiovascular diseases, cancer, neurodegenerative diseases, obesity, diabetes, and skin aging. This review summarizes comprehensive recent findings on the beneficial actions of cocoa-driven phytochemicals in molecular mechanisms of human health.

  7. Neural tube closure: cellular, molecular and biomechanical mechanisms.

    PubMed

    Nikolopoulou, Evanthia; Galea, Gabriel L; Rolo, Ana; Greene, Nicholas D E; Copp, Andrew J

    2017-02-15

    Neural tube closure has been studied for many decades, across a range of vertebrates, as a paradigm of embryonic morphogenesis. Neurulation is of particular interest in view of the severe congenital malformations - 'neural tube defects' - that result when closure fails. The process of neural tube closure is complex and involves cellular events such as convergent extension, apical constriction and interkinetic nuclear migration, as well as precise molecular control via the non-canonical Wnt/planar cell polarity pathway, Shh/BMP signalling, and the transcription factors Grhl2/3, Pax3, Cdx2 and Zic2. More recently, biomechanical inputs into neural tube morphogenesis have also been identified. Here, we review these cellular, molecular and biomechanical mechanisms involved in neural tube closure, based on studies of various vertebrate species, focusing on the most recent advances in the field.

  8. Molecular Mechanisms of Compartmentalization and Biomineralization in Magnetotactic Bacteria

    PubMed Central

    Komeili, Arash

    2011-01-01

    Magnetotactic bacteria are remarkable organisms with the ability to exploit the earth’s magnetic field for navigational purposes. To do this, they build specialized compartments called magnetosomes that consist of a lipid membrane and a crystalline magnetic mineral. These organisms have the potential to serve as models for the study of compartmentalization as well as biomineralization in bacteria. Additionally, they offer the opportunity to design applications that take advantage of the particular properties of magnetosomes. In recent years, a sustained effort to identify the molecular basis of this process has resulted in a clearer understanding of the magnetosome formation and biomineralization. Here, I present an overview of magnetotactic bacteria and explore the possible molecular mechanisms of membrane remodeling, protein sorting, cytoskeletal organization, iron transport and biomineralization that lead to the formation of a functional magnetosome organelle. PMID:22092030

  9. Molecular mechanism of selective binding of peptides to silicon surface.

    PubMed

    Ramakrishnan, Sathish Kumar; Martin, Marta; Cloitre, Thierry; Firlej, Lucyna; Gergely, Csilla

    2014-07-28

    Despite extensive recent research efforts on material-specific peptides, the fundamental problem to be explored yet is the molecular interactions between peptides and inorganic surfaces. Here we used computer simulations (density functional theory and classical molecular dynamics) to investigate the adsorption mechanism of silicon-binding peptides and the role of individual amino acids in the affinity of peptides for an n-type silicon (n(+)-Si) semiconductor. Three silicon binding 12-mer peptides previously elaborated using phage display technology have been studied. The peptides' conformations close to the surface have been determined and the best-binding amino acids have been identified. Adsorption energy calculations explain the experimentally observed different degrees of affinity of the peptides for n(+)-Si. Our residual scanning analysis demonstrates that the binding affinity relies on both the identity of the amino acid and its location in the peptide sequence.

  10. Extrapolated gradientlike algorithms for molecular dynamics and celestial mechanics simulations.

    PubMed

    Omelyan, I P

    2006-09-01

    A class of symplectic algorithms is introduced to integrate the equations of motion in many-body systems. The algorithms are derived on the basis of an advanced gradientlike decomposition approach. Its main advantage over the standard gradient scheme is the avoidance of time-consuming evaluations of force gradients by force extrapolation without any loss of precision. As a result, the efficiency of the integration improves significantly. The algorithms obtained are analyzed and optimized using an error-function theory. The best among them are tested in actual molecular dynamics and celestial mechanics simulations for comparison with well-known nongradient and gradient algorithms such as the Störmer-Verlet, Runge-Kutta, Cowell-Numerov, Forest-Ruth, Suzuki-Chin, and others. It is demonstrated that for moderate and high accuracy, the extrapolated algorithms should be considered as the most efficient for the integration of motion in molecular dynamics simulations.

  11. Neural tube closure: cellular, molecular and biomechanical mechanisms

    PubMed Central

    Nikolopoulou, Evanthia; Galea, Gabriel L.; Rolo, Ana; Greene, Nicholas D. E.; Copp, Andrew J.

    2017-01-01

    Neural tube closure has been studied for many decades, across a range of vertebrates, as a paradigm of embryonic morphogenesis. Neurulation is of particular interest in view of the severe congenital malformations – ‘neural tube defects’– that result when closure fails. The process of neural tube closure is complex and involves cellular events such as convergent extension, apical constriction and interkinetic nuclear migration, as well as precise molecular control via the non-canonical Wnt/planar cell polarity pathway, Shh/BMP signalling, and the transcription factors Grhl2/3, Pax3, Cdx2 and Zic2. More recently, biomechanical inputs into neural tube morphogenesis have also been identified. Here, we review these cellular, molecular and biomechanical mechanisms involved in neural tube closure, based on studies of various vertebrate species, focusing on the most recent advances in the field. PMID:28196803

  12. The molecular mechanism and physiological role of cytoplasmic streaming.

    PubMed

    Tominaga, Motoki; Ito, Kohji

    2015-10-01

    Cytoplasmic streaming occurs widely in plants ranging from algae to angiosperms. However, the molecular mechanism and physiological role of cytoplasmic streaming have long remained unelucidated. Recent molecular genetic approaches have identified specific myosin members (XI-2 and XI-K as major and XI-1, XI-B, and XI-I as minor motive forces) for the generation of cytoplasmic streaming among 13 myosin XIs in Arabidopsis thaliana. Simultaneous knockout of these myosin XI members led to a reduced velocity of cytoplasmic streaming and marked defects of plant development. Furthermore, the artificial modifications of myosin XI-2 velocity changed plant and cell sizes along with the velocity of cytoplasmic streaming. Therefore, we assume that cytoplasmic streaming is one of the key regulators in determining plant size.

  13. Molecular mechanisms of secondary sexual trait development in insects.

    PubMed

    Prakash, Anupama; Monteiro, Antónia

    2016-10-01

    Secondary sexual traits are those traits other than the primary gametes that distinguish the sexes of a species. The development of secondary sexual traits occurs when sexually dimorphic factors, that is, molecules differentially produced by primary sex determination systems in males and females, are integrated into the gene regulatory networks responsible for sexual trait development. In insects, these molecular asymmetric factors were always considered to originate inside the trait-building cells, but recent work points to external factors, such as hormones, as potential candidates mediating secondary sexual trait development. Here, we review examples of the different molecular mechanisms producing sexually dimorphic traits in insects, and suggest a need to revise our understanding of secondary sexual trait development within the insect lineage. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. The molecular mechanism for nuclear transport and its application.

    PubMed

    Kim, Yun Hak; Han, Myoung-Eun; Oh, Sae-Ock

    2017-06-01

    Transportation between the cytoplasm and the nucleoplasm is critical for many physiological and pathophysiological processes including gene expression, signal transduction, and oncogenesis. So, the molecular mechanism for the transportation needs to be studied not only to understand cell physiological processes but also to develop new diagnostic and therapeutic targets. Recent progress in the research of the nuclear transportation (import and export) via nuclear pore complex and four important factors affecting nuclear transport (nucleoporins, Ran, karyopherins, and nuclear localization signals/nuclear export signals) will be discussed. Moreover, the clinical significance of nuclear transport and its application will be reviewed. This review will provide some critical insight for the molecular design of therapeutics which need to be targeted inside the nucleus.

  15. Steered Molecular Dynamics Methods Applied to Enzyme Mechanism and Energetics.

    PubMed

    Ramírez, C L; Martí, M A; Roitberg, A E

    2016-01-01

    One of the main goals of chemistry is to understand the underlying principles of chemical reactions, in terms of both its reaction mechanism and the thermodynamics that govern it. Using hybrid quantum mechanics/molecular mechanics (QM/MM)-based methods in combination with a biased sampling scheme, it is possible to simulate chemical reactions occurring inside complex environments such as an enzyme, or aqueous solution, and determining the corresponding free energy profile, which provides direct comparison with experimental determined kinetic and equilibrium parameters. Among the most promising biasing schemes is the multiple steered molecular dynamics method, which in combination with Jarzynski's Relationship (JR) allows obtaining the equilibrium free energy profile, from a finite set of nonequilibrium reactive trajectories by exponentially averaging the individual work profiles. However, obtaining statistically converged and accurate profiles is far from easy and may result in increased computational cost if the selected steering speed and number of trajectories are inappropriately chosen. In this small review, using the extensively studied chorismate to prephenate conversion reaction, we first present a systematic study of how key parameters such as pulling speed, number of trajectories, and reaction progress are related to the resulting work distributions and in turn the accuracy of the free energy obtained with JR. Second, and in the context of QM/MM strategies, we introduce the Hybrid Differential Relaxation Algorithm, and show how it allows obtaining more accurate free energy profiles using faster pulling speeds and smaller number of trajectories and thus smaller computational cost.

  16. Sexual polyploidization in plants – cytological mechanisms and molecular regulation

    PubMed Central

    De Storme, Nico; Geelen, Danny

    2013-01-01

    In the plant kingdom, events of whole genome duplication or polyploidization are generally believed to occur via alterations of the sexual reproduction process. Thereby, diploid pollen and eggs are formed that contain the somatic number of chromosomes rather than the gametophytic number. By participating in fertilization, these so-called 2n gametes generate polyploid offspring and therefore constitute the basis for the establishment of polyploidy in plants. In addition, diplogamete formation, through meiotic restitution, is an essential component of apomixis and also serves as an important mechanism for the restoration of F1 hybrid fertility. Characterization of the cytological mechanisms and molecular factors underlying 2n gamete formation is therefore not only relevant for basic plant biology and evolution, but may also provide valuable cues for agricultural and biotechnological applications (e.g. reverse breeding, clonal seeds). Recent data have provided novel insights into the process of 2n pollen and egg formation and have revealed multiple means to the same end. Here, we summarize the cytological mechanisms and molecular regulatory networks underlying 2n gamete formation, and outline important mitotic and meiotic processes involved in the ectopic induction of sexual polyploidization. PMID:23421646

  17. DNA intercalation optimized by two-step molecular lock mechanism

    PubMed Central

    Almaqwashi, Ali A.; Andersson, Johanna; Lincoln, Per; Rouzina, Ioulia; Westerlund, Fredrik; Williams, Mark C.

    2016-01-01

    The diverse properties of DNA intercalators, varying in affinity and kinetics over several orders of magnitude, provide a wide range of applications for DNA-ligand assemblies. Unconventional intercalation mechanisms may exhibit high affinity and slow kinetics, properties desired for potential therapeutics. We used single-molecule force spectroscopy to probe the free energy landscape for an unconventional intercalator that binds DNA through a novel two-step mechanism in which the intermediate and final states bind DNA through the same mono-intercalating moiety. During this process, DNA undergoes significant structural rearrangements, first lengthening before relaxing to a shorter DNA-ligand complex in the intermediate state to form a molecular lock. To reach the final bound state, the molecular length must increase again as the ligand threads between disrupted DNA base pairs. This unusual binding mechanism results in an unprecedented optimized combination of high DNA binding affinity and slow kinetics, suggesting a new paradigm for rational design of DNA intercalators. PMID:27917863

  18. Molecular-dynamics study of detonation. II. The reaction mechanism

    NASA Astrophysics Data System (ADS)

    Rice, Betsy M.; Mattson, William; Grosh, John; Trevino, S. F.

    1996-01-01

    In this work, we investigate mechanisms of chemical reactions that sustain an unsupported detonation. The chemical model of an energetic crystal used in this study consists of heteronuclear diatomic molecules that, at ambient pressure, dissociate endothermically. Subsequent association of the products to form homonuclear diatomic molecules provides the energy release that sustains the detonation. A many-body interaction is used to simulate changes in the electronic bonding as a function of local atomic environment. The consequence of the many-body interaction in this model is that the intramolecular bond is weakened with increasing density. The mechanism of the reaction for this model was extracted by investigating the details of the molecular properties in the reaction zone with two-dimensional molecular dynamics. The mechanism for the initiation of the reaction in this model is pressure-induced atomization. There was no evidence of excitation of vibrational modes to dissociative states. This particular result is directly attributable to the functional form and choice of parameters for this model, but might also have more general applicability.

  19. Zika Virus-Induced Microcephaly and Its Possible Molecular Mechanism.

    PubMed

    Faizan, Md Imam; Abdullah, Mohd; Ali, Sher; Naqvi, Irshad H; Ahmed, Anwar; Parveen, Shama

    2016-01-01

    Zika virus is an arthropod-borne re-emerging pathogen associated with the global pandemic of 2015-2016. The devastating effect of Zika viral infection is reflected by its neurological manifestations such as microcephaly in newborns. This scenario evoked our interest to uncover the neurotropic localization, multiplication of the virus, and the mechanism of microcephaly. The present report provides an overview of a possible molecular mechanism of Zika virus-induced microcephaly based on recent publications. Transplacental transmission of Zika viral infection from mother to foetus during the first trimester of pregnancy results in propagation of the virus in human neural progenitor cells (hNPCs), where entry is facilitated by the receptor (AXL protein) leading to the alteration of signalling and immune pathways in host cells. Further modification of the viral-induced TLR3-mediated immune network in the infected hNPCs affects viral replication. Downregulation of neurogenesis and upregulation of apoptosis in hNPCs leads to cell cycle arrest and death of the developing neurons. In addition, it is likely that the environmental, physiological, immunological, and genetic factors that determine in utero transmission of Zika virus are also involved in neurotropism. Despite the global concern regarding the Zika-mediated epidemic, the precise molecular mechanism of neuropathogenesis remains elusive.

  20. Molecular Mechanisms Underlying Occult Hepatitis B Virus Infection

    PubMed Central

    Samal, Jasmine; Kandpal, Manish

    2012-01-01

    Summary: Chronic hepatitis B virus (HBV) infection is a complex clinical entity frequently associated with cirrhosis and hepatocellular carcinoma (HCC). The persistence of HBV genomes in the absence of detectable surface antigenemia is termed occult HBV infection. Mutations in the surface gene rendering HBsAg undetectable by commercial assays and inhibition of HBV by suppression of viral replication and viral proteins represent two fundamentally different mechanisms that lead to occult HBV infections. The molecular mechanisms underlying occult HBV infections, including recently identified mechanisms associated with the suppression of HBV replication and inhibition of HBV proteins, are reviewed in detail. The availability of highly sensitive molecular methods has led to increased detection of occult HBV infections in various clinical settings. The clinical relevance of occult HBV infection and the utility of appropriate diagnostic methods to detect occult HBV infection are discussed. The need for specific guidelines on the diagnosis and management of occult HBV infection is being increasingly recognized; the aspects of mechanistic studies that warrant further investigation are discussed in the final section. PMID:22232374

  1. Advancing neuroscience through epigenetics: molecular mechanisms of learning and memory.

    PubMed

    Molfese, David L

    2011-01-01

    Humans share 96% of our 30,000 genes with Chimpanzees. The 1,200 genes that differ appear at first glance insufficient to describe what makes us human and them apes. However, we are now discovering that the mechanisms that regulate how genes are expressed tell a much richer story than our DNA alone. Sections of our DNA are constantly being turned on or off, marked for easy access, or secluded and hidden away, all in response to ongoing cellular activity. In the brain, neurons encode information-in effect memories-at the cellular level. Yet while memories may last a lifetime, neurons are dynamic structures. Every protein in the synapse undergoes some form of turnover, some with half-lives of only hours. How can a memory persist beyond the lifetimes of its constitutive molecular building blocks? Epigenetics-changes in gene expression that do not alter the underlying DNA sequence-may be the answer. In this article, epigenetic mechanisms including DNA methylation and acetylation or methylation of the histone proteins that package DNA are described in the context of animal learning. Through the interaction of these modifications a "histone code" is emerging wherein individual memories leave unique memory traces at the molecular level with distinct time courses. A better understanding of these mechanisms has implications for treatment of memory disorders caused by normal aging or diseases including schizophrenia, Alzheimer's, depression, and drug addiction.

  2. Molecular mechanisms of dominance evolution in Müllerian mimicry.

    PubMed

    Llaurens, V; Joron, M; Billiard, S

    2015-12-01

    Natural selection acting on dominance between adaptive alleles at polymorphic loci can be sufficiently strong for dominance to evolve. However, the molecular mechanisms underlying such evolution are generally unknown. Here, using Müllerian mimicry as a case-study for adaptive morphological variation, we present a theoretical analysis of the invasion of dominance modifiers altering gene expression through different molecular mechanisms. Toxic species involved in Müllerian mimicry exhibit warning coloration, and converge morphologically with other toxic species of the local community, due to positive frequency-dependent selection acting on these colorations. Polymorphism in warning coloration may be maintained by migration-selection balance with fine scale spatial heterogeneity. We modeled a dominance modifier locus altering the expression of the warning coloration locus, targeting one or several alleles, acting in cis or trans, and either enhancing or repressing expression. We confirmed that dominance could evolve when balanced polymorphism was maintained at the color locus. Dominance evolution could result from modifiers enhancing one allele specifically, irrespective of their linkage with the targeted locus. Nonspecific enhancers could also persist in populations, at frequencies tightly depending on their linkage with the targeted locus. Altogether, our results identify which mechanisms of expression alteration could lead to dominance evolution in polymorphic mimicry. © 2015 The Author(s). Evolution © 2015 The Society for the Study of Evolution.

  3. Lipid Raft Redox Signaling: Molecular Mechanisms in Health and Disease

    PubMed Central

    Zhou, Fan; Katirai, Foad

    2011-01-01

    Abstract Lipid rafts, the sphingolipid and cholesterol-enriched membrane microdomains, are able to form different membrane macrodomains or platforms upon stimulations, including redox signaling platforms, which serve as a critical signaling mechanism to mediate or regulate cellular activities or functions. In particular, this raft platform formation provides an important driving force for the assembling of NADPH oxidase subunits and the recruitment of other related receptors, effectors, and regulatory components, resulting, in turn, in the activation of NADPH oxidase and downstream redox regulation of cell functions. This comprehensive review attempts to summarize all basic and advanced information about the formation, regulation, and functions of lipid raft redox signaling platforms as well as their physiological and pathophysiological relevance. Several molecular mechanisms involving the formation of lipid raft redox signaling platforms and the related therapeutic strategies targeting them are discussed. It is hoped that all information and thoughts included in this review could provide more comprehensive insights into the understanding of lipid raft redox signaling, in particular, of their molecular mechanisms, spatial-temporal regulations, and physiological, pathophysiological relevances to human health and diseases. Antioxid. Redox Signal. 15, 1043–1083. PMID:21294649

  4. Epigenetics: Linking Nutrition to Molecular Mechanisms in Aging.

    PubMed

    Park, Joo Hyun; Yoo, Yeongran; Park, Yoon Jung

    2017-06-01

    Healthy aging has become a major goal of public health. Many studies have provided evidence and theories to explain molecular mechanisms of the aging process. Recent studies suggest that epigenetic mechanisms are responsible for life span and the progression of aging. Epigenetics is a fascinating field of molecular biology, which studies heritable modifications of DNA and histones that regulate gene expression without altering the DNA sequence. DNA methylation is a major epigenetic mark that shows progressive changes during aging. Recent studies have investigated aging-related DNA methylation as a biomarker that predicts cellular age. Interestingly, growing evidence proposes that nutrients play a crucial role in the regulation of epigenetic modifiers. Because various nutrients and their metabolites function as substrates or cofactors for epigenetic modifiers, nutrition can modulate or reverse epigenetic marks in the genome as well as expression patterns. Here, we will review the results on aging-associated epigenetic modifications and the possible mechanisms by which nutrition, including nutrient availability and bioactive compounds, regulate epigenetic changes and affect aging physiology.

  5. Enlightening molecular mechanisms through study of protein interactions

    PubMed Central

    Rizo, Josep; Rosen, Michael K.; Gardner, Kevin H.

    2012-01-01

    The investigation of molecular mechanisms is a fascinating area of current biological research that unites efforts from scientists with very diverse expertise. This review provides a perspective on the characterization of protein interactions as a central aspect of this research. We discuss case studies on the neurotransmitter release machinery that illustrate a variety of principles and emphasize the power of combining nuclear magnetic resonance (NMR) spectroscopy with other biophysical techniques, particularly X-ray crystallography. These studies have shown that: (i) the soluble SNAP receptor (SNARE) proteins form a tight complex that brings the synaptic vesicle and plasma membranes together, which is key for membrane fusion; (ii) the SNARE syntaxin-1 adopts an autoinhibitory closed conformation; (iii) Munc18-1 plays crucial functions through interactions with closed syntaxin-1 and with the SNARE complex; (iv) Munc13s mediate the opening of syntaxin-1; (v) complexins play dual roles through distinct interactions with the SNARE complex; (vi) synaptotagmin-1 acts a Ca2+ sensor, interacting simultaneously with the membranes and the SNAREs; and (vii) a Munc13 homodimer to Munc13-RIM heterodimer switch modulates neurotransmitter release. Overall, this research underlines the complexities involved in elucidating molecular mechanisms and how these mechanisms can depend critically on an interplay between strong and weak protein interactions. PMID:22735643

  6. United polarizable multipole water model for molecular mechanics simulation

    SciTech Connect

    Qi, Rui; Wang, Qiantao; Ren, Pengyu; Wang, Lee-Ping; Pande, Vijay S.

    2015-07-07

    We report the development of a united AMOEBA (uAMOEBA) polarizable water model, which is computationally 3–5 times more efficient than the three-site AMOEBA03 model in molecular dynamics simulations while providing comparable accuracy for gas-phase and liquid properties. In this coarse-grained polarizable water model, both electrostatic (permanent and induced) and van der Waals representations have been reduced to a single site located at the oxygen atom. The permanent charge distribution is described via the molecular dipole and quadrupole moments and the many-body polarization via an isotropic molecular polarizability, all located at the oxygen center. Similarly, a single van der Waals interaction site is used for each water molecule. Hydrogen atoms are retained only for the purpose of defining local frames for the molecular multipole moments and intramolecular vibrational modes. The parameters have been derived based on a combination of ab initio quantum mechanical and experimental data set containing gas-phase cluster structures and energies, and liquid thermodynamic properties. For validation, additional properties including dimer interaction energy, liquid structures, self-diffusion coefficient, and shear viscosity have been evaluated. The results demonstrate good transferability from the gas to the liquid phase over a wide range of temperatures, and from nonpolar to polar environments, due to the presence of molecular polarizability. The water coordination, hydrogen-bonding structure, and dynamic properties given by uAMOEBA are similar to those derived from the all-atom AMOEBA03 model and experiments. Thus, the current model is an accurate and efficient alternative for modeling water.

  7. United polarizable multipole water model for molecular mechanics simulation

    NASA Astrophysics Data System (ADS)

    Qi, Rui; Wang, Lee-Ping; Wang, Qiantao; Pande, Vijay S.; Ren, Pengyu

    2015-07-01

    We report the development of a united AMOEBA (uAMOEBA) polarizable water model, which is computationally 3-5 times more efficient than the three-site AMOEBA03 model in molecular dynamics simulations while providing comparable accuracy for gas-phase and liquid properties. In this coarse-grained polarizable water model, both electrostatic (permanent and induced) and van der Waals representations have been reduced to a single site located at the oxygen atom. The permanent charge distribution is described via the molecular dipole and quadrupole moments and the many-body polarization via an isotropic molecular polarizability, all located at the oxygen center. Similarly, a single van der Waals interaction site is used for each water molecule. Hydrogen atoms are retained only for the purpose of defining local frames for the molecular multipole moments and intramolecular vibrational modes. The parameters have been derived based on a combination of ab initio quantum mechanical and experimental data set containing gas-phase cluster structures and energies, and liquid thermodynamic properties. For validation, additional properties including dimer interaction energy, liquid structures, self-diffusion coefficient, and shear viscosity have been evaluated. The results demonstrate good transferability from the gas to the liquid phase over a wide range of temperatures, and from nonpolar to polar environments, due to the presence of molecular polarizability. The water coordination, hydrogen-bonding structure, and dynamic properties given by uAMOEBA are similar to those derived from the all-atom AMOEBA03 model and experiments. Thus, the current model is an accurate and efficient alternative for modeling water.

  8. United polarizable multipole water model for molecular mechanics simulation

    PubMed Central

    Qi, Rui; Wang, Lee-Ping; Wang, Qiantao; Pande, Vijay S.; Ren, Pengyu

    2015-01-01

    We report the development of a united AMOEBA (uAMOEBA) polarizable water model, which is computationally 3–5 times more efficient than the three-site AMOEBA03 model in molecular dynamics simulations while providing comparable accuracy for gas-phase and liquid properties. In this coarse-grained polarizable water model, both electrostatic (permanent and induced) and van der Waals representations have been reduced to a single site located at the oxygen atom. The permanent charge distribution is described via the molecular dipole and quadrupole moments and the many-body polarization via an isotropic molecular polarizability, all located at the oxygen center. Similarly, a single van der Waals interaction site is used for each water molecule. Hydrogen atoms are retained only for the purpose of defining local frames for the molecular multipole moments and intramolecular vibrational modes. The parameters have been derived based on a combination of ab initio quantum mechanical and experimental data set containing gas-phase cluster structures and energies, and liquid thermodynamic properties. For validation, additional properties including dimer interaction energy, liquid structures, self-diffusion coefficient, and shear viscosity have been evaluated. The results demonstrate good transferability from the gas to the liquid phase over a wide range of temperatures, and from nonpolar to polar environments, due to the presence of molecular polarizability. The water coordination, hydrogen-bonding structure, and dynamic properties given by uAMOEBA are similar to those derived from the all-atom AMOEBA03 model and experiments. Thus, the current model is an accurate and efficient alternative for modeling water. PMID:26156485

  9. Molecular mechanisms of cisplatin resistance in cervical cancer

    PubMed Central

    Zhu, Haiyan; Luo, Hui; Zhang, Wenwen; Shen, Zhaojun; Hu, Xiaoli; Zhu, Xueqiong

    2016-01-01

    Patients with advanced or recurrent cervical cancer have poor prognosis, and their 1-year survival is only 10%–20%. Chemotherapy is considered as the standard treatment for patients with advanced or recurrent cervical cancer, and cisplatin appears to treat the disease effectively. However, resistance to cisplatin may develop, thus substantially compromising the efficacy of cisplatin to treat advanced or recurrent cervical cancer. In this article, we systematically review the recent literature and summarize the recent advances in our understanding of the molecular mechanisms underlying cisplatin resistance in cervical cancer. PMID:27354763

  10. On molecular mechanism of the photodynamic therapy of tumors

    NASA Astrophysics Data System (ADS)

    Mostovnikov, Vasili A.; Mostovnikova, Galina R.; Plavski, Vitali Y.; Tretjakov, S. A.

    1995-01-01

    In this work we present the experimental results indicating that the photodestruction (inactivation) of glycolysis enzymes located in mitochondria and responsible for the energy providing of malignant tumors, could serve as a possible molecular mechanism of a photodynamic therapy of cancer. The formation of complexes between the glycolysis enzymes and sensitizer favors can lead to an effective photodestruction of the former [in the experiments lactate dehydrogenase (LDH), pyruvate kinase (PK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and water-soluble tetra(carboxiphenyl)porphyrine [T(CP)P] (the analogue of coprorphyrin) were used as photosensitizer.

  11. The mechanism of selective molecular capture in carbon nanotube networks.

    PubMed

    Wan, Yu; Guan, Jun; Yang, Xudong; Zheng, Quanshui; Xu, Zhiping

    2014-07-28

    Recently, air pollution issues have drawn significant attention to the development of efficient air filters, and one of the most promising materials for this purpose is nanofibers. We explore here the mechanism of selective molecular capture of volatile organic compounds in carbon nanotube networks by performing atomistic simulations. The results are discussed with respect to the two key parameters that define the performance of nanofiltration, i.e. the capture efficiency and flow resistance, which demonstrate the advantages of carbon nanotube networks with high surface-to-volume ratio and atomistically smooth surfaces. We also reveal the important roles of interfacial adhesion and diffusion that govern selective gas transport through the network.

  12. Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development

    PubMed Central

    Bush, Jeffrey O.; Jiang, Rulang

    2012-01-01

    Mammalian palatogenesis is a highly regulated morphogenetic process during which the embryonic primary and secondary palatal shelves develop as outgrowths from the medial nasal and maxillary prominences, respectively, remodel and fuse to form the intact roof of the oral cavity. The complexity of control of palatogenesis is reflected by the common occurrence of cleft palate in humans. Although the embryology of the palate has long been studied, the past decade has brought substantial new knowledge of the genetic control of secondary palate development. Here, we review major advances in the understanding of the morphogenetic and molecular mechanisms controlling palatal shelf growth, elevation, adhesion and fusion, and palatal bone formation. PMID:22186724

  13. Dietary flavonoids: molecular mechanisms of action as anti- inflammatory agents.

    PubMed

    Marzocchella, Laura; Fantini, Massimo; Benvenuto, Monica; Masuelli, Laura; Tresoldi, Ilaria; Modesti, Andrea; Bei, Roberto

    2011-09-01

    Flavonoids are a large group of polyphenolic compounds, which are ubiquitously expressed in plants. They are grouped according to their chemical structure and function into flavonols, flavones, flavan-3-ols, anthocyanins, flavanones and isoflavones. Many of flavonoids are found in fruits, vegetables and beverages. Flavonoids have been demonstrated to have advantageous effects on human health because their anti-allergic, anti-inflammatory, anti-platelet aggregation, anti-tumor and anti-oxidant behavior. This report reviews the current knowledge on the molecular mechanisms of action of flavonoids as anti-inflammatory agents and also discusses the relevant patents.

  14. Molecular and Electrophysiological Mechanisms Underlying Cardiac Arrhythmogenesis in Diabetes Mellitus

    PubMed Central

    Tse, Vivian; Yeo, Jie Ming

    2016-01-01

    Diabetes is a common endocrine disorder with an ever increasing prevalence globally, placing significant burdens on our healthcare systems. It is associated with significant cardiovascular morbidities. One of the mechanisms by which it causes death is increasing the risk of cardiac arrhythmias. The aim of this article is to review the cardiac (ion channel abnormalities, electrophysiological and structural remodelling) and extracardiac factors (neural pathway remodelling) responsible for cardiac arrhythmogenesis in diabetes. It is concluded by an outline of molecular targets for future antiarrhythmic therapy for the diabetic population. PMID:27642609

  15. Molecular mechanisms of methicillin resistance in Staphylococcus aureus.

    PubMed

    Domínguez, M A; Liñares, J; Martín, R

    1997-09-01

    Methicillin-resistant Staphylococcus aureus (MRSA) strains are among the most common nosocomial pathogens. The most significant mechanism of resistance to methicillin in this-species is the acquisition of a genetic determinant (mecA gene). However, resistance seems to have a more complex molecular basis, since additional chromosomal material is involved in such resistance. Besides, overproduction of penicillinase and/or alterations in the PBPs can contribute to the formation of resistance phenotypes. Genetic and environmental factors leading to MRSA are reviewed.

  16. Molecular mechanics of dihydroxyphenylalanine at a silica interface

    NASA Astrophysics Data System (ADS)

    Qin, Zhao; Buehler, Markus

    2012-08-01

    L-3,4-dihydroxyphenylalanine (DOPA) is an amazing biological glue secreted by marine mussels. Through enhanced sampling molecular dynamics, here we demonstrate that proteins with DOPA residues have a strong affinity to a silica surface with an interfacial strength of several hundreds of thousand N/cm2. The mechanism of such strong adhesion is a pair of hydrogen bonds that forms between DOPA and the substrate, enabling enhanced cooperativity as the DOPA residue lays flat on top the surface. Our predicted adhesion force (743 pN) agrees well with experimental measurements (847 ± 157 pN), including the orientation of the DOPA residue on the surface.

  17. Molecular mechanisms of l-DOPA-induced dyskinesia.

    PubMed

    Fisone, Gilberto; Bezard, Erwan

    2011-01-01

    Parkinson's disease (PD), a common neurodegenerative disorder caused by the loss of the dopaminergic input to the basal ganglia, is commonly treated with l-DOPA. Use of this drug, however, is severely limited by the development of dystonic and choreic motor complications, or dyskinesia. This chapter describes the molecular mechanisms implicated in the emergence and manifestation of l-DOPA-induced dyskinesia (LID). Particular emphasis is given to the role played in this condition by abnormalities in signal transduction at the level of the medium spiny neurons (MSNs) of the striatum, which are the principal target of l-DOPA. Recent evidence pointing to pre-synaptic dysregulation is also discussed.

  18. Molecular Mechanisms Leading to Splanchnic Vasodilation in Liver Cirrhosis.

    PubMed

    Di Pascoli, Marco; Sacerdoti, David; Pontisso, Patrizia; Angeli, Paolo; Bolognesi, Massimo

    2017-01-01

    In liver cirrhosis, portal hypertension is a consequence of enhanced intrahepatic vascular resistance and portal blood flow. Significant vasodilation in the arterial splanchnic district is crucial for an increase in portal flow. In this pathological condition, increased levels of circulating endogenous vasodilators, including nitric oxide, prostacyclin, carbon monoxide, epoxyeicosatrienoic acids, glucagon, endogenous cannabinoids, and adrenomedullin, and a decreased vascular response to vasoconstrictors are the main mechanisms underlying splanchnic vasodilation. In this review, the molecular pathways leading to splanchnic vasodilation will be discussed in detail. © 2017 S. Karger AG, Basel.

  19. Drugs meeting the molecular basis of diabetic kidney disease: bridging from molecular mechanism to personalized medicine.

    PubMed

    Lambers Heerspink, Hiddo J; Oberbauer, Rainer; Perco, Paul; Heinzel, Andreas; Heinze, Georg; Mayer, Gert; Mayer, Bernd

    2015-08-01

    Diabetic kidney disease (DKD) is a complex, multifactorial disease and is associated with a high risk of renal and cardiovascular morbidity and mortality. Clinical practice guidelines for diabetes recommend essentially identical treatments for all patients without taking into account how the individual responds to the instituted therapy. Yet, individuals vary widely in how they respond to medications and therefore optimal therapy differs between individuals. Understanding the underlying molecular mechanisms of variability in drug response will help tailor optimal therapy. Polymorphisms in genes related to drug pharmacokinetics have been used to explore mechanisms of response variability in DKD, but with limited success. The complex interaction between genetic make-up and environmental factors on the abundance of proteins and metabolites renders pharmacogenomics alone insufficient to fully capture response variability. A complementary approach is to attribute drug response variability to individual variability in underlying molecular mechanisms involved in the progression of disease. The interplay of different processes (e.g. inflammation, fibrosis, angiogenesis, oxidative stress) appears to drive disease progression, but the individual contribution of each process varies. Drugs at the other hand address specific targets and thereby interfere in certain disease-associated processes. At this level, biomarkers may help to gain insight into which specific pathophysiological processes are involved in an individual followed by a rational assessment whether a specific drug's mode of action indeed targets the relevant process at hand. This article describes the conceptual background and data-driven workflow developed by the SysKid consortium aimed at improving characterization of the molecular mechanisms underlying DKD at the interference of the molecular impact of individual drugs in order to tailor optimal therapy to individual patients. © The Author 2015. Published by

  20. Forces in molecular recognition: Comparison of experimental data and molecular mechanics calculations

    NASA Astrophysics Data System (ADS)

    Waltho, J. P.; Vinter, J. G.; Davis, A.; Williams, D. H.

    1988-04-01

    NMR studies of the rotation barrier of the disaccharide of the glycopeptide antibiotic vancomycin have been used to test the performance of computer simulation techniques using molecular mechanics. In the absence of any solvated water, no correlation could be found between experiment and calculation. By introducing solvent water molecules into the binding region of the antibiotic, the NMR results could be simulated both qualitatively and quantitatively within experimental error without using massive computational resources.

  1. Molecular View of Protein Crystal Growth: Molecular Interactions, Surface Reconstruction and Growth Mechanism

    NASA Technical Reports Server (NTRS)

    Nadarajah, Arunan; Li, Huayu; Konnert, John H.; Pusey, Marc L.

    2000-01-01

    Studies of the growth and molecular packing of tetragonal lysozyme crystals suggest that there is an underlying molecular growth mechanism, in addition to the classical one involving screw dislocation/2D) nucleation growth. These crystals are constructed by strongly bonded molecular chains forming helices about the 43 axes. The helices are connected to each other by weaker bonds. Crystal growth proceeds by the formation of these 4(sub 3) helices, which would explain some unexpected observations by earlier investigators, such as bimolecular growth steps on the (110) face. Another consequence of these molecular considerations is that only one of two possible packing arrangements could occur on the crystal faces and that their growth unit was at least a tetramer corresponding to the 4(sub 3) helix. Two new high resolution atomic force microscopy (AFM) techniques were developed to directly confirm these predictions on tetragonal lysozyme crystals. Most earlier investigations of protein crystal growth with AFM were in the low resolution mode which is adequate to investigate the classical growth mechanisms, but cannot resolve molecular features and mechanisms. Employing the first of the newly developed techniques, high resolution AFM images of the (110) face were compared with the theoretically constructed images for the two possible packing arrangements on this face. The prediction that the molecular packing arrangement of these faces corresponded to that for complete 4(sub 3) helices was confirmed in this manner. This investigation also showed the occurrence of surface reconstruction on protein crystals. The molecules on the surface of the (110) face were found to pack closer along the 4(sub 3) axes than those in the interior. The second new AFM technique was used to follow the growth process by measuring the dimensions of individual growth units on the (110) face. Linescans across a growth step, performed near the saturation limit of the crystals, allowed the growth

  2. Molecular View of Protein Crystal Growth: Molecular Interactions, Surface Reconstruction and Growth Mechanism

    NASA Technical Reports Server (NTRS)

    Nadarajah, Arunan; Li, Huayu; Konnert, John H.; Pusey, Marc L.

    2000-01-01

    Studies of the growth and molecular packing of tetragonal lysozyme crystals suggest that there is an underlying molecular growth mechanism, in addition to the classical one involving screw dislocation/2D) nucleation growth. These crystals are constructed by strongly bonded molecular chains forming helices about the 43 axes. The helices are connected to each other by weaker bonds. Crystal growth proceeds by the formation of these 4(sub 3) helices, which would explain some unexpected observations by earlier investigators, such as bimolecular growth steps on the (110) face. Another consequence of these molecular considerations is that only one of two possible packing arrangements could occur on the crystal faces and that their growth unit was at least a tetramer corresponding to the 4(sub 3) helix. Two new high resolution atomic force microscopy (AFM) techniques were developed to directly confirm these predictions on tetragonal lysozyme crystals. Most earlier investigations of protein crystal growth with AFM were in the low resolution mode which is adequate to investigate the classical growth mechanisms, but cannot resolve molecular features and mechanisms. Employing the first of the newly developed techniques, high resolution AFM images of the (110) face were compared with the theoretically constructed images for the two possible packing arrangements on this face. The prediction that the molecular packing arrangement of these faces corresponded to that for complete 4(sub 3) helices was confirmed in this manner. This investigation also showed the occurrence of surface reconstruction on protein crystals. The molecules on the surface of the (110) face were found to pack closer along the 4(sub 3) axes than those in the interior. The second new AFM technique was used to follow the growth process by measuring the dimensions of individual growth units on the (110) face. Linescans across a growth step, performed near the saturation limit of the crystals, allowed the growth

  3. Molecular Mechanisms of Two-Component Signal Transduction.

    PubMed

    Zschiedrich, Christopher P; Keidel, Victoria; Szurmant, Hendrik

    2016-09-25

    Two-component systems (TCS) comprising sensor histidine kinases and response regulator proteins are among the most important players in bacterial and archaeal signal transduction and also occur in reduced numbers in some eukaryotic organisms. Given their importance to cellular survival, virulence, and cellular development, these systems are among the most scrutinized bacterial proteins. In the recent years, a flurry of bioinformatics, genetic, biochemical, and structural studies have provided detailed insights into many molecular mechanisms that underlie the detection of signals and the generation of the appropriate response by TCS. Importantly, it has become clear that there is significant diversity in the mechanisms employed by individual systems. This review discusses the current knowledge on common themes and divergences from the paradigm of TCS signaling. An emphasis is on the information gained by a flurry of recent structural and bioinformatics studies. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Molecular mechanisms of the membrane sculpting ESCRT pathway.

    PubMed

    Henne, William Mike; Stenmark, Harald; Emr, Scott D

    2013-09-01

    The endosomal sorting complexes required for transport (ESCRT) drive multivesicular body (MVB) biogenesis and cytokinetic abscission. Originally identified through genetics and cell biology, more recent work has begun to elucidate the molecular mechanisms of ESCRT-mediated membrane remodeling, with special focus on the ESCRT-III complex. In particular, several light and electron microscopic studies provide high-resolution imaging of ESCRT-III rings and spirals that purportedly drive MVB morphogenesis and abscission. These studies highlight unifying principles to ESCRT-III function, in particular: (1) the ordered assembly of the ESCRT-III monomers into a heteropolymer, (2) ESCRT-III as a dynamic complex, and (3) the role of the AAA ATPase Vps4 as a contributing factor in membrane scission. Mechanistic comparisons of ESCRT-III function in MVB morphogenesis and cytokinesis suggest common mechanisms in membrane remodeling.

  5. Molecular and Cellular Regulatory Mechanisms of Tongue Myogenesis

    PubMed Central

    Parada, C.; Han, D.; Chai, Y.

    2012-01-01

    The tongue exerts crucial functions in our daily life. However, we know very little about the regulatory mechanisms of mammalian tongue development. In this review, we summarize recent findings of the molecular and cellular mechanisms that control tissue-tissue interactions during tongue morphogenesis. Specifically, cranial neural crest cells (CNCC) lead the initiation of tongue bud formation and contribute to the interstitial connective tissue, which ultimately compartmentalizes tongue muscles and serves as their attachments. Occipital somite-derived cells migrate into the tongue primordium and give rise to muscle cells in the tongue. The intimate relationship between CNCC- and mesoderm-derived cells, as well as growth and transcription factors that have been shown to be crucial for tongue myogenesis, clearly indicate that tissue-tissue interactions play an important role in regulating tongue morphogenesis. PMID:22219210

  6. HBV DNA Integration: Molecular Mechanisms and Clinical Implications

    PubMed Central

    Tu, Thomas; Budzinska, Magdalena A.; Shackel, Nicholas A.; Urban, Stephan

    2017-01-01

    Chronic infection with the Hepatitis B Virus (HBV) is a major cause of liver-related morbidity and mortality. One peculiar observation in cells infected with HBV (or with closely‑related animal hepadnaviruses) is the presence of viral DNA integration in the host cell genome, despite this form being a replicative dead-end for the virus. The frequent finding of somatic integration of viral DNA suggests an evolutionary benefit for the virus; however, the mechanism of integration, its functions, and the clinical implications remain unknown. Here we review the current body of knowledge of HBV DNA integration, with particular focus on the molecular mechanisms and its clinical implications (including the possible consequences of replication-independent antigen expression and its possible role in hepatocellular carcinoma). HBV DNA integration is likely to influence HBV replication, persistence, and pathogenesis, and so deserves greater attention in future studies. PMID:28394272

  7. Molecular mechanism of action of microtubule-stabilizing anticancer agents.

    PubMed

    Prota, Andrea E; Bargsten, Katja; Zurwerra, Didier; Field, Jessica J; Díaz, José Fernando; Altmann, Karl-Heinz; Steinmetz, Michel O

    2013-02-01

    Microtubule-stabilizing agents (MSAs) are efficacious chemotherapeutic drugs widely used for the treatment of cancer. Despite the importance of MSAs for medical applications and basic research, their molecular mechanisms of action on tubulin and microtubules remain elusive. We determined high-resolution crystal structures of αβ-tubulin in complex with two unrelated MSAs, zampanolide and epothilone A. Both compounds were bound to the taxane pocket of β-tubulin and used their respective side chains to induce structuring of the M-loop into a short helix. Because the M-loop establishes lateral tubulin contacts in microtubules, these findings explain how taxane-site MSAs promote microtubule assembly and stability. Further, our results offer fundamental structural insights into the control mechanisms of microtubule dynamics.

  8. A quest to understand molecular mechanisms for genetic stability.

    PubMed

    Sekiguchi, Mutsuo

    2006-06-10

    In the midst of the post-war turmoil in Japan, I fortunately followed a path to become a scientist. Sometime at an early stage of my career, I encountered the problem of the cellular response to DNA damage and had the chance to discover a DNA repair enzyme. This event greatly influenced the subsequent course of my research, and I extended my studies toward elucidating the molecular mechanisms of mutagenesis as well as of carcinogenesis. Through these studies I came to understand the importance of mechanisms for dealing with the actions of reactive oxygen species to the living systems. These recollections deal with these endeavors with emphasis on the early part of my scientific career.

  9. Cellular and Molecular Mechanisms Underpinning Macrophage Activation during Remyelination

    PubMed Central

    Lloyd, Amy F.; Miron, Veronique E.

    2016-01-01

    Remyelination is an example of central nervous system (CNS) regeneration, whereby myelin is restored around demyelinated axons, re-establishing saltatory conduction and trophic/metabolic support. In progressive multiple sclerosis, remyelination is limited or fails altogether which is considered to contribute to axonal damage/loss and consequent disability. Macrophages have critical roles in both CNS damage and regeneration, such as remyelination. This diverse range in functions reflects the ability of macrophages to acquire tissue microenvironment-specific activation states. This activation is dynamically regulated during efficient regeneration, with a switch from pro-inflammatory to inflammation-resolution/pro-regenerative phenotypes. Although, some molecules and pathways have been implicated in the dynamic activation of macrophages, such as NFκB, the cellular and molecular mechanisms underpinning plasticity of macrophage activation are unclear. Identifying mechanisms regulating macrophage activation to pro-regenerative phenotypes may lead to novel therapeutic strategies to promote remyelination in multiple sclerosis. PMID:27446913

  10. Advances in molecular mechanism of cardioprotection induced by helium

    PubMed Central

    Ding, Yi-ping; Zhang, Ju-yi; Feng, Dong-xia; Kong, Yan; Xu, Zhuan; Chen, Gang

    2017-01-01

    Helium has been classified as a kind of inert gas that is not effortless to spark chemical reactions with other substances in the past decades. Nevertheless, the cognition of scientists has gradually changed accompanied with a variety of studies revealing the potential molecular mechanism underlying organ-protection induced by helium. Especially, as a non-anesthetic gas which is deficient of relevant cardiopulmonary side effects, helium conditioning is recognized as an emerging and promising approach to exert favorable effects by mimicking the cardioprotection of anesthetic gases or xenon. In this review we will summarize advances in the underlying biological mechanisms and clinical applicability with regards to the cardioprotective effects of helium. PMID:28744366

  11. Molecular mechanisms in the pathogenesis of diabetic nephropathy: an update.

    PubMed

    Arora, Mandeep Kumar; Singh, Umesh Kumar

    2013-04-01

    Diabetes mellitus is known to trigger retinopathy, neuropathy and nephropathy. Diabetic nephropathy, a long-term major microvascular complication of uncontrolled hyperglycemia, affects a large population worldwide. Recent findings suggest that numerous pathways are activated during the course of diabetes mellitus and that these pathways individually or collectively play a role in the induction and progression of diabetic nephropathy. However, clinical strategies targeting these pathways to manage diabetic nephropathy remain unsatisfactory, as the number of diabetic patients with nephropathy is increasing yearly. To develop ground-breaking therapeutic options to prevent the development and progression of diabetic nephropathy, a comprehensive understanding of the molecular mechanisms involved in the pathogenesis of the disease is mandatory. Therefore, the purpose of this paper is to discuss the underlying mechanisms and downstream pathways involved in the pathogenesis of diabetic nephropathy.

  12. Dissecting the Molecular Mechanisms of Neurodegenerative Diseases through Network Biology.

    PubMed

    Santiago, Jose A; Bottero, Virginie; Potashkin, Judith A

    2017-01-01

    Neurodegenerative diseases are rarely caused by a mutation in a single gene but rather influenced by a combination of genetic, epigenetic and environmental factors. Emerging high-throughput technologies such as RNA sequencing have been instrumental in deciphering the molecular landscape of neurodegenerative diseases, however, the interpretation of such large amounts of data remains a challenge. Network biology has become a powerful platform to integrate multiple omics data to comprehensively explore the molecular networks in the context of health and disease. In this review article, we highlight recent advances in network biology approaches with an emphasis in brain-networks that have provided insights into the molecular mechanisms leading to the most prevalent neurodegenerative diseases including Alzheimer's (AD), Parkinson's (PD) and Huntington's diseases (HD). We discuss how integrative approaches using multi-omics data from different tissues have been valuable for identifying biomarkers and therapeutic targets. In addition, we discuss the challenges the field of network medicine faces toward the translation of network-based findings into clinically actionable tools for personalized medicine applications.

  13. Molecular mechanisms driving homeostatic plasticity of neurotransmitter release

    PubMed Central

    Lazarevic, Vesna; Pothula, Santosh; Andres-Alonso, Maria; Fejtova, Anna

    2013-01-01

    Homeostatic plasticity is a process by which neurons adapt to the overall network activity to keep their firing rates in a reasonable range. At the cellular level this kind of plasticity comprises modulation of cellular excitability and tuning of synaptic strength. In this review we concentrate on presynaptic homeostatic plasticity controlling the efficacy of neurotransmitter release from presynaptic boutons. While morphological and electrophysiological approaches were successful to describe homeostatic plasticity-induced changes in the presynaptic architecture and function, cellular and molecular mechanisms underlying those modifications remained largely unknown for a long time. We summarize the latest progress made in the understanding of homeostasis-induced regulation of different steps of the synaptic vesicle cycle and the molecular machineries involved in this process. We particularly focus on the role of presynaptic scaffolding proteins, which functionally and spatially organize synaptic vesicle clusters, neurotransmitter release sites and the associated endocytic machinery. These proteins turned out to be major presynaptic substrates for remodeling during homeostatic plasticity. Finally, we discuss cellular processes and signaling pathways acting during homeostatic molecular remodeling and their potential involvement in the maladaptive plasticity occurring in multiple neuropathologic conditions such as neurodegeneration, epilepsy and neuropsychiatric disorders. PMID:24348337

  14. Molecular mechanism of statin-mediated LOX-1 inhibition.

    PubMed

    Biocca, Silvia; Iacovelli, Federico; Matarazzo, Sara; Vindigni, Giulia; Oteri, Francesco; Desideri, Alessandro; Falconi, Mattia

    2015-01-01

    Statins are largely used in clinics in the treatment of patients with cardiovascular diseases for their effect on lowering circulating cholesterol. Lectin-like oxidized low-density lipoprotein (LOX-1), the primary receptor for ox-LDL, plays a central role in the pathogenesis of atherosclerosis and cardiovascular disorders. We have recently shown that chronic exposure of cells to lovastatin disrupts LOX-1 receptor cluster distribution in plasma membranes, leading to a marked loss of LOX-1 function. Here we investigated the molecular mechanism of statin-mediated LOX-1 inhibition and we demonstrate that all tested statins are able to displace the binding of fluorescent ox-LDL to LOX-1 by a direct interaction with LOX-1 receptors in a cell-based binding assay. Molecular docking simulations confirm the interaction and indicate that statins completely fill the hydrophobic tunnel that crosses the C-type lectin-like (CTLD) recognition domain of LOX-1. Classical molecular dynamics simulation technique applied to the LOX-1 CTLD, considered in the entire receptor structure with or without a statin ligand inside the tunnel, indicates that the presence of a ligand largely increases the dimer stability. Electrophoretic separation and western blot confirm that different statins binding stabilize the dimer assembly of LOX-1 receptors in vivo. The simulative and experimental results allow us to propose a CTLD clamp motion, which enables the receptor-substrate coupling. These findings reveal a novel and significant functional effect of statins.

  15. Lactobacilli as multifaceted probiotics with poorly disclosed molecular mechanisms.

    PubMed

    Turpin, Williams; Humblot, Christèle; Thomas, Muriel; Guyot, Jean-Pierre

    2010-10-15

    Lactic acid bacteria and more particularly lactobacilli have been used for the production of fermented foods for centuries. Several lactobacilli have been recognized as probiotics due to their wide range of health-promoting effects in humans. However, little is known about the molecular mechanisms underpinning their probiotic functions. Here we reviewed the main beneficial effects of lactobacilli and discussed, when the information is available, the molecular machinery involved in their probiotic function. Among the beneficial effects, lactobacilli can improve digestion, absorption and availability of nutrients. As an example, some strains are able to degrade carbohydrates such as lactose or α-galactosides that may cause abdominal pain. Furthermore, they can hydrolyze compounds that limit the bioavailability of minerals like tannin and phytate due to tannin acylhydrolase and phytase activities. In addition, it was shown that some lactobacilli strains can improve mineral absorption in Caco-2 cells. Lactobacilli can also contribute to improve the nutritional status of the host by producing B group vitamins. More recently, the role of lactobacilli in energy homeostasis, particularly in obese patients, is the object of an increased interest. Lactobacilli are also involved in the prevention of diseases. They have potential to prevent carcinogenesis through the modulation of enzymes involved in the xenobiotic pathway, and may prevent cardiovascular diseases such as hypertension through the production of a bioactive peptide that may have angiotensin converting enzyme inhibitor activity. Lactobacilli are increasingly studied for the treatment of inflammatory bowel diseases and exhibit interesting potential in the reduction of pain perception. The ability of some strains to bind to intestinal cells, their pathogen-associated molecular patterns and the metabolites they produce confer interesting immunomodulatory effects. Finally, pathogenic fungi, virus or bacteria can be

  16. Molecular Mechanisms of Phosphorus Metabolism and Transport during Leaf Senescence

    PubMed Central

    Stigter, Kyla A.; Plaxton, William C.

    2015-01-01

    Leaf senescence, being the final developmental stage of the leaf, signifies the transition from a mature, photosynthetically active organ to the attenuation of said function and eventual death of the leaf. During senescence, essential nutrients sequestered in the leaf, such as phosphorus (P), are mobilized and transported to sink tissues, particularly expanding leaves and developing seeds. Phosphorus recycling is crucial, as it helps to ensure that previously acquired P is not lost to the environment, particularly under the naturally occurring condition where most unfertilized soils contain low levels of soluble orthophosphate (Pi), the only form of P that roots can directly assimilate from the soil. Piecing together the molecular mechanisms that underpin the highly variable efficiencies of P remobilization from senescing leaves by different plant species may be critical for devising effective strategies for improving overall crop P-use efficiency. Maximizing Pi remobilization from senescing leaves using selective breeding and/or biotechnological strategies will help to generate P-efficient crops that would minimize the use of unsustainable and polluting Pi-containing fertilizers in agriculture. This review focuses on the molecular mechanisms whereby P is remobilized from senescing leaves and transported to sink tissues, which encompasses the action of hormones, transcription factors, Pi-scavenging enzymes, and Pi transporters. PMID:27135351

  17. Zinc and diabetes--clinical links and molecular mechanisms.

    PubMed

    Jansen, Judith; Karges, Wolfram; Rink, Lothar

    2009-06-01

    Zinc is an essential trace element crucial for the function of more than 300 enzymes and it is important for cellular processes like cell division and apoptosis. Hence, the concentration of zinc in the human body is tightly regulated and disturbances of zinc homeostasis have been associated with several diseases including diabetes mellitus, a disease characterized by high blood glucose concentrations as a consequence of decreased secretion or action of insulin. Zinc supplementation of animals and humans has been shown to ameliorate glycemic control in type 1 and 2 diabetes, the two major forms of diabetes mellitus, but the underlying molecular mechanisms have only slowly been elucidated. Zinc seems to exert insulin-like effects by supporting the signal transduction of insulin and by reducing the production of cytokines, which lead to beta-cell death during the inflammatory process in the pancreas in the course of the disease. Furthermore, zinc might play a role in the development of diabetes, since genetic polymorphisms in the gene of zinc transporter 8 and in metallothionein (MT)-encoding genes could be demonstrated to be associated with type 2 diabetes mellitus. The fact that antibodies against this zinc transporter have been detected in type 1 diabetic patients offers new diagnostic possibilities. This article reviews the influence of zinc on the diabetic state including the molecular mechanisms, the role of the zinc transporter 8 and MT for diabetes development and the resulting diagnostic and therapeutic options.

  18. Molecular mechanisms of host cell traversal by malaria sporozoites.

    PubMed

    Yang, Annie S P; Boddey, Justin A

    2017-02-01

    Malaria is a pernicious infectious disease caused by apicomplexan parasites of the genus Plasmodium. Each year, malaria afflicts over 200million people, causing considerable morbidity, loss to gross domestic product of endemic countries, and more than 420,000 deaths. A central feature of the virulence of malaria parasites is the ability of sporozoite forms injected by a mosquito to navigate from the inoculation site in the skin through host tissues to infect the liver. The ability for sporozoites to traverse through different host cell types is very important for the successful development of parasites within the mammalian host. Over the past decade, our understanding of the role of host cell traversal has become clearer through important studies with rodent models of malaria. However, we still do not understand the stepwise process of host cell entry and exit or know the molecular mechanisms governing each step. We know even less about cell traversal by malaria parasite species that infect humans. Here, we review current knowledge regarding the role and molecular mechanisms of sporozoite cell traversal and highlight recent advances that prompt new ways of thinking about this important process. Copyright © 2016 Australian Society for Parasitology. Published by Elsevier Ltd. All rights reserved.

  19. Molecular mechanism of fluoroquinolones resistance in Mycoplasma hominis clinical isolates.

    PubMed

    Meng, Dong-Ya; Sun, Chang-Jian; Yu, Jing-Bo; Ma, Jun; Xue, Wen-Cheng

    2014-01-01

    To evaluate the molecular mechanism of fluoroquinolones resistance in Mycoplasma hominis (MH) clinical strains isolated from urogenital specimens. 15 MH clinical isolates with different phenotypes of resistance to fluoroquinolones antibiotics were screened for mutations in the quinolone resistance-determining regions (QRDRs) of DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE) in comparison with the reference strain PG21, which is susceptible to fluoroquinolones antibiotics. 15 MH isolates with three kinds of quinolone resistance phenotypes were obtained. Thirteen out of these quinolone-resistant isolates were found to carry nucleotide substitutions in either gyrA or parC. There were no alterations in gyrB and no mutations were found in the isolates with a phenotype of resistance to Ofloxacin (OFX), intermediate resistant to Levofloxacin (LVX) and Sparfloxacin (SFX), and those susceptible to all three tested antibiotics. The molecular mechanism of fluoroquinolone resistance in clinical isolates of MH was reported in this study. The single amino acid mutation in ParC of MH may relate to the resistance to OFX and LVX and the high-level resistance to fluoroquinolones for MH is likely associated with mutations in both DNA gyrase and the ParC subunit of topoisomerase IV.

  20. Molecular Mechanisms of Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension

    PubMed Central

    Leopold, Jane A.; Maron, Bradley A.

    2016-01-01

    Pulmonary arterial hypertension (PAH) is a devastating disease that is precipitated by hypertrophic pulmonary vascular remodeling of distal arterioles to increase pulmonary artery pressure and pulmonary vascular resistance in the absence of left heart, lung parenchymal, or thromboembolic disease. Despite available medical therapy, pulmonary artery remodeling and its attendant hemodynamic consequences result in right ventricular dysfunction, failure, and early death. To limit morbidity and mortality, attention has focused on identifying the cellular and molecular mechanisms underlying aberrant pulmonary artery remodeling to identify pathways for intervention. While there is a well-recognized heritable genetic component to PAH, there is also evidence of other genetic perturbations, including pulmonary vascular cell DNA damage, activation of the DNA damage response, and variations in microRNA expression. These findings likely contribute, in part, to dysregulation of proliferation and apoptosis signaling pathways akin to what is observed in cancer; changes in cellular metabolism, metabolic flux, and mitochondrial function; and endothelial-to-mesenchymal transition as key signaling pathways that promote pulmonary vascular remodeling. This review will highlight recent advances in the field with an emphasis on the aforementioned molecular mechanisms as contributors to the pulmonary vascular disease pathophenotype. PMID:27213345

  1. Molecular mechanisms of the plant heat stress response

    SciTech Connect

    Qu, Ai-Li; Ding, Yan-Fei; Jiang, Qiong; Zhu, Cheng

    2013-03-08

    Highlights: ► This review elaborates the response networks of heat stress in plants. ► It elaborates proteins responding to heat stress in special physiological period. ► The proteins and pathways have formed a basic network of the heat stress response. ► Achievements of the various technologies are also combined. -- Abstract: High temperature has become a global concern, which seriously affects the growth and production of plants, particularly crops. Thus, the molecular mechanism of the heat stress response and breeding of heat-tolerant plants is necessary to protect food production and ensure crop safety. This review elaborates on the response networks of heat stress in plants, including the Hsf and Hsp response pathways, the response of ROS and the network of the hormones. In addition, the production of heat stress response elements during particular physiological periods of the plant is described. We also discuss the existing problems and future prospects concerning the molecular mechanisms of the heat stress response in plants.

  2. Molecular mechanisms in the formation of the medial longitudinal fascicle

    PubMed Central

    Ahsan, Mansoor; Riley, Kerry-lyn; Schubert, Frank R

    2007-01-01

    The first neurons in the vertebrate brain form a stereotypical array of longitudinal and transversal axon tracts, the early axon scaffold. This scaffold is thought to lay down the basic structure for the later, more complex neuronal pathways in the brain. The ventral longitudinal tract is pioneered by neurons located at the ventral midbrain–forebrain boundary, which form the medial longitudinal fascicle. Recent studies have shed some light on the molecular mechanisms that control the development of the medial longitudinal fascicle. Here, we show that patterning molecules, notably the ventralizing signalling molecule Shh, are involved in the formation of medial longitudinal fascicle neurons and in medial longitudinal fascicle axon guidance. Downstream of Shh, several homeobox genes are expressed in the tegmentum. We describe the expression patterns of Sax1, Emx2, Six3, Nkx2.2 and Pax6 in the mesencephalon and pretectum in detail. Furthermore, we review the evidence of their molecular interactions, and their involvement in neuronal fate specification. In particular, Sax1 plays a major role in fate determination of medial longitudinal fascicle neurons. Finally, we discuss the available data on axon guidance mechanisms for the medial longitudinal fascicle, which suggest that different guidance molecules such as class 3 Semaphorins, Slits and Netrins act to determine the caudal and ventral course of the medial longitudinal fascicle axons. PMID:17623036

  3. Molecular mechanisms of chemotherapy-induced hair loss.

    PubMed

    Botchkarev, Vladimir A

    2003-06-01

    Hair loss (alopecia) is a much-feared side-effect of many chemotherapy protocols and is one of the most psychological devastating aspects of cancer therapy. So far, no satisfactory strategy for suppressing chemotherapy-induced alopecia is at hand. During the last decade, some progress in understanding molecular mechanisms of chemotherapy-induced hair loss has been achieved using rodent models. However, the pathobiology of the response of human hair follicle to chemotherapy remains largely unknown. Here, we review molecular mechanisms that control apoptosis in the hair follicle induced by chemotherapy and delineate the basic strategy for pharmacological inhibition of this devastating side-effect of cancer treatment. We focus on the roles of p53 and its target genes that are essential in mediating responses of hair follicle cells. We assume that local pharmacological inhibition of p53 activity may serve as an effective treatment to prevent chemotherapy-induced hair loss. Sufficient pharmacological inhibition of chemotherapy-induced hair loss may require a combination of inhibitors to block complementary or redundant pathways of apoptosis in hair follicles.

  4. Molecular mechanisms of ROS production and oxidative stress in diabetes.

    PubMed

    Newsholme, Philip; Cruzat, Vinicius Fernandes; Keane, Kevin Noel; Carlessi, Rodrigo; de Bittencourt, Paulo Ivo Homem

    2016-12-15

    Oxidative stress and chronic inflammation are known to be associated with the development of metabolic diseases, including diabetes. Oxidative stress, an imbalance between oxidative and antioxidative systems of cells and tissues, is a result of over production of oxidative-free radicals and associated reactive oxygen species (ROS). One outcome of excessive levels of ROS is the modification of the structure and function of cellular proteins and lipids, leading to cellular dysfunction including impaired energy metabolism, altered cell signalling and cell cycle control, impaired cell transport mechanisms and overall dysfunctional biological activity, immune activation and inflammation. Nutritional stress, such as that caused by excess high-fat and/or carbohydrate diets, promotes oxidative stress as evident by increased lipid peroxidation products, protein carbonylation and decreased antioxidant status. In obesity, chronic oxidative stress and associated inflammation are the underlying factors that lead to the development of pathologies such as insulin resistance, dysregulated pathways of metabolism, diabetes and cardiovascular disease through impaired signalling and metabolism resulting in dysfunction to insulin secretion, insulin action and immune responses. However, exercise may counter excessive levels of oxidative stress and thus improve metabolic and inflammatory outcomes. In the present article, we review the cellular and molecular origins and significance of ROS production, the molecular targets and responses describing how oxidative stress affects cell function including mechanisms of insulin secretion and action, from the point of view of possible application of novel diabetic therapies based on redox regulation.

  5. Towards identification of molecular mechanisms of short stature

    PubMed Central

    2013-01-01

    Growth evaluations are among the most common referrals to pediatric endocrinologists. Although a number of pathologies, both primary endocrine and non-endocrine, can present with short stature, an estimated 80% of evaluations fail to identify a clear etiology, leaving a default designation of idiopathic short stature (ISS). As a group, several features among children with ISS are suggestive of pathophysiology of the GH–IGF-1 axis, including low serum levels of IGF-1 despite normal GH secretion. Candidate gene analysis of rare cases has demonstrated that severe mutations of genes of the GH–IGF-1 axis can present with a profound height phenotype, leading to speculation that a collection of mild mutations or polymorphisms of these genes can explain poor growth in a larger proportion of patients. Recent genome-wide association studies have identified ~180 genomic loci associated with height that together account for approximately 10% of height variation. With only modest representation of the GH–IGF-1 axis, there is little support for the long-held hypothesis that common genetic variants of the hormone pathway provide the molecular mechanism for poor growth in a substantial proportion of individuals. The height-associated common variants are not observed in the anticipated frequency in the shortest individuals, suggesting rare genetic factors with large effect are more plausible in this group. As we advance towards establishing a molecular mechanism for poor growth in a greater percentage of those currently labeled ISS, we highlight two strategies that will likely be offered with increasing frequency: (1) unbiased genetic technologies including array analysis for copy number variation and whole exome/genome sequencing and (2) epigenetic alterations of key genomic loci. Ultimately data from subsets with similar molecular etiologies may emerge that will allow tailored interventions to achieve the best clinical outcome. PMID:24257104

  6. MATCH: An Atom- Typing Toolset for Molecular Mechanics Force Fields

    PubMed Central

    Yesselman, Joseph D.; Price, Daniel J.; Knight, Jennifer L.; Brooks, Charles L.

    2011-01-01

    We introduce a toolset of program libraries collectively titled MATCH (Multipurpose Atom-Typer for CHARMM) for the automated assignment of atom types and force field parameters for molecular mechanics simulation of organic molecules. The toolset includes utilities for the conversion from multiple chemical structure file formats into a molecular graph. A general chemical pattern-matching engine using this graph has been implemented whereby assignment of molecular mechanics atom types, charges and force field parameters is achieved by comparison against a customizable list of chemical fragments. While initially designed to complement the CHARMM simulation package and force fields by generating the necessary input topology and atom-type data files, MATCH can be expanded to any force field and program, and has core functionality that makes it extendable to other applications such as fragment-based property prediction. In the present work, we demonstrate the accurate construction of atomic parameters of molecules within each force field included in CHARMM36 through exhaustive cross validation studies illustrating that bond increment rules derived from one force field can be transferred to another. In addition, using leave-one-out substitution it is shown that it is also possible to substitute missing intra and intermolecular parameters with ones included in a force field to complete the parameterization of novel molecules. Finally, to demonstrate the robustness of MATCH and the coverage of chemical space offered by the recent CHARMM CGENFF force field (Vanommeslaeghe, et al., JCC., 2010, 31, 671–690), one million molecules from the PubChem database of small molecules are typed, parameterized and minimized. PMID:22042689

  7. Molecular Mechanisms of Biological Aging in Intervertebral Discs

    PubMed Central

    Vo, Nam V.; Hartman, Robert A.; Patil, Prashanti R.; Risbud, Makarand V.; Kletsas, Dimitris; Iatridis, James C.; Hoyland, Judith A.; Le Maitre, Christine L.; Sowa, Gwendolyn A.; Kang, James D.

    2016-01-01

    Advanced age is the greatest risk factor for the majority of human ailments, including spine-related chronic disability and back pain, which stem from age-associated intervertebral disc degeneration (IDD). Given the rapid global rise in the aging population, understanding the biology of intervertebral disc aging in order to develop effective therapeutic interventions to combat the adverse effects of aging on disc health is now imperative. Fortunately, recent advances in aging research have begun to shed light on the basic biological process of aging. Here we review some of these insights and organize the complex process of disc aging into three different phases to guide research efforts to understand the biology of disc aging. The objective of this review is to provide an overview of the current knowledge and the recent progress made to elucidate specific molecular mechanisms underlying disc aging. In particular, studies over the last few years have uncovered cellular senescence and genomic instability as important drivers of disc aging. Supporting evidence comes from DNA repair-deficient animal models that show increased disc cellular senescence and accelerated disc aging. Additionally, stress-induced senescent cells have now been well documented to secrete catabolic factors, which can negatively impact the physiology of neighboring cells and ECM. These along with other molecular drivers of aging are reviewed in depth to shed crucial insights into the underlying mechanisms of age-related disc degeneration. We also highlight molecular targets for novel therapies and emerging candidate therapeutics that may mitigate age-associated IDD. PMID:26890203

  8. Stochasticity and the Molecular Mechanisms of Induced Pluripotency

    PubMed Central

    MacArthur, Ben D.; Please, Colin P.; Oreffo, Richard O. C.

    2008-01-01

    The generation of induced pluripotent stem cells from adult somatic cells by ectopic expression of key transcription factors holds significant medical promise. However, current techniques for inducing pluripotency rely on viral infection and are therefore not, at present, viable within a clinical setting. Thus, there is now a need to better understand the molecular basis of stem cell pluripotency and lineage specification in order to investigate alternative methods to induce pluripotency for clinical application. However, the complexity of the underlying molecular circuitry makes this a conceptually difficult task. In order to address these issues, we considered a computational model of transcriptional control of cell fate specification. The model comprises two mutually interacting sub-circuits: a central pluripotency circuit consisting of interactions between stem-cell specific transcription factors OCT4, SOX2 and NANOG coupled to a differentiation circuit consisting of interactions between lineage-specifying master genes. The molecular switches which arise from feedback loops within these circuits give rise to a well-defined sequence of successive gene restrictions corresponding to a controlled differentiation cascade in response to environmental stimuli. Furthermore, we found that this differentiation cascade is strongly unidirectional: once silenced, core transcription factors cannot easily be reactivated. In the context of induced pluripotency, this indicates that differentiated cells are robustly resistant to reprogramming to a more primitive state. However, our model suggests that under certain circumstances, amplification of low-level fluctuations in transcriptional status (transcriptional “noise”) may be sufficient to trigger reactivation of the core pluripotency switch and reprogramming to a pluripotent state. This interpretation offers an explanation of a number of experimental observations concerning the molecular mechanisms of cellular

  9. Molecular mechanisms of phytochrome signal transduction in higher plants.

    PubMed

    Chu, Li-Ye; Shao, Hong-Bo; Li, Mao-Yau

    2005-11-10

    Phytochromes in higher plants play a great role in development, responses to environmental stresses and signal transduction, which are the fundamental principles for higher plants to be adapted to changing environment. Deep and systematic understanding of the phytochrome in higher plants is of crucial importance to molecular biology, purposeful improvement of environment in practice, especially molecular mechanism by which higher plants perceive UV-B stress. The last more than 10 years have seen rapid progress in this field with the aid of a combination of molecular, genetic and cell biological approaches. No doubt, what is the most important, is the application of Arabidopsis experimental system and the generation of various mutants regarding phytochromes (phy A-E). Increasing evidence demonstrates that phytochrome signaling transduction constitutes a highly ordered multidimensional network of events. Some phytochromes and signaling intermediates show light-dependent nuclear-cytoplasmic partitioning, which implies that early signaling events take place in the nucleus and that subcellular localization patterns most probably represent an important signaling control point. The main subcellular localization includes nucleus, cytosol and chloroplasts, respectively. Additionally, proteasome-mediated degradation of signaling intermediates most possibly function in concert with subcellular partitioning events as an integrated checkpoint. What higher plants do in this way is to execute accurate responses to the changes in the light environment on the basis of interconnected subcellular organelles. By integrating the available data, at the molecular level and from the angle of eco-environment, we should be able to construct a solid foundation for further dissection of phytochrome signaling transduction in higher plants.

  10. Graphene Young's modulus: Molecular mechanics and DFT treatments

    NASA Astrophysics Data System (ADS)

    Memarian, F.; Fereidoon, A.; Darvish Ganji, M.

    2015-09-01

    Despite of the numerous theoretical and experimental investigations on the mechanical properties of graphene as a unique nano-structured material, a precious value for this important property has not yet been presented. In the present work, the Young's modulus of single layer graphene sheet has been investigated by using comprehensive classic as well as quantum mechanics (QM) calculations. Molecular mechanics (MM) approach with various well-defined force-fields such as AIREBO, Tresoff and EDIP potentials have been considered. In QM category, several conventional methods (DFTB and DFT-LDA/GGA) have been employed. The results show that EDIP potential method predicts more accurately the graphene Young's modulus value compared to experimental results. Furthermore, despite the various theoretical results reported elsewhere, the EDIP potential calculations result reveals that Young's modulus has the same value at both zigzag and armchair directions. From the results obtained here, we found that among the various MM and QM methods considered here the EDIP method seems to be the most convenient method for evaluation of both structural geometries and mechanical properties of carbon based graphene-like materials. This is because of its less computational costs accompanied with reliable results comparable with the experiments.

  11. Molecular mechanisms in deformation of cross-linked hydrogel nanocomposite.

    PubMed

    Mathesan, Santhosh; Rath, Amrita; Ghosh, Pijush

    2016-02-01

    The self-folding behavior in response to external stimuli observed in hydrogels is potentially used in biomedical applications. However, the use of hydrogels is limited because of its reduced mechanical properties. These properties are enhanced when the hydrogels are cross-linked and reinforced with nanoparticles. In this work, molecular dynamics (MD) simulation is applied to perform uniaxial tension and pull out tests to understand the mechanism contributing towards the enhanced mechanical properties. Also, nanomechanical characterization is performed using quasi static nanoindentation experiments to determine the Young's modulus of hydrogels in the presence of nanoparticles. The stress-strain responses for chitosan (CS), chitosan reinforced with hydroxyapatite (HAP) and cross-linked chitosan are obtained from uniaxial tension test. It is observed that the Young's modulus and maximum stress increase as the HAP content increases and also with cross-linking process. Load displacement plot from pullout test is compared for uncross-linked and cross-linked chitosan chains on hydroxyapatite surface. MD simulation reveals that the variation in the dihedral conformation of chitosan chains and the evolution of internal structural variables are associated with mechanical properties. Additional results reveal that the formation of hydrogen bonds and electrostatic interactions is responsible for the above variations in different systems.

  12. A Practical Quantum Mechanics Molecular Mechanics Method for the Dynamical Study of Reactions in Biomolecules.

    PubMed

    Mendieta-Moreno, Jesús I; Marcos-Alcalde, Iñigo; Trabada, Daniel G; Gómez-Puertas, Paulino; Ortega, José; Mendieta, Jesús

    2015-01-01

    Quantum mechanics/molecular mechanics (QM/MM) methods are excellent tools for the modeling of biomolecular reactions. Recently, we have implemented a new QM/MM method (Fireball/Amber), which combines an efficient density functional theory method (Fireball) and a well-recognized molecular dynamics package (Amber), offering an excellent balance between accuracy and sampling capabilities. Here, we present a detailed explanation of the Fireball method and Fireball/Amber implementation. We also discuss how this tool can be used to analyze reactions in biomolecules using steered molecular dynamics simulations. The potential of this approach is shown by the analysis of a reaction catalyzed by the enzyme triose-phosphate isomerase (TIM). The conformational space and energetic landscape for this reaction are analyzed without a priori assumptions about the protonation states of the different residues during the reaction. The results offer a detailed description of the reaction and reveal some new features of the catalytic mechanism. In particular, we find a new reaction mechanism that is characterized by the intramolecular proton transfer from O1 to O2 and the simultaneous proton transfer from Glu 165 to C2.

  13. MOLECULAR MECHANISM OF MICROBIAL TECHNETIUM REDUCTION FINAL REPORT

    SciTech Connect

    DiChristina, Thomas J.

    2013-04-30

    Microbial Tc(VII) reduction is an attractive alternative strategy for bioremediation of technetium-contaminated subsurface environments. Traditional ex situ remediation processes (e.g., adsorption or ion exchange) are often limited by poor extraction efficiency, inhibition by competing ions and production of large volumes of produced waste. Microbial Tc(VII) reduction provides an attractive alternative in situ remediation strategy since the reduced end-product Tc(IV) precipitates as TcO2, a highly insoluble hydrous oxide. Despite its potential benefits, the molecular mechanism of microbial Tc(VII) reduction remains poorly understood. The main goal of the proposed DOENABIR research project is to determine the molecular mechanism of microbial Tc(VII) reduction. Random mutagenesis studies in our lab have resulted in generation of a set of six Tc(VII) reduction-deficient mutants of Shewanella oneidensis. The anaerobic respiratory deficiencies of each Tc(VII) reduction-deficient mutant was determined by anaerobic growth on various combinations of three electron donors and 14 terminal electron acceptors. Results indicated that the electron transport pathways to Tc(VII), NO3 -, Mn(III) and U(VI) share common structural or regulatory components. In addition, we have recently found that wild-type Shewanella are also able to reduce Tc(IV) as electron acceptor, producing Tc(III) as an end-product. The recent genome sequencing of a variety of technetium-reducing bacteria and the anticipated release of several additional genome sequences in the coming year, provides us with an unprecedented opportunity to determine the mechanism of microbial technetium reduction across species and genus lines.

  14. Molecular mechanisms of asbestos-induced lung epithelial cell apoptosis.

    PubMed

    Liu, Gang; Beri, Rohinee; Mueller, Amanda; Kamp, David W

    2010-11-05

    Asbestos causes pulmonary fibrosis (asbestosis) and malignancies (bronchogenic lung cancer and mesothelioma) by mechanisms that are not fully elucidated. Accumulating evidence show that alveolar epithelial cell (AEC) apoptosis is a crucial initiating and perpetuating event in the development of pulmonary fibrosis following exposure to a wide variety of noxious stimuli, including asbestos. We review the important molecular mechanisms underlying asbestos-induced AEC apoptosis. Specifically, we focus on the role of asbestos in augmenting AEC apoptosis by the mitochondria- and p53-regulated death pathways that result from the production of iron-derived reactive oxygen species (ROS) and DNA damage. We summarize emerging evidence implicating the endoplasmic reticulum (ER) stress response in AEC apoptosis in patients with idiopathic pulmonary fibrosis (IPF), a disease with similarities to asbestosis. Finally, we discuss a recent finding that a mitochondrial oxidative DNA repair enzyme (8-oxoguanine DNA glycosylase; Ogg1) acts as a mitochondrial aconitase chaperone protein to prevent oxidant (asbestos and H(2)O(2))-induced AEC mitochondrial dysfunction and intrinsic apoptosis. The coupling of mitochondrial Ogg1 to mitochondrial aconitase is a novel mechanism linking metabolism to mitochondrial DNA that may be important in the pathophysiologic events resulting in oxidant-induced toxicity as seen in tumors, aging, and respiratory disorders (e.g. asbestosis, IPF). Collectively, these studies are illuminating the molecular basis of AEC apoptosis following asbestos exposure that may prove useful for developing novel therapeutic strategies. Importantly, the asbestos paradigm is elucidating pathophysiologic insights into other more common pulmonary diseases, such as IPF and lung cancer, for which better therapy is required.

  15. Molecular medicine of fragile X syndrome: based on known molecular mechanisms.

    PubMed

    Luo, Shi-Yu; Wu, Ling-Qian; Duan, Ran-Hui

    2016-02-01

    Extensive research on fragile X mental retardation gene knockout mice and mutant Drosophila models has largely expanded our knowledge on mechanism-based treatment of fragile X syndrome (FXS). In light of these findings, several clinical trials are now underway for therapeutic translation to humans. Electronic literature searches were conducted using the PubMed database and ClinicalTrials.gov. The search terms included "fragile X syndrome", "FXS and medication", "FXS and therapeutics" and "FXS and treatment". Based on the publications identified in this search, we reviewed the neuroanatomical abnormalities in FXS patients and the potential pathogenic mechanisms to monitor the progress of FXS research, from basic studies to clinical trials. The pathological mechanisms of FXS were categorized on the basis of neuroanatomy, synaptic structure, synaptic transmission and fragile X mental retardation protein (FMRP) loss of function. The neuroanatomical abnormalities in FXS were described to motivate extensive research into the region-specific pathologies in the brain responsible for FXS behavioural manifestations. Mechanism-directed molecular medicines were classified according to their target pathological mechanisms, and the most recent progress in clinical trials was discussed. Current mechanism-based studies and clinical trials have greatly contributed to the development of FXS pharmacological therapeutics. Research examining the extent to which these treatments provided a rescue effect or FMRP compensation for the developmental impairments in FXS patients may help to improve the efficacy of treatments.

  16. Structures and stabilities of diacetylene-expanded polyhedranes by quantum mechanics and molecular mechanics.

    PubMed

    Jarowski, Peter D; Diederich, François; Houk, Kendall N

    2005-03-04

    The structures, heats of formation, and strain energies of diacetylene (buta-1,3-diynediyl) expanded molecules have been computed with ab initio and molecular mechanics calculations. Expanded cubane, prismane, tetrahedrane, and expanded monocyclics and bicyclics were optimized at the HF/6-31G(d) and B3LYP/6-31G(d) levels. The heats of formation of these systems were obtained from isodesmic equations at the HF/6-31G(d) level. Heats of formation were also calculated from Benson group equivalents. The strain energies of these expanded molecules were estimated by several independent methods. An adapted MM3 molecular mechanics force field, specifically parametrized to treat conjugated acetylene units, was employed for one measure of strain energy and as an additional method for structural analysis. Expanded dodecahedrane and icosahedrane were calculated by this method. Expanded molecules were considered structurally in the context of their potential material applications.

  17. [Neurovegetative stabilization as a pathogenetic therapy for brain damage].

    PubMed

    Kondrat'ev, A N; Tsentsiper, L M; Kondrat'eva, E A; Nazarov, R V

    2014-01-01

    The article deals with neurovegetative stabilization as a pathogenetic therapy for brain damage. The approach is based on hypothesis that pharmacological effecting on central nervous system is able to make a passive protective medical system which can be close to passive protective systems widely represented in the nature. Complex opioid and clonidine administration provides sufficient level of neurovegetative stability on account of effecting on neuro-regulative structures the brain steam. Neurovegetative stabilization should be carry out in order of warning principle. In our opinion optimal doses are fentanyl 0.2-1.4 mkg kg(-1) per hour, clonidine 0.2-0.7 mkg kg(-1) per hour, propofol 0.5-2 mkg kg(-1) per hour, penthonal sodium 1-4 mkg kg(-1) per hour; diazepam 0.4-0.5 mkg kg(-1), and midazolam 0.05-0.2 mkg kg(-1) per hour. A criterion of the therapy sufficiency is a consistency between changes of different functional parameters. We believe the most important that new level of functioning must be maximally integrated and harmonized. It is possible if all pharmacological agents include the most reliable programs of adaptation complex human body reactions.

  18. Pathogenetic difference between collagen arthritis and adjuvant arthritis

    PubMed Central

    1984-01-01

    Daily treatment with cyclosporin at a dose of 25 mg/kg for 14 d gave complete suppression of the development of collagen arthritis and adjuvant arthritis in Sprague-Dawley rats during an observation period of 45 d. To study whether the immunologic unresponsiveness produced by cyclosporin is antigen specific, we rechallenged the cyclosporin- protected rats with either type II collagen or complete Freund's adjuvant (CFA) after discontinuation of cyclosporin treatment. Type II collagen-immunized, cyclosporin-protected rats did not develop arthritis in response to reimmunization with type II collagen, but, they did develop arthritis in response to a subsequent injection of CFA. Similarly, CFA-injected, cyclosporin-protected rats showed a suppressed arthritogenic reaction in response to reinjection of CFA, whereas their response to a subsequent immunization with type II collagen was unaffected. On the other hand, the rats that were treated with cyclosporin without any prior antigenic challenge could develop arthritis in response to a subsequent injection of CFA or type II collagen after cessation of cyclosporin treatment. These results indicate that specific immunologic unresponsiveness can be induced by cyclosporin in the two experimental models of polyarthritis, collagen arthritis and adjuvant arthritis, and that there is no cross-reactivity between type II collagen and the mycobacterial cell wall components. The results further indicate that immunity to type II collagen plays a critical role in the pathogenesis of collagen arthritis but that its pathogenetic role in adjuvant arthritis is insignificant. PMID:6201583

  19. Molecular mechanism of action of fluoride on bone cells.

    PubMed

    Lau, K H; Baylink, D J

    1998-11-01

    Fluoride is an effective anabolic agent to increase spinal bone density by increasing bone formation, and at therapeutically relevant (i.e., micromolar) concentrations, it stimulates bone cell proliferation and activities in vitro and in vivo. However, the fluoride therapy of osteoporosis has been controversial, in large part because of a lack of consistent antifracture efficacy. However, information regarding the molecular mechanism of action of fluoride may improve its optimum and correct usage and may disclose potential targets for the development of new second generation drugs that might have a better efficacy and safety profile. Accordingly, this review will address the molecular mechanisms of the osteogenic action of fluoride. In this regard, we and other workers have proposed two competing models, both of which involve the mitogen activated protein kinase (MAPK) mitogenic signal transduction pathway. Our model involves a fluoride inhibition of a unique fluoride-sensitive phosphotyrosine phosphatase (PTP) in osteoblasts, which results in a sustained increase in the tyrosine phosphorylation level of the key signaling proteins of the MAPK mitogenic transduction pathway, leading to the potentiation of the bone cell proliferation initiated by growth factors. The competing model proposes that fluoride acts in coordination with aluminum to form fluoroaluminate, which activates a pertussis toxin-sensitive Gi/o protein on bone cell membrane, leading to an activation of cellular protein tyrosine kinases (PTKs), which in turn leads to increases in the tyrosine phosphorylation of signaling proteins of the MAPK mitogenic signal transduction pathway, ultimately leading to a stimulation of cell proliferation. A benefit of our model, but not the other model, is that it accounts for all the unique properties of the osteogenic action of fluoride. These include the low effective fluoride dose, the skeletal tissue specificity, the requirement of PTK-activating growth factors

  20. Cellular and molecular mechanisms for the bone response to mechanical loading

    NASA Technical Reports Server (NTRS)

    Bloomfield, S. A.

    2001-01-01

    To define the cellular and molecular mechanisms for the osteogenic response of bone to increased loading, several key steps must be defined: sensing of the mechanical signal by cells in bone, transduction of the mechanical signal to a biochemical one, and transmission of that biochemical signal to effector cells. Osteocytes are likely to serve as sensors of loading, probably via interstitial fluid flow produced during loading. Evidence is presented for the role of integrins, the cell's actin cytoskeleton, G proteins, and various intracellular signaling pathways in transducing that mechanical signal to a biochemical one. Nitric oxide, prostaglandins, and insulin-like growth factors all play important roles in these pathways. There is growing evidence for modulation of these mechanotransduction steps by endocrine factors, particularly parathyroid hormone and estrogen. The efficiency of this process is also impaired in the aged animal, yet what remains undefined is at what step mechanotransduction is affected.

  1. Cellular and molecular mechanisms for the bone response to mechanical loading

    NASA Technical Reports Server (NTRS)

    Bloomfield, S. A.

    2001-01-01

    To define the cellular and molecular mechanisms for the osteogenic response of bone to increased loading, several key steps must be defined: sensing of the mechanical signal by cells in bone, transduction of the mechanical signal to a biochemical one, and transmission of that biochemical signal to effector cells. Osteocytes are likely to serve as sensors of loading, probably via interstitial fluid flow produced during loading. Evidence is presented for the role of integrins, the cell's actin cytoskeleton, G proteins, and various intracellular signaling pathways in transducing that mechanical signal to a biochemical one. Nitric oxide, prostaglandins, and insulin-like growth factors all play important roles in these pathways. There is growing evidence for modulation of these mechanotransduction steps by endocrine factors, particularly parathyroid hormone and estrogen. The efficiency of this process is also impaired in the aged animal, yet what remains undefined is at what step mechanotransduction is affected.

  2. A quantum mechanical/molecular mechanical approach to the investigation of particle-molecule interactions

    NASA Astrophysics Data System (ADS)

    Sloth, Marianne; Bilde, Merete; Mikkelsen, Kurt V.

    2003-06-01

    A quantum mechanical/molecular mechanical aerosol model is developed to describe the interaction between gas phase molecules and atmospheric particles. The model enables the calculation of interaction energies and time-dependent properties. We use the model to investigate how a succinic acid molecule interacts with an aqueous particle. We show how the interaction energies and linear response properties (excitation energies, transition moments, and polarizabilities) depend on the distance between aerosol particle and molecule and on their relative orientation. The results are compared with those obtained previously using a dielectric continuum model [Sloth et al., J. Phys. Chem. (submitted)].

  3. Characterizing Cardiac Molecular Mechanisms of Mammalian Hibernation via Quantitative Proteogenomics.

    PubMed

    Vermillion, Katie L; Jagtap, Pratik; Johnson, James E; Griffin, Timothy J; Andrews, Matthew T

    2015-11-06

    This study uses advanced proteogenomic approaches in a nonmodel organism to elucidate cardioprotective mechanisms used during mammalian hibernation. Mammalian hibernation is characterized by drastic reductions in body temperature, heart rate, metabolism, and oxygen consumption. These changes pose significant challenges to the physiology of hibernators, especially for the heart, which maintains function throughout the extreme conditions, resembling ischemia and reperfusion. To identify novel cardioadaptive strategies, we merged large-scale RNA-seq data with large-scale iTRAQ-based proteomic data in heart tissue from 13-lined ground squirrels (Ictidomys tridecemlineatus) throughout the circannual cycle. Protein identification and data analysis were run through Galaxy-P, a new multiomic data analysis platform enabling effective integration of RNA-seq and MS/MS proteomic data. Galaxy-P uses flexible, modular workflows that combine customized sequence database searching and iTRAQ quantification to identify novel ground squirrel-specific protein sequences and provide insight into molecular mechanisms of hibernation. This study allowed for the quantification of 2007 identified cardiac proteins, including over 350 peptide sequences derived from previously uncharacterized protein products. Identification of these peptides allows for improved genomic annotation of this nonmodel organism, as well as identification of potential splice variants, mutations, and genome reorganizations that provides insights into novel cardioprotective mechanisms used during hibernation.

  4. Tea and cancer prevention: Molecular mechanisms and human relevance

    SciTech Connect

    Yang, Chung S. Lambert, Joshua D.; Ju Jihyeung; Lu Gang; Sang Shengmin

    2007-11-01

    Tea made from the leaves of the plant Camellia sinensis is a popular beverage. The possible cancer-preventive activity of tea and tea polyphenols has been studied extensively. This article briefly reviews studies in animal models, cell lines, and possible relevance of these studies to the prevention of human cancer. The cancer-preventive activity of tea constituents have been demonstrated in many animal models including cancer of the skin, lung, oral cavity, esophagus, stomach, liver, pancreas, small intestine, colon, bladder, prostate, and mammary gland. The major active constituents are polyphenols, of which (-)-epigallocatechin-3-gallate (EGCG) is most abundant, most active, and most studied, and caffeine. The molecular mechanisms of the cancer-preventive action, however, are just beginning to be understood. Studies in cell lines led to the proposal of many mechanisms on the action of EGCG. However, mechanisms based on studies with very high concentrations of EGCG may not be relevant to cancer prevention in vivo. The autooxidation of EGCG in cell culture may also produce activities that do not occur in many internal organs. In contrast to the cancer prevention activity demonstrated in different animal models, no such conclusion can be convincingly drawn from epidemiological studies on tea consumption and human cancers. Even though the human data are inconclusive, tea constituents may still be used for the prevention of cancer at selected organ sites if sufficient concentrations of the agent can be delivered to these organs. Some interesting examples in this area are discussed.

  5. Aging and Immune Function: Molecular Mechanisms to Interventions

    PubMed Central

    Ponnappan, Subramaniam

    2011-01-01

    Abstract The immune system of an organism is an essential component of the defense mechanism aimed at combating pathogenic stress. Age-associated immune dysfunction, also dubbed “immune senescence,” manifests as increased susceptibility to infections, increased onset and progression of autoimmune diseases, and onset of neoplasia. Over the years, extensive research has generated consensus in terms of the phenotypic and functional defects within the immune system in various organisms, including humans. Indeed, age-associated alterations such as thymic involution, T cell repertoire skewing, decreased ability to activate naïve T cells and to generate robust memory responses, have been shown to have a causative role in immune decline. Further, understanding the molecular mechanisms underlying the generation of proteotoxic stress, DNA damage response, modulation of ubiquitin proteasome pathway, and regulation of transcription factor NFκB activation, in immune decline, have paved the way to delineating signaling pathways that cross-talk and impact immune senescence. Given the role of the immune system in combating infections, its effectiveness with age may well be a marker of health and a predictor of longevity. It is therefore believed that a better understanding of the mechanisms underlying immune senescence will lead to an effective interventional strategy aimed at improving the health span of individuals. Antioxid. Redox Signal. 14, 1551–1585. PMID:20812785

  6. Mechanical properties of borophene films: a reactive molecular dynamics investigation

    NASA Astrophysics Data System (ADS)

    Quy Le, Minh; Mortazavi, Bohayra; Rabczuk, Timon

    2016-11-01

    The most recent experimental advances could provide ways for the fabrication of several atomic thick and planar forms of boron atoms. For the first time, we explore the mechanical properties of five types of boron films with various vacancy ratios ranging from 0.1-0.15, using molecular dynamics simulations with ReaxFF force field. It is found that the Young’s modulus and tensile strength decrease with increasing the temperature. We found that boron sheets exhibit an anisotropic mechanical response due to the different arrangement of atoms along the armchair and zigzag directions. At room temperature, 2D Young’s modulus and fracture stress of these five sheets appear in the range 63-136 N m-1 and 12-19 N m-1, respectively. In addition, the strains at tensile strength are in the ranges of 9%-14%, 11%-19%, and 10%-16% at 1, 300, and 600 K, respectively. This investigation not only reveals the remarkable stiffness of 2D boron, but establishes relations between the mechanical properties of the boron sheets to the loading direction, temperature and atomic structures.

  7. Mechanical Properties of Nanostructured Materials Determined Through Molecular Modeling Techniques

    NASA Technical Reports Server (NTRS)

    Clancy, Thomas C.; Gates, Thomas S.

    2005-01-01

    The potential for gains in material properties over conventional materials has motivated an effort to develop novel nanostructured materials for aerospace applications. These novel materials typically consist of a polymer matrix reinforced with particles on the nanometer length scale. In this study, molecular modeling is used to construct fully atomistic models of a carbon nanotube embedded in an epoxy polymer matrix. Functionalization of the nanotube which consists of the introduction of direct chemical bonding between the polymer matrix and the nanotube, hence providing a load transfer mechanism, is systematically varied. The relative effectiveness of functionalization in a nanostructured material may depend on a variety of factors related to the details of the chemical bonding and the polymer structure at the nanotube-polymer interface. The objective of this modeling is to determine what influence the details of functionalization of the carbon nanotube with the polymer matrix has on the resulting mechanical properties. By considering a range of degree of functionalization, the structure-property relationships of these materials is examined and mechanical properties of these models are calculated using standard techniques.

  8. Causes, effects and molecular mechanisms of testicular heat stress.

    PubMed

    Durairajanayagam, Damayanthi; Agarwal, Ashok; Ong, Chloe

    2015-01-01

    The process of spermatogenesis is temperature-dependent and occurs optimally at temperatures slightly lower than that of the body. Adequate thermoregulation is imperative to maintain testicular temperatures at levels lower than that of the body core. Raised testicular temperature has a detrimental effect on mammalian spermatogenesis and the resultant spermatozoa. Therefore, thermoregulatory failure leading to heat stress can compromise sperm quality and increase the risk of infertility. In this paper, several different types of external and internal factors that may contribute towards testicular heat stress are reviewed. The effects of heat stress on the process of spermatogenesis, the resultant epididymal spermatozoa and on germ cells, and the consequent changes in the testis are elaborated upon. We also discuss the molecular response of germ cells to heat exposure and the possible mechanisms involved in heat-induced germ cell damage, including apoptosis, DNA damage and autophagy. Further, the intrinsic and extrinsic pathways that are involved in the intricate mechanism of germ cell apoptosis are explained. Ultimately, these complex mechanisms of apoptosis lead to germ cell death. Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  9. Environmental antiandrogens: developmental effects, molecular mechanisms, and clinical implications.

    PubMed

    Kelce, W R; Wilson, E M

    1997-03-01

    Industrial chemicals and environmental pollutants can disrupt reproductive development in wildlife and humans by mimicking or inhibiting the action of the gonadal steroid hormones, estradiol and testosterone. The toxicity of these so-called environmental endocrine disruptors is especially insidious during sex differentiation and development due to the crucial role of gonadal steroid hormones in regulating these processes. This review describes the mechanism of toxicity and clinical implications of a new class of environmental chemicals that inhibit androgen-mediated sex development. For several of these chemicals, including the agricultural fungicide vinclozolin and the ubiquitous and persistent 1,1,1-trichloro-2,2-bis (p-chlorophenyl)ethane metabolite, 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene, the molecular mechanism of action and the adverse developmental effects on male sex differentiation have been elucidated and are used as examples. Environmental chemicals with antiandrogenic activity offer profound implications with regard to recent clinical observations that suggest an increasing incidence of human male genital tract malformations, male infertility, and female breast cancer. Finally, in light of increasing concern over the potential endocrine disrupting effects of environmental pollutants, an in vitro/in vivo investigational strategy is presented which has proved useful in identifying chemicals with antiandrogen activity and their mechanism of action.

  10. Molecular mechanisms of alpha-fetoprotein gene expression.

    PubMed

    Lazarevich, N L

    2000-01-01

    Alpha-fetoprotein (AFP) is the main component of mammalian fetal serum. It is synthesized by visceral endoderm of the yolk sac and by fetal liver. Immediately after birth AFP level in blood decreases dramatically. AFP synthesis is reactivated in liver tumors and germinogeneous teratoblastomas, in a lesser degree after chemical and mechanical liver injuries followed by regeneration (i.e., acute viral hepatitis). AFP blood level change is an important marker for liver tumors that is widely used in clinical practice. Therefore, the study of the molecular and cellular mechanisms participating in regulation of the oncoembryonal protein AFP is an important task. On various experimental models it has been shown that the expression is regulated mainly on the transcriptional level, the AFP gene having a 7 kb regulatory region upstream. Within this region a tissue-specific promoter, three independent enhancers, and a silencer that is at least partially responsible for AFP gene expression decrease in adult liver have been defined. Some ubiquitous and some tissue-specific transcription factors, including hepatocyte nuclear factors (HNFs), which mediate the transcription of most of the liver-specific genes, have been shown to bind to the promoter. However, the mechanisms determining drastic changes of AFP synthesis level in the course of ontogenesis and carcinogenesis remain incompletely clarified. Also, little is known about negative regulators of AFP gene expression in cells of non-hepatic origin and in adult liver.

  11. Small-Molecule Hormones: Molecular Mechanisms of Action

    PubMed Central

    Budzińska, Monika

    2013-01-01

    Small-molecule hormones play crucial roles in the development and in the maintenance of an adult mammalian organism. On the molecular level, they regulate a plethora of biological pathways. Part of their actions depends on their transcription-regulating properties, exerted by highly specific nuclear receptors which are hormone-dependent transcription factors. Nuclear hormone receptors interact with coactivators, corepressors, basal transcription factors, and other transcription factors in order to modulate the activity of target genes in a manner that is dependent on tissue, age and developmental and pathophysiological states. The biological effect of this mechanism becomes apparent not earlier than 30–60 minutes after hormonal stimulus. In addition, small-molecule hormones modify the function of the cell by a number of nongenomic mechanisms, involving interaction with proteins localized in the plasma membrane, in the cytoplasm, as well as with proteins localized in other cellular membranes and in nonnuclear cellular compartments. The identity of such proteins is still under investigation; however, it seems that extranuclear fractions of nuclear hormone receptors commonly serve this function. A direct interaction of small-molecule hormones with membrane phospholipids and with mRNA is also postulated. In these mechanisms, the reaction to hormonal stimulus appears within seconds or minutes. PMID:23533406

  12. EGFR gene deregulation mechanisms in lung adenocarcinoma: A molecular review.

    PubMed

    Tsiambas, Evangelos; Lefas, Alicia Y; Georgiannos, Stavros N; Ragos, Vasileios; Fotiades, Panagiotis P; Grapsa, Dimitra; Stamatelopoulos, Athanasios; Kavantzas, Nikolaos; Patsouris, Efstratios; Syrigos, Konstantinos

    2016-08-01

    For the last two decades, evolution in molecular biology has expanded our knowledge in decoding a broad spectrum of genomic imbalances that progressively lead normal cells to a neoplastic state and finally to complete malignant transformation. Concerning oncogenes and signaling transduction pathways mediated by them, identification of specific gene alterations remains a critical process for handling patients by applying targeted therapeutic regimens. The epidermal growth factor receptor (EGFR) signaling pathway plays a crucial role in regulating cell proliferation, differentiation and apoptosis in normal cells. EGFR mutations and amplification represent the gene's main deregulation mechanisms in cancers of different histo-genetic origin. Furthermore, intra-cancer molecular heterogeneity due to clonal rise and expansion mainly explains the variable resistance to novel anti-EGFR monoclonal antibody (mAb), and also tyrosine kinase inhibitors (TKIs). According to recently published 2015 WHO new classification, lung cancer is the leading cause of death related to cancer and its incidence is still on the increase worldwide. The majority of patients suffering from lung cancer are diagnosed with epithelial tumors (adenocarcinoma predominantly and squamous cell carcinoma represent ∼85% of all pathologically defined lung cancer cases). In those patients, EGFR-activating somatic mutations in exons 18/19/20/21 modify patients' sensitivity (i.e. exon 21 L858R, exon 19 LREA deletion) or resistance (ie exon 20 T790M and/or insertion) to TKI mediated targeted therapeutic strategies. Additionally, the role of specific micro-RNAs that affect EGFR regulation is under investigation. In the current review, we focused on EGFR gene/protein structural and functional aspects and the corresponding alterations that occur mainly in lung adenocarcinoma to critically modify its molecular landscape.

  13. A molecular mechanism of chaperone-client recognition

    PubMed Central

    He, Lichun; Sharpe, Timothy; Mazur, Adam; Hiller, Sebastian

    2016-01-01

    Molecular chaperones are essential in aiding client proteins to fold into their native structure and in maintaining cellular protein homeostasis. However, mechanistic aspects of chaperone function are still not well understood at the atomic level. We use nuclear magnetic resonance spectroscopy to elucidate the mechanism underlying client recognition by the adenosine triphosphate-independent chaperone Spy at the atomic level and derive a structural model for the chaperone-client complex. Spy interacts with its partially folded client Im7 by selective recognition of flexible, locally frustrated regions in a dynamic fashion. The interaction with Spy destabilizes a partially folded client but spatially compacts an unfolded client conformational ensemble. By increasing client backbone dynamics, the chaperone facilitates the search for the native structure. A comparison of the interaction of Im7 with two other chaperones suggests that the underlying principle of recognizing frustrated segments is of a fundamental nature. PMID:28138538

  14. Obstructive renal injury: from fluid mechanics to molecular cell biology

    PubMed Central

    Ucero, Alvaro C; Gonçalves, Sara; Benito-Martin, Alberto; Santamaría, Beatriz; Ramos, Adrian M; Berzal, Sergio; Ruiz-Ortega, Marta; Egido, Jesus; Ortiz, Alberto

    2010-01-01

    Urinary tract obstruction is a frequent cause of renal impairment. The physiopathology of obstructive nephropathy has long been viewed as a mere mechanical problem. However, recent advances in cell and systems biology have disclosed a complex physiopathology involving a high number of molecular mediators of injury that lead to cellular processes of apoptotic cell death, cell injury leading to inflammation and resultant fibrosis. Functional studies in animal models of ureteral obstruction using a variety of techniques that include genetically modified animals have disclosed an important role for the renin-angiotensin system, transforming growth factor-β1 (TGF-β1) and other mediators of inflammation in this process. In addition, high throughput techniques such as proteomics and transcriptomics have identified potential biomarkers that may guide clinical decision-making. PMID:24198613

  15. Generic Transport Mechanisms for Molecular Traffic in Cellular Protrusions

    NASA Astrophysics Data System (ADS)

    Graf, Isabella R.; Frey, Erwin

    2017-03-01

    Transport of molecular motors along protein filaments in a half-closed geometry is a common feature of biologically relevant processes in cellular protrusions. Using a lattice-gas model we study how the interplay between active and diffusive transport and mass conservation leads to localized domain walls and tip localization of the motors. We identify a mechanism for task sharing between the active motors (maintaining a gradient) and the diffusive motion (transport to the tip), which ensures that energy consumption is low and motor exchange mostly happens at the tip. These features are attributed to strong nearest-neighbor correlations that lead to a strong reduction of active currents, which we calculate analytically using an exact moment identity, and might prove useful for the understanding of correlations and active transport also in more elaborate systems.

  16. Complement involvement in periodontitis: molecular mechanisms and rational therapeutic approaches

    PubMed Central

    Hajishengallis, George; Maekawa, Tomoki; Abe, Toshiharu; Hajishengallis, Evlambia; Lambris, John D.

    2015-01-01

    The complement system is a network of interacting fluid-phase and cell surface-associated molecules that trigger, amplify, and regulate immune and inflammatory signaling pathways. Dysregulation of this finely balanced network can destabilize host-microbe homeostasis and cause inflammatory tissue damage. Evidence from clinical and animal model-based studies suggests that complement is implicated in the pathogenesis of periodontitis, a polymicrobial community-induced chronic inflammatory disease that destroys the tooth-supporting tissues. This review discusses molecular mechanisms of complement involvement in the dysbiotic transformation of the periodontal microbiome and the resulting destructive inflammation, culminating in loss of periodontal bone support. These mechanistic studies have additionally identified potential therapeutic targets. In this regard, interventional studies in preclinical models have provided proof-of-concept for using complement inhibitors for the treatment of human periodontitis. PMID:26306443

  17. Molecular mechanisms in normal pregnancy and rheumatic diseases.

    PubMed

    Vázquez-Del Mercado, M; Martín-Márquez, B T; Petri, M H; Martínez-García, E A; Muñoz-Valle, J F

    2006-01-01

    Pregnancy is a phenomenon that is not totally understood, based on the complex molecular interactions between the mother and the embrio. Once the fecundation is completed the fetus starts to fight for survival. The first challenge is the implantation process and the second one is the interaction with the maternal immune system. This review discusses how the fetus avoids the immune system rejection, and the mechanisms that the maternal immune system adapts in order to be fit for a successful pregnancy. Also, we focus in this paper on the effects of pregnancy in rheumatic diseases, because the myriad clinical outcomes of the disease itself and the obstetric complications dependent of the disease implicated, as for example in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), spondyloarthropaties and antiphospholipid syndrome (APS).

  18. Molecular Mechanisms Underlying Solute Retention at Heterogeneous Interfaces.

    PubMed

    El Hage, Krystel; Gupta, Prashant Kumar; Bemish, Raymond; Meuwly, Markus

    2017-09-21

    Despite considerable effort, a molecular-level understanding of the mechanisms governing adsorption/desorption in reversed-phase liquid chromatography is still lacking. This impedes rational design of columns and the development of reliable, computationally more efficient approaches to predict the selectivity of a particular column design. Using state-of-the art, validated force fields and free-energy simulations, the adsorption thermodynamics of benzene derivatives is investigated in atomistic detail and provides a quantitative microscopic understanding of retention when compared with experimental data. It is found that pure partitioning or pure adsorption is rather the exception than the rule. Typically, a pronounced ∼1 kcal/mol stabilization on the surface is accompanied by a broad trough indicative of partitioning before the probe molecule incorporates into the mobile phase. The present findings provide a quantitative and rational basis to develop improved effective, coarse-grained computational models and to design columns for specific applications.

  19. Shaping mitotic chromosomes: From classical concepts to molecular mechanisms

    PubMed Central

    Kschonsak, Marc; Haering, Christian H

    2015-01-01

    How eukaryotic genomes are packaged into compact cylindrical chromosomes in preparation for cell divisions has remained one of the major unsolved questions of cell biology. Novel approaches to study the topology of DNA helices inside the nuclei of intact cells, paired with computational modeling and precise biomechanical measurements of isolated chromosomes, have advanced our understanding of mitotic chromosome architecture. In this Review Essay, we discuss – in light of these recent insights – the role of chromatin architecture and the functions and possible mechanisms of SMC protein complexes and other molecular machines in the formation of mitotic chromosomes. Based on the information available, we propose a stepwise model of mitotic chromosome condensation that envisions the sequential generation of intra-chromosomal linkages by condensin complexes in the context of cohesin-mediated inter-chromosomal linkages, assisted by topoisomerase II. The described scenario results in rod-shaped metaphase chromosomes ready for their segregation to the cell poles. PMID:25988527

  20. Osteoporosis in diabetes mellitus: Possible cellular and molecular mechanisms.

    PubMed

    Wongdee, Kannikar; Charoenphandhu, Narattaphol

    2011-03-15

    Osteoporosis, a global age-related health problem in both male and female elderly, insidiously deteriorates the microstructure of bone, particularly at trabecular sites, such as vertebrae, ribs and hips, culminating in fragility fractures, pain and disability. Although osteoporosis is normally associated with senescence and estrogen deficiency, diabetes mellitus (DM), especially type 1 DM, also contributes to and/or aggravates bone loss in osteoporotic patients. This topic highlight article focuses on DM-induced osteoporosis and DM/osteoporosis comorbidity, covering alterations in bone metabolism as well as factors regulating bone growth under diabetic conditions including, insulin, insulin-like growth factor-1 and angiogenesis. Cellular and molecular mechanisms of DM-related bone loss are also discussed. This information provides a foundation for the better understanding of diabetic complications and for development of early screening and prevention of osteoporosis in diabetic patients.

  1. Recent Advances in Methamphetamine Neurotoxicity Mechanisms and Its Molecular Pathophysiology

    PubMed Central

    Yu, Shaobin; Zhu, Ling; Shen, Qiang; Bai, Xue; Di, Xuhui

    2015-01-01

    Methamphetamine (METH) is a sympathomimetic amine that belongs to phenethylamine and amphetamine class of psychoactive drugs, which are widely abused for their stimulant, euphoric, empathogenic, and hallucinogenic properties. Many of these effects result from acute increases in dopamine and serotonin neurotransmission. Subsequent to these acute effects, METH produces persistent damage to dopamine and serotonin release in nerve terminals, gliosis, and apoptosis. This review summarized the numerous interdependent mechanisms including excessive dopamine, ubiquitin-proteasome system dysfunction, protein nitration, endoplasmic reticulum stress, p53 expression, inflammatory molecular, D3 receptor, microtubule deacetylation, and HIV-1 Tat protein that have been demonstrated to contribute to this damage. In addition, the feasible therapeutic strategies according to recent studies were also summarized ranging from drug and protein to gene level. PMID:25861156

  2. Molecular Mechanisms of Floral Boundary Formation in Arabidopsis

    PubMed Central

    Yu, Hongyang; Huang, Tengbo

    2016-01-01

    Boundary formation is a crucial developmental process in plant organogenesis. Boundaries separate cells with distinct identities and act as organizing centers to control the development of adjacent organs. In flower development, initiation of floral primordia requires the formation of the meristem-to-organ (M–O) boundaries and floral organ development depends on the establishment of organ-to-organ (O–O) boundaries. Studies in this field have revealed a suite of genes and regulatory pathways controlling floral boundary formation. Many of these genes are transcription factors that interact with phytohormone pathways. This review will focus on the functions and interactions of the genes that play important roles in the floral boundaries and discuss the molecular mechanisms that integrate these regulatory pathways to control the floral boundary formation. PMID:26950117

  3. Molecular spectroscopic study for suggested mechanism of chrome tanned leather

    NASA Astrophysics Data System (ADS)

    Nashy, Elshahat H. A.; Osman, Osama; Mahmoud, Abdel Aziz; Ibrahim, Medhat

    2012-03-01

    Collagen represents the structural protein of the extracellular matrix, which gives strength of hides and/or skin under tanning process. Chrome tan is the most important tanning agent all over the world. The methods for production of leather evolved over several centuries as art and engineering with little understanding of the underlying science. The present work is devoted to suggest the most probable mechanistic action of chrome tan on hide proteins. First the affect of Cr upon hide protein is indicated by the studied mechanical properties. Then the spectroscopic characterization of the hide protein as well as chrome tanned leather was carried out with Horizontal Attenuated Total Reflection (HATR) FT-IR. The obtained results indicate how the chromium can attached with the active sites of collagen. Molecular modeling confirms that chromium can react with amino as well as carboxylate groups. Four schemes were obtained to describe the possible interactions of chrome tan with hide proteins.

  4. Molecular mechanism of photosignaling by archaeal sensory rhodopsins.

    PubMed

    Hoff, W D; Jung, K H; Spudich, J L

    1997-01-01

    Two sensory rhodopsins (SRI and SRII) mediate color-sensitive phototaxis responses in halobacteria. These seven-helix receptor proteins, structurally and functionally similar to animal visual pigments, couple retinal photoisomerization to receptor activation and are complexed with membrane-embedded transducer proteins (HtrI and HtrII) that modulate a cytoplasmic phosphorylation cascade controlling the flagellar motor. The Htr proteins resemble the chemotaxis transducers from Escherichia coli. The SR-Htr signaling complexes allow studies of the biophysical chemistry of signal generation and relay, from the photobiophysics of initial excitation of the receptors to the final output at the level of the flagellar motor switch, revealing fundamental principles of sensory transduction and more broadly the nature of dynamic interactions between membrane proteins. We review here recent advances that have led to new insights into the molecular mechanism of signaling by these membrane complexes.

  5. Reversible Mechanical Switching of Magnetic Interactions in a Molecular Shuttle

    PubMed Central

    Bleve, Valentina; Schäfer, Christian; Franchi, Paola; Silvi, Serena; Mezzina, Elisabetta; Credi, Alberto; Lucarini, Marco

    2015-01-01

    Invited for this months cover are the groups of Professors Marco Lucarini and Alberto Credi at the University of Bologna. The cover picture shows coupled and uncoupled states of a [2]rotaxane incorporating stable nitroxide radical units in both the ring and dumbbell components. Interaction between nitroxide radicals could be switched between noncoupled (three-line electron paramagnetic resonance (EPR) spectrum) and coupled (five-line EPR spectrum) upon deprotonation of the rotaxane NH2+ centers that effects a quantitative displacement of a dibenzocrown macroring to a 4,4’-bipyridinium recognition site. The complete base- and acid-induced switching cycle of the EPR pattern was repeated several times without an appreciable loss of signal, highlighting the reversibility of the process. Hence, this molecular machine is capable of switching on/off magnetic interactions by chemically driven reversible mechanical effects. For more details, see the Communication on p. 18 ff. PMID:25870780

  6. Molecular Mechanisms of Opioid Receptor-Dependent Signaling and Behavior

    PubMed Central

    Al-Hasani, Ream; Bruchas, Michael R.

    2013-01-01

    Opioid receptors have been targeted for the treatment of pain and related disorders for thousands of years, and remain the most widely used analgesics in the clinic. Mu (μ), kappa (κ), and delta (δ) opioid receptors represent the originally classified receptor subtypes, with opioid receptor like-1 (ORL1) being the least characterized. All four receptors are G-protein coupled, and activate inhibitory G-proteins. These receptors form homo- and hetereodimeric complexes, signal to kinase cascades, and scaffold a variety of proteins. In this review, we discuss classical mechanisms and developments in understanding opioid tolerance, opioid receptor signaling, and highlight advances in opioid molecular pharmacology, behavioral pharmacology, and human genetics. We put into context how opioid receptor signaling leads to the modulation of behavior with the potential for therapeutic intervention. Finally, we conclude that there is a continued need for more translational work on opioid receptors in vivo. PMID:22020140

  7. Communication: Quantum Zeno-based control mechanism for molecular fragmentation

    NASA Astrophysics Data System (ADS)

    Sanz-Sanz, C.; Sanz, A. S.; González-Lezana, T.; Roncero, O.; Miret-Artés, S.

    2012-03-01

    A quantum control mechanism is proposed for molecular fragmentation processes within a scenario grounded on the quantum Zeno effect. In particular, we focus on the van der Waals Ne-Br2 complex, which displays two competing dissociation channels via vibrational and electronic predissociation. Accordingly, realistic three-dimensional wave packet simulations are carried out by using ab initio interaction potentials recently obtained to reproduce available experimental data. Two numerical models to simulate the repeated measurements are reported and analyzed. It is found that the otherwise fast vibrational predissociation is slowed down in favor of the slow electronic (double fragmentation) predissociation, which is enhanced by several orders of magnitude. Based on these theoretical predictions, some hints to experimentalists to confirm their validity are also proposed.

  8. Drug-DNA intercalation: from discovery to the molecular mechanism.

    PubMed

    Mukherjee, Arnab; Sasikala, Wilbee D

    2013-01-01

    The ability of small molecules to perturb the natural structure and dynamics of nucleic acids is intriguing and has potential applications in cancer therapeutics. Intercalation is a special binding mode where the planar aromatic moiety of a small molecule is inserted between a pair of base pairs, causing structural changes in the DNA and leading to its functional arrest. Enormous progress has been made to understand the nature of the intercalation process since its idealistic conception five decades ago. However, the biological functions were detected even earlier. In this review, we focus mainly on the acridine and anthracycline types of drugs and provide a brief overview of the development in the field through various experimental methods that led to our present understanding of the subject. Subsequently, we discuss the molecular mechanism of the intercalation process, free-energy landscapes, and kinetics that was revealed recently through detailed and rigorous computational studies. © 2013 Elsevier Inc. All rights reserved.

  9. Obstructive renal injury: from fluid mechanics to molecular cell biology.

    PubMed

    Ucero, Alvaro C; Gonçalves, Sara; Benito-Martin, Alberto; Santamaría, Beatriz; Ramos, Adrian M; Berzal, Sergio; Ruiz-Ortega, Marta; Egido, Jesus; Ortiz, Alberto

    2010-04-22

    Urinary tract obstruction is a frequent cause of renal impairment. The physiopathology of obstructive nephropathy has long been viewed as a mere mechanical problem. However, recent advances in cell and systems biology have disclosed a complex physiopathology involving a high number of molecular mediators of injury that lead to cellular processes of apoptotic cell death, cell injury leading to inflammation and resultant fibrosis. Functional studies in animal models of ureteral obstruction using a variety of techniques that include genetically modified animals have disclosed an important role for the renin-angiotensin system, transforming growth factor-β1 (TGF-β1) and other mediators of inflammation in this process. In addition, high throughput techniques such as proteomics and transcriptomics have identified potential biomarkers that may guide clinical decision-making.

  10. DNA replication stress: from molecular mechanisms to human disease.

    PubMed

    Muñoz, Sergio; Méndez, Juan

    2017-02-01

    The genome of proliferating cells must be precisely duplicated in each cell division cycle. Chromosomal replication entails risks such as the possibility of introducing breaks and/or mutations in the genome. Hence, DNA replication requires the coordinated action of multiple proteins and regulatory factors, whose deregulation causes severe developmental diseases and predisposes to cancer. In recent years, the concept of "replicative stress" (RS) has attracted much attention as it impinges directly on genomic stability and offers a promising new avenue to design anticancer therapies. In this review, we summarize recent progress in three areas: (1) endogenous and exogenous factors that contribute to RS, (2) molecular mechanisms that mediate the cellular responses to RS, and (3) the large list of diseases that are directly or indirectly linked to RS.

  11. Molecular mechanism of respiratory syncytial virus fusion inhibitors

    SciTech Connect

    Battles, Michael B.; Langedijk, Johannes P.; Furmanova-Hollenstein, Polina; Chaiwatpongsakorn, Supranee; Costello, Heather M.; Kwanten, Leen; Vranckx, Luc; Vink, Paul; Jaensch, Steffen; Jonckers, Tim H. M.; Koul, Anil; Arnoult, Eric; Peeples, Mark E.; Roymans, Dirk; McLellan, Jason S.

    2015-12-07

    Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young children and the elderly. Therapeutic small molecules have been developed that bind the RSV F glycoprotein and inhibit membrane fusion, yet their binding sites and molecular mechanisms of action remain largely unknown. In this paper, we show that these inhibitors bind to a three-fold-symmetric pocket within the central cavity of the metastable prefusion conformation of RSV F. Inhibitor binding stabilizes this conformation by tethering two regions that must undergo a structural rearrangement to facilitate membrane fusion. Inhibitor-escape mutations occur in residues that directly contact the inhibitors or are involved in the conformational rearrangements required to accommodate inhibitor binding. Resistant viruses do not propagate as well as wild-type RSV in vitro, indicating a fitness cost for inhibitor escape. Finally and collectively, these findings provide new insight into class I viral fusion proteins and should facilitate development of optimal RSV fusion inhibitors.

  12. The molecular mechanism of thermal noise in rod photoreceptors.

    PubMed

    Gozem, Samer; Schapiro, Igor; Ferré, Nicolas; Olivucci, Massimo

    2012-09-07

    Spontaneous electrical signals in the retina's photoreceptors impose a limit on visual sensitivity. Their origin is attributed to a thermal, rather than photochemical, activation of the transduction cascade. Although the mechanism of such a process is under debate, the observation of a relationship between the maximum absorption wavelength (λ(max)) and the thermal activation kinetic constant (k) of different visual pigments (the Barlow correlation) indicates that the thermal and photochemical activations are related. Here we show that a quantum chemical model of the bovine rod pigment provides a molecular-level understanding of the Barlow correlation. The transition state mediating thermal activation has the same electronic structure as the photoreceptor excited state, thus creating a direct link between λ(max) and k. Such a link appears to be the manifestation of intrinsic chromophore features associated with the existence of a conical intersection between its ground and excited states.

  13. Recent Advances in Molecular Mechanisms of Taste Signaling and Modifying.

    PubMed

    Shigemura, Noriatsu; Ninomiya, Yuzo

    2016-01-01

    The sense of taste conveys crucial information about the quality and nutritional value of foods before it is ingested. Taste signaling begins with taste cells via taste receptors in oral cavity. Activation of these receptors drives the transduction systems in taste receptor cells. Then particular transmitters are released from the taste cells and activate corresponding afferent gustatory nerve fibers. Recent studies have revealed that taste sensitivities are defined by distinct taste receptors and modulated by endogenous humoral factors in a specific group of taste cells. Such peripheral taste generations and modifications would directly influence intake of nutritive substances. This review will highlight current understanding of molecular mechanisms for taste reception, signal transduction in taste bud cells, transmission between taste cells and nerves, regeneration from taste stem cells, and modification by humoral factors at peripheral taste organs.

  14. Shaping mitotic chromosomes: From classical concepts to molecular mechanisms.

    PubMed

    Kschonsak, Marc; Haering, Christian H

    2015-07-01

    How eukaryotic genomes are packaged into compact cylindrical chromosomes in preparation for cell divisions has remained one of the major unsolved questions of cell biology. Novel approaches to study the topology of DNA helices inside the nuclei of intact cells, paired with computational modeling and precise biomechanical measurements of isolated chromosomes, have advanced our understanding of mitotic chromosome architecture. In this Review Essay, we discuss - in light of these recent insights - the role of chromatin architecture and the functions and possible mechanisms of SMC protein complexes and other molecular machines in the formation of mitotic chromosomes. Based on the information available, we propose a stepwise model of mitotic chromosome condensation that envisions the sequential generation of intra-chromosomal linkages by condensin complexes in the context of cohesin-mediated inter-chromosomal linkages, assisted by topoisomerase II. The described scenario results in rod-shaped metaphase chromosomes ready for their segregation to the cell poles.

  15. Molecular mechanisms of disease-causing missense mutations

    PubMed Central

    Stefl, Shannon; Nishi, Hafumi; Petukh, Marharyta; Panchenko, Anna R.; Alexov, Emil

    2013-01-01

    Genetic variations resulting in a change of amino acid sequence can have a dramatic effect on stability, hydrogen bond network, conformational dynamics, activity and many other physiologically important properties of proteins. The substitutions of only one residue in a protein sequence, so-called missense mutations, can be related to many pathological conditions, and may influence susceptibility to disease and drug treatment. The plausible effects of missense mutations range from affecting the macromolecular stability to perturbing macromolecular interactions and cellular localization. Here we review the individual cases and genome-wide studies which illustrate the association between missense mutations and diseases. In addition we emphasize that the molecular mechanisms of effects of mutations should be revealed in order to understand the disease origin. Finally we report the current state-of-the-art methodologies which predict the effects of mutations on protein stability, the hydrogen bond network, pH-dependence, conformational dynamics and protein function. PMID:23871686

  16. Molecular mechanism of respiratory syncytial virus fusion inhibitors

    PubMed Central

    Battles, Michael B; Langedijk, Johannes P; Furmanova-Hollenstein, Polina; Chaiwatpongsakorn, Supranee; Costello, Heather M; Kwanten, Leen; Vranckx, Luc; Vink, Paul; Jaensch, Steffen; Jonckers, Tim H M; Koul, Anil; Arnoult, Eric; Peeples, Mark E; Roymans, Dirk; McLellan, Jason S

    2016-01-01

    Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young children and the elderly. Therapeutic small molecules have been developed that bind the RSV F glycoprotein and inhibit membrane fusion, yet their binding sites and molecular mechanisms of action remain largely unknown. Here we show that these inhibitors bind to a three-fold-symmetric pocket within the central cavity of the metastable prefusion conformation of RSV F. Inhibitor binding stabilizes this conformation by tethering two regions that must undergo a structural rearrangement to facilitate membrane fusion. Inhibitor-escape mutations occur in residues that directly contact the inhibitors or are involved in the conformational rearrangements required to accommodate inhibitor binding. Resistant viruses do not propagate as well as wild-type RSV in vitro, indicating a fitness cost for inhibitor escape. Collectively, these findings provide new insight into class I viral fusion proteins and should facilitate development of optimal RSV fusion inhibitors. PMID:26641933

  17. Molecular mechanisms of hepatitis C virus-induced hepatocellular carcinoma.

    PubMed

    Vescovo, T; Refolo, G; Vitagliano, G; Fimia, G M; Piacentini, M

    2016-10-01

    Hepatitis C virus (HCV) is a major leading cause of hepatocellular carcinoma (HCC). HCV-induced hepatocarcinogenesis is a multistep process resulting from a combination of pathway alterations that are either caused directly by viral factors or immune mediated as a consequence of a chronic state of inflammation. Host genetic variation is now emerging as an additional element that contribute to increase the risk of developing HCC. The advent of direct-acting antiviral agents foresees a rapid decline of HCC rate in HCV patients. However, a full understanding of the HCV-mediated tumourigenic process is required to elucidate if pro-oncogenic signatures may persist after virus clearance, and to identify novel tools for HCC prevention and therapy. In this review, we summarize the current knowledge of the molecular mechanisms responsible for HCV-induced hepatocarcinogenesis.

  18. Molecular mechanisms underlying phosphate sensing, signaling, and adaptation in plants.

    PubMed

    Zhang, Zhaoliang; Liao, Hong; Lucas, William J

    2014-03-01

    As an essential plant macronutrient, the low availability of phosphorus (P) in most soils imposes serious limitation on crop production. Plants have evolved complex responsive and adaptive mechanisms for acquisition, remobilization and recycling of phosphate (Pi) to maintain P homeostasis. Spatio-temporal molecular, physiological, and biochemical Pi deficiency responses developed by plants are the consequence of local and systemic sensing and signaling pathways. Pi deficiency is sensed locally by the root system where hormones serve as important signaling components in terms of developmental reprogramming, leading to changes in root system architecture. Root-to-shoot and shoot-to-root signals, delivered through the xylem and phloem, respectively, involving Pi itself, hormones, miRNAs, mRNAs, and sucrose, serve to coordinate Pi deficiency responses at the whole-plant level. A combination of chromatin remodeling, transcriptional and posttranslational events contribute to globally regulating a wide range of Pi deficiency responses. In this review, recent advances are evaluated in terms of progress toward developing a comprehensive understanding of the molecular events underlying control over P homeostasis. Application of this knowledge, in terms of developing crop plants having enhanced attributes for P use efficiency, is discussed from the perspective of agricultural sustainability in the face of diminishing global P supplies.

  19. Redox Control of Leukemia: From Molecular Mechanisms to Therapeutic Opportunities

    PubMed Central

    Irwin, Mary E.; Rivera-Del Valle, Nilsa

    2013-01-01

    Abstract Reactive oxygen species (ROS) play both positive and negative roles in the proliferation and survival of a cell. This dual nature has been exploited by leukemia cells to promote growth, survival, and genomic instability—some of the hallmarks of the cancer phenotype. In addition to altered ROS levels, many antioxidants are dysregulated in leukemia cells. Together, the production of ROS and the expression and activity of antioxidant enzymes make up the primary redox control of leukemia cells. By manipulating this system, leukemia cells gain proliferative and survival advantages, even in the face of therapeutic insults. Standard treatment options have improved leukemia patient survival rates in recent years, although relapse and the development of resistance are persistent challenges. Therapies targeting the redox environment show promise for these cases. This review highlights the molecular mechanisms that control the redox milieu of leukemia cells. In particular, ROS production by the mitochondrial electron transport chain, NADPH oxidase, xanthine oxidoreductase, and cytochrome P450 will be addressed. Expression and activation of antioxidant enzymes such as superoxide dismutase, catalase, heme oxygenase, glutathione, thioredoxin, and peroxiredoxin are perturbed in leukemia cells, and the functional consequences of these molecular alterations will be described. Lastly, we delve into how these pathways can be potentially exploited therapeutically to improve treatment regimens and promote better outcomes for leukemia patients. Antioxid. Redox Signal. 18, 1349–1383. PMID:22900756

  20. Molecular Mechanisms and Treatment of Radiation-Induced Lung Fibrosis

    PubMed Central

    Ding, Nian-Hua; Li, Jian Jian; Sun, Lun-Quan

    2014-01-01

    Radiation-induced lung fibrosis (RILF) is a severe side effect of radiotherapy in lung cancer patients that presents as a progressive pulmonary injury combined with chronic inflammation and exaggerated organ repair. RILF is a major barrier to improving the cure rate and well-being of lung cancer patients because it limits the radiation dose that is required to effectively kill tumor cells and diminishes normal lung function. Although the exact mechanism is unclear, accumulating evidence suggests that various cells, cytokines and regulatory molecules are involved in the tissue reorganization and immune response modulation that occur in RILF. In this review, we will summarize the general symptoms, diagnostics, and current understanding of the cells and molecular factors that are linked to the signaling networks implicated in RILF. Potential approaches for the treatment of RILF will also be discussed. Elucidating the key molecular mediators that initiate and control the extent of RILF in response to therapeutic radiation may reveal additional targets for RILF treatment to significantly improve the efficacy of radiotherapy for lung cancer patients. PMID:23909719