Kinetic model based on molecular mechanism for action potential

The Hodgkin-Huxley model for action potentials has been widely used but was not built on a microscopic description of the neuronal membrane. Through molecular dynamics simulations, the molecular mechanism of the channel currents is becoming clear. However, the quantitative link between molecular mechanism and action potential remains to be elucidated. Here, a kinetic model for action potential based on the molecular mechanism of the channel currents is proposed. Using it, the experimental observations about action potential are reproduced quantitatively and explained based on molecular mechanism. We find that the accumulation of Na+ ions near exit of the electivity filter is the dominant event to cause the refractory period of the Na+ channel and the types of the channel currents depend on its rate constants. The channel inductance represents the inertia of the channel to retain a certain ion binding state, the channel resistances include ones against state transition and charge transfer

Insights into the molecular mechanism of Sjogren's syndrome

Sjogren’s syndrome (SS) is a chronic autoimmune disease, that affects primarily salivary and lacrimal glands, leading to increased morbidity. Recent studies indicate that loss of salivary gland function is associated with defective cell polarity, lymphocytic infiltration and fibrosis. Our previous studies showed that deregulation of E-cadherin-mediated adhesion was associated with nuclear localization of YAP and suggested that the latter may be a key event in SS. In this study, our goal was to align altered morphological features in SS with cell polarity regulators. Specifically, we focused on the Par complex, known to play an important role in epithelial polarity, as well as components of tight junctions (TJs), ZO-1 and JAM-1, and compared them to changes in their expression and localization with markers of fibrosis, vimentin and α-smooth muscle actin (α-SMA). Using immunofluorescence staining and confocal microscopy we examined expression levels of YAP, Par3, ZO-1, JAM-1, vimentin, and α-SMA, and correlated them with a ductal differentiation marker K7 and a marker for lymphocytic infiltration, CD45+. Our results showed reduced levels of Par3, ZO-1 and JAM-1, in tissues from SS patients that were associated with increased nuclear localization of YAP. Collectively, these studies suggest that cell polarity cues are critical for normal function of salivary glands and that their deregulation is likely to be the underlying basis of at least a subset of SS patients. These findings will further contribute to a better understanding of the molecular basis of SS and will serve in improved diagnosis and future therapeutic intervention

The role of pharmacology in anticancer drug development

Drug development consists of many sequential and parallel steps; failure in one of the steps can lead to discontinuation of the process. The process is time-consuming and very expensive, especially the clinical phase. In order to enhance cancer drug development in the 1980s, the National Cancer Institute (NCI) adopted a new screening system using 60 different tumour cell lines from various histologies. All standard drugs were tested in this panel and it is still open for testing of new chemical entities (NCE) of potential interest. The European NCI compounds initiative, a collaborative programme of the NCI, the Cancer Research Campaign (CRC; now CRUK) and the Pharmacology and Molecular Mechanism Group (PAMM) of the EORTC (European Organization on Research and Treatment of Cancer), was initiated in 1993. The programme aimed to help the NCI reducing its backlog of in vivo testing by further evaluation of interesting European compounds using a pharmacologically directed approach. Considerable multidisciplinary expertise in drug development was combined by the CRC and EORTC-PAMM: chemists, pharmacists, biologists, pharmacologists, oncologists. Selection criteria for European NCI compounds included novelty of the NCE, in vitro activity, if available in vivo and hollow fibre activity, and COMPARE negativity. Over a period of more than 20 years 95 out of approximately 2,000 reviewed compounds were selected. These compounds were put through a series of stepwise pharmacological tests comprising solubility (suitable formulation to administer the NCE to mice), feasibility to develop a simple analytical assay (usually HPLC), limited toxicology and angiogenic properties. This paper provides examples to illustrate the rigorousness of the elimination process of the compounds and discusses the way to improve the process by inclusion of more physico-chemical parameters

Microtubule-severing enzymes: From cellular functions to molecular mechanism.

Microtubule-severing enzymes generate internal breaks in microtubules. They are conserved in eukaryotes from ciliates to mammals, and their function is important in diverse cellular processes ranging from cilia biogenesis to cell division, phototropism, and neurogenesis. Their mutation leads to neurodegenerative and neurodevelopmental disorders in humans. All three known microtubule-severing enzymes, katanin, spastin, and fidgetin, are members of the meiotic subfamily of AAA ATPases that also includes VPS4, which disassembles ESCRTIII polymers. Despite their conservation and importance to cell physiology, the cellular and molecular mechanisms of action of microtubule-severing enzymes are not well understood. Here we review a subset of cellular processes that require microtubule-severing enzymes as well as recent advances in understanding their structure, biophysical mechanism, and regulation

Elucidating the Molecular Mechanism of CO₂ Capture by Amino Acid Ionic Liquids

Amino acid ionic liquids have received increasing attention as ideal candidates for the CO2 chemisorption process. However, the underlying molecular mechanisms, especially those involving proton transfer, remain unclear. In this work, we elucidate the atomistic-level reaction mechanisms responsible for carbamate formation during CO2 capture by amino acid ionic liquids through explicit ab initio molecular dynamics augmented by well-tempered metadynamics. The resulting ab initio free-energy sampling reveals a two-step reaction pathway in which a zwitterion, initially formed from the reaction between the anion of serine and CO2, undergoes a kinetically facile intermolecular proton transfer to the O atom of the COO– moiety in the nearby serine. Further analysis reveals that the significantly reduced free-energy barriers are attributed to enhanced intermolecular interaction between the zwitterion and serine, thus facilitating the kinetic favorability of the proton transfer, which governs the overall CO2 capture mechanism. This work provides valuable insight into the important mechanistic and kinetic features of these reactions from explicit condensed phase ab initio MD free-energy sampling of the CO2 capture process

Study of Molecular Mechanism of Antibiotic susceptibility against Polymicrobial Oral infection

Abstract

Introduction- Antibiotic to treat dental caries infection are routinely prescribed. Bacteria have increased resistance to the currently recommended antibiotics. The purpose of this investigation was to perform antibiotic susceptibility on a panel pathogenic strain of bacteria isolated step by step from dental caries infection. 
Materials and Methods-Bacteria were isolated from caries site of patients and cultivated identified at the species level. Each of 150 species of bacteria was tested for antibiotics susceptibility to a five antibiotics using Etest. Antibiotic used were Amoxicillin, Cloxocillin, Erythromycin, Tetracycline, Penicillin-V.
Results- The percentages of Resistance in treatment for each antibiotic in this study were penicillin V: 72/150 (48%), Tetracycline: 99/150 (66%), amoxicillin: 135/150 (90%), Cloxocillin: 117/150 (78%), and Erythromycin: 90/150 (60%) (Table 1). If combination antibiotic therapy had been used to treat the bacteria isolated from dental caries, the percentage of Resistance for the combination of penicillin V/Amoxicillin would have been 39/150 (26%), and the combination of amoxicillin/ Erythromycin would have been 45/150 (30%).
Conclusion- This study demonstrated the Molecular Mechanism of antibiotic resistance and susceptibility pattern, of bacteria causing dental caries. The comprehensive results data obtained will allow in investigating spatial distribution of pathogenic antibiotic resistant bacteria in patients of dental caries. In turn this will allow the development of novel diagnostic and treatment methods. 
&#xa

Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition

RIG-I is a viral RNA sensor that induces the production of type I interferon (IFN) in response to infection with a variety of viruses. Modification of RIG-I with K63-linked poly-ubiquitin chains, synthesised by TRIM25, is crucial for activation of the RIG-I/MAVS signalling pathway. TRIM25 activity is targeted by influenza A virus non-structural protein 1 (NS1) to suppress IFN production and prevent an efficient host immune response. Here we present structures of the human TRIM25 coiled-coil-PRYSPRY module and of complexes between the TRIM25 coiled-coil domain and NS1. These structures show that binding of NS1 interferes with the correct positioning of the PRYSPRY domain of TRIM25 required for substrate ubiquitination and provide a mechanistic explanation for how NS1 suppresses RIG-I ubiquitination and hence downstream signalling. In contrast, the formation of unanchored K63-linked poly-ubiquitin chains is unchanged by NS1 binding, indicating that RING dimerisation of TRIM25 is not affected by NS1

Molecular Mechanism Involved in the Pathogenesis of Early-Onset Epileptic Encephalopathy

Recent studies have shown that neurologic inflammation may both precipitate and sustain seizures, suggesting that inflammation may be involved not only in epileptogenesis but also in determining the drug-resistant profile. Extensive literature data during these last years have identified a number of inflammatory markers involved in these processes of "neuroimmunoinflammation" in epilepsy, with key roles for pro-inflammatory cytokines such as: IL-6, IL-17 and IL-17 Receptor (IL-17R) axis, Tumor-Necrosis-Factor Alpha (TNF-α) and Transforming-Growth-Factor Beta (TGF-β), all responsible for the induction of processes of blood-brain barrier (BBB) disruption and inflammation of the Central Nervous System (CNS) itself. Nevertheless, many of these inflammatory biomarkers have also been implicated in the pathophysiologic process of other neurological diseases. Future studies will be needed to identify the disease-specific biomarkers in order to distinguish epilepsies from other neurological diseases, as well as recognize different epileptic semiology. In this context, biological markers of BBB disruption, as well as those reflecting its integrity, can be useful tools to determine the pathological process of a variety of neurological diseases. However; how these molecules may help in the diagnosis and prognostication of epileptic disorders remains yet to be determined. Herein, authors present an extensive literature review on the involvement of both, systemic and neuronal immune systems, in the early onset of epileptic encephalopathy