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On and Off Pathways

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https://www.readbyqxmd.com/read/28922400/protein-folding-misfolding-and-aggregation-the-importance-of-two-electron-stabilizing-interactions
#1
Andrzej Stanisław Cieplak
Proteins associated with neurodegenerative diseases are highly pleiomorphic and may adopt an all-α-helical fold in one environment, assemble into all-β-sheet or collapse into a coil in another, and rapidly polymerize in yet another one via divergent aggregation pathways that yield broad diversity of aggregates' morphology. A thorough understanding of this behaviour may be necessary to develop a treatment for Alzheimer's and related disorders. Unfortunately, our present comprehension of folding and misfolding is limited for want of a physicochemical theory of protein secondary and tertiary structure...
2017: PloS One
https://www.readbyqxmd.com/read/28918071/the-masseteric-nerve-an-anatomical-study-in-thai-population-with-an-emphasis-on-its-use-in-facial-reanimation
#2
Apichai Angspatt, Chirayu Pannanusorn
BACKGROUND: The use of the masseteric nerve has been escalated as a donor nerve for facial reanimation in facial palsy patient (Wang et al., 2014; Manktelow et al., 2006; Klebuc, 2011; Bianchi et al., 2012; Zuker et al., 2000; Bae et al., 2006; Terzis, Konofaos, 2013; Terzis, Olivares, 2009; Bianchi et al., 2014). Previous studies had been done in Euro-Caucasian cadavers (Kaya et al., 2014). However, difference in anatomical details does exist between Asian and Euro-Caucasian population (Tzou et al...
September 13, 2017: Asian Journal of Surgery
https://www.readbyqxmd.com/read/28918038/strategies-for-in%C3%A2-vivo-screening-and-mitigation-of-hepatotoxicity-associated-with-antisense-drugs
#3
Piotr J Kamola, Klio Maratou, Paul A Wilson, Kay Rush, Tanya Mullaney, Tom McKevitt, Paula Evans, Jim Ridings, Probash Chowdhury, Aude Roulois, Ann Fairchild, Sean McCawley, Karen Cartwright, Nigel J Gooderham, Timothy W Gant, Kitty Moores, Stephen A Hughes, Mark R Edbrooke, Kenneth Clark, Joel D Parry
Antisense oligonucleotide (ASO) gapmers downregulate gene expression by inducing enzyme-dependent degradation of targeted RNA and represent a promising therapeutic platform for addressing previously undruggable genes. Unfortunately, their therapeutic application, particularly that of the more potent chemistries (e.g., locked-nucleic-acid-containing gapmers), has been hampered by their frequent hepatoxicity, which could be driven by hybridization-mediated interactions. An early de-risking of this liability is a crucial component of developing safe, ASO-based drugs...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28916726/the-nqo1-bioactivatable-drug-%C3%AE-lapachone-alters-the-redox-state-of-nqo1-pancreatic-cancer-cells-causing-perturbation-in-central-carbon-metabolism
#4
Molly A Silvers, Stanislaw Deja, Naveen Singh, Robert A Egnatchik, Jessica Sudderth, Xiuquan Luo, Muhammad S Beg, Shawn C Burgess, Ralph J DeBerardinis, David A Boothman, Matthew E Merritt
Many cancer treatments, such as those for managing recalcitrant tumors like pancreatic ductal adenocarcinoma, cause off-target toxicities in normal, healthy tissue, highlighting the need for more tumor-selective chemotherapies. β-Lapachone is bioactivated by NAD(P)H:quinone oxidoreductase 1 (NQO1). This enzyme exhibits elevated expression in most solid cancers and therefore is a potential cancer-specific target. β-Lapachone's therapeutic efficacy partially stems from the drug's induction of a futile NQO1-mediated redox cycle that causes high levels of superoxide, then peroxide formation, which damages DNA and causes hyperactivation of poly (ADP-ribose) polymerase (PARP), resulting in extensive NAD+/ATP depletion...
September 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28913831/asymmetry-between-on-and-off-alpha-ganglion-cells-of-mouse-retina-integration-of-signal-and-noise-from-synaptic-inputs
#5
Michael A Freed
ON and OFF pathways in the retina include functional pairs of neurons that, at first glance, appear to have symmetrically similar responses to brightening and darkening, respectively. Upon careful examination, however, functional pairs exhibit asymmetries in receptive field size and response kinetics. Until now, descriptions of how light-adapted retinal circuitry maintains a preponderance of signal over the noise have not distinguished between ON and OFF pathways. Here I present evidence of marked asymmetries between members of a functional pair of sustained alpha ganglion cells in the mouse retina...
September 15, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28910500/is-systems-pharmacology-ready-to-impact-upon-therapy-development-a-study-on-the-cholesterol-biosynthesis-pathway
#6
Helen Benson, Steven Watterson, Joanna Sharman, Chido Mpamhanga, Andrew Parton, Christopher Southan, Anthony Harmar, Peter Ghazal
BACKGROUND AND PURPOSE: An ever-growing wealth of information on current drugs and their pharmacological effects is available from online databases. As our understanding of systems biology increases, we have the opportunity to predict, model and quantify how drug combinations can be introduced that outperform conventional single-drug therapies. Here, we explore the feasibility of such systems pharmacology approaches with an analysis of the mevalonate branch of the cholesterol biosynthesis pathway...
September 14, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28904105/contribution-of-sensory-feedback-to-plantar-flexor-muscle-activation-during-push-off-in-adults-with-cerebral-palsy
#7
Rasmus Feld Frisk, Peter Jensen, Henrik Kirk, Laurent J Bouyer, Jakob Lorentzen, Jens Bo Nielsen
INTRODUCTION: Exaggerated sensory activity has been assumed to contribute to functional impairment following lesion of the central motor pathway. However, recent studies have suggested that sensory contribution to muscle activity during gait is reduced in stroke patients and children with cerebral palsy (CP). We investigated whether this also occurs in CP adults and whether daily treadmill training is accompanied by alterations in sensory contribution to muscle activity. MATERIALS AND METHODS: 17 CP adults and 12 uninjured individuals participated...
September 13, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28903044/engineering-synthetic-signaling-pathways-with-programmable-dcas9-based-chimeric-receptors
#8
Toni A Baeumler, Ahmed Ashour Ahmed, Tudor A Fulga
Synthetic receptors provide a powerful experimental tool for generation of designer cells capable of monitoring the environment, sensing specific input signals, and executing diverse custom response programs. To advance the promise of cellular engineering, we have developed a class of chimeric receptors that integrate a highly programmable and portable nuclease-deficient CRISPR/Cas9 (dCas9) signal transduction module. We demonstrate that the core dCas9 synthetic receptor (dCas9-synR) architecture can be readily adapted to various classes of native ectodomain scaffolds, linking their natural inputs with orthogonal output functions...
September 12, 2017: Cell Reports
https://www.readbyqxmd.com/read/28900911/the-stim-orai-pathway-regulation-of-stim-and-orai-by-thiol-modifications
#9
Barbara A Niemeyer
Cysteines are among the least abundant amino acids found in proteins. Due to their unique nucleophilic thiol group, they are able to undergo a broad range of chemical modifications besides their known role in disulfide formation, such as S-sulfenylation (-SOH), S-sulfinylation (-SO(2)H), S-sufonylation (-SO(3)H), S-glutathionylation (-SSG), and S-sulfhydration (-SSH), among others. These posttranslational modifications can be irreversible and act as transitional modifiers or as reversible on-off switches for the function of proteins...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28894379/mirna-expression-profiling-in-formalin-fixed-paraffin-embedded-endometriosis-and-ovarian-cancer-samples
#10
Ovidiu-Leonard Braicu, Liviuta Budisan, Rares Buiga, Ancuta Jurj, Patriciu Achimas-Cadariu, Laura Ancuta Pop, Cornelia Braicu, Alexandru Irimie, Ioana Berindan-Neagoe
Endometriosis is an inflammatory pathology associated with a negative effect on life quality. Recently, this pathology was connected to ovarian cancer, in particular with endometrioid ovarian cancer. microRNAs (miRNAs) are a class of RNA transcripts ~19-22 nucleotides in length, the altered miRNA pattern being connected to pathological status. miRNAs are highly stable transcripts, and these can be assessed from formalin-fixed paraffin-embedded (FFPE) samples leading to the identification of miRNAs that could be developed as diagnostic and prognostic biomarkers, in particular those involved in malignant transformation...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28890885/evaluation-of-microrna-99a-and-microrna-205-expression-levels-in-bladder-cancer
#11
Sajjad Mohammad Ganji, Massoud Saidijam, Razieh Amini, Seyed Habibollah Mousavi-Bahar, Nooshin Shabab, Saman Seyedabadi, Ali Mahdavinezhad
Bladder cancer is the second most common cancer in the genitourinary tract, showing often recurrence and progress into invasive states. Epigenetic changes, such as microRNA alteration are involved in bladder cancer tumorigenesis through a variety of signaling pathways. The epigenetic state depends on geographic and lifestyle conditions. The aim of this study was to investigate the expression level of microRNA-99a and microRNA-205 in bladder cancer in Iranian populations and to determine the relationship between their expressions with clinicophatological features...
2017: International Journal of Molecular and Cellular Medicine
https://www.readbyqxmd.com/read/28883905/rosmarinic-acid-alleviates-the-endothelial-dysfunction-induced-by-hydrogen-peroxide-in-rat-aortic-rings-via-activation-of-ampk
#12
Hui Zhou, Baocai Fu, Bo Xu, Xiangquan Mi, Gang Li, Chengjun Ma, Jianxin Xie, Ji Li, Zhenhua Wang
Endothelial dysfunction is the key player in the development and progression of vascular events. Oxidative stress is involved in endothelial injury. Rosmarinic acid (RA) is a natural polyphenol with antioxidative, antiapoptotic, and anti-inflammatory properties. The present study investigates the protective effect of RA on endothelial dysfunction induced by hydrogen peroxide (H2O2). Compared with endothelium-denuded aortic rings, the endothelium significantly alleviated the decrease of vasoconstrictive reactivity to PE and KCl induced by H2O2...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28880526/high-performance-charge-transport-in-semiconducting-armchair-graphene-nanoribbons-grown-directly-on-germanium
#13
Robert M Jacobberger, Michael S Arnold
The growth of graphene on Ge(001) via chemical vapor deposition can be highly anisotropic, affording the facile synthesis of crystallographically controlled, narrow, long, oriented nanoribbons of graphene that are semiconducting, whereas unpatterned continuous graphene is semimetallic. This bottom-up growth overcomes long-standing challenges that have limited top-down ribbon fabrication (e.g., inadequate resolution and disordered edges) and yields ribbons with long segments of smooth armchair edges. The charge transport characteristics of sub-10 nm ribbons synthesized by this technique (which are expected to have band gaps sufficiently large for semiconductor electronics applications) have not yet been characterized...
September 14, 2017: ACS Nano
https://www.readbyqxmd.com/read/28874772/antibody-dependent-fragmentation-is-a-newly-identified-mechanism-of-cell-killing-in-vivo
#14
Pei Xiong Liew, Jung Hwan Kim, Woo-Yong Lee, Paul Kubes
The prevailing view is that therapeutic antibodies deplete cells through opsonization and subsequent phagocytosis, complement-dependent lysis or antibody-dependent cellular-cytotoxicity. We used high resolution in vivo imaging to identify a new antibody-dependent cell death pathway where Kupffer cells ripped large fragments off crawling antibody-coated iNKT cells. This antibody-dependent fragmentation process resulted in lethality and depletion of crawling iNKT cells in the liver sinusoids and lung capillaries...
September 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28872233/update-on-the-clinical-use-of-kinase-inhibitors-in-melanoma
#15
REVIEW
Ioana Cosgarea, Cathrin Ritter, Jürgen C Becker, Dirk Schadendorf, Selma Ugurel
The identification of targetable molecules in cellular signaling pathways represents a milestone in the treatment of melanoma. Selective inhibitors of these molecules, known as phosphokinases, allow for individual signaling pathways to be "switched off". This is of particular importance for tumors in which these pathways are constitutively activated by mutations in genes encoding said molecules. Especially patients with BRAF-mutated melanomas significantly benefit from kinase inhibitor therapies, with the current standard of combined BRAF and MEK inhibition providing very good long-term disease control...
September 2017: Journal der Deutschen Dermatologischen Gesellschaft, Journal of the German Society of Dermatology: JDDG
https://www.readbyqxmd.com/read/28871093/fatty-acid-concentration-and-phase-transitions-modulate-a%C3%AE-aggregation-pathways
#16
Pratip Rana, Dexter N Dean, Edward D Steen, Ashwin Vaidya, Vijayaraghavan Rangachari, Preetam Ghosh
Aggregation of amyloid β (Aβ) peptides is a significant event that underpins Alzheimer disease (AD) pathology. Aβ aggregates, especially the low-molecular weight oligomers, are the primary toxic agents in AD and hence, there is increasing interest in understanding their formation and behavior. Aggregation is a nucleation-dependent process in which the pre-nucleation events are dominated by Aβ homotypic interactions. Dynamic flux and stochasticity during pre-nucleation renders the reactions susceptible to perturbations by other molecules...
September 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28870706/bariatric-surgery-in-adolescents-with-severe-obesity-review-and-state-of-the-art-in-france
#17
Régis Coutant, Natacha Bouhours-Nouet, Aurélie Donzeau, Mathilde Fauchard, Anne Decrequy, Jean Malka, Elise Riquin, Marion Beaumesnil, Agnès Sallé, Claire Briet, Philippe Topart, Françoise Schmitt
Severe obesity (body mass index>120% of BMI IOTF-30 cut off) and morbid obesity (BMI>140% of BMI IOTF-30 cut off) affect 5 to 10% of obese adolescents in France. Organic complications can be found in about 50% of these patients, and depressive symptoms in one-third of them. Finally, over 70% will suffer from adult morbid obesity associated with a marked increase in morbidity and mortality. However, the reversion of obesity strongly decreases, and may even cancels, these risks. In controlled randomized studies, lifestyle interventions have limited effectiveness on BMI in children (and none in adolescents)...
September 1, 2017: Annales D'endocrinologie
https://www.readbyqxmd.com/read/28868356/on-off-switchable-electronic-conduction-in-intercalated-metal-organic-frameworks
#18
Nobuhiro Ogihara, Nobuko Ohba, Yoshihiro Kishida
The electrical properties of metal-organic frameworks (MOF) have attracted attention for MOF as electronic materials. We report on/off switchable electronic conduction behavior with thermal responsiveness in intercalated MOF (iMOF) with layered structure, 2,6-naphthalene dicarboxylate dilithium, which was previously reported as a reversible Li-intercalation electrode material. The I-V response of the intercalated sample, which was prepared using a chemically reductive lithiation agent, exhibits current flow with sufficiently high electronic conductivity, even though it displays insulating characteristics in the pristine state...
August 2017: Science Advances
https://www.readbyqxmd.com/read/28867544/standardization-of-radiation-therapy-dose-for-locally-advanced-non-small-cell-lung-cancer-through-changes-to-a-lung-cancer-clinical-pathway-in-a-large-integrated-comprehensive-cancer-center-network
#19
Pooja Karukonda, Brian J Gebhardt, Zachary D Horne, Dwight E Heron, Sushil Beriwal
PURPOSE: The results of Radiation Therapy Oncology Group (RTOG) 0617, which randomized patients with stages IIIA/IIIB non-small cell lung cancer (NSCLC) to definitive chemoradiation therapy to 60 Gy versus 74 Gy, demonstrated a detrimental survival impact with high-dose radiation therapy. We evaluated the impact of changes to a provider-driven clinical pathway (CP) guiding management of NSCLC on practice throughout our cancer center network. METHODS AND MATERIALS: In 2001, we implemented a CP for management of stage IIIA/IIIB NSCLC with definitive chemoradiation therapy...
July 8, 2017: Practical Radiation Oncology
https://www.readbyqxmd.com/read/28861523/monodeuterated-methane-an-isotopic-tool-to-assess-biological-methane-metabolism-rates
#20
Jeffrey J Marlow, Joshua A Steele, Wiebke Ziebis, Silvan Scheller, David Case, Linda M Reynard, Victoria J Orphan
Biological methane oxidation is a globally relevant process that mediates the flux of an important greenhouse gas through both aerobic and anaerobic metabolic pathways. However, measuring these metabolic rates presents many obstacles, from logistical barriers to regulatory hurdles and poor precision. Here we present a new approach for investigating microbial methane metabolism based on hydrogen atom dynamics, which is complementary to carbon-focused assessments of methanotrophy. The method uses monodeuterated methane (CH3D) as a metabolic substrate, quantifying the aqueous D/H ratio over time using off-axis integrated cavity output spectroscopy...
July 2017: MSphere
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