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On and Off Pathways

Paul P Jung, Zhi Zhang, Nicole Paczia, Christian Jaeger, Tomasz Ignac, Patrick May, Carole L Linster
Aging is a complex trait of broad scientific interest, especially because of its intrinsic link with common human diseases. Pioneering work on aging-related mechanisms has been made in Saccharomyces cerevisiae , mainly through the use of deletion collections isogenic to the S288c reference strain. In this study, using a recently published high-throughput approach, we quantified chronological life span (CLS) within a collection of 58 natural strains across seven different conditions. We observed a broad aging variability suggesting the implication of diverse genetic and environmental factors in chronological aging control...
2018: NPJ Aging and Mechanisms of Disease
L Ormesher, E D Johnstone, E Shawkat, A Dempsey, C Chmiel, E Ingram, L E Higgins, J E Myers
OBJECTIVE: To evaluate the use of plasma Placental Growth Factor (PlGF), recommended by the recent NICE guidance, in women with suspected pre-eclampsia (PE) and/or fetal growth restriction (FGR). STUDY DESIGN: Non-randomised prospective clinical evaluation study in high-risk antenatal clinics in a tertiary maternity unit. METHODS: PlGF testing was performed in addition to routine clinical assessment in 260 women >20 weeks' gestation with chronic disease (hypertension, renal disease ± diabetes) with a change in maternal condition or in women with suspected FGR to determine the impact on clinical management...
March 13, 2018: Pregnancy Hypertension
Sarah L Sheu
Tranexamic acid is a procoagulant agent that is approved by the US Food and Drug Administration for treatment of menorrhagia and to prevent hemorrhage in patients with hemophilia undergoing tooth extractions. Through its inhibitory effects on the plasminogen activation pathway, tranexamic acid also mitigates the UV radiation-induced pigmentation response. Systemic tranexamic acid has consistently been reported as an effective treatment of melasma, though its broad use may be limited by the risk for thromboembolism...
February 2018: Cutis; Cutaneous Medicine for the Practitioner
Nancy Nicosia, Ashlesha Datar
INTRODUCTION: Experimental and quasi-experimental evidence on the relationship between adolescents' physical activity and their physical activity environments is scarce. This study provides natural experimental evidence using within-person longitudinal variation in physical activity environments resulting from the compulsory re-assignment of military families to new installations, termed permanent changes of station. METHODS: Adolescents in Army families (N=749) reported usual weekly minutes of moderate and vigorous physical activity in 2013-2015...
March 14, 2018: American Journal of Preventive Medicine
Elhussiny A Aboulnaga, Huibin Zou, Thorsten Selmer, Mo Xian
Cupriavidus necator H16 gains increasing attention in microbial research and biotechnological application due to its diverse metabolic features. Here we present a tightly controlled gene expression system for C. necator including the pBBR1-vector that contains hybrid promoters originating from C. necator native tolC-promoter in combination with a synthetic tetO-operator. The expression of the reporter gene from these plasmids relies on the addition of the exogenous inducer doxycycline (dc). The novel expression system offers a combination of advantageous features as; (i) high and dose-dependent recombinant protein production, (ii) tight control with a high dynamic range (On/Off ratio), which makes it applicable for harmful pathways or for toxic protein production, (iii) comparable cheap inducer (doxycycline, dc), (iv) effective at low inducer concentration, that makes it useful for large scale application, (v) rapid, diffusion controlled induction, and (vi) the inducer does not interfere within the cell metabolism...
March 13, 2018: Journal of Biotechnology
Qinghui Cheng, Zhi-Wen Hu, Katelynne E Doherty, Yuto J Tobin-Miyaji, Wei Qiang
Disruption of the synaptic plasma membrane (SPM) induced by the aggregation of β-amyloid (Aβ) peptides has been considered as a potential mechanism for the neurotoxicity of Aβ in Alzheimer's disease (AD). However, the molecular basis of such membrane disruption process remains unclear, mainly because of the severe systematic heterogeneity problem that prevents the high-resolution studies. Our previous studies using a two-component phosphatidylcholine (PC)/phosphatidylglycerol (PG) model liposome showed the presence of Aβ-induced membrane disruptions that were either on the pathway or off the pathway of fibril formation...
March 13, 2018: Biochimica et Biophysica Acta
María Victoria Repetto, Matthew J Winters, Alan Bush, Wolfgang Reiter, David Maria Hollenstein, Gustav Ammerer, Peter M Pryciak, Alejandro Colman-Lerner
We report an unanticipated system of joint regulation by cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK), involving collaborative multi-site phosphorylation of a single substrate. In budding yeast, the protein Ste5 controls signaling through a G1 arrest pathway. Upon cell-cycle entry, CDK inhibits Ste5 via multiple phosphorylation sites, disrupting its membrane association. Using quantitative time-lapse microscopy, we examined Ste5 membrane recruitment dynamics at different cell-cycle stages...
March 15, 2018: Molecular Cell
Ariel Talavera, Jelle Hendrix, Wim Versées, Dukas Jurėnas, Katleen Van Nerom, Niels Vandenberk, Ranjan Kumar Singh, Albert Konijnenberg, Steven De Gieter, Daniel Castro-Roa, Anders Barth, Henri De Greve, Frank Sobott, Johan Hofkens, Nikolay Zenkin, Remy Loris, Abel Garcia-Pino
Bacterial protein synthesis is intricately connected to metabolic rate. One of the ways in which bacteria respond to environmental stress is through posttranslational modifications of translation factors. Translation elongation factor Tu (EF-Tu) is methylated and phosphorylated in response to nutrient starvation upon entering stationary phase, and its phosphorylation is a crucial step in the pathway toward sporulation. We analyze how phosphorylation leads to inactivation of Escherichia coli EF-Tu. We provide structural and biophysical evidence that phosphorylation of EF-Tu at T382 acts as an efficient switch that turns off protein synthesis by decoupling nucleotide binding from the EF-Tu conformational cycle...
March 2018: Science Advances
Nazario Martin, Alicia López-Andarias, Javier López-Andarias, Carmen Atienza, Francisco J Chichón, José L Carrascosa
Supramolecular chemistry has evolved from the traditional focus on thermodynamic on-pathways to the complex study of kinetic off-pathways, which are strongly dependent of the environmental conditions. Moreover, the control over pathway complexity allows obtaining nanostructures that are inaccessible through spontaneous thermodynamic processes. Here, we present a family of peptide-based π-extended tetrathiafulvalene (exTTF) molecules which show two self-assembly pathways leading to two distinct J-aggregates, namely metastable (M) and thermodynamic (T), with different spectroscopic, chiroptical and electrochemical behavior...
March 14, 2018: Chemistry: a European Journal
Jee Youn Hwang, Kesavan Markkandan, Mun Gyeong Kwon, Jung Soo Seo, Seung-Il Yoo, Seong Don Hwang, Maeng-Hyun Son, Junhyung Park
Olive flounder (Paralichthys olivaceus) is one of the most valuable marine aquatic species in South Korea and faces tremendous exposure to the viral hemorrhagic septicemia virus (VHSV). Given the growing importance of flounder, it is therefore essential to understand the host defense of P. olivaceus against VHSV infection, but studies on its immune mechanism are hindered by the lack of genomic resources. In this study, the P. olivaceus was infected with disease-causing VHSV isolates, ADC-VHS2012-11 and ADC-VHS2014-5 which showed moderate virulent (20% mortality) and high virulent (65% mortality), in order to investigate the effect of difference in pathogenicity in head kidney during 1, 3, 7 days of post-infection using Illumina sequencing...
March 9, 2018: Fish & Shellfish Immunology
Zahra Bahadoran, Parvin Mirmiran, Fereidoun Azizi, Asghar Ghasemi
Inorganic nitrate (NO3 ) due to its potential endogenous conversion to nitric oxide (NO), is suggested as a compensatory fuel for disrupted NO pathways in the case of pathological stats during pregnancy. Dietary NO3 -rich supplement in the NO-deficient pregnant women is now suggested as a more appealing choice with fewer off-target effects which can attenuate hypertension and preeclampsia, improve placental blood flow and subsequently enhance maternal and neonatal health. There is also an increasing public interest and common health claims regarding beneficial effects of NO3 -rich dietary supplements like beetroot byproducts in pregnant women...
January 2018: Pregnancy Hypertension
Douglas S Jones, Anne P Jenney, Brian A Joughin, Peter K Sorger, Douglas A Lauffenburger
Rheumatoid arthritis (RA) is a chronic inflammatory disorder that causes joint pain, swelling, and loss of function. Development of effective new drugs has proven challenging in part because of the complexities and interconnected nature of intracellular signaling networks that complicate the effects of pharmacological interventions. We characterized the kinase signaling pathways that are activated in RA and evaluated the multivariate effects of targeted inhibitors. Synovial fluids from RA patients activated the kinase signaling pathways JAK, JNK, p38, and MEK in synovial fibroblasts (SFs), a stromal cell type that promotes RA progression...
March 6, 2018: Science Signaling
Christina Helmling, Dean-Paulos Klötzner, Florian Sochor, Rachel Anne Mooney, Anna Wacker, Robert Landick, Boris Fürtig, Alexander Heckel, Harald Schwalbe
Transcriptional riboswitches modulate downstream gene expression by a tight coupling of ligand-dependent RNA folding kinetics with the rate of transcription. RNA folding pathways leading to functional ON and OFF regulation involve the formation of metastable states within well-defined sequence intervals during transcription. The kinetic requirements for the formation and preservation of these metastable states in the context of transcription remain unresolved. Here, we reversibly trap the previously defined regulatory relevant metastable intermediate of the Mesoplasma florum 2'-deoxyguanosine (2'dG)-sensing riboswitch using a photocaging-ligation approach, and monitor folding to its native state by real-time NMR in both presence and absence of ligand...
March 5, 2018: Nature Communications
Ida Marabese, Serena Boccella, Monica Iannotta, Livio Luongo, Vito de Novellis, Francesca Guida, Nicola Serra, Antonio Farina, Sabatino Maione, Enza Palazzo
The study investigated the role of the metabotropic glutamate receptor subtype 7 (mGluR7) in pain signalling in the dorsal striatum of sham and neuropathic rats. Supraspinal circuitries involved in the dorsal striatum control of pain were also explored. In the sham rats, microinjection of N,N'-bis(diphenylmethyl)-1,2-ethanediamine (AMN082), a selective mGluR7 positive allosteric modulator, into the dorsal striatum, facilitated pain, increased the activity of the ON cells and inhibited the activity of the OFF cells in the rostral ventromedial medulla, and decreased glutamate levels in the dorsal striatum...
March 2, 2018: Neuropharmacology
Ninning Liu, Gheorghe Chistol, Yuanbo Cui, Carlos Bustamante
Multi-subunit ring-shaped ATPases are molecular motors that harness chemical free energy to perform vital mechanical tasks such as polypeptide translocation, DNA unwinding, and chromosome segregation. Previously we reported the intersubunit coordination and stepping behavior of the hexameric ring-shaped ATPase SpoIIIE (Liu et al., 2015). Here we use optical tweezers to characterize the motor's mechanochemistry. Analysis of the motor response to external force at various nucleotide concentrations identifies phosphate release as the likely force-generating step...
March 5, 2018: ELife
Maud Wilhelm, Fengjuan Wang, Nicolas Schall, Jean-François Kleinmann, Michael Faludi, Emil Pablo Nashi, Jean Sibilia, Thierry Martin, Evelyne Schaeffer, Sylviane Muller
OBJECTIVES: To investigate ex vivo the effect on human T and B cells of P140/LupuzorTM , an inhibitor of autophagy, currently evaluated in phase III-clinical trials for treating lupus. METHODS: B cells, T cells and dendritic cells were analyzed by flow cytometry and cellular assays. The autophagy marker expression was evaluated by immunoblotting and flow cytometry; the levels of B cell receptor signaling markers and HLA molecules expression by flow cytometry. TLR ligand screening was made using transfected HEK cells...
March 2, 2018: Arthritis & Rheumatology
Adriana Mihaela Ilieșiu, Andreea Simona Hodorogea
Heart failure with preserved ejection fraction (HFpEF) is a growing epidemiologic problem affecting more than half of the patients with heart failure (HF). HFpEF has a significant morbidity and mortality and so far no treatment has been clearly demonstrated to improve the outcomes in HFpEF, in contrast to the efficacy of treatment in heart failure with reduced ejection fraction (HFrEF).The failure of proven beneficial drugs in HFrEF to influence the outcome of patients with HFpEF could be related to the heterogeneity of the disease, its various phenotypes and multifactorial pathophysiology, incompletely elucidated yet...
March 2, 2018: Advances in Experimental Medicine and Biology
Osvaldo Filipe, David De Vleesschauwer, Ashley Haeck, Kristof Demeestere, Monica Höfte
Sucrose non-fermenting-1-related protein kinase-1 (SnRK1) belongs to a family of evolutionary conserved kinases with orthologs in all eukaryotes, ranging from yeasts (SnF1) to mammals (AMP-Activated kinase). These kinases sense energy deficits caused by nutrient limitation or stress and coordinate the required adaptations to maintain energy homeostasis and survival. In plants, SnRK1 is a global regulator of plant metabolism and is also involved in abiotic stress responses. Its role in the response to biotic stress, however, is only starting to be uncovered...
March 1, 2018: Scientific Reports
Omar Mubin, Mudassar Arsalan, Abdullah Al Mahmud
Academic conferences offer numerous submission tracks to support the inclusion of a variety of researchers and topics. Work in progress papers are one such submission type where authors present preliminary results in a poster session. They have recently gained popularity in the area of Human Computer Interaction (HCI) as a relatively easier pathway to attending the conference due to their higher acceptance rate as compared to the main tracks. However, it is not clear if these work in progress papers are further extended or transitioned into more complete and thorough full papers or are simply one-off pieces of research...
2018: Scientometrics
Amiran Keshelava, Gonzalo P Solis, Micha Hersch, Alexey Koval, Mikhail Kryuchkov, Sven Bergmann, Vladimir L Katanaev
G protein-coupled receptors (GPCRs) constitute a large family of receptors that activate intracellular signaling pathways upon detecting specific extracellular ligands. While many aspects of GPCR signaling have been uncovered through decades of studies, some fundamental properties, like its channel capacity-a measure of how much information a given transmission system can reliably transduce-are still debated. Previous studies concluded that GPCRs in individual cells could transmit around one bit of information about the concentration of the ligands, allowing only for a reliable on or off response...
February 28, 2018: Nature Communications
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