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https://www.readbyqxmd.com/read/28551817/discovery-of-novel-inhibitors-for-leishmania-nucleoside-diphosphatase-kinase-ndk-based-on-its-structural-and-functional-characterization
#1
Arjun K Mishra, Nidhi Singh, Pragati Agnihotri, Shikha Mishra, Saurabh P Singh, Bala K Kolli, Kwang Poo Chang, Amogh A Sahasrabuddhe, M I Siddiqi, J Venkatesh Pratap
Nucleoside diphosphate kinases (NDKs) are ubiquitous enzymes that catalyze the transfer of the γ-phosphate moiety from an NTP donor to an NDP acceptor, crucial for maintaining the cellular level of nucleoside triphosphates (NTPs). The inability of trypanosomatids to synthesize purines de novo and their dependence on the salvage pathway makes NDK an attractive target to develop drugs for the diseases they cause. Here we report the discovery of novel inhibitors for Leishmania NDK based on the structural and functional characterization of purified recombinant NDK from Leishmania amazonensis...
May 27, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28550372/tnf%C3%AE-induced-dlk-activation-contributes-to-apoptosis-in-the-beta-cell-line-hit
#2
Svenja Börchers, Rohollah Babaei, Catarina Klimpel, Jorge Duque Escobar, Sabine Schröder, Roland Blume, Muhammad Nasir Hayat Malik, Elke Oetjen
Reduction in beta-cell mass and function contributes to the pathogenesis of diabetes mellitus type 2. The proinflammatory cytokines tumor necrosis factor (TNF)α and interleukin (IL)-1β have been implicated in the pathogenesis of this disease. Overexpression of the dual leucine zipper kinase (DLK) inhibits beta-cell function and induces apoptosis in the beta-cell line HIT. In the present study, it was investigated whether TNFα or IL-1β stimulates DLK enzymatic activity. Immunoblot analysis, transient transfection with luciferase reporter gene assays, and immunofluorescence were used...
May 27, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28550290/differential-methylation-is-associated-with-non-syndromic-cleft-lip-and-palate-and-contributes-to-penetrance-effects
#3
Lucas Alvizi, Xiayi Ke, Luciano Abreu Brito, Rimante Seselgyte, Gudrun E Moore, Philip Stanier, Maria Rita Passos-Bueno
Non-syndromic cleft lip and/or palate (NSCLP) is a common congenital malformation with a multifactorial model of inheritance. Although several at-risk alleles have been identified, they do not completely explain the high heritability. We postulate that epigenetic factors as DNA methylation might contribute to this missing heritability. Using a Methylome-wide association study in a Brazilian cohort (67 NSCLP, 59 controls), we found 578 methylation variable positions (MVPs) that were significantly associated with NSCLP...
May 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28549156/early-subjective-sensory-experiences-with-cigalike-e-cigarettes-among-african-american-menthol-smokers-a-qualitative-study
#4
Sabrina L Smiley, Teresa DeAtley, Leslie F Rubin, Emily Harvey, Elexis C Kierstead, Monica Webb Hooper, Raymond S Niaura, David B Abrams, Jennifer L Pearson
Introduction: Despite smoker interest in e-cigarettes as a harm reduction or cessation aid, many smokers prematurely discontinue vaping after trying a product. This study explored the role of early subjective sensory experience in vaping persistence and desistence. Methods: African American menthol cigarette smokers aged ≥18 years (n=15; M=54.1 years; SD=8.2), motivated to quit smoking, and interested in trying e-cigarettes were recruited in Washington, D.C. Participants were followed for three weeks and provided menthol cigalike e-cigarettes after week one...
May 26, 2017: Nicotine & Tobacco Research: Official Journal of the Society for Research on Nicotine and Tobacco
https://www.readbyqxmd.com/read/28549057/both-antenatal-and-postnatal-inflammation-contribute-information-about-the-risk-of-brain-damage-in-extremely-preterm-newborns
#5
Diana Yanni, Steven Korzeniewski, Elizabeth N Allred, Raina N Fichorova, T Michael O'Shea, Karl Kuban, Olaf Dammann, Alan Leviton
BACKGROUNDPreterm newborns exposed to intrauterine inflammation are at increased risk of neurodevelopmental disorders. We hypothesized that adverse outcomes are more strongly associated with a combination of antenatal and postnatal inflammation than with either of them alone.METHODSWe defined antenatal inflammation as histologic inflammation in the placenta. We measured the concentrations of seven inflammation-related proteins in blood obtained on postnatal days 1, 7, and 14 from 763 infants born before 28 weeks of gestation...
May 26, 2017: Pediatric Research
https://www.readbyqxmd.com/read/28548983/cross-the-nursing-and-hit-divide
#6
Nancy Staggers, Beth L Elias
No abstract text is available yet for this article.
June 2017: Nursing Management
https://www.readbyqxmd.com/read/28547816/three-component-aminoalkylations-yielding-dihydronaphthoxazine-based-sirtuin-inhibitors-scaffold-modification-and-exploration-of-space-for-polar-side-chains
#7
Steffen Vojacek, Katja Beese, Zayan Alhalabi, Sören Swyter, Anja Bodtke, Carola Schulzke, Manfred Jung, Wolfgang Sippl, Andreas Link
Nonpolar derivatives of heterocyclic aromatic screening hits like the non-selective sirtuin inhibitor splitomicin tend to be poorly soluble in biological fluids. Unlike sp(3) -rich natural products, flat aromatic compounds are prone to stacking and often difficult to optimize into leads with activity in cellular systems. The aim of this work was to identify anchor points for the introduction of sp(3) -rich fragments with polar functional groups into the newly discovered active (IC50  = 5 μM) but nonpolar scaffold 1,2-dihydro-3H-naphth[1,2-e][1,3]oxazine-3-thione by a molecular modeling approach...
May 26, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28547797/vitamin-d-receptor-agonists-regulate-ocular-developmental-angiogenesis-and-modulate-expression-of-dre-mir-21-and-vegf
#8
Stephanie L Merrigan, Breandán N Kennedy
BACKGROUND AND PURPOSE: Pathological growth of ocular vasculature networks can underpin visual impairment in neovascular age-related macular degeneration, proliferative diabetic retinopathy and retinopathy of prematurity. Our aim was to uncover novel pharmacological regulators of ocular angiogenesis by phenotype-based screening in zebrafish. EXPERIMENTAL APPROACH: A bioactive chemical library of 465 drugs was screened to identify small molecule inhibitors of ocular hyaloid vasculature (HV) angiogenesis in zebrafish larvae...
May 26, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28547003/why-did-people-move-during-the-great-recession-the-role-of-economics-in-migration-decisions
#9
Brian L Levy, Ted Mouw, Anthony Daniel Perez
Labor migration offers an important mechanism to reallocate workers when there are regional differences in employment conditions. Whereas conventional wisdom suggests migration rates should increase during recessions as workers move out of areas that are hit hardest, initial evidence suggested that overall migration rates declined during the Great Recession, despite large regional differences in unemployment and growth rates. In this paper, we use data from the American Community Survey to analyze internal migration trends before and during the economic downturn...
April 2017: Russell Sage Foundation Journal of the Social Sciences: RSF
https://www.readbyqxmd.com/read/28546418/single-cell-dna-sequencing-reveals-a-late-dissemination-model-in-metastatic-colorectal-cancer
#10
Marco L Leung, Alexander Davis, Ruli Gao, Anna Casasent, Yong Wang, Emi Sei, Eduardo Sanchez, Dipen Maru, Scott Kopetz, Nicholas E Navin
Metastasis is a complex biological process that has been difficult to delineate in human colorectal (CRC) cancer patients. A major obstacle in understanding metastatic lineages is the extensive intratumor heterogeneity at the primary and metastatic tumor sites. To address this problem, we developed a highly-multiplexed single cell DNA sequencing approach to trace the metastatic lineages of two CRC patients with matched liver metastases. Single cell copy number or mutational profiling was performed, in addition to bulk exome and targeted deep-sequencing...
May 25, 2017: Genome Research
https://www.readbyqxmd.com/read/28545937/treatment-of-nafld-with-diet-physical-activity-and-exercise
#11
REVIEW
Manuel Romero-Gómez, Shira Zelber-Sagi, Michael Trenell
Lifestyle intervention can be useful across all the spectrum of NAFLD patients. Losing weight decreases cardiovascular / diabetes risk and also regresses liver disease. Weight reductions of ≥ 10% are required for inducing near universal NASH resolution or fibrosis improvement by at least one stage. However, modest weight losses (>5%) also produce important benefits on NAS and its components. In addition, to improve the success of this intervention we need to explore, beyond total calories and type of weight loss diet, the role of micro and macronutrients, evidence-based benefits of physical activity and exercise and finally supporting these modifications through established behaviour change models and techniques...
May 22, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28544942/behavioural-and-neural-evidence-for-the-impact-of-fluency-context-on-conscious-memory
#12
Carlos Alexandre Gomes, Axel Mecklinger, Hubert Zimmer
It has been recently suggested that fluency may impact recognition memory performance when the fluency context varies from trial-to-trial. Surprisingly, such an effect has proved difficult to detect in the masked priming paradigm, one of the most popular means to increase fluency-based memory judgements. We conducted a functional magnetic resonance imaging (fMRI) experiment in which participants encoded words at study and, at test, performed a recognition memory task within a masked priming procedure. In order to optimise the chances of finding priming effects on recognition memory performance, we used low-frequency words, which have been shown to increase hits relative to false alarms and enhance masked priming effects...
April 21, 2017: Cortex; a Journal Devoted to the Study of the Nervous System and Behavior
https://www.readbyqxmd.com/read/28544026/immobilization-and-high-platelet-count-are-associated-with-thromboembolic-complications-in-heparin-induced-thrombocytopenia
#13
Juliane Bolbrinker, Edeltraut Garbe, Antonios Douros, Matthias Huber, Elisabeth Bronder, Andreas Klimpel, Frank Andersohn, Oliver Meyer, Abdulgabar Salama, Reinhold Kreutz
PURPOSE: Immune-mediated heparin-induced thrombocytopenia (HIT type II, HIT) is a potentially serious adverse drug reaction characterized by an increased risk of venous and arterial thrombosis. This study aimed to identify risk factors associated with the development of these complications. METHODS: Our study cohort included patients with HIT assembled in our pharmacovigilance center by reports from 51 collaborating hospitals in Berlin, Germany. To identify risk factors for thromboembolic complications, patients with thromboembolic events (cases) were compared to those without thromboembolic events (controls) in a case-control design...
May 24, 2017: Pharmacoepidemiology and Drug Safety
https://www.readbyqxmd.com/read/28542202/unravelling-the-rate-of-action-of-hits-in-the-leishmania-donovani-box-using-standard-drugs-amphotericin-b-and-miltefosine
#14
Diana Tegazzini, Juan Cantizani, Imanol Peña, Julio Martín, Jose M Coterón
In recent years, the neglected diseases drug discovery community has elected phenotypic screening as the key approach for the identification of novel hit compounds. However, when this approach is applied, important questions related to the mode of action for these compounds remain unanswered. One of such questions is related to the rate of action, a useful piece of information when facing the challenge of prioritising the most promising hit compounds. In the present work, compounds of the "Leishmania donovani box" were evaluated using a rate of action assay adapted from a replicative intracellular high content assay recently developed...
May 25, 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28542049/hitting-the-nail-on-the-head-a-case-report-demonstrating-the-importance-of-a-multidisciplinary-approach-to-an-unusual-penetrating-intracranial-injury
#15
Allison L Thoeny, Iman A Hadaya, Benn M Lancman, Vincent Lew
A 28-year-old man presented with a penetrating injury by a nail gun to the head. Imaging revealed a nail abutting the superior sagittal sinus without active extravasation. An anesthesia-led multidisciplinary team devised a detailed perioperative plan including conception of a complex decision tree, coordination of care, and resource utilization. In the operating room, the nail was removed under general anesthesia, with blood products and equipment for craniotomy readily available, and imaging modalities reserved for immediate use...
May 23, 2017: A & A Case Reports
https://www.readbyqxmd.com/read/28540118/spinal-cord-injury-in-the-geriatric-population-risk-factors-treatment-options-and-long-term-management
#16
REVIEW
Tochukwu C Ikpeze, Addisu Mesfin
Spinal cord injuries (SCIs) are sustained by more than 12 500 patients per year in the United States and more globally. The SCIs disproportionately affect the elderly, especially men. Approximately 60% of these injuries are sustained traumatically through falls, but nontraumatic causes including infections, tumors, and medication-related epidural bleeding have also been documented. Preexisting conditions such as ankylosing spondylitis and diffuse idiopathic skeletal hyperostosis can render the spine stiff and are risk factors as well as cervical spondylosis and ensuing cervical stenosis...
June 2017: Geriatric Orthopaedic Surgery & Rehabilitation
https://www.readbyqxmd.com/read/28539470/the-src-c-abl-pathway-is-a-potential-therapeutic-target-in-amyotrophic-lateral-sclerosis
#17
Keiko Imamura, Yuishin Izumi, Akira Watanabe, Kayoko Tsukita, Knut Woltjen, Takuya Yamamoto, Akitsu Hotta, Takayuki Kondo, Shiho Kitaoka, Akira Ohta, Akito Tanaka, Dai Watanabe, Mitsuya Morita, Hiroshi Takuma, Akira Tamaoka, Tilo Kunath, Selina Wray, Hirokazu Furuya, Takumi Era, Kouki Makioka, Koichi Okamoto, Takao Fujisawa, Hideki Nishitoh, Kengo Homma, Hidenori Ichijo, Jean-Pierre Julien, Nanako Obata, Masato Hosokawa, Haruhiko Akiyama, Satoshi Kaneko, Takashi Ayaki, Hidefumi Ito, Ryuji Kaji, Ryosuke Takahashi, Shinya Yamanaka, Haruhisa Inoue
Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment. We developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival as readout. Motor neurons were generated from induced pluripotent stem cells (iPSCs) derived from an ALS patient with a mutation in superoxide dismutase 1 (SOD1). Results of the screen showed that more than half of the hits targeted the Src/c-Abl signaling pathway. Src/c-Abl inhibitors increased survival of ALS iPSC-derived motor neurons in vitro...
May 24, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28539219/discovery-of-pyrazolo-1-5-a-pyrimidine-3-carbonitrile-derivatives-as-a-new-class-of-histone-lysine-demethylase-4d-kdm4d-inhibitors
#18
Zhen Fang, Tian-Qi Wang, Hui Li, Guo Zhang, Xiao-Ai Wu, Li Yang, Yu-Lan Peng, Jun Zou, Lin-Li Li, Rong Xiang, Sheng-Yong Yang
Herein we report the discovery of a series of new small molecule inhibitors of histone lysine demethylase 4D (KDM4D). Molecular docking was first performed to screen for new KDM4D inhibitors from various chemical databases. Two hit compounds were retrieved. Further structural optimization and structure-activity relationship (SAR) analysis were carried out to the more selective one, compound 2, which led to the discovery of several new KDM4D inhibitors. Among them, compound 10r is the most potent one with an IC50 value of 0...
May 3, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28539181/low-vitamin-d-levels-increase-the-risk-of-type-2-diabetes-in-older-adults-a-systematic-review-and-meta-analysis
#19
REVIEW
Paola Lucato, Marco Solmi, Stefania Maggi, Anna Bertocco, Giulia Bano, Caterina Trevisan, Enzo Manzato, Giuseppe Sergi, Patricia Schofield, Youssef Kouidrat, Nicola Veronese, Brendon Stubbs
Low serum levels of 25 hydroxyvitamin D (25OHD) (hypovitaminosis D) is common in older adults and associated with several negative outcomes. The association between hypovitaminosis D and diabetes in older adults is equivocal, however. We conducted a meta-analysis investigating if hypovitaminosis D is associated with diabetes in prospective studies among older participants. Two investigators systematically searched major electronic databases, from inception until 10/07/2016. The cumulative incidence of diabetes among groups was estimated according to baseline serum 25OHD levels...
June 2017: Maturitas
https://www.readbyqxmd.com/read/28537726/hot-spotting-with-thermal-scanning-a-ligand-and-structure-independent-assessment-of-target-ligandability
#20
Molly Chilton, Ben Clennell, Fredrik Edfeldt, Stefan Geschwindner
Evaluating the ligandability of a protein target is a key component when defining hit-finding strategies or to prioritize amongst drug targets. Computational as well as biophysical approaches based on nuclear magnetic resonance (NMR) fragment screening are powerful approaches, but suffer from specific constraints that limit their usage. Here, we demonstrate the applicability of high-throughput thermal scanning (HTTS) as a simple and generic biophysical fragment screening method to reproduce assessments from NMR-based screening...
May 24, 2017: Journal of Medicinal Chemistry
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