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https://www.readbyqxmd.com/read/27914361/development-of-cxcr4-modulators-by-virtual-hts-of-a-novel-amide-sulfamide-compound-library
#1
Renren Bai, Qi Shi, Zhongxing Liang, Younghyoun Yoon, Yiran Han, Amber Feng, Shuangping Liu, Yoonhyeun Oum, C Chris Yun, Hyunsuk Shim
CXCR4 plays a crucial role in recruitment of inflammatory cells to inflammation sites at the beginning of the disease process. Modulating CXCR4 functions presents a new avenue for anti-inflammatory strategies. However, using CXCR4 antagonists for a long term usage presents potential serious side effect due to their stem cell mobilizing property. We have been developing partial CXCR4 antagonists without such property. A new computer-aided drug design program, the FRESH workflow, was used for anti-CXCR4 lead compound discovery and optimization, which coupled both compound library building and CXCR4 docking screens in one campaign...
November 24, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27914091/toward-clinical-use-of-the-igg-specific-enzymes-ides-and-endos-against-antibody-mediated-diseases
#2
Mattias Collin, Lars Björck
The endoglycosidase EndoS and the protease IdeS from the human pathogen Streptococcus pyogenes are immunomodulating enzymes hydrolyzing human IgG. IdeS cleaves IgG in the lower hinge region, while EndoS hydrolyzes the conserved N-linked glycan in the Fc region. Both enzymes are remarkably specific for human IgG that after hydrolysis loses most of its effector functions, such as binding to leukocytes and complement activation, all contributing to bacterial evasion of adaptive immunity. However, taken out of their infectious context, we and others have shown that IdeS and EndoS can alleviate autoimmune disease in a number of animal models of antibody-mediated disorders...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27914084/the-zebrafish-as-a-model-for-human-bacterial-infections
#3
Melody N Neely
The development of the zebrafish (Danio rerio) infectious disease model has provided new insights and information into pathogenesis. Many of these new discoveries would not have been possible using a typical mammalian model. The advantages of using this model are many and in the last 15 years the model has been exploited for the analysis of many different pathogens. Here, we describe in detail how to perform a bacterial infection using either the adult zebrafish or zebrafish larvae using microinjection. Multiple methods of analysis are described that can be used to address specific questions pertaining to disease progression and the interactions with the immune system...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27914077/making-fluorescent-streptococci-and-enterococci-for-live-imaging
#4
Sarah Shabayek, Barbara Spellerberg
Since the discovery of the green fluorescent protein (GFP) from the jellyfish Aequorea victoria, outstanding fluorescent labeling tools with numerous applications in vastly different areas of life sciences have been developed. To optimize GFP for diverse life science applications, a large variety of GFP derivatives with different environmental characteristics have been generated by mutagenesis. The enhanced green fluorescent protein (EGFP) is a well-known GFP derivative with highly increased fluorescence intensity compared to the GFP wild-type molecule...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27914066/computational-tools-for-allosteric-drug-discovery-site-identification-and-focus-library-design
#5
Wenkang Huang, Ruth Nussinov, Jian Zhang
Allostery is an intrinsic phenomenon of biological macromolecules involving regulation and/or signal transduction induced by a ligand binding to an allosteric site distinct from a molecule's active site. Allosteric drugs are currently receiving increased attention in drug discovery because drugs that target allosteric sites can provide important advantages over the corresponding orthosteric drugs including specific subtype selectivity within receptor families. Consequently, targeting allosteric sites, instead of orthosteric sites, can reduce drug-related side effects and toxicity...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27914038/serotonin-5-ht6-receptor-antagonists-in-alzheimer-s-disease-therapeutic-rationale-and-current-development-status
#6
Hilda Ferrero, Maite Solas, Paul T Francis, Maria J Ramirez
Alzheimer's disease (AD) is the most common cause of dementia in elderly people. Because of the lack of effective treatments for this illness, research focused on identifying compounds that restore cognition and functional impairments in patients with AD is a very active field. Since its discovery in 1993, the serotonin 5-HT6 receptor has received increasing attention, and a growing number of studies supported 5-HT6 receptor antagonism as a target for improving cognitive dysfunction in AD. This article reviews the rationale behind investigations into the targeting of 5-HT6 receptors as a symptomatic treatment for cognitive and/or behavioral symptoms of AD...
December 3, 2016: CNS Drugs
https://www.readbyqxmd.com/read/27913843/molecular-evolution-in-historical-perspective
#7
Edna Suárez-Díaz
In the 1960s, advances in protein chemistry and molecular genetics provided new means for the study of biological evolution. Amino acid sequencing, nucleic acid hybridization, zone gel electrophoresis, and immunochemistry were some of the experimental techniques that brought about new perspectives to the study of the patterns and mechanisms of evolution. New concepts, such as the molecular evolutionary clock, and the discovery of unexpected molecular phenomena, like the presence of repetitive sequences in eukaryotic genomes, eventually led to the realization that evolution might occur at a different pace at the organismic and the molecular levels, and according to different mechanisms...
December 2, 2016: Journal of Molecular Evolution
https://www.readbyqxmd.com/read/27913829/glutamate-fermentation-2-mechanism-of-l-glutamate-overproduction-in-corynebacterium-glutamicum
#8
Takashi Hirasawa, Masaaki Wachi
The nonpathogenic coryneform bacterium, Corynebacterium glutamicum, was isolated as an L-glutamate-overproducing microorganism by Japanese researchers and is currently utilized in various amino acid fermentation processes. L-Glutamate production by C. glutamicum is induced by limitation of biotin and addition of fatty acid ester surfactants and β-lactam antibiotics. These treatments affect the cell surface structures of C. glutamicum. After the discovery of C. glutamicum, many researchers have investigated the underlying mechanism of L-glutamate overproduction with respect to the cell surface structures of this organism...
December 3, 2016: Advances in Biochemical Engineering/biotechnology
https://www.readbyqxmd.com/read/27913811/discovery-of-piperlongumine-as-a-potential-novel-lead-for-the-development-of-senolytic-agents
#9
Yingying Wang, Jianhui Chang, Xingui Liu, Xuan Zhang, Suping Zhang, Xin Zhang, Daohong Zhou, Guangrong Zheng
Accumulating evidence indicates that senescent cells play an important role in many age-associated diseases. The pharmacological depletion of senescent cells (SCs) with a "senolytic agent", a small molecule that selectively kills SCs, is a potential novel therapeutic approach for these diseases. Recently, we discovered ABT-263, a potent and highly selective senolytic agent, by screening a library of rationally-selected compounds. With this screening approach, we also identified a second senolytic agent called piperlongumine (PL)...
November 19, 2016: Aging
https://www.readbyqxmd.com/read/27913752/expression-and-bioactivity-of-human-alpha-fetoprotein-in-a-bac-to-bac-system
#10
Bo Lin, Kun Liu, Wenting Wang, Wei Li, Xu Dong, Yi Chen, Yan Lu, Junli Guo, Mingyue Zhu, Mengsen Li
Alpha-fetoprotein (AFP) is an early serum growth factor in fetal embryonic development and hepatic oncogenesis. A growing number of investigations of AFP as a tumor-specific biomarker have concluded that AFP is an important target for cancer treatment. AFP also plays an immunomodulatory role in the treatment of several autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, myasthenia gravis, and thyroiditis. In an effort to support biochemical screening and drug design and discovery, we attempted to express and purify human AFP in a Bac-to-Bac system...
December 2, 2016: Bioscience Reports
https://www.readbyqxmd.com/read/27913677/phlpping-through-history-a-decade-in-the-life-of-phlpp-phosphatases
#11
REVIEW
Agnieszka T Grzechnik, Alexandra C Newton
In the decade since their discovery, the PH domain leucine-rich repeat protein phosphatases (PHLPP) have emerged as critical regulators of cellular homeostasis, and their dysregulation is associated with various pathophysiologies, ranging from cancer to degenerative diseases, such as diabetes and heart disease. The two PHLPP isozymes, PHLPP1 and PHLPP2, were identified in a search for phosphatases that dephosphorylate Akt, and thus suppress growth factor signaling. However, given that there are over 200 000 phosphorylated residues in a single cell, and fewer than 50 Ser/Thr protein phosphatases, it is not surprising that PHLPP has many other cellular functions yet to be discovered, including a recently identified role in regulating the epigenome...
December 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27913670/screening-for-chemical-modulators-for-lrrk2
#12
REVIEW
Heather Mortiboys
After the discovery of leucine-rich repeat kinase 2 (LRRK2) as a risk factor for sporadic Parkinson's disease (PD) and mutations in LRRK2 as a cause of some forms of familial PD, there has been substantial interest in finding chemical modulators of LRRK2 function. Most of the pathogenic mutations in LRRK2 are within the enzymatic cores of the protein; therefore, many screens have focused on finding chemical modulators of this enzymatic activity. There are alternative screening approaches that could be taken to investigate compounds that modulate LRRK2 cellular functions...
December 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27913643/biogenesis-and-transcriptional-regulation-of-long-noncoding-rnas-in-the-human-immune-system
#13
REVIEW
Charles F Spurlock, Philip S Crooke, Thomas M Aune
The central dogma of molecular biology states that DNA makes RNA makes protein. Discoveries over the last quarter of a century found that the process of DNA transcription into RNA gives rise to a diverse array of functional RNA species, including genes that code for protein and noncoding RNAs. For decades, the focus has been on understanding how protein-coding genes are regulated to influence protein expression. However, with the completion of the Human Genome Project and follow-up ENCODE data, it is now appreciated that only 2-3% of the genome codes for protein-coding gene exons and that the bulk of the transcribed genome, apart from ribosomal RNAs, is at the level of noncoding RNA genes...
December 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27913565/a-24-year-old-male-with-a-painful-and-cold-lower-extremity
#14
Eric A Robinson, Zain I Khalpey, Rajesh Janardhanan
CLINICAL INTRODUCTION: A 24-year-old male presented to the emergency department with intense pain in his right lower extremity. He has a medical history significant for systemic lupus erythematosus and antiphospholipid syndrome. He also had four prior episodes of deep venous thromboses on rivaroxaban. The patient stated that early in the morning, he started to feel intense pain that started from his knee and progressed to his calf, with associated numbness and paraesthesia. On physical examination, the limb felt cold with absent right popliteal and dorsalis pedis pulses...
December 2, 2016: Heart: Official Journal of the British Cardiac Society
https://www.readbyqxmd.com/read/27913528/mutations-in-mpns-prognostic-implications-window-to-biology-and-impact-on-treatment-decisions
#15
Jamile M Shammo, Brady L Stein
The last decade has witnessed tremendous scientific advances, ushered in by the JAK2 V617F discovery, contributing to enhanced diagnostic capability and understanding of the biology of myeloproliferative neoplasms (MPNs). Discovery of the calreticulin mutations filled a diagnostic gap; more recent work sheds light on its contribution to disease pathogenesis, and prognosis. Recent studies have also identified novel JAK2 and MPL mutations in patients with essential thrombocythemia and myelofibrosis (MF). Especially in MF, the driver mutational profile has prognostic implications, with additive contributions from the acquisition of additional somatic mutations...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27913525/checkpoint-inhibition-in-myeloma
#16
Don M Benson
Historically, attempts at cancer immunotherapy have emphasized strategies designed to stimulate or augment the immune system into action. In the past decade, a complementary approach has developed, that of releasing immune cells from inhibitory restraint. Discoveries in the fundamental biology of how immunity is regulated, how the immune system interfaces with malignancy, and how cancer cells may exploit these processes to evade detection have all been translated into the rapidly growing field of therapeutic immune checkpoint inhibition for cancer...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27913493/novel-agents-in-follicular-lymphoma-choosing-the-best-target
#17
Laurie H Sehn
Outcomes in patients with follicular lymphoma (FL) have improved dramatically over the last decade. However, novel agents are greatly needed for those who exhibit treatment resistance, in order to minimize lifelong toxicity and to enable combinations that may allow us to achieve the elusive goal of cure. Biological advances have led to the discovery of a large number of potential therapeutic targets and the development of a plethora of novel agents designed to exploit these processes. Possible targets include tumor cell surface markers, key components of intracellular pathways and epigenetic mechanisms, and reactive cells of the microenvironment...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27913491/prognostic-factors-in-follicular-lymphoma-new-tools-to-personalize-risk
#18
Carla Casulo
Follicular lymphoma (FL) is the most common indolent lymphoma, and it has a long median overall survival (OS). However, the recent discovery of clinical and biological prognostic biomarkers in FL is shedding light on FL heterogeneity and the need for a precise and risk-stratified individual approach at diagnosis and relapse. Many FL patients who are asymptomatic with indolent disease can be vulnerable to the toxicity, emotional distress, and financial burden of overtreatment. Yet a subset of FL patients develop chemoresistance to standard chemoimmunotherapy, experience transformation to aggressive lymphoma and rapid progression, and represent the population most in need of novel therapies and curative approaches...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27913419/benzene-degradation-by-variovorax-sp-within-a-coal-tar-contaminated-groundwater-microbial-community
#19
Kevin M Posman, Christopher M DeRito, Eugene L Madsen
: Investigations of environmental microbial communities are crucial for the discovery of populations capable of degrading hazardous compounds and may lead to improved bioremediation strategies. The goal of this study was to identify microorganisms responsible for aerobic benzene degradation in coal-tar contaminated groundwater. Benzene degradation was monitored in laboratory incubations of well waters using gas chromatography mass spectrometry (GC/MS). Stable isotope probing (SIP) experiments using (13)C-benzene allowed us to obtain (13)C-labled community DNA; from this, 16S rRNA clone libraries identified γ- and β-Proteobacteria as the active benzene metabolizing microbial populations...
December 2, 2016: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/27913395/metabolomic-characterization-of-hepatocellular-carcinoma-in-patients-with-liver-cirrhosis-for-biomarker-discovery
#20
Cristina Di Poto, Alessia Ferrarini, Yi Zhao, Rency S Varghese, Chao Tu, Yiming Zuo, Minkun Wang, Mohammad R Nezami Ranjbar, Yue Luo, Chi Zhang, Chirag S Desai, Kirti Shetty, Mahlet G Tadesse, Habtom W Ressom
BACKGROUND: Metabolomics plays an important role in providing insight into the etiology and mechanisms of hepatocellular carcinoma (HCC). This is accomplished by a comprehensive analysis of patterns involved in metabolic alterations in human specimens. This study compares the levels of plasma metabolites in HCC cases versus cirrhotic patients and evaluates the ability of candidate metabolites in distinguishing the two groups. Also, it investigates the combined use of metabolites and clinical covariates for detection of HCC in patients with liver cirrhosis...
December 2, 2016: Cancer Epidemiology, Biomarkers & Prevention
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