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https://www.readbyqxmd.com/read/28529950/tumor-selective-cytotoxicity-of-nitidine-results-from-its-rapid-accumulation-into-mitochondria
#1
Hironori Iwasaki, Masashi Inafuku, Naoyuki Taira, Seikoh Saito, Hirosuke Oku
We identified a nitidine- (NTD-) accumulating organelle and evaluated the net cytotoxicity of accumulated NTD. To evaluate tumor cell selectivity of the drug, we evaluated its selective cytotoxicity against 39 human cancer cell lines (JFCR39 panel), and the profile was compared with those of known anticancer drugs. Organelle specificity of NTD was visualized using organelle-targeted fluorescent proteins. Real-time analysis of cell growth, proliferation, and cytotoxicity was performed using the xCELLigence system...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28529130/the-future-of-drug-development-for-neglected-tropical-diseases-how-the-european-commission-can-continue-to-make-a-difference
#2
Raymond J Pierce, Jane MacDougall, Rob Leurs, Maria Paola Costi
In this article, the four coordinators of neglected tropical disease (NTD) drug development projects funded under the European Commission (EC) Framework Programme 7 argue that the EC should reassess their funding strategy to cover the steps necessary to translate a lead compound into a drug candidate for testing in clinical trials, and suggest ways in which this might be achieved.
May 18, 2017: Trends in Parasitology
https://www.readbyqxmd.com/read/28516216/the-role-of-intrauterine-magnetic-resonance-in-the-management-of-myelomenigocele
#3
Denise Trigubo, Mercedes Negri, Rosana Mabel Salvatico, Gustavo Leguizamón
OBJECTIVE: To assess the role of magnetic resonance imaging (MRI) in the management of myelomenigocele. BACKGROUND: Spinal dysraphism or neural tube defects (NTD) encompass a heterogeneous group of congenital spinal anomalies that result from the defective closure of the neural tube early in gestation. Myelomeningocele is the most common type of NTD that is compatible with life, with high survival rates but lifelong physical impairments. CONCLUSION: MRI is an important adjunct to ultrasound in assessing NTD, as it pertains to pre-surgical planning and perinatal management...
May 17, 2017: Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery
https://www.readbyqxmd.com/read/28510759/an-intact-mcm10-coiled-coil-interaction-surface-is-important-for-origin-melting-helicase-assembly-and-the-recruitment-of-pol-%C3%AE-to-mcm2-7
#4
Patricia Perez-Arnaiz, Irina Bruck, Max K Colbert, Daniel L Kaplan
Mcm10 is an essential eukaryotic factor required for DNA replication. The replication fork helicase is composed of Cdc45, Mcm2-7 and GINS (CMG). DDK is an S-phase-specific kinase required for replication initiation, and the DNA primase-polymerase in eukaryotes is pol α. Mcm10 forms oligomers in vitro, mediated by the coiled-coil domain at the N-terminal region of the protein. We characterized an Mcm10 mutant at the N-terminal Domain (NTD), Mcm10-4A, defective for self-interaction. We found that the Mcm10-4A mutant was defective for stimulating DDK phosphorylation of Mcm2, binding to eighty-nucleotide ssDNA, and recruiting pol α to Mcm2-7 in vitro...
May 16, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28508509/investigating-the-inter-subunit-subdomain-interactions-and-motions-relevant-to-disease-mutations-in-the-n-terminal-domain-of-ryanodine-receptors-by-molecular-dynamics-simulation
#5
Wenjun Zheng, Zheng Liu
The ryanodine receptors (RyR) are essential to calcium signaling in striated muscles, and numerous disease mutations have been identified in two RyR isoforms, RyR1 in skeletal muscle and RyR2 in cardiac muscle. A deep understanding of the activation/regulation mechanisms of RyRs has been hampered by the shortage of high-resolution structures and dynamic information for this giant tetrameric complex in different functional states. Toward elucidating the molecular mechanisms of disease mutations in RyRs, we performed molecular dynamics simulation of the N-terminal domain (NTD) which is not only the best-resolved structural component of RyRs, but also a hotspot of disease mutations...
May 15, 2017: Proteins
https://www.readbyqxmd.com/read/28506829/an-asymmetric-dimeric-structure-of-trmj-trna-methyltransferase-from-zymomonas-mobilis-with-a-flexible-c-terminal-dimer
#6
Do-Heon Gu, Mi-Young Park, Jeong-Sun Kim
The tRNA methyltransferase J (TrmJ) and D (TrmD) catalyze the transferring reaction of a methyl group to the tRNA anticodon loop. They commonly have the N-terminal domain (NTD) and the C-terminal domain (CTD). Whereas two monomeric CTDs symmetrically interact with a dimeric NTD in TrmD, a CTD dimer has exhibited an asymmetric interaction with the NTD dimer in the presence of a product. The elucidated apo-structure of the full-length TrmJ from Zymomonas mobilis ZM4 shows a dimeric CTD that asymmetrically interacts with the NTD dimer, thereby distributing non-symmetrical potential charge on the both side of the protein surface...
May 12, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28503830/synthetic-ocp-heterodimers-are-photoactive-and-recapitulate-the-fusion-of-two-primitive-carotenoproteins-in-the-evolution-of-cyanobacterial-photoprotection
#7
Sigal Lechno-Yossef, Matthew R Melnicki, Han Bao, Beronda L Montgomery, Cheryl A Kerfeld
The Orange Carotenoid Protein (OCP) governs photoprotection in the majority of cyanobacteria. It is structurally and functionally modular, comprised of a C-terminal regulatory domain (CTD), an N-terminal effector domain (NTD) and a ketocarotenoid; the chromophore spans the two domains in the ground state and translocates fully into the NTD upon illumination. Using both the canonical OCP1 from Fremyella diplosiphon and the presumably more primitive OCP2 paralog from the same organism, we show that an NTD-CTD heterodimer forms when the domains are expressed as separate polypeptides...
May 15, 2017: Plant Journal: for Cell and Molecular Biology
https://www.readbyqxmd.com/read/28495384/medicinal-chemistry-of-antischistosomal-drugs-praziquantel-and-oxamniquine
#8
REVIEW
Vinícius Barros Ribeiro da Silva, Bruna Rafaella Koresch Leiva Campos, Jamerson Ferreira de Oliveira, Jean-Luc Decout, Maria do Carmo Alves de Lima
Neglected tropical diseases (NTDs) are a group of diseases that, besides prevailing in poverty conditions, contribute to the maintenance of social inequality, being a strong barrier to a country development. Schistosomiasis, a NTD, is a tropical and subtropical disease caused by the trematode Schistosoma mansoni (Africa, Middle East, Caribbean, Brazil, Venezuela, Suriname), japonicum (China, Indonesia, the Philippines), mekongi (several districts of Cambodia and the Lao People's Democratic Republic), intercalatum and guianensis (areas of tropical rainforests in Central Africa) and hematobium (Middle East Africa, Corsica, France) whose adult forms inhabit the mesenteric vessels of the host, while the intermediate forms are found in the aquatic gastropod snails of the genus Biomphalaria...
April 27, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28495207/targeting-the-hsp90-c-terminal-domain-to-induce-allosteric-inhibition-and-selective-client-downregulation
#9
Kourtney M Goode, Dino Petrov, Renee E Vickman, Scott A Crist, Pete E Pascuzzi, Tim L Ratliff, V Jo Davisson, Tony R Hazbun
BACKGROUND: Inhibition of Hsp90 is desirable due to potential downregulation of oncogenic clients. Early generation inhibitors bind to the N-terminal domain (NTD) but C-terminal domain (CTD) inhibitors are a promising class because they do not induce a heat shock response. Here we present a new structural class of CTD binding molecules with a unique allosteric inhibition mechanism. METHODS: A hit molecule, NSC145366, and structurally similar probes were assessed for inhibition of Hsp90 activities...
May 8, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28487364/specific-sequences-in-the-n-terminal-domain-of-human-small-heat-shock-protein-hspb6-dictate-preferential-heterooligomerization-with-the-orthologue-hspb1
#10
Michelle Heirbaut, Frederik Lermyte, Esther M Martin, Steven Beelen, Frank Sobott, Sergei V Strelkov, Stephen D Weeks
Small heat shock proteins (sHSPs) are a conserved group of molecular chaperones with important roles in cellular proteostasis. Although sHSPs are characterized by their small monomeric weight, they typically assemble into large polydisperse oligomers that vary in both size and shape but are principally composed of dimeric building blocks. These assemblies can comprise different sHSP orthologues, creating additional complexity that may affect chaperone activity. However, the structural and functional properties of such heterooligomers are poorly understood...
May 9, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28474670/protein-kinase-c-alpha-suppresses-autophagy-and-induces-neural-tube-defects-via-mir-129-2-in-diabetic-pregnancy
#11
Fang Wang, Cheng Xu, E Albert Reece, Xuezheng Li, Yanqing Wu, Christopher Harman, Jingwen Yu, Daoyin Dong, Cheng Wang, Penghua Yang, Jianxiang Zhong, Peixin Yang
Gene deletion-induced autophagy deficiency leads to neural tube defects (NTDs), similar to those in diabetic pregnancy. Here we report the key autophagy regulators modulated by diabetes in the murine developing neuroepithelium. Diabetes predominantly leads to exencephaly, induces neuroepithelial cell apoptosis and suppresses autophagy in the forebrain and midbrain of NTD embryos. Deleting the Prkca gene, which encodes PKCα, reverses diabetes-induced autophagy impairment, cellular organelle stress and apoptosis, leading to an NTD reduction...
May 5, 2017: Nature Communications
https://www.readbyqxmd.com/read/28457226/commentary-restarting-ntd-programme-activities-after-the-ebola-outbreak-in-liberia
#12
Brent C Thomas, Karsor Kollie, Benjamin Koudou, Charles Mackenzie
It is widely known that the recent Ebola Virus Disease (EVD) in West Africa caused a serious disruption to the national health system, with many of ongoing disease focused programmes, such as mass drug administration (MDA) for onchocerciasis (ONC), lymphatic filariasis (LF) and schistosomiasis (SCH), being suspended or scaled-down. As these MDA programmes attempt to restart post-EVD it is important to understand the challenges that may be encountered. This commentary addresses the opinions of the major health sectors involved, as well as those of community members, regarding logistic needs and challenges faced as these important public health programmes consider restarting...
May 1, 2017: Infectious Diseases of Poverty
https://www.readbyqxmd.com/read/28446667/disparate-contributions-of-human-retrovirus-capsid-subdomains-to-gag-gag-oligomerization-virus-morphology-and-particle-biogenesis
#13
Jessica L Martin, Luiza Mendonça, Isaac Angert, Joachim D Mueller, Wei Zhang, Louis M Mansky
The capsid domain (CA) of the retroviral Gag protein is a primary determinant of Gag oligomerization, which is a critical step for immature Gag lattice formation and virus particle budding. Although the human immunodeficiency virus type 1 (HIV-1) CA carboxy-terminal domain (CTD) is essential for CA-CA interactions, the CA CTD has been suggested to be largely dispensable for human T-cell leukemia virus type 1 (HTLV-1) particle biogenesis. To more clearly define the roles of the HTLV-1 CA amino-terminal domain (NTD) and CA CTD in particle biogenesis, we generated and analyzed a panel of Gag proteins with chimeric HIV-1/HTLV-1 CA domains...
April 26, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28446240/molecular-mechanisms-by-which-herv-k-gag-interferes-with-hiv-1-gag-assembly-and-particle-infectivity
#14
Kazuaki Monde, Hiromi Terasawa, Yusuke Nakano, Ferri Soheilian, Kunio Nagashima, Yosuke Maeda, Akira Ono
BACKGROUND: Human endogenous retroviruses (HERVs), the remnants of ancient retroviral infections, constitute approximately 8% of human genomic DNA. Since HERV-K Gag expression is induced by HIV-1 Tat in T cells, induced HERV-K proteins could affect HIV-1 replication. Indeed, previously we showed that HERV-K Gag and HIV-1 Gag coassemble and that this appears to correlate with the effect of HERV-K Gag expression on HIV-1 particle release and its infectivity. We further showed that coassembly requires both MA and NC domains, which presumably serve as scaffolding for Gag via their abilities to bind membrane and RNA, respectively...
April 26, 2017: Retrovirology
https://www.readbyqxmd.com/read/28440746/dual-interaction-of-scaffold-protein-tim44-of-mitochondrial-import-motor-with-channel-forming-translocase-subunit-tim23
#15
See-Yeun Ting, Nicholas L Yan, Brenda A Schilke, Elizabeth A Craig
Proteins destined for the mitochondrial matrix are targeted to the inner membrane Tim17/23 translocon by their presequences. Inward movement is driven by the matrix-localized, Hsp70-based motor. The scaffold Tim44, interacting with the matrix face of the translocon, recruits other motor subunits and binds incoming presequence. The basis of these interactions and their functional relationships remains unclear. Using site-specific in vivo crosslinking and genetic approaches in Saccharomyces cerevisiae, we found that both domains of Tim44 interact with the major matrix-exposed loop of Tim23, with the C-terminal domain (CTD) binding Tim17 as well...
April 25, 2017: ELife
https://www.readbyqxmd.com/read/28440111/quality-of-life-outcomes-in-a-pediatric-thalassemia-population-in-egypt
#16
Soheir Adam, Hanan Afifi, Manal Thomas, Phoebe Magdy, Ghada El-Kamah
Thalassemia is a disorder of hemoglobin (Hb) synthesis characterized by chronic hemolysis. In β-thalassemias major (β-TM), patients require regular transfusion at an early age due to severe anemia. Subsequently, intensive chelation therapy is initiated to mitigate the effects of the resultant iron overload. Clinical disease burden and the demanding treatment can affect health-related quality of life (HRQoL) outcomes in this population. The aim of this study was to assess HRQoL outcomes in Egyptian pediatric thalassemia patients...
April 25, 2017: Hemoglobin
https://www.readbyqxmd.com/read/28438917/disease-ecology-health-and-the-environment-a-framework-to-account-for-ecological-and-socio-economic-drivers-in-the-control-of-neglected-tropical-diseases
#17
A Garchitorena, S H Sokolow, B Roche, C N Ngonghala, M Jocque, A Lund, M Barry, E A Mordecai, G C Daily, J H Jones, J R Andrews, E Bendavid, S P Luby, A D LaBeaud, K Seetah, J F Guégan, M H Bonds, G A De Leo
Reducing the burden of neglected tropical diseases (NTDs) is one of the key strategic targets advanced by the Sustainable Development Goals. Despite the unprecedented effort deployed for NTD elimination in the past decade, their control, mainly through drug administration, remains particularly challenging: persistent poverty and repeated exposure to pathogens embedded in the environment limit the efficacy of strategies focused exclusively on human treatment or medical care. Here, we present a simple modelling framework to illustrate the relative role of ecological and socio-economic drivers of environmentally transmitted parasites and pathogens...
June 5, 2017: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/28438169/ivermectin-and-malaria-control
#18
Satoshi Ōmura, Andy Crump
As the world begins to realize the very real prospect of eliminating malaria as a public health problem globally, the scientific community is acutely aware that novel and innovative new tools will be required if that lofty goal is to be accomplished. Moreover, the need for comprehensive, integrated products and interventions is being recognized in order for the critical 'final steps' toward elimination to be taken successfully. Failure to take these crucial last steps have dogged all past global disease elimination programmes, except for smallpox...
April 24, 2017: Malaria Journal
https://www.readbyqxmd.com/read/28434941/dysregulation-of-the-sirt1-oct6-axis-contributes-to-environmental-stress-induced-neural-induction-defects
#19
Guoping Li, Zeyidan Jiapaer, Rong Weng, Yi Hui, Wenwen Jia, Jiajie Xi, Guiying Wang, Songcheng Zhu, Xin Zhang, Dandan Feng, Ling Liu, Xiaoqing Zhang, Jiuhong Kang
Environmental stresses are increasingly acknowledged as core causes of abnormal neural induction leading to neural tube defects (NTDs). However, the mechanism responsible for environmental stress-triggered neural induction defects remains unknown. Here, we report that a spectrum of environmental stresses, including oxidative stress, starvation, and DNA damage, profoundly activate SIRT1, an NAD(+)-dependent lysine deacetylase. Both mouse embryos and in vitro differentiated embryonic stem cells (ESCs) demonstrated a negative correlation between the expression of SIRT1 and that of OCT6, a key neural fate inducer...
May 9, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28432198/folate-dependent-methylation-of-septins-governs-ciliogenesis-during-neural-tube-closure
#20
Manami Toriyama, Michinori Toriyama, John B Wallingford, Richard H Finnell
Periconception maternal folic acid (vitamin B9) supplementation can reduce the prevalence of neural tube defects (NTDs), although just how folates benefit the developing embryo and promote closing of the neural tube and other morphologic processes during development remains unknown. Folate contributes to a 1-carbon metabolism, which is essential for purine biosynthesis and methionine recycling and affects methylation of DNA, histones, and nonhistone proteins. Herein, we used animal models and cultured mammalian cells to demonstrate that disruption of the methylation pathway mediated by folate compromises normal neural tube closure (NTC) and ciliogenesis...
April 21, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
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