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https://www.readbyqxmd.com/read/27926996/small-molecule-modulator-of-sigma-2-receptor-is-neuroprotective-and-reduces-cognitive-deficits-and-neuro-inflammation-in-experimental-models-of-alzheimer-s-disease
#1
Bitna Yi, James J Sahn, Pooneh Memar Ardestani, Andrew K Evans, Luisa Scott, Jessica Z Chan, Sangeetha Iyer, Ashley Crisp, Gabriella Zuniga, Jonathan Pierce-Shimomura, Stephen F Martin, Mehrdad Shamloo
Accumulating evidence suggests that modulating the sigma 2 receptor (Sig2R) can provide beneficial effects for neurodegenerative diseases. Herein, we report the identification of a novel class of Sig2R binding ligands and their cellular and in vivo activity in experimental models of Alzheimer's disease (AD). We report that SAS-0132 and DKR-1051, selective ligands of Sig2R, modulate intracellular Ca(2+) levels in human SK-N-SH neuroblastoma cells. The Sig2R antagonists SAS-0132 and JVW-1009 are neuroprotective in a C...
December 7, 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27926944/targeting-neutrophils-to-prevent-malaria-associated-acute-lung-injury-acute-respiratory-distress-syndrome-in-mice
#2
Michelle K Sercundes, Luana S Ortolan, Daniela Debone, Paulo V Soeiro-Pereira, Eliane Gomes, Elizabeth H Aitken, Antonio Condino Neto, Momtchilo Russo, Maria R D' Império Lima, José M Alvarez, Silvia Portugal, Claudio R F Marinho, Sabrina Epiphanio
Malaria remains one of the greatest burdens to global health, causing nearly 500,000 deaths in 2014. When manifesting in the lungs, severe malaria causes acute lung injury/acute respiratory distress syndrome (ALI/ARDS). We have previously shown that a proportion of DBA/2 mice infected with Plasmodium berghei ANKA (PbA) develop ALI/ARDS and that these mice recapitulate various aspects of the human syndrome, such as pulmonary edema, hemorrhaging, pleural effusion and hypoxemia. Herein, we investigated the role of neutrophils in the pathogenesis of malaria-associated ALI/ARDS...
December 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27926929/functional-and-evolutionary-analyses-identify-proteolysis-as-a-general-mechanism-for-nlrp1-inflammasome-activation
#3
Joseph Chavarría-Smith, Patrick S Mitchell, Alvin M Ho, Matthew D Daugherty, Russell E Vance
Inflammasomes are cytosolic multi-protein complexes that initiate immune responses to infection by recruiting and activating the Caspase-1 protease. Human NLRP1 was the first protein shown to form an inflammasome, but its physiological mechanism of activation remains unknown. Recently, specific variants of mouse and rat NLRP1 were found to be activated upon N-terminal cleavage by the anthrax lethal factor protease. However, agonists for other NLRP1 variants, including human NLRP1, are not known, and it remains unclear if they are also activated by proteolysis...
December 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27926872/deletion-of-the-polycomb-group-protein-ezh2-leads-to-compromised-self-renewal-and-differentiation-defects-in-human-embryonic-stem-cells
#4
Adam Collinson, Amanda J Collier, Natasha P Morgan, Arnold R Sienerth, Tamir Chandra, Simon Andrews, Peter J Rugg-Gunn
Through the histone methyltransferase EZH2, the Polycomb complex PRC2 mediates H3K27me3 and is associated with transcriptional repression. PRC2 regulates cell-fate decisions in model organisms; however, its role in regulating cell differentiation during human embryogenesis is unknown. Here, we report the characterization of EZH2-deficient human embryonic stem cells (hESCs). H3K27me3 was lost upon EZH2 deletion, identifying an essential requirement for EZH2 in methylating H3K27 in hESCs, in contrast to its non-essential role in mouse ESCs...
December 6, 2016: Cell Reports
https://www.readbyqxmd.com/read/27925510/passive-therapy-with-humanized-anti-staphylococcal-enterotoxin-b-antibodies-attenuates-systemic-inflammatory-response-and-protects-from-lethal-pneumonia-caused-by-staphylococcal-enterotoxin-b-producing-staphylococcus-aureus
#5
Melissa J Karau, Mulualem E Tilahun, Ashton Krogman, Barbara A Osborne, Richard A Goldsby, Chella S David, Jayawant N Mandrekar, Robin Patel, Govindarajan Rajagopalan
Drugs such as linezolid that inhibit bacterial protein synthesis may be beneficial in treating infections caused by toxigenic Staphylococcus aureus. As protein synthesis inhibitors have no effect on preformed toxins, neutralization of pathogenic exotoxins with anti-toxin antibodies may be beneficial in conjunction with antibacterial therapy. Herein, we evaluated the efficacy of human-mouse chimeric high-affinity neutralizing anti-staphylococcal enterotoxin B (SEB) antibodies in the treatment of experimental pneumonia caused by SEB-producing S...
December 7, 2016: Virulence
https://www.readbyqxmd.com/read/27925336/non-exponential-growth-of-mycobacterium-leprae-thai-53-strain-cultured-in-vitro
#6
Kazunobu Amako, Ken-Ichiro Iida, Mitsumasa Saito, Yoshitosi Ogura, Tetsuya Hayashi, Shin-Ichi Yoshida
To determine why cultivation of Mycobacterium leprae in vitro has not been successful, we attempted to culture this bacterium in media supplemented with a variety of biological materials. We observed a slight increase in the number of cells in medium supplemented with human blood plasma and an extract of nude mouse tissue after more than 3 months of cultivation at 30°C. To ascertain whether this increase was real growth, we analyzed the growth by droplet digital PCR. The analysis had the following two results: the slow increase in the copy number of cell-associated DNA and the release of a large amount of DNA into the culture medium from bacterial cells during cultivation...
December 7, 2016: Microbiology and Immunology
https://www.readbyqxmd.com/read/27924938/the-secretome-of-periodontal-ligament-stem-cells-from-ms-patients-protects-against-eae
#7
Thangavelu Soundara Rajan, Sabrina Giacoppo, Francesca Diomede, Patrizia Ballerini, Michele Paolantonio, Marco Marchisio, Adriano Piattelli, Placido Bramanti, Emanuela Mazzon, Oriana Trubiani
Manipulation of stem cells or stem cells-derived secretome has emerged as a novel alternative therapeutic option for multiple sclerosis (MS). Here we show that human periodontal ligament stem cells (hPDLSCs)-derived conditioned medium (hPDLSCs-CM) and purified exosomes/microvesicles (hPDLSCs-EMVs) obtained from Relapsing Remitting (RR)-MS patients and healthy donors block experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by inducing anti-inflammatory and immunosuppressive effects in spinal cord and spleen, and reverse disease progression by restoring tissue integrity via remyelination in the spinal cord...
December 7, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27924612/proteomic-analysis-of-dental-tissue-microsamples
#8
Jonathan E Mangum, Jew C Kon, Michael J Hubbard
Improved understanding of dental enamel development will benefit not only dentistry but also biomedicine more generally. Rat and mouse models of enamel development are relatively well characterized and experimentally powerful. However, the diminutive size of murine teeth makes them difficult to study using standard proteomics approaches. Here, we describe gel-based proteomic methods that enable parallel quantification, identification, and functional characterization of proteins from developing rat and mouse teeth...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27924159/in-vitro-and-in-vivo-evaluation-of-89-zr-ds-8273a-as-a-theranostic-for-anti-death-receptor-5-therapy
#9
Ingrid J G Burvenich, Fook-Thean Lee, Nancy Guo, Hui K Gan, Angela Rigopoulos, Adam C Parslow, Graeme J O'Keefe, Sylvia J Gong, Henri Tochon-Danguy, Stacey E Rudd, Paul S Donnelly, Masakatsu Kotsuma, Toshiaki Ohtsuka, Giorgio Senaldi, Andrew M Scott
Background: DS-8273a, an anti-human death receptor 5 (DR5) agonistic antibody, has cytotoxic activity against human cancer cells and induces apoptosis after specific binding to DR5. DS-8273a is currently being used in clinical Phase I trials. This study evaluated the molecular imaging of DR5 expression in vivo in mouse tumor models using SPECT/CT and PET/MRI, as a tool for drug development and trial design. Methods: DS-8273a was radiolabeled with indium-111 and zirconium-89. Radiochemical purity, immunoreactivity, antigen binding affinity and serum stability were assessed in vitro...
2016: Theranostics
https://www.readbyqxmd.com/read/27924046/new-data-and-features-for-advanced-data-mining-in-manteia
#10
Olivier Tassy
Manteia is an integrative database available online at http://manteia.igbmc.fr which provides a large array of OMICs data related to the development of the mouse, chicken, zebrafish and human. The system is designed to use different types of data together in order to perform advanced datamining, test hypotheses or provide candidate genes involved in biological processes or responsible for human diseases. In this new version of the database, Manteia has been enhanced with new expression data originating from microarray and next generation sequencing experiments...
October 24, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27924024/gtrd-a-database-of-transcription-factor-binding-sites-identified-by-chip-seq-experiments
#11
Ivan Yevshin, Ruslan Sharipov, Tagir Valeev, Alexander Kel, Fedor Kolpakov
GTRD-Gene Transcription Regulation Database (http://gtrd.biouml.org)-is a database of transcription factor binding sites (TFBSs) identified by ChIP-seq experiments for human and mouse. Raw ChIP-seq data were obtained from ENCODE and SRA and uniformly processed: (i) reads were aligned using Bowtie2; (ii) ChIP-seq peaks were called using peak callers MACS, SISSRs, GEM and PICS; (iii) peaks for the same factor and peak callers, but different experiment conditions (cell line, treatment, etc.), were merged into clusters; (iv) such clusters for different peak callers were merged into metaclusters that were considered as non-redundant sets of TFBSs...
October 24, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27924012/l1base-2-more-retrotransposition-active-line-1s-more-mammalian-genomes
#12
Tobias Penzkofer, Marten Jäger, Marek Figlerowicz, Richard Badge, Stefan Mundlos, Peter N Robinson, Tomasz Zemojtel
LINE-1 (L1) insertions comprise as much as 17% of the human genome sequence, and similar proportions have been recorded for other mammalian species. Given the established role of L1 retrotransposons in shaping mammalian genomes, it becomes an important task to track and annotate the sources of this activity: full length elements, able to encode the cis and trans acting components of the retrotransposition machinery. The L1Base database (http://l1base.charite.de) contains annotated full-length sequences of LINE-1 transposons including putatively active L1s...
October 18, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27923996/binding-of-mbd-proteins-to-dna-blocks-tet1-function-thereby-modulating-transcriptional-noise
#13
Anne K Ludwig, Peng Zhang, Florian D Hastert, Stephanie Meyer, Cathia Rausch, Henry D Herce, Udo Müller, Anne Lehmkuhl, Ines Hellmann, Carina Trummer, Christian Storm, Heinrich Leonhardt, M Cristina Cardoso
Aberrant DNA methylation is a hallmark of various human disorders, indicating that the spatial and temporal regulation of methylation readers and modifiers is imperative for development and differentiation. In particular, the cross-regulation between 5-methylcytosine binders (MBD) and modifiers (Tet) has not been investigated. Here, we show that binding of Mecp2 and Mbd2 to DNA protects 5-methylcytosine from Tet1-mediated oxidation. The mechanism is not based on competition for 5-methylcytosine binding but on Mecp2 and Mbd2 directly restricting Tet1 access to DNA...
December 6, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27923949/novel-bumped-kinase-inhibitors-are-safe-and-effective-therapeutics-in-the-calf-clinical-model-for-cryptosporidiosis
#14
Deborah A Schaefer, Dana P Betzer, Kylie D Smith, Zachary G Millman, Hannah C Michalski, Sarah E Menchaca, Jennifer A Zambriski, Kayode K Ojo, Matthew A Hulverson, Samuel L M Arnold, Kasey L Rivas, Rama S R Vidadala, Wenlin Huang, Lynn K Barrett, Dustin J Maly, Erkang Fan, Wesley C Van Voorhis, Michael W Riggs
Cryptosporidiosis, caused by the apicomplexan parasite Cryptosporidium parvum, is a diarrheal disease that has produced a large global burden in mortality and morbidity in humans and livestock. There are currently no consistently effective parasite-specific pharmaceuticals available for this disease. Bumped kinase inhibitors (BKIs) specific for parasite calcium-dependent protein kinases (CDPKs) have been shown to reduce infection in several parasites having medical and veterinary importance, including Toxoplasma gondii, Plasmodium falciparum, and C...
December 15, 2016: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/27923832/ese3-inhibits-pancreatic-cancer-metastasis-by-upregulating-e-cadherin
#15
Tiansuo Zhao, Wenna Jiang, Xiuchao Wang, Hongwei Wang, Chen Zheng, Yang Li, Yan Sun, Chongbiao Huang, Zhi-Bo Han, Shengyu Yang, Zhiliang Jia, Keping Xie, He Ren, Jihui Hao
The ETS family transcription factor ESE3 is a crucial element in differentiation and development programs for many epithelial tissues. Here we report its role as a tumor suppressor in pancreatic cancer. We observed drastically lower ESE3 expression in pancreatic ductal adenocarcinomas (PDAC) compared to adjacent normal pancreatic tissue. Reduced expression of ESE3 in PDAC correlated closely with an increase in lymph node metastasis and vessel invasion and a decrease in relapse-free and overall survival in patients...
December 6, 2016: Cancer Research
https://www.readbyqxmd.com/read/27923803/whole-exome-sequencing-validates-a-preclinical-mouse-model-for-the-prevention-and-treatment-of-cutaneous-squamous-cell-carcinoma
#16
Elena V Knatko, Brandon Praslicka, Maureen Higgins, Alan Evans, Karin J Purdie, Catherine A Harwood, Charlotte M Proby, Aikseng Ooi, Albena T Dinkova-Kostova
Cutaneous squamous cell carcinomas (cSCC) are among the most common and highly mutated human malignancies. Solar UV radiation is the major factor in the etiology of cSCC. Whole exome sequencing of 18 microdissected tumor samples (cases) derived from SKH-1 hairless mice that had been chronically exposed to solar-simulated UV (SSUV) radiation showed a median point mutation (single nucleotide polymorphism, SNP) rate of 155 per megabase. The majority (78.6%) of the SNPs are C.G>T.A transitions, a characteristic UVR-induced mutational signature...
December 6, 2016: Cancer Prevention Research
https://www.readbyqxmd.com/read/27923544/niemann-pick-disease-type-c-and-roscoe-brady
#17
REVIEW
Marc C Patterson, Steven U Walkley
The Niemann-Pick family of diseases was poorly understood until Roscoe Brady and his colleagues began their investigations in the 1960s. Following Brady's discovery of the defect in acid sphingomyelinase in Niemann-Pick disease, types A and B, Peter Pentchev, a senior scientist in the group, launched a series of investigations of an unusual lipid storage disease in a spontaneous mouse model. These led initially to identification of the cholesterol trafficking defect in the mouse, and then in human Niemann-Pick disease, type C (NPC)...
November 29, 2016: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/27923455/micrornas-an-adaptive-mechanism-in-the-pancreatic-%C3%AE-cell%C3%A2-and-beyond
#18
REVIEW
Matthew N Poy
Recent protocols have been developed to differentiate human stem cells and fibroblasts into insulin-producing cells capable of releasing the hormone in a glucose-stimulated manner. Limitations remain which prevent bringing these protocols to a clinical setting as these models must still undergo complete characterization. Advances in sequencing technologies have driven the identification of several non-coding RNA species including microRNAs (miRNAs). While their diversity and unique expression patterns across different tissues have made deciphering their precise functional role a significant challenge, studies using both cell lines and transgenic mouse models have made substantial progress in understanding their regulatory role on exocytosis and proliferation of the β-cell...
October 2016: Best Practice & Research. Clinical Endocrinology & Metabolism
https://www.readbyqxmd.com/read/27923320/3d-co-culture-model-to-analyze-the-crosstalk-between-endothelial-and-smooth-muscle-cells
#19
Minu Karthika Ganesan, Richard Finsterwalder, Heide Leb, Ulrike Resch, Karin Neumüller, Rainer de Martin, Peter Petzelbauer
The response of blood vessels to physiological and pathological stimuli partly depends on the crosstalk between endothelial cells (EC) lining the luminal side and smooth muscle cells (SMC) building the inner part of the vascular wall. Thus, the in vitro analysis of the pathophysiology of blood vessels requires co-culture systems of EC and SMC. We have developed and validated a modified 3D sandwich co-culture (3D SW-CC) of EC and SMC employing open µ-Slides with a thin glass bottom allowing direct imaging. The culture dish comprises of an intermediate plate to minimize the meniscus resulting in homogenous cell distribution...
December 6, 2016: Tissue Engineering. Part C, Methods
https://www.readbyqxmd.com/read/27923179/structural-dynamics-of-casein-kinase-i-cki-from-malarial-parasite-plasmodium-falciparum-isolate-3d7-insights-from-theoretical-modelling-and-molecular-simulations
#20
Budheswar Dehury, Santosh Kumar Behera, Namita Mahapatra
The protein kinases (PKs), belonging to serine/threonine kinase (STKs), are important drug targets for a wide spectrum of diseases in human. Among protein kinases, the Casein Kinases (CKs) are vastly expanded in various organisms, where, the malarial parasite Plasmodium falciparum possesses a single member i.e., PfCKI, which can phosphorylate various proteins in parasite extracts in vitro condition. But, the structure-function relationship of PfCKI and dynamics of ATP binding is yet to be understood. Henceforth, an attempt was made to study the dynamics, stability, and ATP binding mechanisms of PfCKI through computational modelling, docking, molecular dynamics (MD) simulations, and MM/PBSA binding free energy estimation...
November 21, 2016: Journal of Molecular Graphics & Modelling
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