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https://www.readbyqxmd.com/read/28090637/diltiazem-prevents-stress-induced-contractile-deficits-in-cardiomyocytes-but-does-not-reverse-the-cardiomyopathy-phenotype-in-mybpc3-knock-in-mice
#1
Frederik Flenner, Birgit Geertz, Silke Reischmann-Düsener, Florian Weinberger, Thomas Eschenhagen, Lucie Carrier, Felix W Friedrich
Left ventricular hypertrophy, diastolic dysfunction and fibrosis are main features of hypertrophic cardiomyopathy (HCM). Guidelines recommend β-adrenoceptor or Ca(2+) channel antagonists as pharmacological treatment. The Ca(2+) channel blocker diltiazem recently showed promising beneficial effects in pre-clinical HCM, particularly in patients carrying MYBPC3 mutations. In the present study we evaluated whether diltiazem could ameliorate or reverse the disease phenotype in cells and in vivo in Mybpc3-targeted knock-in (KI) mouse model of HCM...
January 15, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28088328/altered-myocyte-contractility-and-calcium-homeostasis-in-alpha-myosin-heavy-chain-point-mutations-linked-to-familial-dilated-cardiomyopathy
#2
Matthew Klos, Lakshmi Mundada, Indroneal Banerjee, Sherry Morgenstern, Stephanie Myers, Michael Leone, Mark Kleid, Todd Herron, Eric Devaney
Mutations in the human cardiac motor protein beta-myosin heavy chain (βMHC) have been long recognized as a cause of familial hypertrophic cardiomyopathy. Recently, mutations (P830L and A1004S) in the less abundant but faster isoform alpha-myosin heavy chain (αMHC) have been linked to dilated cardiomyopathy (DCM). In this study, we sought to determine the cellular contractile phenotype associated with these point mutations. Ventricular myocytes were isolated from 2 month male Sprague Dawley rats. Cells were cultured in M199 media and infected with recombinant adenovirus containing the P830L or the A1004S mutant human αMHC at a MOI of 500 for 18 h...
January 11, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28087715/sf3b1-hsh155-heat-motif-mutations-affect-interaction-with-the-spliceosomal-atpase-prp5-resulting-in-altered-branch-site-selectivity-in-pre-mrna-splicing
#3
Qing Tang, Susana Rodriguez-Santiago, Jing Wang, Jia Pu, Andrea Yuste, Varun Gupta, Alberto Moldón, Yong-Zhen Xu, Charles C Query
Mutations in the U2 snRNP component SF3B1 are prominent in myelodysplastic syndromes (MDSs) and other cancers and have been shown recently to alter branch site (BS) or 3' splice site selection in splicing. However, the molecular mechanism of altered splicing is not known. We show here that hsh155 mutant alleles in Saccharomyces cerevisiae, counterparts of SF3B1 mutations frequently found in cancers, specifically change splicing of suboptimal BS pre-mRNA substrates. We found that Hsh155p interacts directly with Prp5p, the first ATPase that acts during spliceosome assembly, and localized the interacting regions to HEAT (Huntingtin, EF3, PP2A, and TOR1) motifs in SF3B1 associated with disease mutations...
December 15, 2016: Genes & Development
https://www.readbyqxmd.com/read/28086929/early-virological-failure-and-hiv-drug-resistance-in-ugandan-adults-co-infected-with-tuberculosis
#4
Amrei von Braun, Christine Sekaggya-Wiltshire, Alexandra U Scherrer, Brian Magambo, Andrew Kambugu, Jan Fehr, Barbara Castelnuovo
PURPOSE: This cross-sectional study took place in the integrated tuberculosis (TB) clinic of a large outpatient clinic for HIV-infected patients in Kampala, Uganda. The purpose of this study was to describe the proportion of TB/HIV co-infected adults with virological failure, type and frequency of HIV drug resistance-associated mutations, and the proportion of patients with suboptimal efavirenz levels. METHODS: HIV-1 plasma viral loads, CD4 cell count measurements, and efavirenz serum concentrations were done in TB/HIV co-infected adults...
January 5, 2017: AIDS Research and Therapy
https://www.readbyqxmd.com/read/28081591/new-perspectives-of-biomarkers-for-the-management-of-chronic-hepatitis-b
#5
REVIEW
Chih-Lin Lin, Jia-Horng Kao
With recent advances in molecular and genomic investigations, the impact of hepatitis B viral and host factors on the progression of chronic HBV infection has been explored. For viral factors, hepatitis B viral load is a strong predictor for liver disease progression. Hepatitis B viral kinetics appear to be important for successful anti-viral therapy. Serum HBsAg level serves as a complementary marker to viral load for the prediction of HBV-related adverse outcomes in patients with low viral load. In those with low viral load, high serum HBsAg level is associated with higher risks of cirrhosis and HCC...
December 2016: Clinical and Molecular Hepatology
https://www.readbyqxmd.com/read/28076335/infrequent-development-of-drug-resistance-in-hiv-1-infected-treatment-naive-subjects-after-96-weeks-of-treatment-with-elvitegravir-cobicistat-emtricitabine-tenofovir-alafenamide-or-elvitegravir-cobicistat-emtricitabine-tenofovir-disoproxil-fumarate
#6
Nicolas Margot, Stephanie Cox, Moupali Das, Scott McCallister, Michael D Miller, Christian Callebaut
BACKGROUND: Tenofovir alafenamide (TAF) is a novel prodrug of the nucleotide RT inhibitor (NtRTI) tenofovir (TFV) that loads lymphocytes with TFV-diphosphate more efficiently than tenofovir disoproxil fumarate (TDF). The single-tablet regimen (STR) composed of elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF) has demonstrated non-inferiority to the STR of E/C/F/TDF in clinical studies, with high proportions of subjects achieving HIV-1 RNA <50 copies/mL at week 48, and maintained through week 96...
January 11, 2017: Antiviral Therapy
https://www.readbyqxmd.com/read/28070553/predicted-neoantigen-load-in-non-hypermutated-endometrial-cancers-correlation-with-outcome-and-tumor-specific-genomic-alterations
#7
Sachet A Shukla, Brooke E Howitt, Catherine J Wu, Panagiotis A Konstantinopoulos
Elevated neoantigen load has been previously correlated with improved outcome and response to immune checkpoint blockade in various tumor types. In endometrial cancer, previous studies of neoantigen load prediction have shown that the hypermutated MSI and POLE-mutated tumors harbor significantly higher predicted neoantigen load compared to the hypomutated CN-low/endometrioid and CN-high/serous-like tumors. Here, we report that predicted neoantigen load may be a prognostic factor in hypomutated endometrial cancers, both in CN-low/endometrioid and CN-high/serous-like tumors...
February 2017: Gynecologic Oncology Reports
https://www.readbyqxmd.com/read/28068346/mutation-accumulation-in-an-asexual-relative-of-arabidopsis
#8
John T Lovell, Robert J Williamson, Stephen I Wright, John K McKay, Timothy F Sharbel
Asexual populations experience weaker responses to natural selection, which causes deleterious mutations to accumulate over time. Additionally, stochastic loss of individuals free of deleterious mutations can lead to an irreversible increase in mutational load in asexuals (the "click" in Muller's Ratchet). Here we report on the genomic divergence and distribution of mutations across eight sympatric pairs of sexual and apomictic (asexual) Boechera (Brassicaceae) genotypes. We show that apomicts harbor a greater number of derived mutations than sympatric sexual genotypes...
January 9, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28067894/unexpected-uvr-and-non-uvr-mutation-burden-in-some-acral-and-cutaneous-melanomas
#9
Robert V Rawson, Peter A Johansson, Nicholas K Hayward, Nicola Waddell, Ann-Marie Patch, Serigne Lo, John V Pearson, John F Thompson, Graham J Mann, Richard A Scolyer, James S Wilmott
Ultraviolet radiation (UVR) mutagenesis causes nearly all cutaneous melanomas, however, since UVR signatures are largely absent in acral melanoma, as well as melanoma in sun-protected sites, the cause of these melanomas is unknown. Whole-genome sequencing data generated as part of the Australian Melanoma Genome Project was supplemented with a detailed histopathological assessment with the melanomas then classified as UVR or non-UVR related, based on their mutation signatures. The clinicopathological characteristics of melanomas with mutation signatures for their subtype were compared...
January 9, 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28066030/sparse-exponential-family-principal-component-analysis
#10
Meng Lu, Jianhua Z Huang, Xiaoning Qian
We propose a Sparse exponential family Principal Component Analysis (SePCA) method suitable for any type of data following exponential family distributions, to achieve simultaneous dimension reduction and variable selection for better interpretation of the results. Because of the generality of exponential family distributions, the method can be applied to a wide range of applications, in particular when analyzing high dimensional next-generation sequencing data and genetic mutation data in genomics. The use of sparsity-inducing penalty helps produce sparse principal component loading vectors such that the principal components can focus on informative variables...
December 2016: Pattern Recognition
https://www.readbyqxmd.com/read/28060274/gap-junctional-intercellular-communication-a-functional-biomarker-to-assess-adverse-effects-of-toxicants-and-toxins-and-health-benefits-of-natural-products
#11
Brad L Upham, Iva Sovadinová, Pavel Babica
This protocol describes a scalpel loading-fluorescent dye transfer (SL-DT) technique that measures intercellular communication through gap junction channels, which is a major intercellular process by which tissue homeostasis is maintained. Interruption of gap junctional intercellular communication (GJIC) by toxicants, toxins, drugs, etc. has been linked to numerous adverse health effects. Many genetic-based human diseases have been linked to mutations in gap junction genes. The SL-DT technique is a simple functional assay for the simultaneous assessment of GJIC in a large population of cells...
December 25, 2016: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28059608/near-future-of-tumor-immunology-anticipating-resistance-mechanisms-to-immunotherapies-a-big-challenge-for-clinical-trials
#12
João Paulo Portela Catani, Sandy Adjemian, Rachel P Riechelmann, Bryan E Strauss
The success of immunotherapies brings hope for the future of cancer treatment. Even so, we are faced with a new challenge, that of understanding which patients will respond initially and, possibly, develop resistance. The examination of the immune profile, especially approaches related to the immunoscore, may foretell which tumors will have a positive initial response. Ideally, the mutation load would also be analysed, helping to reveal tumor associated antigens that are predictive of an effective cytolytic attack...
January 6, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/28057179/biomarqueurs-pr%C3%A3-dictifs-de-r%C3%A3-ponse-aux-traitements-bloquant-les-voies-de-costimulation-inhibitrices
#13
Franck Pagès, Clémence Granier, Amos Kirilovsky, Carine Elsissy, Eric Tartour
Immunotherapies targeting co-inhibitory receptors recently open a new promising approach of cancer treatment. Indeed, an objective clinical response was observed after treatment by anti-CTLA-4 and anti-PD-1 in many indications but the treatment still failed in 70 to 80 % of cases treated. Given the adverse effects and the high cost of these therapies, there is a need for the development of biomarkers. This review focus on potential predictive biomarkers. In peripheral blood, high level of Il-2 soluble receptor at baseline and absence of ICOS+ CD4-T lymphocytes induction may be associated with the absence of clinical response for melanoma patients treated by ipilimumab (anti-CTLA-4)...
November 2016: Bulletin du Cancer
https://www.readbyqxmd.com/read/28057123/-ptps-gene-analysis-and-prenatal-diagnosis-in-patients-with-6-pyruvoyl-tetra-hydropterin-synthase-deficiency
#14
N Liu, D H Zhao, X L Li, L X Cui, Q H Wu, M Jiang, X D Kong
Objective: To analyze the variations of PTPS gene in patients with suspected 6-pyruvoyl-tetra hydropterin synthase deficiency (PTPSD) and to make prenatal diagnosis in high-risk families. Methods: Chemiluminescence was used for phenylalanine detection in blood or dried blood spots.Patients with phenylalanine concentration over 120 μmol/L were detected by urine pterin analysis, and the activity of dihydropteridine reductase (DHPR) was detected. tetrahydrobiopterin loading tests were performed in suspected patients with abnormal urinary pterin profiles...
December 25, 2016: Zhonghua Fu Chan Ke za Zhi
https://www.readbyqxmd.com/read/28054750/somatic-med12-nonsense-mutation-escapes-mrna-decay-and-reveals-a-motif-required-for-nuclear-entry
#15
Tuomas Heikkinen, Kati Kämpjärvi, Salla Keskitalo, Pernilla von Nandelstadh, Xiaonan Liu, Ville Rantanen, Esa Pitkänen, Matias Kinnunen, Heikki Kuusanmäki, Mika Kontro, Mikko Turunen, Netta Mäkinen, Jussi Taipale, Caroline Heckman, Kaisa Lehti, Satu Mustjoki, Markku Varjosalo, Pia Vahteristo
MED12 is a key component of the transcription-regulating Mediator complex. Specific missense and in-frame insertion/deletion mutations in exons 1 and 2 have been identified in uterine leiomyomas, breast tumors, and chronic lymphocytic leukemia. Here, we characterize the first MED12 5' end nonsense mutation (c.97G>T, p.E33X) identified in acute lymphoblastic leukemia and show that it escapes nonsense-mediated mRNA decay (NMD) by using an alternative translation initiation site. The resulting N-terminally truncated protein is unable to enter the nucleus due to the lack of identified nuclear localization signal (NLS)...
January 5, 2017: Human Mutation
https://www.readbyqxmd.com/read/28053029/mutant-%C3%AE-synuclein-overexpression-induces-stressless-pacemaking-in-vagal-motoneurons-at-risk-in-parkinson-s-disease
#16
Efrat Lasser-Katz, Alon Simchovitz, Wei-Hua Chiu, Wolfgang H Oertel, Ronit Sharon, Hermona Soreq, Jochen Roeper, Joshua A Goldberg
: α-Synuclein overexpression (ASOX) drives the formation of toxic aggregates in neurons vulnerable in Parkinson's disease (PD), including dopaminergic neurons of the substantia nigra (SN) and cholinergic neurons of the dorsal motor nucleus of the vagus (DMV). Just as these populations differ in when they exhibit α-synucleinopathies during PD pathogenesis, they could also differ in their physiological responses to ASOX. An ASOX-mediated hyperactivity of SN dopamine neurons, which was caused by oxidative dysfunction of Kv4...
January 4, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28046022/association-of-tlr3-l412f-polymorphism-with-cytomegalovirus-infection-in-children
#17
Mirosława Studzińska, Agnieszka Jabłońska, Małgorzata Wiśniewska-Ligier, Dorota Nowakowska, Zuzanna Gaj, Zbigniew J Leśnikowski, Teresa Woźniakowska-Gęsicka, Jan Wilczyński, Edyta Paradowska
Intracellular Toll-like receptor 3 (TLR3) recognizes viral double-stranded RNA (dsRNA) and activates antiviral immune responses through the production of type I interferons (IFNs) and inflammatory cytokines. This receptor binds to dsRNA molecules produced during human cytomegalovirus (HCMV) replication. TLR7 senses viral single-stranded RNA (ssRNA) in endosomes, and it can interact with endogenous RNAs. We determined the genotype distribution of single-nucleotide polymorphisms (SNPs) within the TLR3 and TLR7 genes in children with HCMV infection and the relationship between TLR polymorphisms and viral infection...
2017: PloS One
https://www.readbyqxmd.com/read/28044000/painful-locking-of-the-wrist-in-a-patient-with-pseudoachondroplasia-confirmed-by-comp-mutation
#18
Hirokazu Ideta, Shigeharu Uchiyama, Masanori Hayashi, Tomoki Kosho, Yukio Nakamura, Hiroyuki Kato
We report the case of a 40-year-old woman with pseudoachondroplasia (PSACH), with a heterozygous mutation (c.806A > G, p.Asp269Gly) located in the Type 3 repeats domain of the cartilage oligomeric matrix protein gene, who complained of the unusual symptom of painful locking of the wrist. Her condition was caused by a non-traumatic enlargement of the extensor carpi radialis longus (ECRL) and brevis (ECRB) tendons along with bulbous swelling of the synoviums around them. Surgical treatment resolved these unusual tendon-related symptoms...
January 2, 2017: Journal of Surgical Case Reports
https://www.readbyqxmd.com/read/28043564/trfa1-gene-in-clinical-isolates-of-mycobacterium-tuberculosis
#19
Azam Ahmadi, Mohammad Arjomandzadegan, Masoomeh Saberpoor, Mona Moghadasi
OBJECTIVE/BACKGROUND: The incidence of resistant strains of Mycobacterium tuberculosis (MTB), including multi-drug resistant, extensively drug resistant, or totally drug resistant, is one of the major problems of health policies worldwide. The accumulation of mutations causes multi-drug resistant strains. Mycobacterium abscessus has a plasmid called pMab2401 containing the trfA1 gene in its integron part. The aim of the present study was to investigate the possible existence of the trfA1 gene in clinical strains of MTB for the first time...
December 2016: International Journal of Mycobacteriology
https://www.readbyqxmd.com/read/28041795/experimental-evidence-for-the-negative-effects-of-self-fertilization-on-the-adaptive-potential-of-populations
#20
Elsa Noël, Philippe Jarne, Sylvain Glémin, Alicia MacKenzie, Adeline Segard, Violette Sarda, Patrice David
Self-fertilization is widely believed to be an "evolutionary dead end" [1, 2], increasing the risk of extinction [3] and the accumulation of deleterious mutations in genomes [4]. Strikingly, while the failure to adapt has always been central to the dead-end hypothesis [1, 2], there are no quantitative genetic selection experiments comparing the response to positive selection in selfing versus outcrossing populations. Here we studied the response to selection on a morphological trait in laboratory populations of a hermaphroditic, self-fertile snail under either selfing or outcrossing...
December 22, 2016: Current Biology: CB
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