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https://www.readbyqxmd.com/read/29142210/millisecond-dynamics-of-btk-reveal-kinome-wide-conformational-plasticity-within-the-apo-kinase-domain
#1
Mohammad M Sultan, Rajiah Aldrin Denny, Ray Unwalla, Frank Lovering, Vijay S Pande
Bruton tyrosine kinase (BTK) is a key enzyme in B-cell development whose improper regulation causes severe immunodeficiency diseases. Design of selective BTK therapeutics would benefit from improved, in-silico structural modeling of the kinase's solution ensemble. However, this remains challenging due to the immense computational cost of sampling events on biological timescales. In this work, we combine multi-millisecond molecular dynamics (MD) simulations with Markov state models (MSMs) to report on the thermodynamics, kinetics, and accessible states of BTK's kinase domain...
November 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29141709/rapid-diagnostic-testing-of-hospitalized-malawian-children-reveals-opportunities-for-improved-hiv-diagnosis-and-treatment
#2
Theresa F Madaline, Sarah E Hochman, Karl B Seydel, Alice Liomba, Alex Saidi, Grace Matebule, Wenzhu B Mowrey, Bernadette O'Hare, Danny A Milner, Kami Kim
Recent World Health Organization (WHO) guidelines recommend antiretroviral therapy (ART) for all HIV-infected people; previously CD4+ T lymphocyte quantification (CD4 count) or clinical staging determined eligibility for children ≥ 5 years old in low- and middle-income countries. We examined positive predictive value (PPV) of a rapid diagnostic test (RDT) algorithm and ART eligibility for hospitalized children with newly diagnosed HIV infection. We enrolled 363 hospitalized Malawian children age 2 months to 16 years with two serial positive HIV RDT from 2013 to 2015...
October 16, 2017: American Journal of Tropical Medicine and Hygiene
https://www.readbyqxmd.com/read/29140551/b-cell-receptor-repertoire-sequencing-in-patients-with-primary-immunodeficiency-a-review
#3
REVIEW
Marie Ghraichy, Jacob D Galson, Dominic F Kelly, Johannes Trück
The advent of next-generation sequencing now allows a detailed assessment of the adaptive immune system in health and disease. In particular, high-throughput B-cell receptor (BCR) repertoire sequencing provides detailed information about the functionality and abnormalities of the B-cell system. However, it is mostly unknown how the BCR repertoire is altered in the context of primary immunodeficiencies (PID) and whether findings are consistent across phenotypes and genotypes. We have performed an extensive literature search of the published work on BCR repertoire sequencing in PID patients, including several forms of predominantly antibody disorders and combined immunodeficiencies...
November 15, 2017: Immunology
https://www.readbyqxmd.com/read/29137597/reduction-of-pluripotent-gene-expression-in-murine-embryonic-stem-cells-exposed-to-mechanical-loading-or-cyclo-rgd-peptide
#4
Olesja Hazenbiller, Neil A Duncan, Roman J Krawetz
BACKGROUND: Self-renewal and differentiation of embryonic stem cells (ESCs) is directed by biological and/or physical cues that regulate multiple signaling cascades. We have previously shown that mESCs seeded in a type I collagen matrix demonstrate a loss of pluripotent marker expression and differentiate towards an osteogenic lineage. In this study, we examined if this effect was mediated in part through Arginylglycylaspartic acid (RGD) dependent integrin activity and/or mechano-transduction...
November 14, 2017: BMC Cell Biology
https://www.readbyqxmd.com/read/29136115/estradiol-levels-are-altered-in-human-immunodeficiency-virus-infected-pregnant-women-randomized-to-efavirenz-versus-lopinavir-ritonavir-based-antiretroviral-therapy
#5
Chloe R McDonald, Andrea L Conroy, Joel L Gamble, Eszter Papp, Michael Hawkes, Peter Olwoch, Paul Natureeba, Moses Kamya, Michael Silverman, Deborah Cohan, Catherine A Koss, Grant Dorsey, Kevin C Kain, Lena Serghides
Background: Combination antiretroviral therapy (cART) use in pregnancy has been associated with hormonal dysregulation. We performed a secondary retrospective analysis of longitudinal progesterone and estradiol levels in pregnancy using specimens from the Protease Inhibitors to Reduce Malaria Morbidity in HIV-infected Pregnant Women study, which randomized Ugandan human immunodeficiency virus (HIV)-infected ART-naive women to initiate either lopinavir/ritonavir (LPV/r)-based or efavirenz (EFV)-based cART...
November 10, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/29133261/dual-inhibition-of-brd4-and-pi3k-by-sf2523-suppresses-human-prostate-cancer-cell-growth-in-vitro-and-in-vivo
#6
Gang Shen, Minjun Jiang, Jinxian Pu
Bromodomain-containing protein 4 (BRD4) and phosphatidylinositol 3-kinase (PI3K) are both key oncogenic proteins in human prostate cancer. In the current study, we examined the anti-prostate cancer cell activity by SF2523, a BRD4 and PI3K dual inhibitor. We showed that SF2523 potently inhibited survival and proliferation of the primary human prostate cancer cells. SF2523 induced profound apoptosis activation in prostate cancer cells. The dual inhibitor was yet non-cytotoxic to the prostate epithelial cells...
November 10, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29130604/expanding-the-phenotypic-spectrum-of-tp63-related-disorders-including-the-first-set-of-monozygotic-twins
#7
Tara Wenger, Dong Li, Margaret H Harr, Wen-Hann Tan, Renata Pellegrino, Zornitza Stark, Hakon Hakonarson, Elizabeth J Bhoj
Individuals with Tumor Protein P63 (TP63)-related disorders are known to present with a range of phenotypic features, including ectrodactyly, ectodermal dysplasia, cleft lip/palate, Rapp-Hodgkin, Hay-Wells, and limb-mammary syndromes. We present six individuals from three families, including a set of monozygotic twins, with pathogenic TP63 variants who had novel clinical findings. The twins were discordant for cleft lip and palate, and the type of hand malformations, but concordant for choanal atresia, and bilateral volar nail...
November 12, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29128673/bi-allelic-irf8-mutation-a-complex-immunodeficiency-syndrome-with-dendritic-cell-deficiency-monocytopenia-and-immune-dysregulation
#8
Venetia Bigley, Sheetal Maisuria, Urszula Cytlak, Laura Jardine, Matthew A Care, Kile Green, Merry Gunawan, Paul Milne, Rachel Dickinson, Sarah Wiscombe, David Parry, Rainer Doffinger, Arian Laurence, Claudia Fonseca Lic, Oda Stoevesandt, Andrew Gennery, Andrew Cant, Reuben Tooze, A John Simpson, Sophie Hambleton, Sinisa Savic, Gina Doody, Matthew Collin
BACKGROUND: Homozygous K108E mutation of interferon regulatory factor 8 (IRF8) is reported to cause dendritic cell and monocyte deficiency. However, more widespread immune dysfunction is predicted from the multiple roles ascribed to IRF8 in immune cell development and function. OBJECTIVE: We sought to describe the effect on hematopoiesis and immunity of compound heterozygous R83C/ R291Q mutation of IRF8, present in a patient with recurrent viral infection, granulo-proliferation and intracerebral calcification...
November 8, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29126877/chidamide-a-histone-deacetylase-inhibitor-based-anticancer-drug-effectively-reactivates-latent-hiv-1-provirus
#9
Wenqian Yang, Zhiwu Sun, Chen Hua, Qian Wang, Wei Xu, Qiwen Deng, Yanbin Pan, Lu Lu, Shibo Jiang
Although combination antiretroviral therapy (cART) is highly effective in suppressing human immunodeficiency virus type 1 (HIV-1) replication, it fails to eradicate the virus from HIV-1-infected individuals because HIV-1 integrates into the resting CD4(+) T cells, establishing latently infected reservoirs. Histone deacetylation is a key element in regulating HIV-1 latent infection. Chidamide, a new anticancer drug, is a novel type of selective histone deacetylase inhibitor. Here we showed that chidamide effectively reactivated HIV-1 latent provirus in different latently infected cell lines in a dose- and time-dependent manner...
November 8, 2017: Microbes and Infection
https://www.readbyqxmd.com/read/29123649/the%C3%A2-%C3%AE-c%C3%A2-family-of-cytokines-fine-tuning-signals-from-il-2-and-il-21-in-the-regulation-of-the-immune-response
#10
REVIEW
Rosanne Spolski, Daniel Gromer, Warren J Leonard
Interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 form a family of cytokines based on the sharing of a receptor component, the common cytokine receptor γ chain, γ c, which is encoded by the gene mutated in humans with X-linked severe combined immunodeficiency (XSCID). Together, these cytokines play critical roles in lymphoid development, differentiation, growth, and survival as well as mediating effector function. Here, we provide an overview of the main actions of members of this cytokine family but then primarily focus on IL-2 and IL-21, discussing their dynamic interplay and contributions to a fine-tuned immune response...
2017: F1000Research
https://www.readbyqxmd.com/read/29117661/a-rare-case-of-infectious-multifocal-serpiginoid-choroiditis
#11
Miloš Mitrašević, Svetlana Jovanović, Filip Radotić, Snežana Pešić, Zorica Jovanović
Multifocal serpiginoid choroiditis is an infectious variety of serpiginous choroiditis. The disease is characterized by infectious etiology and overlapping clinical features in an intermediary form of acute posterior multifocal placoid pigment epitheliopathy and serpiginous choroiditis. In a 33-year-old patient, bilateral multiple placoid partially confluent chorioretinal lesions were diagnosed after a febrile flu-like episode. On the right eye, there was a progressive decrease in visual acuity. Later, the lesions had a prolonged progressive devastating clinical course and widespread distribution of placoid lesions, and took the form of serpiginoid choroiditis...
December 2016: Acta Clinica Croatica
https://www.readbyqxmd.com/read/29117236/effects-of-cd49d-targeted-antisense-oligonucleotide-on-%C3%AE-4-integrin-expression-and-function-of-acute-lymphoblastic-leukemia-cells-results-of-in-vitro-and-in-vivo-studies
#12
Yann Duchartre, Stefanie Bachl, Hye Na Kim, Eun Ji Gang, Solah Lee, Hsiao-Chuan Liu, Kirk Shung, Ruth Xu, Aaron Kruse, George Tachas, Halvard Bonig, Yong-Mi Kim
We recently demonstrated the effectiveness of blocking CD49d with anti-functional antibodies or small molecule inhibitors as a rational targeted approach to the treatment of acute leukemia in combination with chemotherapy. Antisense oligonucleotide promises to be no less specific than antibodies and inhibitors, but more interesting for pharmacokinetics and pharmacodynamics. We addressed this using the published CD49d antisense drug ATL1102. In vitro, we incubated/nucleofected the ALL cell line Kasumi-2 with ATL1102...
2017: PloS One
https://www.readbyqxmd.com/read/29116556/newborn-screening-for-primary-immunodeficiency-diseases-history-current-and-future-practice
#13
Jovanka R King, Lennart Hammarström
The primary objective of population-based newborn screening is the early identification of asymptomatic infants with a range of severe diseases, for which effective treatment is available and where early diagnosis and intervention prevent serious sequelae. Primary immunodeficiency diseases (PID) are a heterogeneous group of inborn errors of immunity. Severe combined immunodeficiency (SCID) is one form of PID which is uniformly fatal without early, definitive therapy, and outcomes are significantly improved if infants are diagnosed and treated within the first few months of life...
November 8, 2017: Journal of Clinical Immunology
https://www.readbyqxmd.com/read/29115976/gmp-production-of-purified-human-b-lymphocytes-for-the-adoptive-transfer-in-patients-after-allogeneic-hematopoietic-stem-cell-transplantation
#14
Hannes Tittlbach, Andrea Schneider, Julian Strobel, Robert Zimmermann, Stefanie Maas, Bernd Gebhardt, Georg Rauser, Michael Mach, Andreas Mackensen, Thomas H Winkler, Julia Winkler
BACKGROUND: We have recently shown that memory B cells from murine CMV immune donor animals adoptively transferred into immunodeficient mice were highly effective in protecting from a viral infection indicating a therapeutic potential of virus specific memory B cells. These preclinical data provided evidence that a cell-based strategy supporting the humoral immune response might be effective in a clinical setting of immunodeficiency after allogeneic hematopoietic stem cell transplantation...
November 7, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/29115572/talens-mediated-homozygous-ccr5%C3%AE-32-mutations-endow-cd4-u87-cells-with-resistance-against-hiv%C3%A2-1-infection
#15
Ai Qing Yu, Yan Ding, Zhi Yong Lu, Yan Zhe Hao, Zhi Ping Teng, Shi Rong Yan, Dong Sheng Li, Yi Zeng
Since evidence suggests that transplantation of bone marrow stem cells with the C‑C chemokine receptor type 5 (CCR5)Δ32/Δ32 genotype may cure patients infected with human immunodeficiency virus (HIV)‑1, the present study aimed to reproduce the CCR5Δ32 mutation in cluster of differentiation (CD)4+ U87 cells using genome engineering methods. A modified transcription activator‑like effector nucleases (TALENs) technique, combined with homologous recombination for site‑specific, size‑controlled and homozygous DNA deletions, was used to reproduce the homozygous CCR5Δ32 mutation in CD4+ U87 cells...
October 26, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29113169/lentivirus-mediated-rna-interference-inhibits-the-tumorigenicity-of-cluster-of-differentiation-44-tumor-cells-in-hypopharyngeal-cancer
#16
Chenling Shen, Bin Ye, Haixia Hu, Chen Nie, Yan Ma, Jingrong Lv, Hao Wu, Mingliang Xiang
The present study aimed to investigate whether the inhibition of cluster of differentiation (CD)44 expression reduces the tumorigenicity of CD44(+) cancer stem cells in hypopharyngeal cancer. To assess this, effective recombinant CD44 short hairpin RNA-expressing lentiviruses were produced. Lentivirus-mediated RNA interference (RNAi) was then used to knockdown CD44 gene expression in the hypopharyngeal cancer FaDu cell line. The viability of FaDu cells in the two control groups and the RNAi group (RNAi-CD44 lentiviral vector) was detected using an MTT assay in vitro...
November 2017: Oncology Letters
https://www.readbyqxmd.com/read/29112744/research-roadmap-for-tuberculosis-transmission-science-where-do-we-go-from-here-and-how-will-we-know-when-we-re-there
#17
REVIEW
Sara C Auld, Anne G Kasmar, David W Dowdy, Barun Mathema, Neel R Gandhi, Gavin J Churchyard, Roxana Rustomjee, N Sarita Shah
High rates of tuberculosis transmission are driving the ongoing global tuberculosis epidemic, and there is a pressing need for research focused on understanding and, ultimately, halting transmission. The ongoing tuberculosis-human immunodeficiency virus (HIV) coepidemic and rising rates of drug-resistant tuberculosis in parts of the world add further urgency to this work. Success in this research will require a concerted, multidisciplinary effort on the part of tuberculosis scientists, clinicians, programs, and funders and must span the research spectrum from biomedical sciences to the social sciences, public health, epidemiology, cost-effectiveness analyses, and operations research...
November 3, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/29110871/prevalence-of-rifampicin-resistant-mycobacterium-tuberculosis-among-human-immunodeficiency-virus-seropositive-patients-and-their-treatment-outcomes
#18
C K Vidyaraj, A Chitra, S Smita, M Muthuraj, S Govindarajan, B Usharani, S Anbazhagi
Multidrug resistant (MDR) and extensively drug resistant tuberculosis (TB) are a threat to the TB control programs in developing countries, and the situation is worsened by the human immunodeficiency virus (HIV) pandemic. This study was performed to correlate treatment outcome with the resistance patterns in HIV-seropositive patients coinfected with pulmonary TB. Sputum specimens were collected from 1643 HIV-seropositive patients and subjected to microscopy and liquid culture for TB. The smear- and culture-positive Mycobacterium tuberculosis isolates were subjected to Genotype MTBDRplus assay version 2...
December 2017: Journal of Epidemiology and Global Health
https://www.readbyqxmd.com/read/29109851/safety-and-efficacy-of-ledipasvir-sofosbuvir-on-hepatitis-c-eradication-in-hepatitis-c-virus-human-immunodeficiency-virus-co-infected-patients
#19
Xiaoping He, Lynne Hopkins, George Everett, Willie M Carter, Cynthia SchroppDyce, Khalid Abusaada, Vincent Hsu
AIM: To evaluate the safety and efficacy of ledipasvir/sofosbuvir on hepatitis C eradication in patients with hepatitis C virus (HCV)/human immunodeficiency virus (HIV) co-infection in an urban HIV clinic. METHODS: A retrospective cohort study of 40 subjects co-infected with HIV-1 and HCV treated with the fixed-dose combination of ledipasvir and sofosbuvir for 12 wk from 2014 to 2016. All patients included were receiving antiretroviral therapy (ART) with HIV RNA values of 100 copies/mL or fewer regardless of baseline HCV RNA level...
October 28, 2017: World Journal of Hepatology
https://www.readbyqxmd.com/read/29105400/effects-of-klf4-and-c-myc-knockdown-on-pluripotency-maintenance-in-porcine-induced-pluripotent-stem-cell
#20
Yu-Jing Liao, Yi-Shiou Chen, Ja-Xin Lee, Lih-Ren Chen, Jenn-Rong Yang
OBJECTIVES: The importance of Oct4 and Sox2 in maintaining pluripotency and self-renewal is well-understood, but the functions of Klf4 and c-Myc has not been fully investigated. In the present study, we attempted to determine the roles of Klf4 and c-Myc on pluripotency maintenance of porcine induced pluripotent stem (piPS) cells. MATERIALS AND METHODS: In this experimental study, we performed short hairpin RNA (shRNA) to knock down the Klf4 and c-Myc functions of piPS cells and examined pluripotency markers and teratoma formation to evaluate piPS cell pluripotency...
January 2018: Cell Journal
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