In silico modeling indicates the development of HIV-1 resistance to multiple shRNA gene therapy differs to standard antiretroviral therapy

<p>Abstract</p> <p>Background</p> <p>Gene therapy has the potential to counter problems that still hamper standard HIV antiretroviral therapy, such as toxicity, patient adherence and the development of resistance. RNA interference can suppress HIV replication as a gene therapeutic via expressed short hairpin RNAs (shRNAs). It is now clear that multiple shRNAs will likely be required to suppress infection and prevent the emergence of resistant virus.</p> <p>Results</p> <p>We have developed the first biologically relevant stochastic model in which multiple shRNAs are introduced into CD34+ hematopoietic stem cells. This model has been used to track the production of gene-containing CD4+ T cells, the degree of HIV infection, and the development of HIV resistance in lymphoid tissue for 13 years. In this model, we found that at least four active shRNAs were required to suppress HIV infection/replication effectively and prevent the development of resistance. The inhibition of incoming virus was shown to be critical for effective treatment. The low potential for resistance development that we found is largely due to a pool of replicating wild-type HIV that is maintained in non-gene containing CD4+ T cells. This wild-type HIV effectively out-competes emerging viral strains, maintaining the viral <it>status quo</it>.</p> <p>Conclusions</p> <p>The presence of a group of cells that lack the gene therapeutic and is available for infection by wild-type virus appears to mitigate the development of resistance observed with systemic antiretroviral therapy.</p

A Visual History of the King James Bible: The Dramatic Story of the World\u27s Best-Known Translation

For 400 years, the King James Version of the Holy Bible has been the most influential book to be published in the English language. Now, Bible collector and expert Donald L. Brake brings to life the fascinating story of its creation and proliferation throughout the English-speaking world. With beautiful and informative photos, illustrations, charts, and sidebars, Brake invites readers to explore the KJV\u27s mysterious beginnings, the men who translated it, the manuscripts upon which that translation was based, the important people and places that influenced its production, and even Shakespeare\u27s involvement in it. In an age where a new translation of the Bible seems to come about every few years, discover what has made the King James Version endure for four centuries.https://digitalcommons.cedarville.edu/alum_books/1234/thumbnail.jp

A Visual History of the English Bible: The Tumultuous Tale of the World\u27s Bestselling Book

Dozens of English Translations of the Bible are available today, but Scripture was not always so easy to obtain. Donald L. Brake invites you to discover the tumultuous tale of how the Bible was transformed from medieval manuscripts read only by clergy to a bestseller widely available in contemporary languages.https://digitalcommons.cedarville.edu/alum_books/1233/thumbnail.jp

Jesus, A Visual History: The Dramatic Story of the Messiah in the Holy Land

Jesus, A Visual History, offers a unique vantage point into Jesus’ story, introducing readers to the historical context of Gospel accounts. Its easy reading style, thorough research, and visual presentation will leave you with a greater and lasting appreciation for Jesus the Messiah. Maps and charts summarize and visualize the events of Jesus’ life, along with full-color photos and 19th-century black-and-white images of the modern sites where biblical events took place. In addition, original artwork researched for accuracy illuminates Jesus’ life and work. This engaging, visually-driven book provides an accessible yet accurate invitation to better understand both the Holy Land and the Savior who walked it.https://digitalcommons.cedarville.edu/alum_books/1417/thumbnail.jp

A Royal Monument of English Literature: The King James Bible 1611-2011

https://digitalcommons.cedarville.edu/alum_books/1391/thumbnail.jp

Pediatric tuberculous meningitis: Model-based approach to determining optimal doses of the anti-tuberculosis drugs rifampin and levofloxacin for children

Pediatric tuberculous meningitis (TBM) is a highly morbid, often fatal disease. Standard treatment includes isoniazid, rifampin, pyrazinamide, and ethambutol. Current rifampin dosing achieves low cerebrospinal fluid (CSF) concentrations, and CSF penetration of ethambutol is poor. In adult trials, higher-dose rifampin and/or a fluoroquinolone reduced mortality and disability. To estimate optimal dosing of rifampin and levofloxacin for children, we compiled plasma and CSF pharmacokinetic (PK) and outcomes data from adult TBM trials plus plasma PK data from children. A population PK/pharmacodynamic (PD) model using adult data defined rifampin target exposures (plasma area under the curve (AUC)0-24 = 92 mg*h/L). Levofloxacin targets and rifampin pediatric drug disposition information were literature-derived. To attain target rifampin exposures, children require daily doses of at least 30 mg/kg orally or 15 mg/kg intravenously (i.v.). From our pediatric population PK model, oral levofloxacin doses needed to attain exposure targets were 19-33 mg/kg. Our results provide data-driven guidance to maximize pediatric TBM treatment while we await definitive trial results

Mechanical behaviour and failure modes in the Whakaari (White Island volcano) hydrothermal system, New Zealand

International audienceVolcanic hydrothermal systems host a prodigious variety of physico-chemical conditions. The physico-chemical state and mechanical behaviour of rocks within is correspondingly complex and often characterised by vast heterogeneity. Here, we present uniaxial and triaxial compression experiments designed to investigate the breadth of mechanical behaviour and failure modes (dilatant or compactant) for hydrothermally-altered lava and ash tuff deposits from Whakaari (White Island volcano) in New Zealand, a volcano with a well-documented and very active hydrothermal system. Our deformation experiments show that the failure mode of low porosity lava remains dilatant over a range of depths (up to pressures corresponding to depths of about 2 km). Upon failure, shear fractures, the result of the coalescence of dilatational microcracks, are universally present. The high porosity ash tuffs switch however from a dilatant to a compactant failure mode (driven by progressive distributed pore collapse) at relatively low pressure (corresponding to a depth of about 250 m). We capture the salient features of the dynamic conditions (e.g., differential stress, effective pressure) in a schematic cross section for the Whakaari hydrothermal system and map, for the different lithologies, areas susceptible to either dilatant vs. compactive modes of failure. The failure mode will impact, for example, the evolution of rock physical properties (e.g., porosity, permeability, and elastic wave velocity) and the nature of the seismicity accompanying periods of unrest. We outline accordingly the potential implications for the interpretation of seismic signals, outgassing, ground deformation, and the volcanic structural stability for Whakaari and similar hydrothermally-active volcanoes worldwide

A multidisciplinary approach to quantify the permeability of the Whakaari/White Island volcanic hydrothermal system (Taupo Volcanic Zone, New Zealand)

International audienceOur multidisciplinary study aims to better understand the permeability of active volcanic hydrothermal systems, a vital prerequisite for modelling and understanding their behaviour and evolution. Whakaari/White Island volcano (an active stratovolcano at the north-eastern end of the Taupo Volcanic Zone of New Zealand) hosts a highly reactive hydrothermal system and represents an ideal natural laboratory to undertake such a study. We first gained an appreciation of the different lithologies at Whakaari and (where possible) their lateral and vertical extent through reconnaissance by land, sea, and air. The main crater, filled with tephra deposits, is shielded by a volcanic amphitheatre comprising interbedded lavas, lava breccias, and tuffs. We deployed field techniques to measure the permeability and density/porosity of (1) N100 hand-sized sample blocks and (2) layered unlithified deposits in eight purpose-dug trenches. Our field measurements were then groundtruthed using traditional laboratory techniques on almost 150 samples. Our measurements highlight that the porosity of the materials at Whakaari varies from ∼0.01 to ∼0.7 and permeability varies by eight orders of magnitude (from ∼10−19 to ∼10−11 m2). The wide range in physical and hydraulic properties is the result of the numerous lithologies and their varied microstructures and alteration intensities, as exposed by a combination of macroscopic and microscopic (scanning electron microscopy) observations, quantitative mineralogical studies (X-ray powder diffraction), and mercury porosimetry. An understanding of the spatial distribution of lithology and alteration style/intensity is therefore important to decipher fluid flow within the Whakaari volcanic hydrothermal system. We align our field observations and porosity/permeability measurements to construct a schematic cross section of Whakaari that highlights the salient findings of our study. Taken together, the alteration typical of a volcanic hydrothermal system can result in increases (due to alteration-induced dissolution and fracturing) and decreases (due to hydrothermal precipitation) to permeability. Importantly, a decrease in permeability—be it due to fracture sealing in lava, pore-filling alunite precipitation in tuff, near-vent cementation by sulphur, and/or wellsorted layers of fine ash—can result in pore pressure augmentation. An increase in pore pressure could result in ground deformation, seismicity, jeopardise the stability of the volcanic slopes, and/or drive the wide variety of eruptions observed at Whakaari. Our systematic study offers the most complete porosity-permeability dataset for a volcanic hydrothermal system to date. These new data will inform and support modelling, unrest monitoring, and eruption characterisation at Whakaari and other hydrothermally modified volcanic systems worldwide