Exploring structure-function relationships in engineered receptor performance using computational structure prediction.

Engineered receptors play increasingly important roles in transformative cell-based therapies. However, the structural mechanisms that drive differences in performance across receptor designs are often poorly understood. Recent advances in protein structural prediction tools have enabled the modeling of virtually any user-defined protein, but how these tools might build understanding of engineered receptors has yet to be fully explored.

Enhancing extracellular vesicle cargo loading and functional delivery by engineering protein-lipid interactions.

Naturally generated lipid nanoparticles termed extracellular vesicles (EVs) hold significant promise as engineerable therapeutic delivery vehicles. However, active loading of protein cargo into EVs in a manner that is useful for delivery remains a challenge. Here, we demonstrate that by rationally designing proteins to traffic to the plasma membrane and associate with lipid rafts, we can enhance loading of protein cargo into EVs for a set of structurally diverse transmembrane and peripheral membrane proteins.

The sound of silence: Transgene silencing in mammalian cell engineering.

To elucidate principles operating in native biological systems and to develop novel biotechnologies, synthetic biology aims to build and integrate synthetic gene circuits within native transcriptional networks. The utility of synthetic gene circuits for cell engineering relies on the ability to control the expression of all constituent transgene components. Transgene silencing, defined as the loss of expression over time, persists as an obstacle for engineering primary cells and stem cells with transgenic cargos.

The evolution of synthetic receptor systems.

Receptors enable cells to detect, process and respond to information about their environments. Over the past two decades, synthetic biologists have repurposed physical parts and concepts from natural receptors to engineer synthetic receptors. These technologies implement customized sense-and-respond programs that link a cell's interaction with extracellular and intracellular cues to user-defined responses.

Control of mammalian cell-based devices with genetic programming.

Synthetic biology increasingly enables the construction of sophisticated functions in mammalian cells. A particularly promising frontier combines concepts drawn from industrial process control engineering-which is used to confer and balance properties such as stability and efficiency-with understanding as to how living systems have evolved to perform similar tasks with biological components. In this review, we first survey the state-of-the-art for both technologies and strategies available for genetic programming in mammalian cells.

Responsiveness to perturbations is a hallmark of transcription factors that maintain cell identity in vitro.

Identifying the particular transcription factors that maintain cell type in vitro is important for manipulating cell type. Identifying such transcription factors by their cell-type-specific expression or their involvement in developmental regulation has had limited success. We hypothesized that because cell type is often resilient to perturbations, the transcriptional response to perturbations would reveal identity-maintaining transcription factors.

Primary nasal Kaposi Sarcoma in well-controlled HIV-positive patient with normal CD4 count associated with long-term nasal steroid use.

Kaposi sarcoma (KS) is an angioproliferative disease that is caused by human herpesvirus 8. The epidemic form of KS is associated with acquired immunodeficiency syndrome (AIDS) and is common in HIV-positive patients with CD4 counts less than 200 cells/mm. We present the case of a 63-year-old man with well-controlled HIV and normal CD4 count developing atypical nasal KS associated with intranasal steroid use.

Elucidation and refinement of synthetic receptor mechanisms.

Synthetic receptors are powerful tools for engineering mammalian cell-based devices. These biosensors enable cell-based therapies to perform complex tasks such as regulating therapeutic gene expression in response to sensing physiological cues. Although multiple synthetic receptor systems now exist, many aspects of receptor performance are poorly understood.

The COMET toolkit for composing customizable genetic programs in mammalian cells.

Engineering mammalian cells to carry out sophisticated and customizable genetic programs requires a toolkit of multiple orthogonal and well-characterized transcription factors (TFs). To address this need, we develop the COmposable Mammalian Elements of Transcription (COMET)-an ensemble of TFs and promoters that enable the design and tuning of gene expression to an extent not, to the best of our knowledge, previously possible. COMET currently comprises 44 activating and 12 inhibitory zinc-finger TFs and 83 cognate promoters, combined in a framework that readily accommodates new parts.

Microphysiological Engineering of Self-Assembled and Perfusable Microvascular Beds for the Production of Vascularized Three-Dimensional Human Microtissues.

The vasculature is an essential component of the circulatory system that plays a vital role in the development, homeostasis, and disease of various organs in the human body. The ability to emulate the architecture and transport function of blood vessels in the integrated context of their associated organs represents an important requirement for studying a wide range of physiological processes. Traditional models of the vasculature, however, largely fail to offer such capabilities.

Similar neurocognitive outcomes after 48 weeks in HIV-1-infected participants randomized to continue tenofovir/emtricitabine + atazanavir/ritonavir or simplify to abacavir/lamivudine + atazanavir.

Human immunodeficiency virus (HIV)-associated neurocognitive disorders can persist in many patients despite achieving viral suppression while on antiretroviral therapy (ART). Neurocognitive function over 48 weeks was evaluated using a Cogstate test battery assessing psychomotor function, attention, learning, and working memory in 293 HIV-1-infected, ART-experienced, and virologically suppressed adults. The ASSURE study randomized participants 1:2 to remain on tenofovir/emtricitabine (TDF/FTC) and ritonavir-boosted atazanavir (ATV/r) or simplify to abacavir/lamivudine + atazanavir (ABC/3TC + ATV).

Bloodstream Infections Caused by Contaminants: Epidemiology and Risk Factors: A 10-Year Surveillance.

Background: Skin colonization of microorganisms in blood cultures (BCs) are generally considered clinically non-significant and can be the source of a true infection, particularly in immunosuppressed patients.

Objectives: To study the epidemiology and risk factors for bacteremia caused by contaminants.

Methods: This retrospective, descriptive study is based on adult BCs collected (2004-2013) and categorized as positive (True bacteremia [TrueB] or contamination) or negative.

Detection of Ureaplasma Species by a Semi-Quantitative PCR Test in Urine Samples: Can It Predict Clinical Significance?

Background: Ureaplasma species (Usp) are the most prevalent genital Mycoplasma isolated from the urogenital tract of both men and women. Usp may be commensals in the genital tract but may also be contributors to a number of pathological conditions of the genital tract. Because they can also just colonize the genital tract of healthy people, their pathogenic role can be difficult to prove.

Lack of MTTP Activity in Pluripotent Stem Cell-Derived Hepatocytes and Cardiomyocytes Abolishes apoB Secretion and Increases Cell Stress.

Abetalipoproteinemia (ABL) is an inherited disorder of lipoprotein metabolism resulting from mutations in microsomal triglyceride transfer protein (MTTP). In addition to expression in the liver and intestine, MTTP is expressed in cardiomyocytes, and cardiomyopathy has been reported in several ABL cases. Using induced pluripotent stem cells (iPSCs) generated from an ABL patient homozygous for a missense mutation (MTTP), we show that human hepatocytes and cardiomyocytes exhibit defects associated with ABL disease, including loss of apolipoprotein B (apoB) secretion and intracellular accumulation of lipids.

Microbiologic Data in Acute Cholecystitis: Ten Years' Experience from Bile Cultures Obtained during Percutaneous Cholecystostomy.

Background: The aim of the study was to describe the microbiology and susceptibility patterns in acute cholecystitis by examining bile culture results from patients who underwent percutaneous cholecystostomy and examine concordance with empiric treatment.

Patients And Methods: A total of 124 patients with acute cholecystitis underwent percutaneous cholecystostomy between 2003 and 2012 at Emek Medical Center, Israel. Data on bile and blood culture results, isolate susceptibility, and clinical outcomes were retrieved from patient files.

Children with medical complexity: a scoping review of interventions to support caregiver stress.

Background: Caring for children with chronic and complex medical needs places extraordinary stress on parents and other family members. A scoping review was undertaken to identify and describe the full range of current interventions for reducing caregiver stress.

Methods: Applying a broad definition of caregiver stress, a systematic search of three scientific databases (CINAHL, Embase and Ovid Medline), a general internet search and hand searching of key peer-reviewed articles were conducted.

Efficacy and Safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate in Asian Subjects with Human Immunodeficiency Virus 1 Infection: A Sub-Analysis of Phase 3 Clinical Trials.

The efficacy and safety of a single tablet regimen (STR) of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) were analyzed in Phase 3 clinical trials in antiretroviral therapy (ART)-naïve and ART-experienced Asian subjects infected with human immunodeficiency virus (HIV)-1. Studies GS-US-236-102 and GS-US-236-103 were randomized, double-blind, placebo-controlled, 144-week studies conducted in ART-naïve subjects, comparing E/C/F/TDF versus efavirenz (EFV)/F/TDF or ritonavir-boosted atazanavir (ATV+RTV) plus emtricitabine/tenofovir DF (F/TDF), respectively. Studies GS-US-236-115 and GS-US-236-121 were randomized, open-label, 96-week long conducted in ART-experienced subjects, who switched to E/C/F/TDF from ritonavir-boosted protease inhibitors (PI+RTV)+F/TDF, or non-nucleoside reverse transcriptase inhibitors (NNRTI)+F/TDF regimens.

Susceptibility of Group A Streptococcus to Antimicrobial Agents in Northern Israel: A Surveillance Study.

Background: Resistant pathogens are an increasing threat affecting millions of people globally. More complicated patients are presented with pathogens harboring new resistance mechanisms, while the pipeline of new antimicrobials hardly proposes solutions. In such a scenario, more severely ill patients remain with no adequate treatment to offer.

The ASSURE study: HIV-1 suppression is maintained with bone and renal biomarker improvement 48 weeks after ritonavir discontinuation and randomized switch to abacavir/lamivudine + atazanavir.

Objectives: HIV treatment guidelines endorse switching or simplification of antiretroviral therapy in therapy-experienced patients with suppressed viraemia; ritonavir discontinuation may also enhance tolerability and reduce long-term adverse events (AEs). This open-label, multicentre, noninferiority study enrolled HIV-1-infected, treatment-experienced adults with confirmed HIV-1 RNA ≤ 75 HIV-1 RNA copies/mL currently receiving tenofovir/emtricitabine + atazanavir/ritonavir (TDF/FTC + ATV/r) for ≥ 6 months with no reported history of virological failure.

Methods: Participants were randomized 1:2 to continue current treatment or switch to abacavir/lamivudine + atazanavir (ABC/3TC + ATV).

Hospitalization Rates and Reasons Among HIV Elite Controllers and Persons With Medically Controlled HIV Infection.

Background: Elite controllers spontaneously suppress human immunodeficiency virus (HIV) viremia but also demonstrate chronic inflammation that may increase risk of comorbid conditions. We compared hospitalization rates and causes among elite controllers to those of immunologically intact persons with medically controlled HIV.

Methods: For adults in care at 11 sites from 2005 to 2011, person-years with CD4 T-cell counts ≥350 cells/mm(2) were categorized as medical control, elite control, low viremia, or high viremia.

Simplification to abacavir/lamivudine + atazanavir maintains viral suppression and improves bone and renal biomarkers in ASSURE, a randomized, open label, non-inferiority trial.

Objective: Simplification of antiretroviral therapy in patients with suppressed viremia may minimize long-term adverse effects. The study's primary objective was to determine whether abacavir/lamivudine + atazanavir (ABC/3TC+ATV) was virologically non-inferior to tenofovir/emtricitabine + atazanavir/ritonavir (TDF/FTC+ATV/r) over 24 weeks in a population of virologically suppressed, HIV-1 infected patients.

Design: This open-label, multicenter, non-inferiority study enrolled antiretroviral experienced, HIV-infected adults currently receiving a regimen of TDF/FTC+ATV/r for ≥ 6 months with no history of virologic failure and whose HIV-1 RNA had been ≤ 75 copies/mL on 2 consecutive measurements including screening.

Providing detailed information about latent tuberculosis and compliance with the PPD test among healthcare workers in Israel: a randomized controlled study.

Background: The compliance of screening for latent tuberculosis (TB) with the tuberculin purified protein derivative (PPD) test is very low among healthcare workers (HCWs) in Israel.

Methods: This randomized controlled study uses the Health Belief Model (HBM) as a conceptual framework to examine whether providing more information about latent TB and the PPD test increases the response rate for PPD screening among HCWs. All candidate HCWs for latent TB screening were randomly allocated to one of the following two invitations to perform the PPD test: regular letter (control group, n=97), and a letter with information about latent TB and the PPD test (intervention group, n=196).

Trends in the burden of infectious disease hospitalizations among the elderly in the last decade.

Background: Infectious disease is a leading cause of hospitalization. We investigated trends in infectious disease hospitalizations among the elderly in the last decade.

Methods: A total of 81,077 hospitalizations of elderly patients between 2001 and 2010 were available on the computerized database of the Ha'emek Medical Center, Israel.

Evaluation of cardiovascular biomarkers in a randomized trial of fosamprenavir/ritonavir vs. efavirenz with abacavir/lamivudine in underrepresented, antiretroviral-naïve, HIV-infected patients (SUPPORT): 96-week results.

Background: Rates of cardiovascular disease are higher among HIV-infected patients as a result of the complex interplay between traditional risk factors, HIV-related inflammatory and immunologic changes, and effects of antiretroviral therapy (ART). This study prospectively evaluated changes in cardiovascular biomarkers in an underrepresented, racially diverse, HIV-1-infected population receiving abacavir/lamivudine as backbone therapy.

Methods: This 96-week, open-label, randomized, multicenter study compared once-daily fosamprenavir/ritonavir 1400/100 mg and efavirenz 600 mg, both with ABC/3TC 600 mg/300 mg, in antiretroviral-naïve, HLA-B*5701-negative adults without major resistance mutations to study drugs.