Atovaquone and ELQ-300 Combination Therapy as a Novel Dual-Site Cytochrome bc1 Inhibition Strategy for Malaria.

Antimalarial combination therapies play a crucial role in preventing the emergence of drug-resistant Plasmodium parasites. Although artemisinin-based combination therapies (ACTs) comprise the majority of these formulations, inhibitors of the mitochondrial cytochrome bc1 complex (cyt bc1) are among the few compounds that are effective for both acute antimalarial treatment and prophylaxis. There are two known sites for inhibition within cyt bc1: atovaquone (ATV) blocks the quinol oxidase (Qo) site of cyt bc1, while some members of the endochin-like quinolone (ELQ) family, including preclinical candidate ELQ-300, inhibit the quinone reductase (Qi) site and retain full potency against ATV-resistant Plasmodium falciparum strains with Qo site mutations.

The effect of flexor digitorum profundus tendon shortening on jersey finger surgical repair: a cadaveric biomechanical study.

Delayed diagnosis of jersey finger injuries often results in retraction of the flexor digitorum profundus tendon. Current practice recommends limiting tendon advancement to 1 cm in delayed repairs. The purpose of this study was to investigate the biomechanical consequences of tendon shortening on the force required to form a fist.

Interaction analysis of the new pooled cohort equations for 10-year atherosclerotic cardiovascular disease risk estimation: a simulation analysis.

Objectives: To evaluate the individual and interacting impacts of the continuous variables (age, total cholesterol (total-C), high-density lipoprotein cholesterol (HDL-C) and systolic blood pressure(BP)) on 10-year atherosclerotic cardiovascular disease (ASCVD) risk and better understand the pattern of predicted 10-year risk with change of each variable using recently published new pooled cohort equations.

Design: Simulation analysis was performed across the whole range of the boundary limits suggested for the continuous variables for groupings based on race and gender in the pooled cohort 10-year risk equations.

Setting: Computer-based simulation analysis.

Subtle changes in endochin-like quinolone structure alter the site of inhibition within the cytochrome bc1 complex of Plasmodium falciparum.

The cytochrome bc1 complex (cyt bc1) is the third component of the mitochondrial electron transport chain and is the target of several potent antimalarial compounds, including the naphthoquinone atovaquone (ATV) and the 4(1H)-quinolone ELQ-300. Mechanistically, cyt bc1 facilitates the transfer of electrons from ubiquinol to cytochrome c and contains both oxidative (Qo) and reductive (Qi) catalytic sites that are amenable to small-molecule inhibition. Although many antimalarial compounds, including ATV, effectively target the Qo site, it has been challenging to design selective Qi site inhibitors with the ability to circumvent clinical ATV resistance, and little is known about how chemical structure contributes to site selectivity within cyt bc1.

HIV-1 envelope glycan moieties modulate HIV-1 transmission.

Unlabelled: The HIV-1 envelope protein (Env) is heavily glycosylated, with approximately 50% of the Env molecular mass being contributed by N-glycans. HIV-1 Env N-glycans shield the protein backbone and have been shown to play key roles in determining Env structure, surface exposure, and, consequently, antigenicity, infectivity, antibody neutralization, and carbohydrate and receptor binding. Studies of HIV-1 glycosylation have focused mainly on the position of glycosylation, rather than the types of glycans.

The value of resident choice during daily care: do staff and families differ?

Allowing long-term care (LTC) residents to make choices about their daily life activities is a central tenet of resident-centered care. This study examined whether staff and family rated care episodes involving choice differently from care episodes not involving choice. Seventeen nurse aide and 15 family participants were shown paired video vignettes of care interactions.

Clinical questions raised by providers in the care of older adults: a prospective observational study.

Objective: To characterise clinical questions raised by providers in the care of complex older adults in order to guide the design of interventions that can help providers answer these questions.

Materials And Methods: To elicit clinical questions, we observed and audio recorded outpatient visits at three healthcare organisations. At the end of each appointment, providers were asked to identify clinical questions raised in the visit.

Vaginal myeloid dendritic cells transmit founder HIV-1.

We report that primary human vaginal dendritic cells (DCs) display a myeloid phenotype and express CD4, CCR5, and CXCR4. Vaginal CD13(+) CD11c(+) DCs rapidly and efficiently bound transmitted/founder (T/F) CCR5-tropic (R5) viruses, transported them through explanted vaginal mucosa, and transmitted them in trans to vaginal and blood lymphocytes. Vaginal myeloid DCs may play a key role in capturing and disseminating T/F R5 HIV-1 in vivo and are candidate "gatekeeper" cells in HIV-1 transmission.

The impact of family visitation on feeding assistance quality in nursing homes.

The purpose of this study was to determine: (a) the frequency of family visitation during mealtime and (b) whether the presence of family during meals had an impact on the quality of feeding assistance care and resident intake. Participants included 74 nursing home residents from two Veterans Affairs (VA) and four community facilities in one geographic region. Mealtime periods in which family was present were compared with mealtime periods when family was not present for the same resident.

Follistatin-like protein 1 regulates chondrocyte proliferation and chondrogenic differentiation of mesenchymal stem cells.

Objectives: Chondrocytes, the only cells in the articular cartilage, play a pivotal role in osteoarthritis (OA) because they are responsible for maintenance of the extracellular matrix (ECM). Follistatin-like protein 1 (FSTL1) is a secreted protein found in mesenchymal stem cells (MSCs) and cartilage but whose function is unclear. FSTL1 has been shown to modify cell growth and survival.

Comparison of anti-endotoxin activity of apoE and apoA mimetic derivatives of a model amphipathic peptide 18A.

Endotoxemia is a major cause of chronic inflammation, and is an important pathogenic factor in the development of metabolic syndrome and atherosclerosis. Human apolipoprotein E (apoE) and apoA-I are protein components of high-density lipoprotein, which have strong anti-endotoxin activity. Here, we compared anti-endotoxin activity of Ac-hE18A-NH2 and 4F peptides, modified from model amphipathic helical 18A peptide, to mimic, respectively, apoE and apoA-I properties.

MyD88 mediates the decision to die by apoptosis or necroptosis after UV irradiation.

UV irradiation-induced cellular damage is classically associated with apoptosis and is known to result in systemic immunosuppression. How the decision to undergo apoptosis is made following UV is not fully understood. We hypothesize that a central mediator of TLR signaling, MyD88, determines cell fate after UV exposure.

Genomic loci and candidate genes underlying inflammatory nociception.

Heritable genetic factors contribute significantly to inflammatory nociception. To determine candidate genes underlying inflammatory nociception, the current study used a mouse model of abdominal inflammatory pain. BXD recombinant inbred (RI) mouse strains were administered the intraperitoneal acetic acid test, and genome-wide quantitative trait locus (QTL) mapping was performed on the mean number of abdominal contraction and extension movements in 3 distinct groups of BXD RI mouse strains in 2 separate experiments.

Efficacy of systemic morphine suggests a fundamental difference in the mechanisms that generate bone cancer vs inflammatory pain.

Pain is the cancer related event that is most disruptive to the cancer patient's quality of life. Although bone cancer pain is one of the most severe and common of the chronic pains that accompany breast, prostate and lung cancers, relatively little is known about the mechanisms that generate and maintain this pain. Recently, we developed a mouse model of bone cancer pain and 16 days following tumor implantation into the intramedullary space of the femur, significant bone destruction and bone cancer pain-related behaviors were observed.