Insulin-like growth factor 1 rescues R28 retinal neurons from apoptotic death through ERK-mediated BimEL phosphorylation independent of Akt.

Insulin-like growth factor 1 (IGF-1) can provide long-term neurotrophic support by activation of Akt, inhibition of FoxO nuclear localization and suppression of Bim gene transcription in multiple neuronal systems. However, MEK/ERK activation can also promote neuron survival through phosphorylation of BimEL. We explored the contribution of the PI3K/Akt/FoxO and MEK/ERK/BimEL pathways in IGF-1 stimulated survival after serum deprivation (SD) of R28 cells differentiated to model retinal neurons.

Prolactin protects retinal pigment epithelium by inhibiting sirtuin 2-dependent cell death.

The identification of pathways necessary for retinal pigment epithelium (RPE) function is fundamental to uncover therapies for blindness. Prolactin (PRL) receptors are expressed in the retina, but nothing is known about the role of PRL in RPE. Using the adult RPE 19 (ARPE-19) human cell line and mouse RPE, we identified the presence of PRL receptors and demonstrated that PRL is necessary for RPE cell survival via anti-apoptotic and antioxidant actions.

Isotopic Evidence for Early Trade in Animals between Old Kingdom Egypt and Canaan.

Isotope data from a sacrificial ass and several ovicaprines (sheep/goat) from Early Bronze Age household deposits at Tell es-Safi/Gath, Israel provide direct evidence for the movement of domestic draught/draft and husbandry animals between Old Kingdom Egypt (during the time of the Pyramids) and Early Bronze Age III Canaan (ca. 2900-2500 BCE). Vacillating, bi-directional connections between Egypt and Canaan are known throughout the Early Bronze Age, but here we provide the first concrete evidence of early trade in animals from Egypt to Canaan.

Conformational States of HIV-1 Reverse Transcriptase for Nucleotide Incorporation vs Pyrophosphorolysis-Binding of Foscarnet.

HIV-1 reverse transcriptase (RT) catalytically incorporates individual nucleotides into a viral DNA strand complementing an RNA or DNA template strand; the polymerase active site of RT adopts multiple conformational and structural states while performing this task. The states associated are dNTP binding at the N site, catalytic incorporation of a nucleotide, release of a pyrophosphate, and translocation of the primer 3'-end to the P site. Structural characterization of each of these states may help in understanding the molecular mechanisms of drug activity and resistance and in developing new RT inhibitors.

Social networks and social support among ball-attending African American men who have sex with men and transgender women are associated with HIV-related outcomes.

The House Ball Community (HBC) is an understudied network of African American men who have sex with men and transgender women, who join family-like houses that compete in elaborate balls in cities across the United States. From 2011 to 2012, we surveyed 274 recent attendees of balls in the San Francisco Bay Area, focusing on social networks, social support, and HIV-related behaviours. Participants with a high percentage of alters who were supportive of HIV testing were significantly more likely to have tested in the past six months (p = .

'I am not a man': Trans-specific barriers and facilitators to PrEP acceptability among transgender women.

The frequent conflation of transgender ('trans') women with 'men who have sex with men (MSM)' in HIV prevention obscures trans women's unique gender identities, social and behavioural vulnerabilities, and their disproportionately high rates of HIV infection. Pre-exposure prophylaxis (PrEP) is an efficacious biomedical HIV prevention approach. However, trans women are underrepresented in PrEP research, and are often aggregated with MSM without consideration for their unique positions within sociocultural contexts.

Convergence Insufficiency Treatment Trial - Attention and Reading Trial (CITT-ART): Design and Methods.

Objective: To describe the design and methodology of the Convergence Insufficiency Treatment Trial: Attention and Reading Trial (CITT-ART), the first randomized clinical trial evaluating the effect of vision therapy on reading and attention in school-age children with symptomatic convergence insufficiency (CI).

Methods: CITT-ART is a multicenter, placebo-controlled, randomized clinical trial of 324 children ages 9 to 14 years in grades 3 to 8 with symptomatic CI. Participants are randomized to 16 weeks of office-based vergence/accommodative therapy (OBVAT) or placebo therapy (OBPT), both supplemented with home therapy.

Rapid experimental SAD phasing and hot-spot identification with halogenated fragments.

Through X-ray crystallographic fragment screening, 4-bromopyrazole was discovered to be a 'magic bullet' that is capable of binding at many of the ligand 'hot spots' found in HIV-1 reverse transcriptase (RT). The binding locations can be in pockets that are 'hidden' in the unliganded crystal form, allowing rapid identification of these sites for in silico screening. In addition to hot-spot identification, this ubiquitous yet specific binding provides an avenue for X-ray crystallographic phase determination, which can be a significant bottleneck in the determination of the structures of novel proteins.

ACR Appropriateness Criteria Osteonecrosis of the Hip.

Osteonecrosis of the hip (Legg-Calvé-Perthes) is a common disease, with 10,000-20,000 symptomatic cases annually in the United States. The disorder affects both adults and children and is most frequently associated with trauma and corticosteroid usage. The initial imaging evaluation of suspected hip osteonecrosis is done using radiography.

Exploring the role of the α-carboxyphosphonate moiety in the HIV-RT activity of α-carboxy nucleoside phosphonates.

As α-carboxy nucleoside phosphonates (α-CNPs) have demonstrated a novel mode of action of HIV-1 reverse transcriptase inhibition, structurally related derivatives were synthesized, namely the malonate 2, the unsaturated and saturated bisphosphonates 3 and 4, respectively and the amide 5. These compounds were evaluated for inhibition of HIV-1 reverse transcriptase in cell-free assays. The importance of the α-carboxy phosphonoacetic acid moiety for achieving reverse transcriptase inhibition, without the need for prior phosphorylation, was confirmed.

CNS uptake of bortezomib is enhanced by P-glycoprotein inhibition: implications for spinal muscular atrophy.

The development of therapeutics for neurological disorders is constrained by limited access to the central nervous system (CNS). ATP-binding cassette (ABC) transporters, particularly P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), are expressed on the luminal surface of capillaries in the CNS and transport drugs out of the endothelium back into the blood against the concentration gradient. Survival motor neuron (SMN) protein, which is deficient in spinal muscular atrophy (SMA), is a target of the ubiquitin proteasome system.

Performance of an ICD algorithm to detect lead noise and reduce inappropriate shocks.

Background: Implantable cardioverter-defibrillators (ICD) provide treatment for life-threatening ventricular tachyarrhythmias. Failure of the pace/sense conductor of an ICD lead can cause noise on the sensing electrogram (EGM) that may be misinterpreted as ventricular activity, triggering inappropriate therapy. An algorithm based upon the confirmation of ventricular activity from a far-field EGM has been developed to reduce inappropriate therapies resulting from this type of lead failure, while ensuring that appropriate therapy is delivered.

Can Emotional and Behavioral Dysregulation in Youth Be Decoded from Functional Neuroimaging?

Introduction: High comorbidity among pediatric disorders characterized by behavioral and emotional dysregulation poses problems for diagnosis and treatment, and suggests that these disorders may be better conceptualized as dimensions of abnormal behaviors. Furthermore, identifying neuroimaging biomarkers related to dimensional measures of behavior may provide targets to guide individualized treatment. We aimed to use functional neuroimaging and pattern regression techniques to determine whether patterns of brain activity could accurately decode individual-level severity on a dimensional scale measuring behavioural and emotional dysregulation at two different time points.

The Development of a Counseling-Based HIV Prevention Intervention for African American Men Who Have Sex With Men and Women: The Bruthas Project.

African American men who have sex with both men and women (AAMSMW) are at high risk for acquiring and transmitting HIV, yet few interventions exist to address their unique prevention needs. We conducted 3 focus groups, 21 in-depth interviews, and a pilot test of our intervention with = 61 AAMSMW, which showed significant reductions in sexual risk behavior after 6 months. The intervention is currently being tested in a randomized controlled trial (RCT).

Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1.

Adeno-associated virus (AAV) vector-mediated delivery of inhibitors of blood-retinal barrier breakdown (BRBB) offers promise for the treatment of diabetic macular edema. Here, we demonstrated a reversal of blood-retinal barrier pathology mediated by AAV type 2 (AAV2) vectors encoding vasoinhibin or soluble VEGF receptor 1 (sFlt-1) when administered intravitreally to diabetic rats. Efficacy and safety of the AAV2 vasoinhibin vector were tested by monitoring its effect on diabetes-induced changes in the retinal vascular bed and thickness, and in the electroretinogram (ERG).

Factors influencing the efficacy of rilpivirine in HIV-1 subtype C in low- and middle-income countries.

Objectives: The use of the NNRTI rilpivirine in low- and middle-income countries (LMICs) is under debate. The main objective of this study was to provide further clinical insights and biochemical evidence on the usefulness of rilpivirine in LMICs.

Patients And Methods: Rilpivirine resistance was assessed in 5340 therapy-naive and 13,750 first-generation NNRTI-failed patients from Europe and therapy-naive HIV-1 subtype C (HIV-1C)-infected individuals from India (n = 617) and Ethiopia (n = 127).

Physical appearance comparisons in ethnically diverse college women.

Research demonstrates ethnic differences in rates of body dissatisfaction and disordered eating. Appearance comparison frequency is related to these outcomes, however, research has not examined possible ethnic differences in levels of appearance comparisons nor their relation to body dissatisfaction and disordered eating. The current study examined the frequency of appearance comparisons and the strength of the relationships between appearance comparisons, appearance evaluation, and disordered eating among White, Black, and Hispanic women.

Pronounced Inhibition Shift from HIV Reverse Transcriptase to Herpetic DNA Polymerases by Increasing the Flexibility of α-Carboxy Nucleoside Phosphonates.

Alpha-carboxynucleoside phosphonates (α-CNPs) are novel viral DNA polymerase inhibitors that do not need metabolic conversion for enzyme inhibition. The prototype contains a cyclopentyl linker between nucleobase and α-carboxyphosphonate and preferentially (50- to 100-fold) inhibits HIV-1 RT compared with herpetic DNA polymerases. A synthesis methodology involving three steps has been developed for the synthesis of a series of novel α-CNPs, including a Rh(II)-catalyzed O-H insertion that connects the carboxyphosphonate group to a linker moiety and an attachment of a nucleobase to the other end of the linker by a Mitsunobu reaction followed by final deprotection.

Drug use and emotional distress differentiate unstably- versus stably-housed adults living with HIV who engage in unprotected sex.

Among adults living with HIV, unstable housing is a barrier to health. Stably- and unstably-housed adults living with HIV were assessed for over 25 months. At baseline, unstably-housed adults living with HIV had a more recent HIV diagnosis, higher viral loads, worse physical and mental health, lower rates of antiretroviral therapy use and insurance coverage, and higher rates of hard drug use than stably-housed adults living with HIV.

Analysis of the Zidovudine Resistance Mutations T215Y, M41L, and L210W in HIV-1 Reverse Transcriptase.

Although anti-human immunodeficiency virus type 1 (HIV-1) therapies have become more sophisticated and more effective, drug resistance continues to be a major problem. Zidovudine (azidothymidine; AZT) was the first nucleoside reverse transcriptase (RT) inhibitor (NRTI) approved for the treatment of HIV-1 infections and is still being used, particularly in the developing world. This drug targets the conversion of single-stranded RNA to double-stranded DNA by HIV-1 RT.

Structure of HIV-1 reverse transcriptase bound to a novel 38-mer hairpin template-primer DNA aptamer.

The development of a modified DNA aptamer that binds HIV-1 reverse transcriptase (RT) with ultra-high affinity has enabled the X-ray structure determination of an HIV-1 RT-DNA complex to 2.3 Å resolution without the need for an antibody Fab fragment or RT-DNA cross-linking. The 38-mer hairpin-DNA aptamer has a 15 base-pair duplex, a three-deoxythymidine hairpin loop, and a five-nucleotide 5'-overhang.

Inhibition of Cytosolic Phospholipase A2α (cPLA2α) by Medicinal Plants in Relation to Their Phenolic Content.

The cytosolic phospholipase A2α(cPLA2α) is one of the potential targets for anti-inflammatory drugs, since this enzyme plays a key role in the inflammation processes seen in health disorders, like asthma, allergic reactions, arthritis and neuronal diseases. In this study, cPLA2α inhibition by 43 methanol extracts from medicinal plants rich in polyphenols was determined. The eight most active extracts were derived from Ribes nigrum (IC50 of 27.

Workforce and Leader Development: Learning From the Baldrige Winners in Health Care.

It is ironic that perhaps the only constant in health care organizations today is change. To compete successfully in health care and position an organization for high performance amid continuous change, it is very important for managers to have knowledge of the best learning and development practices of high-performing organizations in their industry. The rapid increases in the rate of technological change and geometric increases in knowledge make it virtually imperative that human resources are developed effectively.