Distinct Antiretroviral Mechanisms Elicited by a Viral Mutagen.

5-aza-cytidine (5-aza-C) has been shown to be a potent human immunodeficiency virus type 1 (HIV-1) mutagen that induces G-to-C hypermutagenesis by incorporation of the reduced form (i.e., 5-aza-dC, 5-aza-dCTP).

RNA sequencing of whole blood in dogs with primary immune-mediated hemolytic anemia (IMHA) reveals novel insights into disease pathogenesis.

Immune-mediated hemolytic anemia (IMHA) is a life-threatening autoimmune disorder characterized by a self-mediated attack on circulating red blood cells. The disease occurs naturally in both dogs and humans, but is significantly more prevalent in dogs. Because of its shared features across species, dogs offer a naturally occurring model for studying IMHA in people.

Single-Strand Consensus Sequencing Reveals that HIV Type but not Subtype Significantly Impacts Viral Mutation Frequencies and Spectra.

A long-standing question of human immunodeficiency virus (HIV) genetic variation and evolution has been whether differences exist in mutation rate and/or mutation spectra among HIV types (i.e., HIV-1 versus HIV-2) and among HIV groups (i.

Synergistic reduction of HIV-1 infectivity by 5-azacytidine and inhibitors of ribonucleotide reductase.

Although many compounds have been approved for the treatment of human immunodeficiency type-1 (HIV-1) infection, additional anti-HIV-1 drugs (particularly those belonging to new drug classes) are still needed due to issues such as long-term drug-associated toxicities, transmission of drug-resistant variants, and development of multi-class resistance. Lethal mutagenesis represents an antiviral strategy that has not yet been clinically translated for HIV-1 and is based on the use of small molecules to induce excessive levels of deleterious mutations within the viral genome. Here, we show that 5-azacytidine (5-aza-C), a ribonucleoside analog that induces the lethal mutagenesis of HIV-1, and multiple inhibitors of the enzyme ribonucleotide reductase (RNR) interact in a synergistic fashion to more effectively reduce the infectivity of HIV-1.

Dual anti-HIV mechanism of clofarabine.

Background: HIV-1 replication kinetics inherently depends on the availability of cellular dNTPs for viral DNA synthesis. In activated CD4(+) T cells and other rapidly dividing cells, the concentrations of dNTPs are high and HIV-1 reverse transcription occurs in an efficient manner. In contrast, nondividing cells such as macrophages have lower dNTP pools, which restricts efficient reverse transcription.

Expansion Thoracoplasty for Thoracic Insufficiency Syndrome Associated with Jarcho-Levin Syndrome.

Introduction: Although surgical treatment of spondylothoracic dysplasia (STD) is controversial, we have found that an expansion thoracoplasty using a Vertical Expandable Prosthetic Titanium Rib (VEPTR; DePuy Synthes) results in favorable outcomes, including 100% survivability (at an average follow-up of 6.2 years), increased thoracic spinal length, and decreased requirements for ventilation support.

Step 1 Preoperative Preparation: Make anteroposterior and lateral radiographs of the spine.

Management of Thoracic Insufficiency Syndrome in Patients With Jeune Syndrome Using the 70 mm Radius Vertical Expandable Prosthetic Titanium Rib.

Background: Jeune syndrome (JS) often results in lethal thoracic insufficiency syndrome. Since 1991, vertical expandable prosthetic titanium rib Dynamic PosteroLateral Expansion Thoracoplasty was used at our institution for treatment of JS. This study assesses the safety and efficacy of this procedure.

Management of thoracic insufficiency syndrome in patients with Jarcho-Levin syndrome using VEPTRs (vertical expandable prosthetic titanium ribs).

Background: Jarcho-Levin syndrome represents a spectrum of clinical and radiographic irregularities including abnormal vertebral segmentation or formation defects, rib deformities, and short-trunk dwarfism. These abnormalities cause reduced thoracic capacity for lung development, resulting in thoracic insufficiency syndrome. In the present study, we reviewed outcome measures related to scoliotic curve correction, thoracic growth, and respiratory function following VEPTR treatment in patients with Jarcho-Levin syndrome.

Rapid genetic modification of mouse embryonic stem cells by Inducible Cassette Exchange recombination.

Embryonic stem cell (ESC) differentiation is a useful means by which to produce large quantities of cells in vitro representing early stages of embryonic development. A conditional gene expression system allows interrogation of factors at specific time points in the differentiation of ES cells to defined cell types. We have developed a method for rapidly generating conditional inducible murine ES cells by targeting genes into an Inducible Cassette Exchange (ICE) locus.

Effects of chronic plus acute prolonged stress on measures of coping style, anxiety, and evoked HPA-axis reactivity.

Exposure to psychological trauma is the precipitating factor for PTSD. In addition, a history of chronic or traumatic stress exposure is a predisposing risk factor. We have developed a Chronic plus Acute Prolonged Stress (CAPS) treatment for rats that models some of the characteristics of stressful events that can lead to PTSD in humans.

CCR7/CCL19 controls expression of EDG-1 in T cells.

T lymphocytes circulate between the blood, tissues, and lymph. These T cells carry out immune functions, using the C-C chemokine receptor 7 (CCR7) and its cognate ligands, CCL19 and CCL21, to enter and travel through the lymph nodes. Distinct roles for each ligand in regulating T lymphocyte trafficking have remained elusive.

OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies.

The human organic anion and cation transporters are classified within two SLC superfamilies. Superfamily SLCO (formerly SLC21A) consists of organic anion transporting polypeptides (OATPs), while the organic anion transporters (OATs) and the organic cation transporters (OCTs) are classified in the SLC22A superfamily. Individual members of each superfamily are expressed in essentially every epithelium throughout the body, where they play a significant role in drug absorption, distribution and elimination.

The expression and function of organic anion transporting polypeptides in normal tissues and in cancer.

Organic anion transporting polypeptides (OATPs) are members of the SLCO gene superfamily of proteins. The 11 human OATPs are classified into 6 families and subfamilies on the basis of their amino acid sequence similarities. OATPs are expressed in several epithelial tissues throughout the body and transport mainly amphipathic molecules with molecular weights of more than 300 kDa.

Isolation of modulators of the liver-specific organic anion-transporting polypeptides (OATPs) 1B1 and 1B3 from Rollinia emarginata Schlecht (Annonaceae).

Organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3) are liver-specific transporters that mediate the uptake of a broad range of drugs into hepatocytes, including statins, antibiotics, and many anticancer drugs. Compounds that alter transport by one or both of these OATPs could potentially be used to target drugs to hepatocytes or improve the bioavailability of drugs that are cleared by the liver. In this study, we applied a bioassay-guided isolation approach to identify such compounds from the organic extract of Rollinia emarginata Schlecht (Annonaceae).

Interactions of green tea catechins with organic anion-transporting polypeptides.

Organic anion-transporting polypeptides (OATPs) are multispecific transporters that mediate the uptake of numerous drugs and xenobiotics into cells. Here, we examined the effect of green tea (Camellia sinensis) catechins on the function of the four OATPs expressed in human enterocytes and hepatocytes. Uptake of the model substrate estrone-3-sulfate by cells expressing OATP1A2, OATP1B1, OATP1B3, or OATP2B1 was measured in the absence and presence of the four most abundant flavonols found in green tea.

Mechanism of polybrominated diphenyl ether uptake into the liver: PBDE congeners are substrates of human hepatic OATP transporters.

Polybrominated diphenyl ethers (PBDEs) are flame-retardants that upon chronic exposure enter the liver where they are biotransformed to potentially toxic metabolites. The mechanism by which PBDEs enter the liver is not known. However, due to their large molecular weights (MWs approximately 485 to 1000 Da), they cannot enter hepatocytes by simple diffusion.

Farnesoid X receptor deficiency in mice leads to increased intestinal epithelial cell proliferation and tumor development.

Increased dietary fat consumption is associated with colon cancer development. The exact mechanism by which fat induces colon cancer is not clear, however, increased bile acid excretion in response to high-fat diet may promote colon carcinogenesis. The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily, and bile acids are endogenous ligands of FXR.

Effects of gender and menstrual cycle phase on food-maintained responding under a progressive-ratio schedule in cynomolgus monkeys.

Clinical and preclinical data suggest that fluctuations in ovarian steroid hormones across the menstrual/estrous cycle influence spontaneous feeding behavior in females. The effects of gender, menstrual cycle phase, and ovarian hormone fluctuations on food-maintained responding under a progressive-ratio schedule were investigated in four female and three male cynomolgus monkeys. Females were studied across 21 menstrual cycles, and ovulatory cycles were defined by analysis of ovarian steroid hormone levels.

Effect of short- vs. long-term estrogen on reinstatement of cocaine-seeking behavior in female rats.

Estrogen effects on cocaine-induced reinstatement of lever responding were examined in sham-operated, vehicle-treated (SH+VEH), ovariectomized (OVX+VEH), and OVX female Wistar rats with estrogen replacement (OVX+EB). The effect of long- (64+/-1.56 days) and short-term (9 days) EB treatment on reinstatement of cocaine-seeking behavior was compared in Experiment 1 and 2, respectively, in order to compare the effect of EB when it was present during the development vs.

Sex differences in the vulnerability to drug abuse: a review of preclinical studies.

Clinical and preclinical findings indicate that males and females differ on several aspects of drug reinforcement. Females are more vulnerable than males during transition periods of drug use that are characteristic of drug addiction and relapse. Females are also more sensitive than males to the reinforcing effects of stimulants.

Sex differences in the escalation of intravenous cocaine intake following long- or short-access to cocaine self-administration.

Preclinical data have indicated that extended access to cocaine self-administration (e.g., 6-12 h/day) facilitates an escalation in daily cocaine intake that is not seen when rats are given shorter (e.

The effects of cocaine on gonadal steroid hormones and LH in male and female rhesus monkeys.

Cocaine stimulates significant increases in estradiol, testosterone (T), and luteinizing hormone (LH) in rhesus monkeys, but the temporal interactions between the gonadal steroid hormones and LH have not been determined. The effects of i.v.