Autocrine regulation of cell cycle progression in normal human keratinocytes

Summary Removal of competence factors insulin and pituitary extract from the culture medium, concomitant with the addition of picomolar concentrations of the late-G₁ inhibitor transforming growth factor-beta, effectively arrested cell cycle progression of normal human keratinocytes prior to their entry into the DNA synthesis phase; arrest continued for a minimum of 36 h following removal of unbound inhibitor and subsequent addition of factor-deficient medium. To demonstrate the reversibility of transforming growth factor-beta-induced arrest, two dissimilar cell populations were recruited to synthesize DNA in a predictable and reproducible manner; whereas the reinstatement of omitted competence factors induced noncycling cells to begin synthesizing DNA within 24 h, addition of keratinocyte-conditioned medium prompted an immediate progression of late-G₁ cells into S phase. Studies to determine the extent that autocrine signaling regulates cell cycle progression revealed that nontransformed keratinocytes produce an endogenous factor required for DNA replication and that production of this progression factor required competence factors insulin and pituitary extract. Keratinocyte progression factor recruited late-G₁ cells into S phase within 1–2 h, reversed transforming growth factor-beta-induced arrest in the presence of bound inhibitor, and elicited a calcium mobilization response consistent with receptor-mediated signaling. Hence, these studies demonstrate that G₁ progression of nontransformed keratinocytes into S phase requires an endogenous progression factor and suggest that this factor may direct G₁ progression by modulating the activity of a calcium-dependent kinase.     

Association Between Adult Attention Deficit/Hyperactivity Disorder and Obesity in the US Population

Attention deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder that affects ～2.9–4.7% of US adults. Studies have revealed high rates of ADHD (26–61%) in patients seeking weight loss treatment suggesting an association between ADHD and obesity. The objective of the present study was to test the association between ADHD and overweight and obesity in the US population. Cross‐sectional data from the Collaborative Psychiatric Epidemiology Surveys were used. Participants were 6,735 US residents (63.9% white; 51.6% female) aged 18–44 years. A retrospective assessment of childhood ADHD and a self‐report assessment of adult ADHD were administered. Diagnosis was defined by three categories: never met diagnostic criteria, met full childhood criteria with no current symptoms, and met full childhood criteria with current symptoms. The prevalence of overweight and obesity was 33.9 and 29.4%, respectively, among adults with ADHD, and 28.8 and 21.6%, respectively, among persons with no history of ADHD. Adult ADHD was associated with greater likelihood of overweight, (odds ratio (OR) = 1.58; 95% confidence interval (CI) = 1.05, 2.38) and obesity (OR = 1.81; 95% CI = 1.14, 2.64). Results were similar when adjusting for demographic characteristics and depression. Mediation analyses suggest that binge eating disorder (BED), but not depression, partially mediates the associations between ADHD and both overweight and obesity. Results suggest that adult ADHD is associated with overweight and obesity.     

Fishers' knowledge and seahorse conservation in Brazil

From a conservationist perspective, seahorses are threatened fishes. Concomitantly, from a socioeconomic perspective, they represent a source of income to many fishing communities in developing countries. An integration between these two views requires, among other things, the recognition that seahorse fishers have knowledge and abilities that can assist the implementation of conservation strategies and of management plans for seahorses and their habitats. This paper documents the knowledge held by Brazilian fishers on the biology and ecology of the longsnout seahorse Hippocampus reidi. Its aims were to explore collaborative approaches to seahorse conservation and management in Brazil; to assess fishers' perception of seahorse biology and ecology, in the context evaluating potential management options; to increase fishers' involvement with seahorse conservation in Brazil. Data were obtained through questionnaires and interviews made during field surveys conducted in fishing villages located in the States of Piauí, Ceará, Paraíba, Maranhão, Pernambuco and Pará. We consider the following aspects as positive for the conservation of seahorses and their habitats in Brazil: fishers were willing to dialogue with researchers; although captures and/or trade of brooding seahorses occurred, most interviewees recognized the importance of reproduction to the maintenance of seahorses in the wild (and therefore of their source of income), and expressed concern over population declines; fishers associated the presence of a ventral pouch with reproduction in seahorses (regardless of them knowing which sex bears the pouch), and this may facilitate the construction of collaborative management options designed to eliminate captures of brooding specimens; fishers recognized microhabitats of importance to the maintenance of seahorse wild populations; fishers who kept seahorses in captivity tended to recognize the condtions as poor, and as being a cause of seahorse mortality.     

Science – A life fully lived: Joe Sodroski wins the 2006 Retrovirology Prize

The 2006 M Jeang Retrovirology Prize for HIV research has been awarded to Dr Joe Sodroski     

Measuring Antimicrobial Activity Against Biofilm Bacteria

Standardization of methodology and interpretation has proved essential to scientific progress in studies of the activity of antimicrobial agents against planktonic bacteria. Current studies of antimicrobial activity against biofilm bacteria lack standardization of methodology. The principles applied to standardization of methods for planktonic bacteria can serve as a template in developing standards for studying biofilm bacteria. Such standards are essential to allow meaningful comparison between published studies.     

Preclinical and early clinical development of GNbAC1, a humanized IgG4 monoclonal antibody targeting endogenous retroviral MSRV-Env protein

Monoclonal antibodies (mAbs) play an increasing important role in the therapeutic armamentarium against multiple sclerosis (MS), an inflammatory and degenerative disorder of the central nervous system. Most of the mAbs currently developed for MS are immunomodulators blocking the inflammatory immune process. In contrast with mAbs targeting immune function, GNbAC1, a humanized IgG4 mAb, targets the multiple sclerosis associated retrovirus envelope (MSRV-Env) protein, an upstream factor in the pathophysiology of MS. MSRV-Env protein is of endogenous retroviral origin, expressed in MS brain lesions, and it is pro-inflammatory and toxic to the remyelination process, by preventing the differentiation of oligodendrocyte precursor cells. We present the preclinical and early clinical development results of GNbAC1. The specificity of GNbAC1 for its endogenous retroviral target is described. Efficacy of different mAb versions of GNbAC1 were assessed in MSRV-Env induced experimental allergic encephalitis (EAE), an animal model of MS. Because the target MSRV-Env is not expressed in animals, no relevant animal model exists for a proper in vivo toxicological program. An off-target 2-week toxicity study in mice was thus performed, and it showed an absence of safety risk. Additional in vitro analyses showed an absence of complement or antibody-dependent cytotoxicity as well as a low level of cross-reactivity to human tissues. The first-in-man clinical study in 33 healthy subjects and a long-term clinical study in 10 MS patients showed that GNbAC1 is well tolerated in humans without induction of immunogenicity and that it induces a pharmacodynamic response on MSRV biomarkers. These initial results suggest that the mAb GNbAC1 could be a safe long-term treatment for patients with MS with a unique therapeutic mechanism of action.