Where have all the antibiotic patents gone?

Patent and regulatory hurdles combined with low returns on investment are stifling antibiotic R&D in the pharmaceutical industry.     

Where have all the interactions gone? Estimating the coverage of two-hybrid protein interaction maps

Yeast two-hybrid screens are an important method for mapping pairwise physical interactions between proteins. The fraction of interactions detected in independent screens can be very small, and an outstanding challenge is to determine the reason for the low overlap. Low overlap can arise from either a high false-discovery rate (interaction sets have low overlap because each set is contaminated by a large number of stochastic false-positive interactions) or a high false-negative rate (interaction sets have low overlap because each misses many true interactions). We extend capture-recapture theory to provide the first unified model for false-positive and false-negative rates for two-hybrid screens. Analysis of yeast, worm, and fly data indicates that 25% to 45% of the reported interactions are likely false positives. Membrane proteins have higher false-discovery rates on average, and signal transduction proteins have lower rates. The overall false-negative rate ranges from 75% for worm to 90% for fly, which arises from a roughly 50% false-negative rate due to statistical undersampling and a 55% to 85% false-negative rate due to proteins that appear to be systematically lost from the assays. Finally, statistical model selection conclusively rejects the Erd?s-Rényi network model in favor of the power law model for yeast and the truncated power law for worm and fly degree distributions. Much as genome sequencing coverage estimates were essential for planning the human genome sequencing project, the coverage estimates developed here will be valuable for guiding future proteomic screens. All software and datasets are available in and , -, and -, and are also available from our Web site, http://www.baderzone.org.     

Venus: Where has all the water gone?

Conditions on the surface of venus are reviewed and evidence for the existence of a hydrosphere assessed. Escape mechanisms are examined and found to be insufficient to explain the presumed absence of liquid water on venus. The consequences of a hot, acidic hydrosphere are explored as is marginal evidence for biological activity.Supported by research grants from National Aeronautics and Space Administration NGR 012-001-042, the Life Insurance Medical Research Foundation, and the University of Hawaii.     

Where have all the tadpoles gone? Individual genetic tracking of amphibian larvae until adulthood

Reliably marking larvae and reidentifying them after metamorphosis is a challenge that has hampered studies on recruitment, dispersal, migration and survivorship of amphibians for a long time, as conventional tags are not reliably retained through metamorphosis. Molecular methods allow unique genetic fingerprints to be established for individuals. Although microsatellite markers have successfully been applied in mark–recapture studies on several animal species, they have never been previously used in amphibians to follow individuals across different life cycle stages. Here, we evaluate microsatellites for genetic across‐stages mark–recapture studies in amphibians and test the suitability of available software packages for genotype matching. We sampled tadpoles of the dendrobatid frog Allobates femoralis, which we introduced on a river island in the Nature Reserve ‘Les Nouragues’ in French Guiana. In two subsequent recapture sessions, we searched for surviving juveniles and adults, respectively. All individuals were genotyped at 14 highly variable microsatellite loci, which yielded unique genetic fingerprints for all individuals. We found large differences in the identification success of the programs tested. The pairwise‐relatedness‐based approach, conducted with the programs kingroup or ML‐Relate, performed best with our data set. Matching ventral patterns of juveniles and adult individuals acted as a control for the reliability of the genetic identification. Our results demonstrate that microsatellite markers are a highly powerful tool for studying amphibian populations on an individual basis. The ability to individually track amphibian tadpoles throughout metamorphosis until adulthood will be of substantial value for future studies on amphibian population ecology and evolution.     

Where have all the Na+ channels gone? In search of functional ENaC in exocrine pancreas

Many epithelia express specific Na(+) channels (ENaC) together with the cystic fibrosis regulator (CFTR) Cl(-) channels. Pancreatic ducts secrete HCO(3)(-)-rich fluid and express CFTR. However, the question whether they possess ENaC has not been consistently addressed. The aim of the present study was to investigate if pancreatic ducts express functional ENaC. Membrane voltages (V) of ducts isolated from rat pancreas were measured with microelectrodes or whole-cell patch-clamp technique. Amiloride and benzamil given from bath or luminal sides did not hyperpolarize V. Lowering of extracellular Na(+) concentrations had effects that were not consistent with a simple Na(+) conductance, but rather with a Na(+)/Ca(2+) exchange. Acute or long-lasting treatment of pancreatic ducts with mineralocorticoids had no effect on V of unstimulated or secretin-stimulated preparations. Furthermore, pre-treatment of animals with glucocorticoids had no effect on pancreatic fluid secretion evoked from ducts, or from acini. Hence, our study shows that pancreas especially pancreatic ducts do not express functional ENaC.     

Where have all the fathers gone? An extensive microsatellite analysis of paternity in the grey seal (Halichoerus grypus)

Microsatellites were used to conduct an extensive analysis of paternity of grey seals from two Scottish breeding colonies at North Rona (n = 1189) and the Isle of May (n = 694), spanning more than a decade. A maximum of 46% of pups at North Rona and 29% of pups at the Isle of May could be allocated a father, even though the majority of candidate males for specific study sites within each colony were believed to have been sampled. Based on the paternities which could be assigned, both colonies showed evidence of reproductive skew, apparently due to the presence of approximately five males who were exceptionally successful. Some males were assigned paternities at least 10 years before, and colleagues 10 years after, being sampled, implying a reproductive lifespan of at least 10 years, and there are indications that the real maximum lies in the range 15-20 years. Male grey seals appear to have at least two breeding strategies they can adopt. On land, some males benefit from a traditionally polygynous system. However, between 50 and 70% of grey seal pups born at a particular colony are not fathered by males who are likely to be sampled by us, implying that these males seldom venture ashore here. We conclude that aquatic mating may play a much larger role in the grey seal than has previously been thought.     

Where has all the racism gone? Views of racism within constabularies after Macpherson

Drawing on evidence from a study of Black Police Associations in English and Welsh constabularies, this article addresses perceived changes in the articulation of racialized relations within the police during the years following Lord Macpherson's Report about the police investigation of Stephen Lawrence's murder. Association officials argued that overt racism has been replaced by covert racism, evidence of which is, by definition, difficult to establish. Black Police Association officials’ and senior officers’ views of this change are discussed. Sources of evidence of covert racism are described and analysed, often related to Macpherson's definition of ‘institutional racism’. The wider implications of the article for the study of race and ethnicity are then discussed, with particular reference to Brubaker's recent work on ethnicity as cognition, which underpins the analysis of all the data gathered.     

Where have all the giants gone? Reconciling medical education and the traditions of patient care with limitations on resident work hours

The Accreditation Council for Graduate Medical Education recently approved regulations that would prohibit residents from working more than 80 hours per week and more than 24 hours at a stretch. These regulations are scheduled to take effect in all U.S. teaching hospitals on 1 July 2003. Those who approve of the proposed regulations argue that house staff fatigue is responsible for physician error, depression, anger, and a lack of compassion for patients. But critics point to the adverse effects on key goals of house staff training--the development of accountability and responsibility. Can the rigorous discipline of medical education and the long tradition of medicine as a profession be reconciled with the current calls for limiting resident duty hours and on-call schedules? The intensity of patient care in teaching hospitals today is far greater than it was in the past. These changes in medical care make it critical to develop new programs that will reconcile rigorous, scientifically based humanistic medicine with the needs of patients and physicians. This will require imaginative and creative solutions that take a larger view of medical education and medical care than mere manpower calculations and numerical solutions focused simply on compliance with an 80-hour work week.     

Where do all the proteins go?

The subcellular localization of a protein can be very informative in identifying its function and in understanding the regulatory mechanisms by which it is controlled. Past efforts to define protein localization have typically entailed methods of immunological and fluorescence-based detection applied to a limited number of gene products. Several current studies are shifting this paradigm – utilizing traditional and novel approaches in molecular biology, proteomics, histochemistry and bioinformatics to define protein localization on a proteome-wide scale. Selected studies highlighting each of these approaches are presented here as an overview of the diverse avenues by which protein localization may be investigated for the identification of new drug targets.