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.     

Where have all the flowers gone? Are our woodland flowers disappearing?

The owner of a wood in Norfolk once told me that he thought that the lily of the valley has declined over the last 20 years. In Wytham Woods near Oxford the dense bramble patches I studied in the 1970s didn't seem so thick ten years later. Were these slips of the memory or did Pete Seeger have a point with his 1961 song - Where have all the flowers gone?     

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.     

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 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 has all the fire gone? Quantifying the spatial and temporal extent of fire exclusion in Byron Shire,Australia

Fire is a major determinant of vegetation structure worldwide, and structural vegetation change following fire exclusion is well documented throughout Australia. Such changes include the displacement of treeless ecosystems by forest and the transition of open forest to rainforest. These changes displace essential habitat for myriad plant and animal species and are likely drivers of localised species extinctions. Despite these potential consequences, research identifying the spatial extent of fire‐excluded ecosystems is largely absent from the ecological literature. This study identifies the spatial and temporal extent of fire exclusion in Byron Shire in north‐east New South Wales. GIS analysis compared modern fire history with recommended fire intervals for the maintenance of fire‐dependent vegetation types. Fire exclusion (low‐frequency fire) vastly exceeded high‐frequency fire, comprising 99.1% of areas affected by inappropriate fire frequency. Most fire‐dependent vegetation was fire‐excluded, with less than 10% within recommended fire interval thresholds. Most affected areas were fire‐excluded for multiple recommended fire‐return cycles, increasing the likelihood of vegetation change and localised extinctions. These findings demonstrate the operation of a major threatening process affecting Byron Shire's biodiversity that has previously been little recognised. A growing body of ecological literature suggests that irreversible change to fire‐excluded vegetation is likely wherever plant growth resources are sufficient to enable transition. Irreversible vegetation change and rapid species declines have been reported for several communities in Byron Shire, and there is compelling evidence that further change may be widespread. With increasing time since fire, efforts to restore these sites may be complicated by encroaching trees resistant to removal by fire alone and the difficulties of reintroducing low‐intensity understorey fires where the flammable understorey has been lost through shading. Further research into the impacts of fire exclusion is urgently required, as is the reinstatement of fire to fire‐excluded vegetation to prevent ongoing displacement of fire‐dependent biodiversity values.     

Pollen movement in declining populations of California Valley oak,Quercus lobata: where have all the fathers gone?

The fragmented populations and reduced population densities that result from human disturbance are issues of growing importance in evolutionary and conservation biology. A key issue is whether remnant individuals become reproductively isolated. California Valley oak (Quercus lobata) is a widely distributed, endemic species in California, increasingly jeopardized by anthropogenic changes in biota and land use. We studied pollen movement in a savannah population of Valley oak at Sedgwick Reserve, Santa Barbara County, to estimate effective number of pollen donors (Nep) and average distance of effective pollen movement (delta). Using twogener, our recently developed hybrid model of paternity and genetic structure treatments that analyses maternal and progeny multilocus genotypes, we found that current Nep = 3.68 individuals. Based on an average adult density of d= 1.19 stems/ha, we assumed a bivariate normal distribution to model current average pollen dispersal distance (delta) and estimated delta= 64.8 m. We then deployed our parameter estimates in spatially explicit models of the Sedgwick population to evaluate the extent to which Nep may have changed, as a consequence of progressive stand thinning between 1944 and 1999. Assuming that pollen dispersal distance has not changed, we estimate Nep was 4.57 individuals in 1944, when stand density was 1.48. Both estimates indicate fewer effective fathers than one might expect for wind-pollinated species and fewer than observed elsewhere. The results presented here provide a basis for further refinements on modelling pollen movement. If the trends continue, then ongoing demographic attrition could further reduce neighbourhood size in Valley oak resulting in increased risk of reproductive failure and genetic isolation.     

Where have all the carbonates gone? A model comparison of calcium carbonate budgets before and after the 1982–1983 El Nino at Uva Island in the eastern Pacific

El Nifio related coral mortality and a subsequent increase in crustose coralline algae and sea urchins have resulted in profound changes to the coral reef ecosystem at Uva Island, Panama (Pacific coast). New data and a model are presented that analyze the CaCO₃ budget of the reef. The model accounts for production by corals and coralline algae, erosion byDiadema, infauna, fish and other motile organisms, and the retention of sediments as a function of size. The 2.5 ha reef is currently eroding at an average rate of 4,800 kg/y or –0.19 kg/m²/y but there is tremendous variation among reef zones. While deposition in other zones range from +0.1 to 0.4 kg/m²/y, erosion of the seaward reef base averages about –3.65 kg/m²/y. The damselfish/algal lawn symbiosis protects portions of the reef framework, reducing net losses there by 2,000 kg/y (up to 0.33 kg/m²/y). Before the 1982-1983 El Niño, the overall reef was depositional. At that time, estimated production exceeded erosion in most zones, resulting in a net deposition of approximately 8,600 kg/y or 0.34 kg/m²/y.     

Two types of modified cardiac Na+ channels after cytosolic interventions at the α-subunit capable of removing Na+ inactivation

Failure of inactivation is the typical response of voltage-gated Na⁺ channels to the cytosolic presence of proteolytic enzymes, protein reagents such as N-bromoacetamide (NBA) or iodate, and antibodies directed against the linker between domains III and IV of the α-subunit. The present patch clamp experiments with cardiac Na⁺ channels aimed to test the hypothesis that these interventions may provoke the occurrence of non-inactivating Na⁺ channels with distinct kinetic properties. A site-directed polyclonal antibody (anti-SLP2, target sequence 1481–1496 of the cardiac Na⁺ channel α-subunit) eliminated fast Na⁺ inactivation to induce burst activity which was accompanied by the occurrence of two open states. A deactivation process terminated channel activity during membrane depolarization proceeding with time constants of close to 40 ms (at –40 mV). NBA-modified and iodate-modified Na⁺ channels were kinetically indistinguishable from the anti-SLP2-modified type since they likewise deactivate and, thus, attain an only moderate P_o of close to 20%. This is fundamentally different from the behaviour of enzymatically-modified Na⁺ channels: after cytosolic proteolysis with α-chymotrypsin, trypsin or pronase, mean P_o during membrane depolarization amounted to approximately 40% because deactivation operated extremely slowly and less efficiently (time constants 100–200 ms at –40 mV, as a minimum) or was virtually non-operating. In-vitro cleavage of the synthetic linker sequence 1481–1496 confirmed that this part of the α-subunit provides a substrate for these peptidases or reactants for NBA but cannot be chemically modified by iodate. This iodate resistance indicates that iodate-modified Na⁺ channels are based on a structural alteration of still another region which is also involved in Na⁺ inactivation, besides the linker between domains III and IV of the α-subunit. Endogenous peptidases such as calpain did not affect Na⁺ inactivation. This stresses the stochastic nature of a kinetic peculiarity of cardiac Na⁺ channels, mode-switching to a non-inactivating mode. Received: 25 May 1996 / Accepted: 12 September 1996