A freely diffusible form of Sonic hedgehog mediates long-range signalling

The secreted protein Sonic hedgehog (Shh) exerts many of its patterning effects through a combination of short- and long-range signalling. Three distinct mechanisms, which are not necessarily mutually exclusive, have been proposed to account for the long-range effects of Shh: simple diffusion of Shh, a relay mechanism in which Shh activates secondary signals, and direct delivery of Shh through cytoplasmic extensions, termed cytonemes. Although there is much data (using soluble recombinant Shh (ShhN)) to support the simple diffusion model of long-range Shh signalling, there has been little evidence to date for a native form of Shh that is freely diffusible and not membrane-associated. Here we provide evidence for a freely diffusible form of Shh (s-ShhNp) that is cholesterol modified, multimeric and biologically potent. We further demonstrate that the availability of s-ShhNp is regulated by two functional antagonists of the Shh pathway, Patched (Ptc) and Hedgehog-interacting protein (Hip). Finally, we show a gradient of s-ShhNp across the anterior-posterior axis of the chick limb, demonstrating the physiological relevance of s-ShhNp.     

Enhanced supercurrent density in polycrystalline YBa2Cu3O(7-delta) at 77 K from calcium doping of grain boundaries

With the discovery of high-temperature superconductivity, it seemed that the vision of superconducting power cables operating at the boiling point of liquid nitrogen (77 K) was close to realization. But it was soon found that the critical current density Jc of the supercurrents that can pass through these polycrystalline materials without destroying superconductivity is remarkably small. In many materials, Jc is suppressed at grain boundaries, by phenomena such as interface charging and bending of the electronic band structure. Partial replacement ('doping') of the yttrium in YBa2Cu3O(7-delta) with calcium has been used to increase grain-boundary Jc values substantially, but only at temperatures much lower than 77 K (ref. 9). Here we show that preferentially overdoping the grain boundaries, relative to the grains themselves, yields values of Jc at 77 K that far exceed previously published values. Our results indicate that grain-boundary doping is a viable approach for producing a practical, cost-effective superconducting power cable operating at liquid-nitrogen temperatures.     

Defensive alkaloid in blood of Mexican bean beetle (Epilachna varivestis)

The blood of the Mexican bean beetle (Epilachna varivestis) contains a homotropane alkaloid, euphococcinine (1). The beetles 'reflex bleed' when disturbed, thereby deploying the alkaloid, which is provenly deterrent to spiders and ants. Newly emerged adults lack the alkaloid, but the compound builds up to deterrent levels in their blood within days. Eggs and larvae of Epilachna are devoid of the compound.     

Lucibufagins,IV. New defensive steroids and a pterin from the firefly,Photinus pyralis (coleoptera: Lampyridae)

Summary Two new defensive steroids (lucibufagins6 and7) and a fluorescent pterin (8) have been isolated and characterized from the fireflyPhotinus pyralis.Acknowledgment. We are grateful to the Fonds National Suisse de la Recherche Scientifique (bourse de relève to M.G.). Partial support of this work by the NIH (grants No. AI 12020 and AI 02908), the NSF (grant No. PCM-77-25807), and the American Heart Association is acknowledged with pleasure. Paper No. 66 of the series Defense Mechanism of Arthropods.     

Timing of single daily meal influences relations among human circadian rhythms in urinary cyclic AMP and hemic glucagon,insulin and iron

Summary Relations among circadian rhythms in serum iron, glucagon and insulin and urinary cyclic AMP excretion differ drastically when diurnally active, nocturnally resting human adults consume all daily food for one week as breakfast only and for another week as dinner only—a finding of interest to diverse fields, e.g., for optimizing certain kinds of therapy or for a better utilization of calories.Supported by grants (No. RR-400 from the General Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health, USPHS and Nos. 5-K6-GM-13, 981 and 1RO1-CA-14445-01) and grant No. 20, Fondation de l'industrie pharmaceutique pour la recherche.     

Consumer Participation in Designing Community Based Consumer-Directed Disability Care: Lessons from a Participatory Action Research-Inspired Project

User participation has been embraced worldwide as a means to provide better consumer outcomes in health and community care. However, methodologies to achieve effective consumer engagement at the programme design level have remained under-explored. The purpose of this study was to evaluate the impact of a Participatory Action Research (PAR)-inspired methodology used to develop a consumer-directed community care/individualised funding service model for people with disabilities. A retrospective analysis of case notes and internal reports for the first 6 years of an ongoing project were examined. The findings suggest that PAR methodologies need to take into account community development, group support, and capacity building as well as succession planning and risk management issues in order to facilitate the often lengthy policy and project development process. Drawing on these findings, this article discusses five lessons and their methodological implications for PAR in a health or social policy/programme design context.

Defensive alkaloid in blood of Mexican bean beetle (Epilachna varivestis)

Summary The blood of the Mexican bean beetle (Epilachna varivestis) contains a homotropane alkaloid, euphococcinine (1). The beetles reflex bleed when disturbed, thereby deploying the alkaloid, which is provenly deterrent to spiders and ants. Newly emerged adults lack the alkaloid, but the compound builds up to deterrent levels in their blood within days. Eggs and larvae ofEpilachna are devoid of the compound.Paper No 79 of the series: Defense Mechanisms of Arthropods. Study supported by NIH (Grants AI-02908 and AI-12020) and Hatch Funds (NYC-191409). We thank G. Eidens, K. Hicks, and M. Eisner for excellent technical help, and an anonymous reviewer for calling two critical references to our attention. The ant tests were done at the Archbold Biological Station, Lake Placid, Florida. The hospitality of the Fogarty Scholar-in-Residence Program (to J.M.) is acknowledged with pleasure.     

Stress and the nonsense-mediated RNA decay pathway

Cells respond to internal and external cellular stressors by activating stress-response pathways that re-establish homeostasis. If homeostasis is not achieved in a timely manner, stress pathways trigger programmed cell death (apoptosis) to preserve organism integrity. A highly conserved stress pathway is the unfolded protein response (UPR), which senses excessive amounts of unfolded proteins in the ER. While a physiologically beneficial pathway, the UPR requires tight regulation to provide a beneficial outcome and avoid deleterious consequences. Recent work has demonstrated that a conserved and highly selective RNA degradation pathway—nonsense-mediated RNA decay (NMD)—serves as a major regulator of the UPR pathway. NMD degrades mRNAs encoding UPR components to prevent UPR activation in response to innocuous ER stress. In response to strong ER stress, NMD is inhibited by the UPR to allow for a full-magnitude UPR response. Recent studies have indicated that NMD also has other stress-related functions, including promoting the timely termination of the UPR to avoid apoptosis; NMD also regulates responses to non-ER stressors, including hypoxia, amino-acid deprivation, and pathogen infection. NMD regulates stress responses in species across the phylogenetic scale, suggesting that it has conserved roles in shaping stress responses. Stress pathways are frequently constitutively activated or dysregulated in human disease, raising the possibility that “NMD therapy” may provide clinical benefit by downmodulating stress responses.