Platensimycin is a selective FabF inhibitor with potent antibiotic properties

Bacterial infection remains a serious threat to human lives because of emerging resistance to existing antibiotics. Although the scientific community has avidly pursued the discovery of new antibiotics that interact with new targets, these efforts have met with limited success since the early 1960s. Here we report the discovery of platensimycin, a previously unknown class of antibiotics produced by Streptomyces platensis. Platensimycin demonstrates strong, broad-spectrum Gram-positive antibacterial activity by selectively inhibiting cellular lipid biosynthesis. We show that this anti-bacterial effect is exerted through the selective targeting of beta-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B) in the synthetic pathway of fatty acids. Direct binding assays show that platensimycin interacts specifically with the acyl-enzyme intermediate of the target protein, and X-ray crystallographic studies reveal that a specific conformational change that occurs on acylation must take place before the inhibitor can bind. Treatment with platensimycin eradicates Staphylococcus aureus infection in mice. Because of its unique mode of action, platensimycin shows no cross-resistance to other key antibiotic-resistant strains tested, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant enterococci. Platensimycin is the most potent inhibitor reported for the FabF/B condensing enzymes, and is the only inhibitor of these targets that shows broad-spectrum activity, in vivo efficacy and no observed toxicity.     

Penetration barrier to sodium fluorescein and fluorescein-labelled dextrans of various molecular sizes in brain capillaries

Summary The permeability of the blood-brain barrier to sodium fluorescein, or fluorescein-labelled dextrans of various molecular weights, was investigated. Unlike the capillaries in both the area postrema and the eminentia mediana, the capillaries of the cerebral cortex were impermeable to all the intravenous tracer substances used.Part of the experimental work was carried out when F.J. worked at the Department of Anatomy, University of Helsinki on a fellowship from the Finnish-Hungarian Exchange Programme. The authors are grateful to Miss Irma Hiltunen for excellent technical assistance.     

Modern systematics and environmental significance of stable isotopic variations in Wanxiang Cave, Wudu, Gansu, China

This paper presents the stable isotopic compositions from the cave dripwater and actively forming soda straw stalactites collected from Wanxiang Cave, Wudu, Gansu, located on the Qinghai-Tibetan Plateau and Loess Plateau transition zone, China. The δ^18Odw and δDdw of dripwater samples in the cave plot directly on the local MWL, constructed by using GNIP data from 3 sites surrounding the cave regions (Lanzhou, Xi‘an, and Chengdu), the nearest site to the cave, suggesting that there is a close relationship be-tween the δ^18Odw of the cave water and the δ^18O of the pre-cipitations. Using the measured δ^18Odw and δ^18Omc values from the mid-farthest parts from the cave entrance and the carbonate paleotemperature equation, the calculated temperatures range from 8.9 to 12.4℃, with the mean value of 10.7℃ and the temperature calculated at 8 locations in the farthest part of the cave is in the range of 10.I--12.4℃, with the mean value of 11.5℃, being consistent with the survey value(10.99℃)in the cave, slightly lower than the mean annual temperature (14.4℃) in Wudu. This suggests that modern speleothems are forming under isotopic equilibrium and their isotopic composition accurately reflects the mean annual temperature at the surface, indicating that the isotopic composition of the modern speleothems records local temperature change with credibility.     

Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult

Serotonin is implicated in mood regulation, and drugs acting via the serotonergic system are effective in treating anxiety and depression. Specifically, agonists of the serotonin1A receptor have anxiolytic properties, and knockout mice lacking this receptor show increased anxiety-like behaviour. Here we use a tissue-specific, conditional rescue strategy to show that expression of the serotonin1A receptor primarily in the hippocampus and cortex, but not in the raphe nuclei, is sufficient to rescue the behavioural phenotype of the knockout mice. Furthermore, using the conditional nature of these transgenic mice, we suggest that receptor expression during the early postnatal period, but not in the adult, is necessary for this behavioural rescue. These findings show that postnatal developmental processes help to establish adult anxiety-like behaviour. In addition, the normal role of the serotonin1A receptor during development may be different from its function when this receptor is activated by therapeutic intervention in adulthood.     

Abnormal TNF activity in Timp3-/- mice leads to chronic hepatic inflammation and failure of liver regeneration

Tumor-necrosis factor (TNF), a pleiotropic cytokine, triggers physiological and pathological responses in several organs. Here we show that deletion of the mouse gene Timp3 resulted in an increase in TNF-alpha converting enzyme activity, constitutive release of TNF and activation of TNF signaling in the liver. The increase in TNF in Timp3(-/-) mice culminated in hepatic lymphocyte infiltration and necrosis, features that are also seen in chronic active hepatitis in humans. This pathology was prevented when deletion of Timp3 was combined with Tnfrsf1a deficiency. In a liver regeneration model that requires TNF signaling, Timp3(-/-) mice succumbed to liver failure. Hepatocytes from Timp3(-/-) mice completed the cell cycle but then underwent cell death owing to sustained activation of TNF. This hepatocyte cell death was completely rescued by a neutralizing antibody to TNF. Dysregulation of TNF occurred specifically in Timp3(-/-), and not Timp1(-/-) mice. These data indicate that TIMP3 is a crucial innate negative regulator of TNF in both tissue homeostasis and tissue response to injury.     

Human dynamics: Darwin and Einstein correspondence patterns

In an era when letters were the main means of exchanging scientific ideas and results, Charles Darwin (1809-82) and Albert Einstein (1879-1955) were notably prolific correspondents. But did their patterns of communication differ from those associated with the instant-access e-mail of modern times? Here we show that, although the means have changed, the communication dynamics have not: Darwin's and Einstein's patterns of correspondence and today's electronic exchanges follow the same scaling laws. However, the response times of their surface-mail communication is described by a different scaling exponent from e-mail communication, providing evidence for a new class of phenomena in human dynamics.     

Same-sex mating and the origin of the Vancouver Island Cryptococcus gattii outbreak

Genealogy can illuminate the evolutionary path of important human pathogens. In some microbes, strict clonal reproduction predominates, as with the worldwide dissemination of Mycobacterium leprae, the cause of leprosy. In other pathogens, sexual reproduction yields clones with novel attributes, for example, enabling the efficient, oral transmission of the parasite Toxoplasma gondii. However, the roles of clonal or sexual propagation in the origins of many other microbial pathogen outbreaks remain unknown, like the recent fungal meningoencephalitis outbreak on Vancouver Island, Canada, caused by Cryptococcus gattii. Here we show that the C. gattii outbreak isolates comprise two distinct genotypes. The majority of isolates are hypervirulent and have an identical genotype that is unique to the Pacific Northwest. A minority of the isolates are significantly less virulent and share an identical genotype with fertile isolates from an Australian recombining population. Genotypic analysis reveals evidence of sexual reproduction, in which the majority genotype is the predicted offspring. However, instead of the classic a-alpha sexual cycle, the majority outbreak clone appears to have descended from two alpha mating-type parents. Analysis of nuclear content revealed a diploid environmental isolate homozygous for the major genotype, an intermediate produced during same-sex mating. These studies demonstrate how cryptic same-sex reproduction can enable expansion of a human pathogen to a new geographical niche and contribute to the ongoing production of infectious spores. This has implications for the emergence of other microbial pathogens and inbreeding in host range expansion in the fungal and other kingdoms.