A germline mutation in BLOC1S3/reduced pigmentation causes a novel variant of Hermansky-Pudlak syndrome (HPS8)

Hermansky-Pudlak syndrome (HPS) is genetically heterogeneous, and mutations in seven genes have been reported to cause HPS. Autozygosity mapping studies were undertaken in a large consanguineous family with HPS. Affected individuals displayed features of incomplete oculocutaneous albinism and platelet dysfunction. Skin biopsy demonstrated abnormal aggregates of melanosomes within basal epidermal keratinocytes. A homozygous germline frameshift mutation in BLOC1S3 (p.Gln150ArgfsX75) was identified in all affected individuals. BLOC1S3 mutations have not been previously described in patients with HPS, but BLOC1S3 encodes a subunit of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Mutations in other BLOC-1 subunits have been associated with an HPS phenotype in humans and/or mouse, and a nonsense mutation in the murine orthologue of BLOC1S3 causes the reduced pigmentation (rp) model of HPS. Interestingly, eye pigment formation is reported to be normal in rp, but we found visual defects (nystagmus, iris transilluminancy, foveal hypoplasia, reduced visual acuity, and evidence of optic pathway misrouting) in affected individuals. These findings define a novel form of human HPS (HPS8) and extend genotype-phenotype correlations in HPS.     

Using cross-dating techniques to validate ages of aurora rockfish (<Emphasis Type="Italic">Sebastes aurora</Emphasis>): estimates of age,growth and female maturity

Since fishery management regulations have shifted much of the groundfish trawl effort in the northeastern Pacific from the continental shelf to the slope, fishery impacts on unassessed demersal slope rockfish species like the aurora rockfish (Sebastes aurora) may have increased. Understanding the life history of these species is a critical first step in developing management strategies to protect them from overharvest. In this study we employ cross-dating methods to validate the annual periodicity of growth increments and investigate the age, growth and maturity of aurora rockfish, a species for which life history information is quite limited. Specimens were collected on an opportunistic basis from Oregon commercial landings and from research cruises, over the years 2003–2006. Age was estimated for 438 individuals using otoliths processed via the break-and-burn method. The maximum estimated age was 118 years for females (n = 324) and 81 years for males (n = 114). The von Bertalanffy growth function showed that males grow faster and reach a smaller maximum size than females (males: L _inf = 34, K = 0.09, t ₀ = −1.9; females: L _inf = 37, K = 0.06, t ₀ = −5.5), though both sexes demonstrate relatively slow growth. Visual assessment of ovaries showed that the aurora rockfish is a synchronous spawner with parturition occurring in May and June off Oregon. Female age and length at 50% maturity were calculated at 12.6 years and 26 cm, respectively (n = 307). Maturity and age data provided evidence for a protracted adolescence in this species.     

PIN-G – A novel reporter for imaging and defining the effects of trafficking signals in membrane proteins

Background  

The identification of protein trafficking signals, and their interacting mechanisms, is a fundamental objective of modern biology. Unfortunately, the analysis of trafficking signals is complicated by their topography, hierarchical nature and regulation. Powerful strategies to test candidate motifs include their ability to direct simpler reporter proteins, to which they are fused, to the appropriate cellular compartment. However, present reporters are limited by their endogenous expression, paucity of cloning sites, and difficult detection in live cells.     

Selection of genomic target RNAs by iterative screening

A growing number of proteins are known to exert their regulatory or biological functions via RNA binding. In some cases genetic interactions allow us to infer candidate targets for RNA directed regulation, but in many other cases identification of potential regulatory targets is problematic. We have developed an in vitro biochemical screen, SETIS (SElection of Target RNAs by Iterative Screening) that allows screening of a major portion of the genome for identification of potential targets for RNA binding proteins.     

Is conservation triage just smart decision making?

Conservation efforts and emergency medicine face comparable problems: how to use scarce resources wisely to conserve valuable assets. In both fields, the process of prioritising actions is known as triage. Although often used implicitly by conservation managers, scientists and policymakers, triage has been misinterpreted as the process of simply deciding which assets (e.g. species, habitats) will not receive investment. As a consequence, triage is sometimes associated with a defeatist conservation ethic. However, triage is no more than the efficient allocation of conservation resources and we risk wasting scarce resources if we do not follow its basic principles.     

Repression of CFTR activity in human MMNK-1 cholangiocytes induces sulfotransferase 1E1 expression in co-cultured HepG2 hepatocytes

Mouse models of cystic fibrosis (CF) indicate that sulfotransferase (SULT) 1E1 is significantly induced in livers of many mice lacking cystic fibrosis transmembrane receptor (CFTR) activity. Increased SULT1E1 activity results in the alteration of estrogen-regulated protein expression in the livers of these mice. In this study, human MMNK-1 cholangiocytes with repressed CFTR function were used to induce SULT1E1 expression in human HepG2 hepatocytes to investigate whether SULT1E1 can be increased in human CF liver. CFTR expression was inhibited in MMNK-1 cholangiocytes using CFTR-siRNA, then the MMNK-1 and HepG2 cells were co-cultured in a membrane-separated Transwell system. Expression of SULT1E1 and selected estrogen-regulated proteins were then assayed in the HepG2 cells. Results demonstrate that inhibition of CFTR expression in MMNK-1 cells results in the induction of SULT1E1 message and activity in HepG2 cells in the Transwell system. The expression of estrogen-regulated proteins including insulin-like growth factor (IGF)-1, glutathione-S-transferase (GST) P1 and carbonic anhydrase (CA) II expression are repressed in the HepG2 cells cultured with the CFTR-siRNA-MMNK-1 cells apparently in response to the increased sulfation of beta-estradiol. Thus, we have shown that co-culture of HepG2 hepatocytes with MMNK-1 cholangiocytes with siRNA repressed CFTR expression results in the selective induction of SULT1E1 in the HepG2 cells. Loss of CFTR function in cholangiocytes may have a paracrine regulatory effect on hepatocytes via the induction of SULT1E1 and the increased sulfation of beta-estradiol. Experiments are presently underway in our laboratory to elucidate the identity of these paracrine regulatory factors.     

Comparison of cardiovascular risk between patients with type 2 diabetes and those who had had a myocardial infarction: cross sectional and cohort studies

ObjectiveTo compare risks of cardiovascular outcomes between patients with type 2 diabetes and patients with established coronary heart disease.DesignCross sectional study and cohort study using routinely collected datasets.SettingTayside, Scotland (population 400 000) during 1988-95.SubjectsIn the cross sectional study, among patients aged 45-64, 1155 with type 2 diabetes were compared with 1347 who had had a myocardial infarction in the preceding 8 years. In the cohort study 3477 patients of all ages with newly diagnosed type 2 diabetes were compared with 7414 patients who had just had a myocardial infarction.ResultsIn the cross sectional study the adjusted risk ratio for death from all causes was 2.27 (95% confidence interval 1.82 to 2.83) for patients who had had myocardial infarction compared with those with diabetes, and the risk ratio for hospital admission for myocardial infarction was 1.33 (1.14 to 1.55). In the cohort study, patients who had just had a myocardial infarction had a higher risk of death from all causes (adjusted risk ratio 1.35 (1.25 to 1.44)), cardiovascular death (2.93 (2.54 to 3.41)), and hospital admission for myocardial infarction (3.10 (2.57 to 3.73)).ConclusionsPatients with type 2 diabetes were at lower risk of cardiovascular outcomes than patients with established coronary heart disease.

What is already known on this topic

A recent influential study suggested that patients with type 2 diabetes without established cardiovascular disease have as high a risk of cardiovascular events and death as non-diabetic patients who have had a myocardial infarctionSome clinicians therefore advocate aggressive treatment of cardiovascular risk factors in the presence of diabetes

What this study adds

Patients with type 2 diabetes are at lower risk of death from all causes or cardiovascular causes and of hospital admission for myocardial infarction than patients with established coronary heart disease     

The potential of seaweed as a source of drugs for use in cancer chemotherapy

This review discusses studies on marine macroalgae that have been investigated for their potential as sources of novel anti-cancer drugs. The review highlights the very large number of studies of crude, partially purified and purified seaweed extracts, collected from many locations, which have shown potential as sources of potent anti-cancer drugs when tested in vitro and/or in vivo. The activity of polysaccharides, polyphenols, proteinaceous molecules, carotenoids, alkaloids, terpenes and others is described here. In some reports, mechanistic studies have identified specific inhibitory activity on a number of key cellular processes including apoptosis pathways, telomerase and tumour angiogenesis. However, despite the potential shown by these studies, translation to clinically useful preparations is almost non-existent. It is hoped this review will serve as a source document and guide for those carrying out research into the potential use of macroalgae as a source of novel anti-cancer agents.     

Cheap and Nasty? The Potential Perils of Using Management Costs to Identify Global Conservation Priorities

The financial cost of biodiversity conservation varies widely around the world and such costs should be considered when identifying countries to best focus conservation investments. Previous global prioritizations have been based on global models for protected area management costs, but this metric may be related to other factors that negatively influence the effectiveness and social impacts of conservation. Here we investigate such relationships and first show that countries with low predicted costs are less politically stable. Local support and capacity can mitigate the impacts of such instability, but we also found that these countries have less civil society involvement in conservation. Therefore, externally funded projects in these countries must rely on government agencies for implementation. This can be problematic, as our analyses show that governments in countries with low predicted costs score poorly on indices of corruption, bureaucratic quality and human rights. Taken together, our results demonstrate that using national-level estimates for protected area management costs to set global conservation priorities is simplistic, as projects in apparently low-cost countries are less likely to succeed and more likely to have negative impacts on people. We identify the need for an improved approach to develop global conservation cost metrics that better capture the true costs of avoiding or overcoming such problems. Critically, conservation scientists must engage with practitioners to better understand and implement context-specific solutions. This approach assumes that measures of conservation costs, like measures of conservation value, are organization specific, and would bring a much-needed focus on reducing the negative impacts of conservation to develop projects that benefit people and biodiversity.