A Novel Missense Mutation,I890T,in the Pore Region of Cardiac Sodium Channel Causes Brugada Syndrome

Brugada syndrome (BrS) is a life-threatening, inherited arrhythmogenic syndrome associated with autosomal dominant mutations in SCN5A, the gene encoding the cardiac Na⁺ channel alpha subunit (Na_v1.5). The aim of this work was to characterize the functional alterations caused by a novel SCN5A mutation, I890T, and thus establish whether this mutation is associated with BrS. The mutation was identified by direct sequencing of SCN5A from the proband’s DNA. Wild-type (WT) or I890T Na_v1.5 channels were heterologously expressed in human embryonic kidney cells. Sodium currents were studied using standard whole cell patch-clamp protocols and immunodetection experiments were performed using an antibody against human Na_v1.5 channel. A marked decrease in current density was observed in cells expressing the I890T channel (from −52.0±6.5 pA/pF, n = 15 to −35.9±3.4 pA/pF, n = 22, at −20 mV, WT and I890T, respectively). Moreover, a positive shift of the activation curve was identified (V _1/2 = −32.0±0.3 mV, n = 18, and −27.3±0.3 mV, n = 22, WT and I890T, respectively). No changes between WT and I890T currents were observed in steady-state inactivation, time course of inactivation, slow inactivation or recovery from inactivation parameters. Cell surface protein biotinylation analyses confirmed that Na_v1.5 channel membrane expression levels were similar in WT and I890T cells. In summary, our data reveal that the I890T mutation, located within the pore of Na_v1.5, causes an evident loss-of-function of the channel. Thus, the BrS phenotype observed in the proband is most likely due to this mutation.     

Genome of the cyanobacterium Microcoleus vaginatus FGP-2, a photosynthetic ecosystem engineer of arid land soil biocrusts worldwide

The filamentous cyanobacterium Microcoleus vaginatusis found in arid land soils worldwide. The genome of M. vaginatus strain FGP-2 allows exploration of genes involved in photosynthesis, desiccation tolerance, alkane production, and other features contributing to this organism's ability to function as a major component of biological soil crusts in arid lands.     

Prostate-derived sterile 20-like kinases (PSKs/TAOKs) are activated in mitosis and contribute to mitotic cell rounding and spindle positioning

Prostate-derived sterile 20-like kinases (PSKs) 1-α, 1-β, and 2 are members of the germinal-center kinase-like sterile 20 family of kinases. Previous work has shown that PSK 1-α binds and stabilizes microtubules whereas PSK2 destabilizes microtubules. Here, we have investigated the activation and autophosphorylation of endogenous PSKs and show that their catalytic activity increases as cells accumulate in G(2)/M and declines as cells exit mitosis. PSKs are stimulated in synchronous HeLa cells as they progress through mitosis, and these proteins are activated catalytically during each stage of mitosis. During prophase and metaphase activated PSKs are located in the cytoplasm and at the spindle poles, and during telophase and cytokinesis stimulated PSKs are present in trans-Golgi compartments. In addition, small interfering RNA (siRNA) knockdown of PSK1-α/β or PSK2 expression inhibits mitotic cell rounding as well as spindle positioning and centralization. These results show that PSK catalytic activity increases during mitosis and suggest that these proteins can contribute functionally to mitotic cell rounding and spindle centralization during cell division.     

Population and genomic lessons from genetic analysis of two Indian populations

Indian demographic history includes special features such as founder effects, interpopulation segregation, complex social structure with a caste system and elevated frequency of consanguineous marriages. It also presents a higher frequency for some rare mendelian disorders and in the last two decades increased prevalence of some complex disorders. Despite the fact that India represents about one-sixth of the human population, deep genetic studies from this terrain have been scarce. In this study, we analyzed high-density genotyping and whole-exome sequencing data of a North and a South Indian population. Indian populations show higher differentiation levels than those reported between populations of other continents. In this work, we have analyzed its consequences, by specifically assessing the transferability of genetic markers from or to Indian populations. We show that there is limited genetic marker portability from available genetic resources such as HapMap or the 1,000 Genomes Project to Indian populations, which also present an excess of private rare variants. Conversely, tagSNPs show a high level of portability between the two Indian populations, in contrast to the common belief that North and South Indian populations are genetically very different. By estimating kinship from mates and consanguinity in our data from trios, we also describe different patterns of assortative mating and inbreeding in the two populations, in agreement with distinct mating preferences and social structures. In addition, this analysis has allowed us to describe genomic regions under recent adaptive selection, indicating differential adaptive histories for North and South Indian populations. Our findings highlight the importance of considering demography for design and analysis of genetic studies, as well as the need for extending human genetic variation catalogs to new populations and particularly to those with particular demographic histories.     

Virtual screening on an α‐helix to β‐strand switchable region of the FGFR2 extracellular domain revealed positive and negative modulators

The secondary structure of some protein segments may vary between α‐helix and β‐strand. To predict these switchable segments, we have developed an algorithm, Switch‐P, based solely on the protein sequence. This algorithm was used on the extracellular parts of FGF receptors. For FGFR2, it predicted that β4 and β5 strands of the third Ig‐like domain were highly switchable. These two strands possess a high number of somatic mutations associated with cancer. Analysis of PDB structures of FGF receptors confirmed the switchability prediction for β5. We thus evaluated if compound‐driven α‐helix/β‐strand switching of β5 could modulate FGFR2 signaling. We performed the virtual screening of a library containing 1.4 million of chemical compounds with two models of the third Ig‐like domain of FGFR2 showing different secondary structures for β5, and we selected 32 compounds. Experimental testing using proliferation assays with FGF7‐stimulated SNU‐16 cells and a FGFR2‐dependent Erk1/2 phosphorylation assay with FGFR2‐transfected L6 cells, revealed activators and inhibitors of FGFR2. Our method for the identification of switchable proteinic regions, associated with our virtual screening approach, provides an opportunity to discover new generation of drugs with under‐explored mechanism of action. Proteins 2014; 82:2982–2997. © 2014 Wiley Periodicals, Inc.     

Benign and Malignant Nodular Thyroid Disease in Acromegaly. Is a Routine Thyroid Ultrasound Evaluation Advisable?

Data on the prevalence of benign and malignant nodular thyroid disease in patients with acromegaly is a matter of debate. In the last decade an increasing incidence of thyroid cancer has been reported. The aim of this study was to evaluate the prevalence of goiter, thyroid nodules and thyroid cancer in a large series of patients with acromegaly with a cross-sectional study with a control group. Six Spanish university hospitals participated. One hundred and twenty three patients (50% men; mean age 59±13 years; disease duration 6.7±7.2 years) and 50 controls (51% males, mean age 58±15 years) were studied. All participants underwent thyroid ultrasound and fine needle aspiration. Cytological analysis was performed in suspicious nodules between 0.5 and 1.0 cm and in all nodules greater than 1.0 cm. Goiter was more frequently found in patients than in controls (24.9 vs. 8.3%, respectively; p<0.001). Nodular thyroid disease as well as nodules greater than 1 cm were also more prevalent in acromegalic patients (64.6%, vs. 28.6%, p<0.05 and 53.3 vs. 28.6%, respectively; p<0.05), and all underwent fine needle aspiration. Suspicious cytology was detected in 4 patients and in none of the controls. After thyroidectomy, papillary thyroid carcinoma was confirmed in two cases (3.3% of patients with thyroid nodules), representing 1.6% of the entire group of patients with acromegaly (2.4% including a case with previously diagnosed papillary thyroid carcinoma). These data indicated that thyroid nodular disease and cancer are increased in acromegaly, thus justifying its routine ultrasound screening.     

Relationship between Aldosterone and the Metabolic Syndrome in Patients with Obstructive Sleep Apnea Hypopnea Syndrome: Effect of Continuous Positive Airway Pressure Treatment

Background

Metabolic syndrome (MS) occurs frequently in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). We hypothesized that aldosterone levels are elevated in OSAHS and associated with the presence of MS.

Methods

We studied 66 patients with OSAHS (33 with MS and 33 without MS) and 35 controls. The occurrence of the MS was analyzed according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) clinical criteria. Measurements of plasma renin activity (PRA), aldosterone, aldosterone:PRA ratio, creatinine, glucose, triglycerides, cholesterol and HDL cholesterol were obtained at baseline and after CPAP treatment.

Results

Aldosterone levels were associated with the severity of OSAHS and higher than controls (p = 0.046). Significant differences in aldosterone levels were detected between OSAHS patients with and without MS (p = 0.041). A significant reduction was observed in the aldosterone levels in patients under CPAP treatment (p = 0.012).

Conclusion

This study shows that aldosterone levels are elevated in OSAHS in comparison to controls, and that CPAP therapy reduces aldosterone levels. It also shows that aldosterone levels are associated with the presence of metabolic syndrome, suggesting that aldosterone excess might predispose or aggravate the metabolic and cardiovascular complications of OSAHS.

Trial registration

The study is not a randomized controlled trial and was not registered.

What is the key question?

Are aldosterone levels elevated in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS), and associated with the presence of metabolic syndrome (MS)?

What is the bottom line?

Current data indicate that OSAHS is highly associated with MS. The underlying mechanistic links between OSAHS and MS are not well delineated to date.There is a close relationship between the Renin-Angiotensin-Aldosterone system and hypertension, and recent evidence involves aldosterone in the pathogenesis of MS.

Why read on?

These findings show that aldosterone levels are elevated in OSAHS in comparison to controls, and continuous positive airway pressure (CPAP) therapy reduces aldosterone levels. They also show that aldosterone levels are associated with the presence of metabolic syndrome, suggesting a potential role of aldosterone excess in the development of metabolic and cardiovascular complications in patients with OSAHS.

What is the bottom line?

Current data indicate that OSAHS is highly associated with MS. The underlying mechanistic links between OSAHS and MS are not well delineated to date.There is a close relationship between the Renin-Angiotensin-Aldosterone system and hypertension, and recent evidence involves aldosterone in the pathogenesis of MS.

Why read on?

These findings show that aldosterone levels are elevated in OSAHS in comparison to controls, and continuous positive airway pressure (CPAP) therapy reduces aldosterone levels. They also show that aldosterone levels are associated with the presence of metabolic syndrome, suggesting a potential role of aldosterone excess in the development of metabolic and cardiovascular complications in patients with OSAHS.     

Balance between microbial calcification and metazoan bioerosion in modern stromatolitic oncolites

Stromatolites date back some 3.5 billion years and constitute the most common and conspicuous fossils through the Proterozoic. These organosedimentary structures decreased dramatically in diversity and abundance by the late Neoproterozoic, a phenomenon often ascribed to destructive grazing by newly evolved metazoans. We investigated the concurrent processes of microbial calcification and metazoan bioerosion in one of the few locations (Rio Mesquites, Cuatro Ciénegas, Coahuila, Mexico) where living freshwater stromatolites, formed by cyanobacteria and diatoms, coexist with significant populations of metazoan grazers. We used microsensor chemical profiling and monitoring of bulk water Ca²⁺ concentrations to determine calcification rates and their dependence on microbial metabolism. The bioerosive impact resulting from grazing by endemic hydrobiid gastropods was assessed by gravimetric quantification of carbonaceous faecal pellet production. Calcification was clearly light‐dependent, reaching maximal rates (saturation) at low incident light intensity, and was surprisingly efficient, with O₂/Ca²⁺ exchange ratios well above unity, and with absolute rates similar to those found in corals. However, the erosive action of grazing snails removed most of these carbonate inputs from the oncolites. Thus, a precarious balance between constructive and destructive geobiological processes was at play in the system. The fact that accretion barely exceeded bioerosion in an environment highly conducive to calcification supports the potential impact of faunal grazing as causal agent in the demise of stromatolites in the late Proterozoic. Our findings indicate that a search for fossil evidence of bioerosive grazing in the form of carbonaceous faecal pellets associated with fossil stromatolites may provide a means to test that hypothesis directly.     

Guiding Classical Biological Control of an Invasive Mealybug Using Integrative Taxonomy

Delottococcus aberiae De Lotto (Hemiptera: Pseudococcidae) is a mealybug of Southern African origin that has recently been introduced into Eastern Spain. It causes severe distortions on young citrus fruits and represents a growing threat to Mediterranean citrus production. So far, biological control has proven unsatisfactory due to the absence of efficient natural enemies in Spain. Hence, the management of this pest currently relies only on chemical control. The introduction of natural enemies of D. aberiae from the native area of the pest represents a sustainable and economically viable alternative to reduce the risks linked to pesticide applications. Since biological control of mealybugs has been traditionally challenged by taxonomic misidentification, an intensive survey of Delottococcus spp. and their associated parasitoids in South Africa was required as a first step towards a classical biological control programme. Combining morphological and molecular characterization (integrative taxonomy) a total of nine mealybug species were identified in this study, including three species of Delottococcus. Different populations of D. aberiae were found on wild olive trees, in citrus orchards and on plants of Chrysanthemoides monilifera, showing intra-specific divergences according to their host plants. Interestingly, the invasive mealybug populations from Spanish orchards clustered together with the population on citrus from Limpopo Province (South Africa), sharing COI haplotypes. This result pointed to an optimum location to collect natural enemies against the invasive mealybug. A total of 14 parasitoid species were recovered from Delottococcus spp. and identified to genus and species level, by integrating morphological and molecular data. A parasitoid belonging to the genus Anagyrus, collected from D. aberiae in citrus orchards in Limpopo, is proposed here as a good biological control agent to be introduced into Spain.