Mutation of IGFBP7 causes upregulation of BRAF/MEK/ERK pathway and familial retinal arterial macroaneurysms

Insulin-like growth factor binding proteins (IGFBPs) play important physiological functions through the modulation of IGF signaling as well as IGF-independent mechanisms. Despite the established role of IGFs in development, a similar role for the seven known IGFBPs has not been established in humans. Here, we show that an autosomal-recessive syndrome that consists of progressive retinal arterial macroaneurysms and supravalvular pulmonic stenosis is caused by mutation of IGFBP7. Consistent with the recently established inhibitory role of IGFBP7 on BRAF signaling, the BRAF/MEK/ERK pathway is upregulated in these patients, which may explain why the cardiac phenotype overlaps with other disorders characterized by germline mutations in this pathway. The retinal phenotype appears to be mediated by a role in vascular endothelium, where IGFBP7 is highly expressed.     

Conformational coupling of the nucleotide-binding and the transmembrane domains in ABC transporters

Basic architecture of ABC transporters includes two transmembrane domains (TMDs) and two nucleotide-binding domains (NBDs). Although the transport process takes place in the TMDs, which provide the substrate translocation pathway across the cell membrane and control its accessibility between the two sides of the membrane, the energy required for the process is provided by conformational changes induced in the NBDs by binding and hydrolysis of ATP. Nucleotide-dependent conformational changes in the NBDs, therefore, need to be coupled to structural changes in the TMDs. Using molecular dynamics simulations, we have investigated the structural elements involved in the conformational coupling between the NBDs and the TMDs in the Escherichia coli maltose transporter, an ABC importer for which an intact structure is available both in inward-facing and outward-facing conformations. The prevailing model of coupling is primarily based on a single structural motif, known as the coupling helices, as the main structural element for the NBD-TMD coupling. Surprisingly, we find that in the absence of the NBDs the coupling helices can be conformationally decoupled from the rest of the TMDs, despite their covalent connection. That is, the structural integrity of the coupling helices and their tight coupling to the core of the TMDs rely on the contacts provided by the NBDs. Based on the conformational and dynamical analysis of the simulation trajectories, we propose that the core coupling elements in the maltose transporter involve contributions from several structural motifs located at the NBD-TMD interface, namely, the EAA loops from the TMDs, and the Q-loop and the ENI motifs from the NBDs. These three structural motifs in small ABC importers show a high degree of correlation in motion and mediate the necessary conformational coupling between the core of TMDs and the helical subdomains of NBDs. A comprehensive analysis of the structurally known ABC transporters shows a high degree of conservation of the identified 3-motif coupling elements only in the subfamily of small ABC importers, suggesting a distinct mode of NBD-TMD coupling from the other two major ABC transporter folds, namely large ABC importers and ABC exporters.     

Mortality Trends in Women and Men Presenting with Acute Coronary Syndrome: Insights from a 20-Year Registry

Background

Coronary artery disease (CAD) is the leading cause of mortality worldwide. The present study evaluated the impact of gender in patients hospitalized with acute coronary syndromes (ACS) over a 20-year period in Qatar.

Methods

Data were collected retrospectively from the registry of the department of cardiology for all patients admitted with ACS during the study period (1991–2010) and were analyzed according to gender.

Results

Among 16,736 patients who were admitted with ACS, 14262 (85%) were men and 2474 (15%) were women. Cardiovascular risk factors were more prevalent among women in comparison to men. On admission, women presented mainly with non-ST-elevation ACS and were more likely to be undertreated with β-blockers (BB), antiplatelet agents and reperfusion therapy in comparison to men. However, from 1999 through 2010, the use of aspirin, angiotensin-converting enzyme inhibitors and BB increased from 66% to 79%, 27% to 41% and 17% to 49%, respectively in women. In the same period, relative risk reduction for mortality was 64% in women and 51% in men. Across the 20-year period, the mortality rate decreased from 27% to 7% among the Middle Eastern Arab women. Multivariate logistic regression analysis showed that female gender was independent predictor of in-hospital mortality (odd ratio 1.51, 95% CI 1.27–1.79).

Conclusions

Women presenting with ACS are high-risk population and their in-hospital mortality remains higher for all age groups in comparison to men. Although, substantial improvement in the hospital outcome has been observed, guidelines adherence and improvement in the hospital care have not yet been optimized.     

Angiotensin-converting enzyme gene polymorphisms and T2DM in a case�Ccontrol association study of the Bahraini population

Bahrain has one of the highest incidence rates of type 2 diabetes mellitus (T2DM). Development of diabetic nephropathy (DN) as a complication was noticed in some patients while absent in others. This interesting observation raises the role of certain genetic risk factors for the development of DN. Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism was found to be associated with T2DM. While some patients have predisposition to DN in the population, others have negative association. The present case-control association study was designed to investigate the association of ACE I/D polymorphism in T2DM patients in Bahrain especially in those who developed DN. A total of 360 T2DM patients (110 with DN and 250 without DN) and 360 healthy (non-diabetic) age-matched subjects were recruited for this study for comparison. The presence (insertion)/absence (deletion) (I/D) polymorphism of a 287-bp Alu1 element inside intron 16 of the ACE gene was investigated using PCR-gel electrophoresis. The results show that the distribution of the homozygote DD genotype of the ACE gene was high among Bahraini T2DM patients compared to the healthy non-diabetic subjects. In addition, the distribution of the deletion (D) allele was high among Bahraini T2DM patients with DN when compared to the healthy non-diabetic subjects. However, there was no significant difference in the distribution of ACE I/D allele and genotypes between DN patients when compared to those T2DM patients without DN. The results obtained in this study are in closely agreement with some previous reports which show a strong association of ACE polymorphism with T2DM patients, yet not a risk factor for development of DN.     

Fertile fungal spores collected on different faced surfaces in the atmosphere of Giza,Egypt

A quantitative and qualitative survey was carried out for airborne fungus spores coming into contact with horizontally and vertically gravitation sampling oriented surfaces in the atmosphere of Giza city. Czapek Dox agar, malt extract agar, potato dextrose agar and Sabouraud dextrose agar Petri dishes were exposed monthly to the five oriented surfaces of a polystyrene cube, throughout a one-year period. Significant differences (P < 0.01) were observed between the total counts of caught airborne fungi contacting with the horizontal compared to other vertically oriented surfaces. Conversely, there were no significant differences observed between the total catch of airborne fungi using the various sampling media. The results revealed that vertical sampling provides valuable information that may be lost from horizontal sampling alone. A total of 5,053 colonies belonging to 40 fungal organisms were identified. Alternaria (24.26%), Aspergillus (19.2%), Cladosporium (14.5%) and Penicillium (11.43%) were the most predominant fungal genera. Collected fungi were grouped into high, medium, low and rare components depending upon their frequency in the studied atmosphere. Aspergillus niger, Aspergillus parasiticus, Alternaria, Cladosporium and Penicillium were regularly found on all oriented surfaces. However, Arthrobotrys, Biospora, Chaetomium, Pleospora, Trichothecium and Verticillium were rarely found in the air. Positive and/or negative correlations were observed between the total fungal counts and the predominant fungal types with meteorological parameters during sampling days.     

Mechanics of force propagation in TonB-dependent outer membrane transport

For the uptake of scarce yet essential organometallic compounds, outer membrane transporters of Gram-negative bacteria work in concert with an energy-generating inner membrane complex, thus spanning the periplasmic space to drive active transport. Here, we examine the interaction of TonB, an inner membrane protein, with an outer membrane transporter based upon a recent crystal structure of a TonB-transporter complex to characterize two largely unknown steps of the transport cycle: how energy is transmitted from TonB to the transporter and how energy transduction initiates transport. Simulations of TonB in complex with BtuB reveal that force applied to TonB is transmitted to BtuB without disruption of the very small connection between the two, supporting a mechanical mode of coupling. Based on the results of different pulling simulations, we propose that the force transduction instigates a partial unfolding of the pore-occluding luminal domain of the transporter, a potential step in the transport cycle. Furthermore, analysis of the electrostatic potentials and salt bridge interactions between the two proteins during the simulations hints at involvement of electrostatic forces in long-range interaction and binding of TonB and BtuB.     

Deep aspirations: towards a sustainable offshore Blue Economy

Reviews in Fish Biology and Fisheries - The ocean economy is experiencing rapid growth that will provide benefits but will also pose environmental and social risks. With limited space and degraded...     

Rosiglitazone treatment restores renal responsiveness to atrial natriuretic peptide in rats with congestive heart failure

The thiazolidinedione (TZD) class of Peroxisome proliferator‐activated receptor gamma agonists has restricted clinical use for diabetes mellitus due to fluid retention and potential cardiovascular risks. These side effects are attributed in part to direct salt‐retaining effect of TZDs at the renal collecting duct. A recent study from our group revealed that prolonged rosiglitazone (RGZ) treatment caused no Na+/H₂O retention or up‐regulation of Na⁺ transport‐linked channels/transporters in experimental congestive heart failure (CHF) induced by surgical aorto‐caval fistula (ACF). The present study examines the effects of RGZ on renal and cardiac responses to atrial natriuretic peptide (ANP), Acetylcholine (Ach) and S‐Nitroso‐N‐acetylpenicillamine (SNAP‐NO donor). Furthermore, we assessed the impact of RGZ on gene expression related to the ANP signalling pathway in animals with ACF. Rats subjected to ACF (or sham) were treated with either RGZ (30 mg/kg/day) or vehicle for 4 weeks. Cardiac chambers pressures and volumes were assessed invasively via Miller catheter. Kidney excretory and renal hemodynamic in response to ANP, Ach and SNAP were examined. Renal clearance along with cyclic guanosine monophosphate (cGMP), gene expression of renal CHF‐related genes and ANP signalling in the kidney were determined. RGZ‐treated CHF rats exhibited significant improvement in the natriuretic responses to ANP infusion. This ‘sensitization’ to ANP was not associated with increases in neither urinary cGMP nor in vitro cGMP production. However, RGZ caused down‐regulation of several genes in the renal cortex (Ace, Nos3 and Npr1) and up‐regulation of ACE2, Agtrla, Mme and Cftr along down‐regulation of Avpr2, Npr1,2, Nos3 and Pde3 in the medulla. In conclusion, CHF+RGZ rats exhibited significant enhancement in the natriuretic responses to ANP infusion, which are known to be blunted in CHF. This ‘sensitization’ to ANP is independent of cGMP signalling, yet may involve post‐cGMP signalling target genes such as ACE2, CFTR and V2 receptor. The possibility that TZD treatment in uncomplicated CHF may be less detrimental than thought before deserves additional investigations.