Biophysical Interactions Underpin the Emergence of Information in the Genetic Code.

The genetic code conceals a 'code within the codons', which hints at biophysical interactions between amino acids and their cognate nucleotides. Yet, research over decades has failed to corroborate systematic biophysical interactions across the code. Using molecular dynamics simulations and NMR, we have analysed interactions between the 20 standard proteinogenic amino acids and 4 RNA mononucleotides in 3 charge states. Our simulations show that 50% of amino acids bind best with their anticodonic middle base in the -1 charge state common to the backbone of RNA, while 95% of amino acids interact most strongly with at least 1 of their codonic or anticodonic bases. Preference for the cognate anticodonic middle base was greater than 99% of randomised assignments. We verify a selection of our results using NMR, and highlight challenges with both techniques for interrogating large numbers of weak interactions. Finally, we extend our simulations to a range of amino acids and dinucleotides, and corroborate similar preferences for cognate nucleotides. Despite some discrepancies between the predicted patterns and those observed in biology, the existence of weak stereochemical interactions means that random RNA sequences could template non-random peptides. This offers a compelling explanation for the emergence of genetic information in biology.

Efficiency of Ferritin bio-nanomaterial in reducing the pollutants level of water in the underground corridors of metro rail using GIS.

The underground developments are likely to deteriorate the water quality, which causes damage to the structure. The pollutant levels largely affect the aquifer properties and alter the characteristics of the water quality. Ferritin nanoparticle usage proves to be an effective technology for reducing the pollutant level of the salts, which are likely to affect the underground structure. The observation wells are selected around the underground Metro Rail Corridor, and the secondary observation wells are selected around the corridors. Ferritin is a common iron storage protein as a powder used in the selected wells identified in the path of underground metro rail corridors. Water sampling was done to assess the water quality in the laboratory. The water quality index plots for the two phases (1995-2008) and (2009-2014) using GIS explains the water quality scenario before and after the Ferritin treatment. The Ferritin treatment in water was very effective in reducing the pollutants level of Fluoride and sulphate salts which is likely to bring damage to the structure.

Takayasu arteritis presenting as type A intramural hematoma--an unusual presentation.

Takayasu arteritis which typically affects the aorta and its branches usually presents with obstructive lesions leading to ischemia. We report an unusual case of Takayasu arteritis presenting as an acute Type A intramural hematoma.

Use of ECMO to temporize circulatory instability during severe Brugada electrical storm.

We describe the use of extracorporeal membrane oxygenation to temporize circulatory instability during almost incessant ventricular fibrillation in a patient with Brugada syndrome who had electively discontinued chronic amiodarone therapy. The extracorporeal membrane oxygenation was continued for 3 days after emergent delivery of the neonate, during which time the number of ventricular fibrillation episodes and internal defibrillations markedly decreased concomitant with administration of intravenous amiodarone and verapamil. Oral anti-arrhythmic therapy was subsequently reinstituted, and the remainder of the patient's hospital course was uneventful.

Supravalvular aortic membrane with severe aortic regurgitation: an unusual presentation in adults.

Aortic stenosis due to supravalvular membrane usually presents in children. It may be associated with fusion of the left coronary leaflet and the supravalvular membrane, causing obstruction of the left coronary ostium, and resulting in myocardial ischemia. Despite the immobilization of the left coronary leaflet, these patients present in childhood with aortic stenosis and not regurgitation, with or without accompanying myocardial ischemia. The case is described of an adult patient with supravalvular aortic membrane presenting with severe aortic regurgitation and myocardial infarction due to fusion of the left coronary leaflet with the supravalvular membrane.

Selection of surgical or percutaneous coronary intervention provides differential longevity benefit.

BACKGROUND: Treatment of coronary artery disease (CAD) is evolving with better medications, improvements in percutaneous coronary intervention (PCI), and enhanced techniques for coronary artery bypass grafting (CABG). METHODS: In this study, 18,481 patients with significant (>75% stenosis) CAD treated at a single center between 1986 and 2000 were assigned to one of three groups based on initial treatment strategy: medical therapy (MED) (n = 6862), PCI (n = 6292), or CABG (n = 5327). Each group was categorized into 3 groups according to baseline severity of CAD: low-severity (predominantly 1-vessel), intermediate-severity (predominantly 2-vessel), and high-severity (all 3-vessel), and prospectively evaluated in Cox models for all-cause mortality adjusted for cardiac risk, comorbidity, and propensity for selection of a specific treatment. Treatments were compared for the entire period and three eras (1: 1986 to 1990; 2: 1991 to 1995; 3: 1996 to 2000), the last encompassing widespread availability of PCI with stenting. RESULTS: Survival significantly improved in all groups for all degrees of CAD, despite increasing severity of illness. Revascularization strategies provided significant survival over MED with 8.1, 10.6, and 23.6 additional months per 15 years of follow-up for low-severity, intermediate-severity, and high-severity CAD, respectively. Therapeutic improvements led to increased survival of 5.3 additional months per 7 years of follow-up (95% confidence interval, 0.2 to 10.2; p = 0.039) in era 3 for CABG compared with PCI for high-severity CAD. CONCLUSIONS: Initial revascularization strategies result in significant survival advantage over MED for all CAD levels. Patients with high-severity CAD have reduced survival with PCI compared with those initially treated with CABG.

Beating heart surgery.

Off-pump beating heart coronary revascularization is a valuable surgical technique for high-risk patients, particularly those with severe atherosclerotic changes of the aorta, COPD, recent stroke, or for those in whom blood administration is contraindicated. Advances in clampless surgical techniques should further the benefit of OPCAB versus conventional CABG mostly in terms of stroke risk reduction. For now, routine use of OPCAB for all surgical revascularization procedures remains in question.

Gene therapy in a murine model for clinical application to multiple sclerosis.

Female SJL/J mice, suffering from experimental autoimmune encephalomyelitis (EAE), were injected with 1 x 10(7) cells from a syngeneic fibroblast line transduced with a retroviral vector designed to encode proteolipid protein (101-157) targeted for secretion. A striking abrogation of both clinical and histological signs of disease resulted. The treatment was efficacious when given after the first or the third relapses, protected naive mice from challenge with spinal cord homogenate, and was dose dependent. This strategy was devised to provide a systemic, antigen-specific signal to pathogenic T cells in the absence of costimulation and, hence, render them anergic. Cytokine analyses of brain and spinal cord lymphocytes demonstrate that the treatment induces an antiinflammatory Th2 profile, indicating that this antigen-specific therapy acts by a cytokine-induced pathway. This study was designed for translation to the clinic. We envision using allogeneic transduced fibroblasts, encapsulated in a chamber, to deliver the antigen-specific signal. This will enable us to use one therapeutic cell line for all patients and to remove the device should the therapy exacerbate disease.

Effect of preoperative sonographic mapping on vascular access outcomes in hemodialysis patients.

BACKGROUND: Current DOQI guidelines encourage placing arteriovenous (AV) fistulas in more hemodialysis patients. However, many new fistulas fail to mature sufficiently to be usable for hemodialysis. Preoperative vascular mapping to identify suitable vessels may improve vascular access outcomes. The present study prospectively evaluated the effect of routine preoperative vascular mapping on the type of vascular accesses placed and their outcomes. METHODS: During a 17-month period, preoperative sonographic evaluation of the upper extremity arteries and veins was obtained routinely. The surgeons used the information obtained to plan the vascular access procedure. The types of access placed, their initial adequacy for dialysis, and their long-term outcomes were compared to institutional historical controls placed on the basis of physical examination alone. RESULTS: The proportion of fistulas placed increased from 34% during the historical control period to 64% with preoperative vascular mapping (P < 0.001). When all fistulas were assessed, the initial adequacy rate for dialysis increased mildly from 46 to 54% (P = 0.34). For the subset of forearm fistulas, the initial adequacy increased substantially from 34 to 54% (P = 0.06); the greatest improvement occurred among women (from 7 to 36%, P = 0.06) and diabetic patients (from 21 to 50%, P = 0.055). In contrast, the initial adequacy rate of upper arm fistulas was not improved by preoperative vascular mapping (59 vs. 56%, P = 0.75). Primary access failure was higher for fistulas than grafts (46.4 vs. 20.6%, P = 0.001), but the subsequent long-term failure rate was higher for grafts than fistulas (P < 0.05). Moreover, grafts required a threefold higher intervention rate (1.67 vs. 0.57 per year, P < 0.001) to maintain their patency. The overall effect of this strategy was to double the proportion of patients dialyzing with a fistula in our population from 16 to 34% (P < 0.001). CONCLUSIONS: Routine preoperative vascular mapping results in a marked increase in placement of AV fistulas, as well as an improvement in the adequacy of forearm fistulas for dialysis. This approach resulted in a substantial increase in the proportion of patients dialyzing with a fistula in our patient population. Fistulas have a higher primary failure rate than grafts, but have a lower subsequent failure rate and require fewer procedures to maintain their long-term patency.

Predictors of arteriovenous graft patency after radiologic intervention in hemodialysis patients.

Arteriovenous grafts in hemodialysis patients are prone to recurrent stenosis and thrombosis, requiring frequent radiologic and surgical interventions to optimize their long-term patency. Little is known about the factors that determine graft outcome after a radiologic intervention. The present study examined the clinical and radiologic predictors of intervention-free graft survival after elective angioplasty or thrombectomy. A prospective computerized database was used to determine the outcomes subsequent to all graft angioplasties (n = 330) and thrombectomies (n = 326) performed at the University of Alabama at Birmingham between April 1, 1996, and June 30, 1999. Primary graft survival rates after angioplasty and thrombectomy were 86% versus 43% at 1 month, 71% versus 30% at 3 months, 51% versus 19% at 6 months, and 28% versus 8% at 12 months, respectively. The median intervention-free graft survival time was substantially longer after angioplasty than thrombectomy (6.7 versus 0.6 months; P < 0.001). The superior outcome of angioplasty over thrombectomy was observed even for the subset of procedures with no residual stenosis (median survival, 6.9 versus 2.5 months; P < 0.001). The median graft survival was inversely related to the magnitude of residual stenosis for both elective angioplasty and thrombectomy. Median intervention-free graft survival after angioplasty was inversely related to the postangioplasty intragraft to systemic systolic pressure ratio (7.6, 6.9, and 5.6 months for ratios <0.4, 0.4 to 0.6, and >0.6, respectively; P < 0.001). Intervention-free graft survival after angioplasty or thrombectomy was not affected by graft location (forearm versus upper arm), number of stenotic sites, or presence of diabetes. In conclusion, graft survival is substantially longer after elective angioplasty than thrombectomy, even when the radiologic appearance after the procedure suggests complete resolution of the stenotic lesion. Moreover, the risk for requiring a subsequent graft intervention can be predicted from two simple radiologic measurements: grade of stenosis and intragraft to systemic systolic blood pressure ratio. These parameters may help determine the frequency of monitoring for recurrent stenosis in a given graft.

In vivo ventricular gene delivery of a beta-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction.

BACKGROUND: Genetic manipulation to reverse molecular abnormalities associated with dysfunctional myocardium may provide novel treatment. This study aimed to determine the feasibility and functional consequences of in vivo beta-adrenergic receptor kinase (betaARK1) inhibition in a model of chronic left ventricular (LV) dysfunction after myocardial infarction (MI). METHODS AND RESULTS: Rabbits underwent ligation of the left circumflex (LCx) marginal artery and implantation of sonomicrometric crystals. Baseline cardiac physiology was studied 3 weeks after MI; 5x10(11) viral particles of adenovirus was percutaneously delivered through the LCx. Animals received transgenes encoding a peptide inhibitor of betaARK1 (Adeno-betaARKct) or an empty virus (EV) as control. One week after gene delivery, global LV and regional systolic function were measured again to assess gene treatment. Adeno-betaARKct delivery to the failing heart through the LCx resulted in chamber-specific expression of the betaARKct. Baseline in vivo LV systolic performance was improved in Adeno-betaARKct-treated animals compared with their individual pre-gene delivery values and compared with EV-treated rabbits. Total beta-AR density and betaARK1 levels were unchanged between treatment groups; however, beta-AR-stimulated adenylyl cyclase activity in the LV was significantly higher in Adeno-betaARKct-treated rabbits compared with EV-treated animals. CONCLUSIONS: In vivo delivery of Adeno-betaARKct is feasible in the infarcted/failing heart by coronary catheterization; expression of betaARKct results in marked reversal of ventricular dysfunction. Thus, inhibition of betaARK1 provides a novel treatment strategy for improving the cardiac performance of the post-MI heart.

Early effects of right ventricular volume overload on ventricular performance and beta-adrenergic signaling.

OBJECTIVE: Right ventricular dysfunction is a poorly understood but persistent clinical problem. This study was undertaken to evaluate ventricular performance and beta-adrenergic receptor signaling in a tricuspid regurgitation model of right ventricular overload. METHODS: Seventeen dogs were chronically instrumented with epicardial dimension transducers. By means of the shell-subtraction model, right ventricular pressure-volume relationships were evaluated in normal and right ventricular overload states. Right ventricular chamber performance was quantified by the stroke work at an end-diastolic volume relationship. RESULTS: Right ventricular volume overload caused a 28% +/- 11% and 31% +/- 9% decline in chamber performance acutely and at 1 week, respectively, whereas end-diastolic volume increased from 45 +/- 21 to 60 +/- 30 mL (P =. 019). beta-Adrenergic receptor signaling in myocardial samples was assessed, examining adenylyl cyclase and G-protein-coupled receptor kinase activity. Stimulated adenylyl cyclase activity significantly decreased, and G-protein-coupled receptor kinase activity significantly increased in both left and right ventricular samples caused by increased levels of beta-adrenergic receptor kinase 1. No change in beta-adrenergic receptor density was seen at 1 week. CONCLUSIONS: Early right ventricular overload is associated with impaired right ventricular chamber contractility, dilation, and, importantly, a biventricular alteration of beta-adrenergic receptor signaling.

Culture-specific models of men's sexual aggression: intra- and interpersonal determinants.

The role of intra- and interpersonal variables was examined in samples of Asian American (N = 91) and European American (N = 377) men. A path model for Asian American men suggested 2 interpersonal paths and 1 intrapersonal path to sexual aggression. For Asian Americans, concern about social standing is a risk factor among those who hold misogynous beliefs and who use alcohol before sex. Concern about the negative reputational impact of sexual aggression is a protective factor among Asian Americans who do not hold these negative attitudes. A European American model suggested only an intrapersonal path to sexual aggression consisting of misogynous beliefs, with interpersonal variables not being predictive of sexual aggression. These results suggest both individualist and collectivist determinants of Asian American sexual aggression, whereas only individualist determinants were found for European American sexual aggression.