Exceptional convergent evolution in a virus

Replicate lineages of the bacteriophage phiX 174 adapted to growth at high temperature on either of two hosts exhibited high rates of identical, independent substitutions. Typically, a dozen or more substitutions accumulated in the 5.4-kilobase genome during propagation. Across the entire data set of nine lineages, 119 independent substitutions occurred at 68 nucleotide sites. Over half of these substitutions, accounting for one third of the sites, were identical with substitutions in other lineages. Some convergent substitutions were specific to the host used for phage propagation, but others occurred across both hosts. Continued adaptation of an evolved phage at high temperature, but on the other host, led to additional changes that included reversions of previous substitutions. Phylogenetic reconstruction using the complete genome sequence not only failed to recover the correct evolutionary history because of these convergent changes, but the true history was rejected as being a significantly inferior fit to the data. Replicate lineages subjected to similar environmental challenges showed similar rates of substitution and similar rates of fitness improvement across corresponding times of adaptation. Substitution rates and fitness improvements were higher during the initial period of adaptation than during a later period, except when the host was changed.     

Effect of ETA receptor antagonists on cardiovascular responses induced by centrally administered sarafotoxin 6b: role of sympathetic nervous system

The present study was carried out to investigate the cardiovascular effects of centrally administered SRT6b in saline, BQ123 and BMS182874 pretreated male Sprague-Dawley rats, using a radioactive microsphere technique. SRT6b (100 ng, ICV) produced a transient increase (40%) in blood pressure at 5 min followed by a sustained decrease (-42%) at 30 and 60 min in control rats. Total peripheral resistance and heart rate were not significantly altered. Cardiac output increased (16%) at 5 min and decreased 30 and 60 min following SRT6b administration. Central venous pressure was not affected by SRT6b. Regional blood flow and vascular resistance did not change at 5 min following administration of SRT6b. However, a significant decrease in blood flow to the brain, heart, kidneys, liver, spleen, gastrointestinal tract and mesentery and pancreas was observed 30 and 60 min following administration of SRT6b in control (saline treated) rats. Pretreatment with ETA selective receptor antagonists, BQ123 (10 micrograms, ICV) or BMS182874 (50 micrograms, ICV) significantly attenuated the pressor and depressor effects of centrally administered SRT6b. SRT6b induced decrease in blood flow was completely blocked by pretreatment with BQ123 or BMS182874. ET-1 (100 ng, ICV) produced an increase followed by a decrease similar to SRT6b. Reserpine (5 mg/kg, IP) pretreatment attenuated the cardiovascular effects of ET-1. Role of sympathetic nervous system was determined by measuring splanchnic nerve activity. SRT6b when administered in the lateral cerebral ventricle did not produce any significant effect at 5 min, however, a significant decrease in sympathetic nerve activity was observed 30 min after its administration. It is concluded that centrally administered SRT6b produces significant changes in systematic and regional blood circulation which can be completely blocked by ETA receptor antagonist. The cardiovascular effects of centrally administered SRT6b appear to be mediated through the sympathetic nervous system.     

An Overview of Next-Generation Androgen Receptor-Targeted Therapeutics in Development for the Treatment of Prostate Cancer

Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol (DES; an estrogen) produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the first-line PCa therapy. Insufficiency of ADT over time leads to castration-resistant PCa (CRPC) in which the AR axis is still active, despite castrate levels of circulating androgens. Despite the approval and use of multiple generations of competitive AR antagonists (antiandrogens), antiandrogen resistance emerges rapidly in CRPC due to several mechanisms, mostly converging in the AR axis. Recent evidence from multiple groups have defined noncompetitive or noncanonical direct binding sites on AR that can be targeted to inhibit the AR axis. This review discusses new developments in the PCa treatment paradigm that includes the next-generation molecules to noncanonical sites, proteolysis targeting chimera (PROTAC), or noncanonical N-terminal domain (NTD)-binding of selective AR degraders (SARDs). A few lead compounds targeting each of these novel noncanonical sites or with SARD activity are discussed. Many of these ligands are still in preclinical development, and a few early clinical leads have emerged, but successful late-stage clinical data are still lacking. The breadth and diversity of targets provide hope that optimized noncanonical inhibitors and/or SARDs will be able to overcome antiandrogen-resistant CRPC.     

Color-coded measures of myocardial velocity throughout the cardiac cycle by tissue Doppler imaging to quantify regional left ventricular function

TDI is a new echocardiographic technique that calculates and displays color-coded myocardial velocity on-line. To determine the feasibility of endocardial velocity throughout the cardiac cycle as a means to quantify regional function, 20 normal subjects aged 30 +/- 5 years and 12 patients with heart disease aged 62 +/- 17 years were studied with a prototype TDI system. TDI M-mode images were acquired by using a multicolored velocity map (display range, -30 to 30 mm/sec; temporal resolution, 90 Hz). Color-coded velocity data were then converted to numeric values off-line at 50 msec intervals. Posterior wall velocities throughout the cardiac cycle by TDI were closely correlated with velocity calculations from the first derivative of routine digitized M-mode tracings (group mean r = 0.88 +/- 0.03, SEE = 7.0 +/- 1.1 mm/sec). Anteroseptal TDI color-coded systolic velocity occurred 164 +/- 84 msec from the onset of the electrocardiographic QRS compared with 203 +/- 33 msec in the posterior wall (P < 0.05) in normal subjects, consistent with normal electrical activation. Significant differences in systolic and diastolic posterior wall TDI velocity data were observed in patients with hypokinetic or akinetic segments assessed by independent routine study when compared with normal controls. Calculated systolic and early diastolic posterior wall TDI indexes correlated significantly with percentage of wall thickening. Of abnormal anteroseptal segments, TDI systolic time velocity integrals were significantly different than normal and correlated with percentage of wall thickening. TDI has potential to quantitatively assess regional left ventricular function.     

Adsorption of Pb(II) from aqueous solution by Azadirachta indica (Neem) leaf powder

An adsorbent was developed from the mature leaves of the Neem (Azadirachta indica) tree for removing Pb(II) from water. Adsorption was carried out in a batch process with several different concentrations of Pb(II) by varying amount of adsorbent, pH, agitation time and temperature. The uptake of the metal was very fast initially, but gradually slowed down indicating penetration into the interior of the adsorbent particles. Both first-order and second-order kinetics were tested and it was found that the latter gave a better explanation. The experimental data closely followed both Langmuir and Freundlich isotherms. The adsorbent had a considerably high Langmuir monolayer capacity of 300 mg/g. A small amount of the adsorbent (1.2 g/L) could remove as much as 93% of Pb(II) in 300 min from a solution of concentration 100mg/L at 300 K. The adsorption continuously increased in the pH range of 2.0-7.0, beyond which the adsorption could not be carried out due to the precipitation of the metal. The adsorption was exothermic at ambient temperature and the computation of the parameters, DeltaH, DeltaS and DeltaG, indicated the interactions to be thermodynamically favourable.     

Preparation of Oil-Encapsulated Microcapsules and Tribological Property of Ni Composite Coating

Microcapsules containing oil are potential candidate materials for preparing electrocomposite coatings with excellent tribological properties. In the present study, the preparation of oil-encapsulated microcapsules and electrodeposition of Ni-microcapsule composite coating are presented along with the properties of the coating. In situ interfacial polymerization method was used for the preparation of lubricating oil-encapsulated urea-formaldehyde microcapsules. The synthesized microcapsules were incorporated into the nickel matrix by electrodeposition using Ni-Watts bath. The Ni-composite coating containing microcapsules exhibited smaller Ni grain size, higher microhardness and lower surface roughness compared to plain Ni coating. Electrodeposited Ni coating containing oil-encapsulated microcapsules exhibited improved tribological properties with lower wear loss and coefficient of friction compared to plain nickel coating.     

Efficiency of Urban Water Supply Utilities in India

The two parameters of services output of water utilities are the per capita water available for consumption and the hours for which water is supplied per day. However, water utilities in India differ on the level of these outputs substantially. This paper uses the data for water utilities in 31 cities to analyse their performance in delivery of services. Using data envelopment analysis, a measure of technical efficiency for various utilities is calculated. The results indicate that water utilities can increase the delivery of water on a per capita basis and increase the hours of supply per day by about 18%. Nearly 37% of the increase in services could result from changing the scale of operation. This paper also discusses if the institutional framework within which these utilities operate has implications on their efficiency.     

Edge Strength Testing of Thin Glasses

Following a brief history of various tests for measuring edge strength, we present the theory and application of four-point vertical bend test (VBT). The latter is similar to a standard four-point bend test except that the specimen is turned on its edge so as to permit application of uniform tension to a majority of the edge flaws. The article cautions against lateral buckling of the VBT specimen, resulting in failure initiation from the “compression” edge, if its dimensions are not optimized. We provide guidelines for designing the width and thickness of the VBT specimen relative to its length, which obviates the onset of lateral buckling. Three simple inspections to verify the validity of VBT include the shape of load versus deflection curve, location of failure origin, and fracture pattern. Two examples, one involving edge quality of an aluminosilicate glass and the other involving factors that affect edge strength of automotive glass, help illustrate the application of VBT.     

Concatenated codes for fading channels based on recursive space-time trellis codes

We propose a class of codes which combine the principles of turbo coding and space-time trellis codes. It is first shown that several classes of space-time codes have an equivalent recursive realization. This fact is then exploited to design serial concatenated coding schemes with an outer code, interleaver, and an inner recursive space-time encoder. Two solutions are proposed in this paper - the use of convolutional outer codes aimed mainly to improve the power efficiency and the use of very high-rate outer codes to obtain significant improvement in power efficiency with a marginal decrease in spectral efficiency. We show that single parity check based turbo product codes are a good candidate for very high-rate outer codes. Finally, we propose an automatic repeat request scheme based on recursive realizations of space-time codes and show that the proposed scheme provides significant reduction in frame error rate.