Early male initiation (time frame shift): a possible contributor to their shortened lifespan

Diosgenyl alpha-L-rhamnopyranosyl-(1--2)-[beta-glucopyranosyl-(1--3)]- beta-D-glucopyranoside (gracillin), a monodesmosidic saponin isolated from paris, dioscorea, and costacea species with promising cardiovascular and antitumor activities, was synthesized by stepwise glycosylation.     

Chromophore‐Linked Substrate (CLS405): Probing Metallo‐β‐Lactamase Activity and Inhibition

Serine‐ and metallo‐β‐lactamases present a threat to the clinical use of nearly all β‐lactam antibiotics, including penicillins, cephalosporins, and carbapenems. Efforts to develop metallo‐β‐lactamase (MBL) inhibitors require suitable screening platforms to allow the rapid determination of β‐lactamase activity and efficient inhibition. Unfortunately, the platforms currently available are not ideal for this purpose. Further progress in MBL inhibitor identification requires inexpensive and widely applicable assays. Herein the identification of an inexpensive and stable chromogenic substrate suitable for use in assays of clinically relevant MBLs is described. (6R,7R)‐3‐((4‐Nitrophenoxy)methyl)‐8‐oxo‐7‐(2‐phenylacetamido)‐5‐thia‐1‐azabicyclo[4.2.0]oct‐2‐ene‐2‐carboxylic acid 5,5‐dioxide (CLS405) was synthesised in a three‐step protocol. CLS405 was then characterised spectroscopically, and its stability and kinetic properties evaluated. With a Δλ_max value of 100 nm between the parent and hydrolysis product, a higher analytical accuracy is possible with CLS405 than with commonly used chromogenic substrates. The use of CLS405 in assays was validated by MBL activity measurements and inhibitor screening that resulted in the identification of N‐hydroxythiazoles as new inhibitor scaffolds for MBLs. Further evaluation of the identified N‐hydroxythiazoles against a panel of clinically relevant MBLs showed that they possess inhibitory activities in the mid‐ to low‐micromolar range. The findings of this study provide both a useful tool compound for further inhibitor identification, and novel scaffolds for the design of improved MBL inhibitors with potential as antibiotics against resistant strains of bacteria.     

Isolation of Ambient Particles of Known Critical Supersaturation: The Differential Activation Separator (DAS)

A field-deployable instrument has been developed that isolates from an ambient aerosol those particles that have critical supersaturations, S_c, within a narrow, user-specified, range. This Differential Activation Separator (DAS) consists of two continuous flow diffusion chambers housed within a single enclosure. Particles are introduced into the upstream chamber referred to as the CCN remover (CCNR) near the centerline between a warm, water-soaked, plate and a cool, continuously circulated, water bath. Those particles that activate at the resulting peak supersaturation, S_p, grow quickly and fall into the water bath. The remaining aerosol enters the second chamber referred to as the CCN separator (CCNS), which differs from the CCNR primarily in the use of a salt solution in the lower bath. The imposed temperature differential establishes an S_p slightly higher than that maintained in the upstream chamber, while the presence of a salt solution at the lower boundary results in a subsaturated region in roughly the lower half of the chamber. Those particles having (S_p)_CCNR < S _c < (S_p)_CCNS activate in this chamber and begin to fall due to gravitational settling. Before reaching the lower bath, the droplets evaporate in the subsaturated environment and continue to travel towards the chamber exit. The previously activated particles in the lower half of the chamber and the unactivated particles in the upper half are extracted in separate flows that are subsequently dried. Calibration of the DAS was achieved by measuring the size distribution of separated particles when a polydisperse ammonium sulfate aerosol was introduced.     

MODEL REFERENCE ADAPTIVE CONTROL BASED ON LIAPUNOV'S DIRECT METHOD Part II: Hybrid Computer Simulation and Experimental Application

A Model Reference Adaptive Control (MRAC) system is evaluated via hybrid computer simulation and experimental application to a computer-controlled, pilot plant evaporator. In both the simulation and experimental studies, the MRAC system performed well and was insensitive to unmeasured process disturbances, to the choice of the initial control policy and to changes in plant operating conditions. In addition to providing an algorithm for adapting control systems to accommodate changing process parameters, MRAC also provides a systematic approach for tuning or developing multivariable control systems for time-invariant processes.     

GRAVITATIONAL SETTLING OF SUSPENDED PARTICLES FROM A FULLY DEVELOPED FLOW IN A CURVED TUBE

The gravitational settling of monodisperse particles from fully developed laminar flow in a horizontal curved tube is considered. The particle size is small compared with the tube radius, and their concentration is small so that they do not interact with each other or affect the flow. It was found that for sufficiently heavy particles, or for tubes with very small curvature, or for very small flow Reynolds numbers, the settling to the tube surface versus axial distance is much the same as that for a straight tube. However, for the opposite size of these parameters, the settling behavior becomes much different than that of a straight tube. Particles are maintained in the flow in helical spiral motions and do not settle to the tube surface.     

Nanopore-Based Analysis of Chemically Modified DNA and Nucleic Acid Drug Targets

Nucleic acids are central figures in many of life’s key molecular processes, e.g., enzymatic activity, epigenetics/gene regulation, viral replication, aging, cancer, and other diseases. Over the past two decades, nanopores have emerged as a new tool for studying the properties of nucleic acids at the single-molecule level. In this review, we summarize the use of nanopores as sensors of nucleic acid structure, particularly for studying chemically modified and damaged DNA, and for probing the interactions of small-molecule drugs with nucleic acid targets.     

The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers

This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists) induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers.     

Nonlinear gain coefficients in semiconductor quantum-well lasers:effects of carrier diffusion, capture, and escape

Effective nonlinear gain coefficients due to the effects of carrier diffusion, capture, and escape are derived from the carrier transport equations. The quantum capture and escape processes between the confined states and the unconfined states are calculated from first principles by evaluating the carrier-polar longitudinal optical phonon interactions. The dc and ac capture times and escape times are derived from evaluating the net capture current of carriers. The differences in capture and escape times between dc and ac operating conditions are numerically investigated. We find that both dc and ac escape times are strongly dependent on the quantum well structure. This differs from the dc and ac capture times that are not sensitive to the quantum well structure. We also find that the dc escape time predicted by the classical thermionic emission theory will no longer be valid for narrow or shallow quantum wells. We show that both dc and ac capture and escape time ratios will increase as the carrier temperature and the carrier density in the quantum well increase. Therefore, we suggest that the possible cause of the resonant frequency degradation and dramatic increase in the damping rate results from the increase of the ac capture to escape time ratio by the effects of carrier heating. Two theoretical models (2N and 3N models) were used to study the effects of carrier diffusion-capture-escape on the modulation response of quantum-well lasers and a distributed model of carrier transport in quantum-well lasers is proposed. Their implications in designing high-speed quantum-well lasers are discussed     

Deliberately Losing Control of C−H Activation Processes in the Design of Small-Molecule-Fragment Arrays Targeting Peroxisomal Metabolism

Combined photochemical arylation, “nuisance effect” (S_NAr) reaction sequences have been employed in the design of small arrays for immediate deployment in medium-throughput X-ray protein–ligand structure determination. Reactions were deliberately allowed to run “out of control” in terms of selectivity; for example the ortho-arylation of 2-phenylpyridine gave five products resulting from mono- and bisarylations combined with S_NAr processes. As a result, a number of crystallographic hits against NUDT7, a key peroxisomal CoA ester hydrolase, have been identified.