Pyrazole-Thiazole Core-Containing Analogs Exhibit Adjunctive Activity with Meropenem against Carbapenem-Resistant Enterobacteriaceae (CRE)

Pyrazole-thiazole core-containing compound KP-40 and 20 novel derivatives were designed and synthesized through traditional SAR analysis. These molecules displayed adjunctive activity with meropenem against Gram-negative bacteria evidenced by a range of fractional inhibitory concentration (FIC=0.5–0.25) and minimum adjunctive concentration (MAC=128–32 μM) values. Of this series of molecules, four compounds displayed notable adjunctive potential, with FIC and MAC values of 0.25 and 32 μM, respectively. Moreover, the solubility of these compounds was improved to an acceptable range. Further analysis using our “in house” permeation and efflux multi parameter optimization (PEMPO) algorithm revealed key physicochemical properties that may be critical for the development of active Gram-negative antibacterials. Taking PEMPO scores into consideration prior to executing synthesis of analogs may be a simple, yet rapid and effective strategy that can be used in conjunction with traditional SAR approaches to aid in the design of potent Gram-negative antibacterials.     

Structural Consequences of the 1,2,3-Triazole as an Amide Bioisostere in Analogues of the Cystic Fibrosis Drugs VX-809 and VX-770

Although the 1,2,3-triazole is a commonly used amide bioisostere in medicinal chemistry, the structural implications of this replacement have not been fully studied. Employing X-ray crystallography and computational studies, we report the spatial and electronic consequences of replacing an amide with the triazole in analogues of cystic fibrosis drugs in the VX-770 and VX-809 series. Crystallographic analyses quantify subtle differences in the relative positions and conformational preferences of the R¹ and R² substituents attached to the amide and triazole bioisosteres. Computational studies derived from the X-ray data highlight the improved hydrogen bonding donor and acceptor capabilities of the amide in comparison to the triazole. This analysis of the spatial and electronic differences between the amide and 1,2,3-triazole will inform medicinal chemists as they consider using the triazole as an amide bioisostere.     

Advanced Postirradiation Characterization of Nuclear Fuels Using Pulsed Neutrons

Methods for postirradiation characterization of bulk (cm³) irradiated materials or even spent nuclear fuels are sparse due to their extremely radioactive nature. While several methods exist to characterize smaller volumes (<?1 mm³) of such samples, selecting these volumes from larger samples is challenging. X-ray-based methods are prohibitive due to the strong γ-radiation from the sample flooding the detectors. Neutron-based methods available in the proximity of irradiation reactors allow for thermal neutron radiography or computed tomography using a small reactor source, but one cannot assess isotope distributions or microstructural features such as phases, texture, or strain from diffraction measurements due to flux limitations. We present herein a pathway to provide pulsed neutron characterization of bulk irradiated samples using time-of-flight neutron diffraction for microstructural characterization and energy-resolved neutron imaging for assessment of isotopic densities and distributions. Ultimately, laser-driven pulsed neutron sources may allow deployment of these techniques pool-side at irradiation reactors.

     

A patient-specific computational model of hypoxia-modulated radiation resistance in glioblastoma using 18F-FMISO-PET

Glioblastoma multiforme (GBM) is a highly invasive primary brain tumour that has poor prognosis despite aggressive treatment. A hallmark of these tumours is diffuse invasion into the surrounding brain, necessitating a multi-modal treatment approach, including surgery, radiation and chemotherapy. We have previously demonstrated the ability of our model to predict radiographic response immediately following radiation therapy in individual GBM patients using a simplified geometry of the brain and theoretical radiation dose. Using only two pre-treatment magnetic resonance imaging scans, we calculate net rates of proliferation and invasion as well as radiation sensitivity for a patient''s disease. Here, we present the application of our clinically targeted modelling approach to a single glioblastoma patient as a demonstration of our method. We apply our model in the full three-dimensional architecture of the brain to quantify the effects of regional resistance to radiation owing to hypoxia in vivo determined by [¹⁸F]-fluoromisonidazole positron emission tomography (FMISO-PET) and the patient-specific three-dimensional radiation treatment plan. Incorporation of hypoxia into our model with FMISO-PET increases the model–data agreement by an order of magnitude. This improvement was robust to our definition of hypoxia or the degree of radiation resistance quantified with the FMISO-PET image and our computational model, respectively. This work demonstrates a useful application of patient-specific modelling in personalized medicine and how mathematical modelling has the potential to unify multi-modality imaging and radiation treatment planning.     

Mixed-Metal MOF-74 Templated Catalysts for Efficient Carbon Dioxide Capture and Methanation

The vast chemical and structural tunability of metal–organic frameworks (MOFs) are beginning to be harnessed as functional supports for catalytic nanoparticles spanning a range of applications. However, a lack of straightforward methods for producing nanoparticle-encapsulated MOFs as efficient heterogeneous catalysts limits their usage. Herein, a mixed-metal MOF, NiMg-MOF-74, is utilized as a template to disperse small Ni nanoclusters throughout the parent MOF. By exploiting the difference in Ni O and Mg O coordination bond strength, Ni²⁺ is selectively reduced to form highly dispersed Ni nanoclusters constrained by the parent MOF pore diameter, while Mg²⁺ remains coordinated in the framework. By varying the ratio of Ni to Mg in the parent MOF, accessible surface area and crystallinity can be tuned upon thermal treatment, influencing CO₂ adsorption capacity and hydrogenation selectivity. The resulting Ni nanoclusters prove to be an active catalyst for CO₂ methanation and are examined using extended X-ray absorption fine structure and X-ray photoelectron spectroscopy. By preserving a segment of the Mg²⁺-containing MOF framework, the composite system retains a portion of its CO₂ adsorption capacity while continuing to deliver catalytic activity. The approach is thus critical for designing materials that can bridge the gap between carbon capture and CO₂ utilization.     

The reported point centromeres of Scheffersomyces stipitis are retrotransposon long terminal repeats

Point centromeres, found in some ascomycete yeasts such Saccharomyces cerevisiae, are very different in structure from the centromeres of other eukaryotes. They are tiny and nonrepetitive and contain only two short conserved sequence motifs. Until recently, point centromeres were thought to have a single evolutionary origin, in the budding yeast family Saccharomycetaceae. Most yeasts outside this family have centromeres that are many kilobases in size. Some have centromeres consisting of a large inverted repeat sequence, others have centromeric clusters of retrotransposons, and a third group including Candida albicans has centromeres with no conserved sequence features. It was recently reported that Scheffersomyces stipitis has point centromeres with a strongly conserved 125-bp core sequence, which is unexpected because S. stipitis is only distantly related to the known point-centromere species. We show here that the 125-bp core sequence is actually part of the long terminal repeat (LTR) of the Ty5-like retrotransposon Tps5, which forms a cluster in the centromeric region of each S. stipitis chromosome. Thus, the LTR of a centromere-associated retrotransposon confers centromere-like mitotic stability when cloned into a plasmid. The centromeric regions of S. stipitis contain three types of Tps5 element (Tps5a, Tps5b, and Tps5c) and a noncoding nonautonomous large retrotransposon derivative.     

Long-run urban dynamics: understanding local housing market change in London

Abstract

Recently, a literature has emerged using empirical techniques to study the evolution of international cities over many centuries; however, few studies examine long-run change within cities. Conventional models and concepts are not always appropriate and data issues make long-run neighbourhood analysis particularly problematic. This paper addresses some of these points. First, it discusses why the analysis of long-run urban change is important for modern urban policy and considers the most important concepts. Second, it constructs a novel data set at the micro level, which allows consistent comparisons of London neighbourhoods in 1881 and 2001. Third, the paper models some of the key factors that affected long-run change, including the role of housing. There is evidence that the relative social positions of local urban areas persist over time but, nevertheless, at fine spatial scales, local areas still exhibit change, arising from aggregate population dynamics, from advances in technology, and also from the effects of shocks, such as wars. In general, where small areas are considered, long-run changes are likely to be greater, because individuals are more mobile over short than long distances. Finally, the paper considers the implications for policy.