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"Crooks, Peter"
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Empires and bureaucracy in world history : from late antiquity to the twentieth century
\"How did empires rule different peoples across vast expanses of space and time? And how did small numbers of imperial bureaucrats govern large numbers of subordinated peoples? Empires and Bureaucracy in World History seeks answers to these fundamental problems in imperial studies by exploring the power and limits of bureaucracy. The book is pioneering in bringing together historians of antiquity and the Middle Ages with scholars of post-medieval European empires, while a genuinely world-historical perspective is provided by chapters on China, the Incas and the Ottomans. The editors identify a paradox in how bureaucracy operated on the scale of empires and so help explain why some empires endured for centuries while, in the contemporary world, empires fail almost before they begin. By adopting a cross-chronological and world-historical approach, the book challenges the abiding association of bureaucratic rationality with 'modernity' and the so-called 'Rise of the West'\"-- Provided by publisher.
Book
Perverse Sheaves and the Cohomology of Regular Hessenberg Varieties
We use the Springer correspondence to give a partial characterization of the irreducible representations which appear in the Tymoczko dot action of the Weyl group on the cohomology ring of a regular semisimple Hessenberg variety. In type
A
, we apply these techniques to prove that all irreducible summands which appear in the pushforward of the constant sheaf on the universal Hessenberg family have full support. We also observe that the recent results of Brosnan and Chow, which apply the local invariant cycle theorem to the family of regular Hessenberg varieties in type
A
, extend to arbitrary Lie type. We use this extension to prove that regular Hessenberg varieties, though not necessarily smooth, always have the “Kähler package.”
Journal Article
Design and Synthesis of Novel Hybrid 8-Hydroxy Quinoline-Indole Derivatives as Inhibitors of Aβ Self-Aggregation and Metal Chelation-Induced Aβ Aggregation
A series of novel hybrid 8-hydroxyquinoline-indole derivatives (7a–7e, 12a–12b and 18a–18h) were synthesized and screened for inhibitory activity against self-induced and metal-ion induced Aβ1–42 aggregation as potential treatments for Alzheimer’s disease (AD). In vitro studies identified the most inhibitory compounds against self-induced Aβ1–42 aggregation as 18c, 18d and 18f (EC50 = 1.72, 1.48 and 1.08 µM, respectively) compared to the known anti-amyloid drug, clioquinol (1, EC50 = 9.95 µM). The fluorescence of thioflavin T-stained amyloid formed by Aβ1–42 aggregation in the presence of Cu2+ or Zn2+ ions was also dramatically decreased by treatment with 18c, 18d and 18f. The most potent hybrid compound 18f afforded 82.3% and 88.3% inhibition, respectively, against Cu2+- induced and Zn2+- induced Aβ1–42 aggregation. Compounds 18c, 18d and 18f were shown to be effective in reducing protein aggregation in HEK-tau and SY5Y-APPSw cells. Molecular docking studies with the most active compounds performed against Aβ1–42 peptide indicated that the potent inhibitory activity of 18d and 18f were predicted to be due to hydrogen bonding interactions, π–π stacking interactions and π–cation interactions with Aβ1–42, which may inhibit both self-aggregation as well as metal ion binding to Aβ1–42 to favor the inhibition of Aβ1–42 aggregation.
Journal Article
Structural modeling of GSK3β implicates the inactive (DFG-out) conformation as the target bound by TDZD analogs
Glycogen synthase kinase-3β (GSK3β) controls many physiological pathways, and is implicated in many diseases including Alzheimer’s and several cancers. GSK3β-mediated phosphorylation of target residues in microtubule-associated protein tau (MAPTAU) contributes to MAPTAU hyperphosphorylation and subsequent formation of neurofibrillary tangles. Inhibitors of GSK3β protect against Alzheimer’s disease and are therapeutic for several cancers. A thiadiazolidinone drug, TDZD-8, is a non-ATP-competitive inhibitor targeting GSK3β with demonstrated efficacy against multiple diseases. However, no experimental data or models define the binding mode of TDZD-8 with GSK3β, which chiefly reflects our lack of an established inactive conformation for this protein. Here, we used metadynamic simulation to predict the three-dimensional structure of the inactive conformation of GSK3β. Our model predicts that phosphorylation of GSK3β Serine9 would hasten the DFG-flip to an inactive state. Molecular docking and simulation predict the TDZD-8 binding conformation of GSK3β to be inactive, and are consistent with biochemical evidence for the TDZD-8–interacting residues of GSK3β. We also identified the pharmacophore and assessed binding efficacy of second-generation TDZD analogs (TDZD-10 and Tideglusib) that bind GSK3β as non-ATP-competitive inhibitors. Based on these results, the predicted inactive conformation of GSK3β can facilitate the identification of novel GSK3β inhibitors of high potency and specificity.
Journal Article
High flux novel polymeric membrane for renal applications
Biocompatibility and the ability to mediate the appropriate flux of ions, urea, and uremic toxins between blood and dialysate components are key parameters for membranes used in dialysis. Oxone-mediated TEMPO-oxidized cellulose nanomaterials have been demonstrated to be excellent additives in the production and tunability of ultrafiltration and dialysis membranes. In the present study, nanocellulose ionic liquid membranes (NC-ILMs) were tested in vitro and ex vivo. An increase in flux of up to two orders of magnitude was observed with increased rejection (about 99.6%) of key proteins compared to that of polysulfone (PSf) and other commercial membranes. NC-ILMs have a sharper molecular weight cut-off than other phase inversion polymeric membranes, allowing for high throughput of urea and a uremic toxin surrogate and limited passage of proteins in dialysis applications. Superior anti-fouling properties were also observed for the NC-ILMs, including a > 5-h operation time with no systemic anticoagulation in blood samples. Finally, NC-ILMs were found to be biocompatible in rat ultrafiltration and dialysis experiments, indicating their potential clinical utility in dialysis and other blood filtration applications. These superior properties may allow for a new class of membranes for use in a wide variety of industrial applications, including the treatment of patients suffering from renal disease.
Journal Article
Biobanked Glioblastoma Patient-Derived Organoids as a Precision Medicine Model to Study Inhibition of Invasion
Glioblastoma (GBM) is highly resistant to treatment and invasion into the surrounding brain is a cancer hallmark that leads to recurrence despite surgical resection. With the emergence of precision medicine, patient-derived 3D systems are considered potentially robust GBM preclinical models. In this study, we screened a library of 22 anti-invasive compounds (i.e., NF-kB, GSK-3-B, COX-2, and tubulin inhibitors) using glioblastoma U-251 MG cell spheroids. We evaluated toxicity and invasion inhibition using a 3D Matrigel invasion assay. We next selected three compounds that inhibited invasion and screened them in patient-derived glioblastoma organoids (GBOs). We developed a platform using available macros for FIJI/ImageJ to quantify invasion from the outer margin of organoids. Our data demonstrated that a high-throughput invasion screening can be done using both an established cell line and patient-derived 3D model systems. Tubulin inhibitor compounds had the best efficacy with U-251 MG cells, however, in ex vivo patient organoids the results were highly variable. Our results indicate that the efficacy of compounds is highly related to patient intra and inter-tumor heterogeneity. These results indicate that such models can be used to evaluate personal oncology therapeutic strategies.
Journal Article
Thiadiazolidinone (TDZD) Analogs Inhibit Aggregation-Mediated Pathology in Diverse Neurodegeneration Models, and Extend C. elegans Life- and Healthspan
Chronic, low-grade inflammation has been implicated in aging and age-dependent conditions, including Alzheimer’s disease, cardiomyopathy, and cancer. One of the age-associated processes underlying chronic inflammation is protein aggregation, which is implicated in neuroinflammation and a broad spectrum of neurodegenerative diseases such as Alzheimer’s, Huntington’s, and Parkinson’s diseases. We screened a panel of bioactive thiadiazolidinones (TDZDs) from our in-house library for rescue of protein aggregation in human-cell and C. elegans models of neurodegeneration. Among the tested TDZD analogs, PNR886 and PNR962 were most effective, significantly reducing both the number and intensity of Alzheimer-like tau and amyloid aggregates in human cell-culture models of pathogenic aggregation. A C. elegans strain expressing human Aβ1–42 in muscle, leading to AD-like amyloidopathy, developed fewer and smaller aggregates after PNR886 or PNR962 treatment. Moreover, age-progressive paralysis was reduced 90% by PNR886 and 75% by PNR962, and “healthspan” (the median duration of spontaneous motility) was extended 29% and 62%, respectively. These TDZD analogs also extended wild-type C. elegans lifespan by 15–30% (p < 0.001), placing them among the most effective life-extension drugs. Because the lead drug in this family, TDZD-8, inhibits GSK3β, we used molecular-dynamic tools to assess whether these analogs may also target GSK3β. In silico modeling predicted that PNR886 or PNR962 would bind to the same allosteric pocket of inactive GSK3β as TDZD-8, employing the same pharmacophore but attaching with greater avidity. PNR886 and PNR962 are thus compelling candidate drugs for treatment of tau- and amyloid-associated neurodegenerative diseases such as AD, potentially also reducing all-cause mortality.
Journal Article
Deuterated buprenorphine retains pharmacodynamic properties of buprenorphine and resists metabolism to the active metabolite norbuprenorphine in rats
Introduction: An active metabolite of buprenorphine ( BUP ), called norbuprenorphine ( NorBUP ), is implicated in neonatal opioid withdrawal syndrome when BUP is taken during pregnancy. Therefore, reducing or eliminating metabolism of BUP to NorBUP is a novel strategy that will likely lower total fetal exposure to opioids and thus improve offspring outcomes. Precision deuteration alters pharmacokinetics of drugs without altering pharmacodynamics. Here, we report the synthesis and testing of deuterated buprenorphine ( BUP-D2 ). Methods: We determined opioid receptor affinities of BUP-D2 relative to BUP with radioligand competition receptor binding assays, and the potency and efficacy of BUP-D2 relative to BUP to activate G-proteins via opioid receptors with [ 35 S]GTPγS binding assays in homogenates containing the human mu, delta, or kappa opioid receptors. The antinociceptive effects of BUP-D2 and BUP were compared using the warm-water tail withdrawal assay in rats. Blood concentration versus time profiles of BUP, BUP-D2, and NorBUP were measured in rats following intravenous BUP-D2 or BUP injection. Results: The synthesis provided a 48% yield and the product was ≥99% deuterated. Like BUP, BUP-D2 had sub-nanomolar affinity for opioid receptors. BUP-D2 also activated opioid receptors and induced antinociception with equal potency and efficacy as BUP. The maximum concentration and the area under the curve of NorBUP in the blood of rats that received BUP-D2 were over 19- and 10-fold lower, respectively, than in rats that received BUP. Discussion: These results indicate that BUP-D2 retains key pharmacodynamic properties of BUP and resists metabolism to NorBUP and therefore holds promise as an alternative to BUP.
Journal Article
Characterizing the Access of Cholinergic Antagonists to Efferent Synapses in the Inner Ear
Stimulation of cholinergic efferent neurons innervating the inner ear has profound, well-characterized effects on vestibular and auditory physiology, after activating distinct ACh receptors (AChRs) on afferents and hair cells in peripheral endorgans. Efferent-mediated fast and slow excitation of vestibular afferents are mediated by α4β2*-containing nicotinic AChRs (nAChRs) and muscarinic AChRs (mAChRs), respectively. On the auditory side, efferent-mediated suppression of distortion product otoacoustic emissions (DPOAEs) is mediated by α9α10nAChRs. Previous characterization of these synaptic mechanisms utilized cholinergic drugs, that when systemically administered, also reach the CNS, which may limit their utility in probing efferent function without also considering central effects. Use of peripherally-acting cholinergic drugs with local application strategies may be useful, but this approach has remained relatively unexplored. Using multiple administration routes, we performed a combination of vestibular afferent and DPOAE recordings during efferent stimulation in mouse and turtle to determine whether charged mAChR or α9α10nAChR antagonists, with little CNS entry, can still engage efferent synaptic targets in the inner ear. The charged mAChR antagonists glycopyrrolate and methscopolamine blocked efferent-mediated slow excitation of mouse vestibular afferents following intraperitoneal, middle ear, or direct perilymphatic administration. Both mAChR antagonists were effective when delivered to the middle ear, contralateral to the side of afferent recordings, suggesting they gain vascular access after first entering the perilymphatic compartment. In contrast, charged α9α10nAChR antagonists blocked efferent-mediated suppression of DPOAEs only upon direct perilymphatic application, but failed to reach efferent synapses when systemically administered. These data show that efferent mechanisms are viable targets for further characterizing drug access in the inner ear.
Journal Article
Oxone®-Mediated TEMPO-Oxidized Cellulose Nanomaterials form I and form II
The 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) oxidation of cellulose, when mediated with Oxone® (KHSO5), can be performed simply and under mild conditions. Furthermore, the products of the reaction can be isolated into two major components: Oxone®-mediated TEMPO-oxidized cellulose nanomaterials Form I and Form II (OTO-CNM Form I and Form II). This study focuses on the characterization of the properties of OTO-CNMs. Nanoparticle-sized cellulose fibers of 5 and 16 nm, respectively, were confirmed through electron microscopy. Infrared spectroscopy showed that the most carboxylation presented in Form II. Conductometric titration showed a two-fold increase in carboxylation from Form I (800 mmol/kg) to Form II (1600 mmol/kg). OTO-CNMs showed cellulose crystallinity in the range of 64–68% and crystallite sizes of 1.4–3.3 nm, as shown through XRD. OTO-CNMs show controlled variability in hydrophilicity with contact angles ranging from 16 to 32°, within or below the 26–47° reported in the literature for TEMPO-oxidized CNMs. Newly discovered OTO-CNM Form II shows enhanced hydrophilic properties as well as unique crystallinity and chemical functionalization in the field of bio-sourced material and nanocomposites.
Journal Article