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1.
Sumei Ren Paul McNamara Pernilla Royster Jae Lee Surinderjit S. Saluja David Koharski Sharon Hendershot Van Truong 《Journal of labelled compounds & radiopharmaceuticals》2007,50(7):643-648
1‐Benzyl‐4‐hydroxy[2‐14C]piperidine, a useful intermediate in labeled compound synthesis, was prepared from [14C]formaldehyde in high yield. The distribution pattern of 14C in the product is consistent with a mechanism involving reversible iminium ion formation and rapid equilibration of the iminium ion through a cationic aza‐Cope rearrangement. These steps precede the rate‐determining intramolecular cyclization step. SCH 351125 is a potent, selective CCR5 receptor antagonist with potential as a treatment for HIV infection. [14C]SCH 351125, required for metabolism studies, was prepared from 1‐benzyl‐4‐hydroxy[2‐14C]piperidine in six steps. [14C]SCH 351125 is a mixture of four atropisomers. Preparation of [14C]SCH 351125 besylate salt of the desired atropisomer pair is also described. Copyright © 2007 John Wiley & Sons, Ltd. 相似文献
2.
Salnikov AV Roswall P Sundberg C Gardner H Heldin NE Rubin K 《Laboratory investigation; a journal of technical methods and pathology》2005,85(4):512-521
A pathologically elevated interstitial fluid pressure (IFP) is a characteristic of both clinical and experimental carcinoma. The soluble TGF-beta receptor type II-murine Fc:IgG2A chimeric protein (Fc:TbetaRII) lowers IFP in the KAT-4 experimental model for anaplastic thyroid carcinoma. Analyses of messenger RNA (mRNA) expressions by Affymetrix microarrays and RNase protection assays, as well as of protein expressions identified tumor macrophages as targets for Fc:TbetaRII. Treatment with Fc:TbetaRII reduced albumin extravasation, increased coverage of alpha-smooth muscle actin-positive cells and reduced expression of NG2, a marker of activated pericytes, in KAT-4 carcinoma blood vessels. Specific inhibition of interleukin-1 (IL-1), a major cytokine produced by activated macrophages, lowered carcinoma IFP to a similar degree as Fc:TbetaRII but had no significant effect on the parameters of blood vessel maturation. Neither Fc:TbetaRII nor inhibition of IL-1 changed blood vessel density. Finally, pretreatment of KAT-4 carcinomas with Fc:TbetaRII increased the antitumor efficacy of doxorubicin. Our data emphasize a potential role of tumor macrophages in carcinoma physiology and identify these cells as potential stromal targets for treatment aimed to improve efficacy of chemotherapy. 相似文献
3.
Pelin Sahlén Rapolas Spalinskas Samina Asad Kunal Das Mahapatra Pontus Höjer Anandashankar Anil Jesper Eisfeldt Ankit Srivastava Pernilla Nikamo Anaya Mukherjee Kyu-Han Kim Otto Bergman Mona Ståhle Enikö Sonkoly Andor Pivarcsi Carl-Fredrik Wahlgren Magnus Nordenskjöld Fulya Taylan Isabel Tapia-Páez 《The Journal of allergy and clinical immunology》2021,147(5):1742-1752
4.
Royster LH Driscoll DP Thomas WG Royster JD 《American Industrial Hygiene Association journal》1980,41(2):113-119
A nonindustrial noise exposed population (NINEP) that describes the age effects for a black male and female population has been established. The mean hearing threshold levels for the black NINEP are significantly lower (better hearing) than the previously established mean HTLs for a white NINEP when compared by sex. The availability of the black NINEP now makes it possible to more accurately evaluate a typical industrial noise exposed population (INEP). 相似文献
5.
6.
Peter Gennemark Rasmus Jansson-Löfmark Gina Hyberg Maria Wigstrand Dorota Kakol-Palm Pernilla Håkansson Daniel Hovdal Peter Brodin Maria Fritsch-Fredin Madeleine Antonsson Karolina Ploj Johan Gabrielsson 《Journal of pharmacokinetics and pharmacodynamics》2013,40(6):651-667
Body composition and body mass are pivotal clinical endpoints in studies of welfare diseases. We present a combined effort of established and new mathematical models based on rigorous monitoring of energy intake (EI) and body mass in mice. Specifically, we parameterize a mechanistic turnover model based on the law of energy conservation coupled to a drug mechanism model. Key model variables are fat-free mass (FFM) and fat mass (FM), governed by EI and energy expenditure (EE). An empirical Forbes curve relating FFM to FM was derived experimentally for female C57BL/6 mice. The Forbes curve differs from a previously reported curve for male C57BL/6 mice, and we thoroughly analyse how the choice of Forbes curve impacts model predictions. The drug mechanism function acts on EI or EE, or both. Drug mechanism parameters (two to three parameters) and system parameters (up to six free parameters) could be estimated with good precision (coefficients of variation typically <20 % and not greater than 40 % in our analyses). Model simulations were done to predict the EE and FM change at different drug provocations in mice. In addition, we simulated body mass and FM changes at different drug provocations using a similar model for man. Surprisingly, model simulations indicate that an increase in EI (e.g. 10 %) was more efficient than an equal lowering of EI. Also, the relative change in body mass and FM is greater in man than in mouse at the same relative change in either EI or EE. We acknowledge that this assumes the same drug mechanism impact across the two species. A set of recommendations regarding the Forbes curve, vehicle control groups, dual action on EI and loss, and translational aspects are discussed. This quantitative approach significantly improves data interpretation, disease system understanding, safety assessment and translation across species. 相似文献
7.
Istvan Horvath Pernilla Wittung-Stafshede 《Proceedings of the National Academy of Sciences of the United States of America》2016,113(44):12473-12477
In type-2 diabetes (T2D) and Parkinson’s disease (PD), polypeptide assembly into amyloid fibers plays central roles: in PD, α-synuclein (aS) forms amyloids and in T2D, amylin [islet amyloid polypeptide (IAPP)] forms amyloids. Using a combination of biophysical methods in vitro we have investigated whether aS, IAPP, and unprocessed IAPP, pro-IAPP, polypeptides can cross-react. Whereas IAPP forms amyloids within minutes, aS takes many hours to assemble into amyloids and pro-IAPP aggregates even slower under the same conditions. We discovered that preformed amyloids of pro-IAPP inhibit, whereas IAPP amyloids promote, aS amyloid formation. Amyloids of aS promote pro-IAPP amyloid formation, whereas they inhibit IAPP amyloid formation. In contrast, mixing of IAPP and aS monomers results in coaggregation that is faster than either protein alone; moreover, pro-IAPP can incorporate aS monomers into its amyloid fibers. From this intricate network of cross-reactivity, it is clear that the presence of IAPP can accelerate aS amyloid formation. This observation may explain why T2D patients are susceptible to developing PD.Parkinson’s disease (PD) is the second most common neurological disorder and the most common movement disorder. It is characterized by widespread degeneration of subcortical structures of the brain, especially dopaminergic neurons in the substantia nigra. These changes are coupled with bradykinesia, rigidity, and tremor, resulting in difficulties in walking and abnormal gait in patients (1). The assembly process of the intrinsically unstructured 140-residue protein α-synuclein (aS) into amyloid fibers has been linked to the molecular basis of PD. aS is a major component of amyloid aggregates found in Lewy body inclusions, which are the pathological hallmark of PD, and duplications, triplications, and point mutations in the aS gene are related to familial PD cases (2, 3). The exact function of aS is unknown, but it is suggested to be involved in synaptic vesicle release and trafficking, regulation of enzymes and transporters, and control of the neuronal apoptotic response (4, 5). aS is present at presynaptic nerve terminals (6–8) and, intriguingly, also in many cells outside the brain (e.g., red blood cells and pancreatic β-cells). aS can assemble via oligomeric intermediates to amyloid fibrils under pathological conditions (9). Although soluble aS oligomers have been proposed to be toxic (10, 11), work with preformed aS fibrils has demonstrated that the amyloid fibrils themselves are toxic and can be transmitted from cell to cell and are also able to cross the blood–brain barrier (12–14).Type-2 diabetes (T2D) is another disease involving amyloid formation. Here, the primary pathological characteristic is islet amyloid of the hormone amylin, also known as islet amyloid polypeptide (IAPP), in pancreatic β-cells (15–18). The process of islet amyloid formation (19–21) leads to pancreatic β-cell dysfunction, cell death, and development of diabetes. IAPP (37 residues, natively unfolded) is cosecreted with insulin after enzymatic maturation of prohormones pro-IAPP (67 residues) and proinsulin in secretory granules. IAPP and insulin play roles in controlling gastric emptying, glucose homeostasis, and in the suppression of glucagon release. Although not understood on a mechanistic level, impairment of prohormone processing has been thought to play a role in initiation and progression of T2D (22, 23). Insulin and pro-IAPP (22, 24–26), but not proinsulin, can inhibit IAPP amyloid formation in vitro and in mice, suggesting that accumulation of unprocessed proinsulin may promote IAPP amyloid formation (22, 24). Insulin-degrading enzyme (IDE) is a conserved metallopeptidase that can degrade insulin and a variety of other small peptides including IAPP in the pancreas (27, 28). Genome-wide association studies have linked IDE to T2D (29, 30) and Ide mutant mice were found to have impaired glucose-stimulated insulin secretion as well as increased levels of IAPP, insulin, and, surprisingly, aS in pancreatic islets (31, 32). Here, aS may be associated with insulin biogenesis and exocytic release, as it was found to localize with insulin-secretory granules in pancreatic β-cells (33). We recently demonstrated in vitro that IDE readily inhibits aS amyloid formation via C-terminal binding and, in parallel, IDE activity toward insulin and other small substrates increases (34, 35).Together, the key role of aS in PD and the inverse correlation of impaired insulin secretion and increased aS levels in the pancreatic β-cells, imply that PD and T2D may be connected. In support, reports have suggested that patients with T2D are predisposed toward PD (36, 37). For Alzheimer’s disease (AD), a direct link with T2D was found (15, 38). Amyloid fiber seeds of the AD peptide, amyloid-β, were shown to efficiently accelerate amyloid formation of IAPP in vitro (39, 40) and IAPP was part of amyloid-β plaque found in mice brains (41). To address the unexplored question of cross-reactivity between the amyloidogenic peptides in PD and T2D, we here investigated cross-reactivity among aS, IAPP, and pro-IAPP using biophysical methods in vitro. 相似文献
8.
Homouz D Perham M Samiotakis A Cheung MS Wittung-Stafshede P 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(33):11754-11759
How the crowded environment inside cells affects the structures of proteins with aspherical shapes is a vital question because many proteins and protein–protein complexes in vivo adopt anisotropic shapes. Here we address this question by combining computational and experimental studies of a football-shaped protein (i.e., Borrelia burgdorferi VlsE) in crowded, cell-like conditions. The results show that macromolecular crowding affects protein-folding dynamics as well as overall protein shape. In crowded milieus, distinct conformational changes in VlsE are accompanied by secondary structure alterations that lead to exposure of a hidden antigenic region. Our work demonstrates the malleability of “native” proteins and implies that crowding-induced shape changes may be important for protein function and malfunction in vivo. 相似文献
9.
Unlicensed personnel administering medications to older persons living at home: a challenge for social and care services 下载免费PDF全文
10.