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41.
Dr. Subhabrata Chaudhury Dr. Penchala Narasimharao Meka Dr. Monimoy Banerjee Caitlin N. Kent Prof. Dr. Brian S. J. Blagg 《Chemistry (Weinheim an der Bergstrasse, Germany)》2021,27(59):14747-14764
The 90 kDa heat shock proteins (Hsp90) are molecular chaperones that are responsible for the folding and/or trafficking of ∼400 client proteins, many of which are directly associated with cancer progression. Consequently, inhibition of Hsp90 can exhibit similar activity as combination therapy as multiple signaling nodes can be targeted simultaneously. In fact, seventeen small-molecule inhibitors that bind the Hsp90 N-terminus entered clinical trials for the treatment of cancer, all of which exhibited pan-inhibitory activity against all four Hsp90 isoforms. Unfortunately, most demonstrated undesired effects alongside induction of the pro-survival heat shock response. As a result, isoform-selective inhibitors have been sought to overcome these detriments. Described herein is a structure-based approach to design Hsp90β-selective inhibitors along with preliminary SAR. In the end, compound 5 was shown to manifest ∼370-fold selectivity for Hsp90β versus Hsp90α, and induced the degradation of select Hsp90β-dependent clients. These data support the development of Hsp90β-selective inhibitors as a new paradigm to overcome the detriments associated with pan-inhibition of Hsp90. 相似文献
42.
H. Herzmann 《Isotopes in environmental and health studies》2013,49(2):45-52
Radioaktiv markierte Präparate haben in denletzten Jahren in schnell zunehmendem Maße Eingang in die klinische Medizin gefunden. Sie sind beieiner Reihe von Indikationen schon jetzt außerordentlich wertvolle Hilfsmittel bei der Diagnose, besonders bei der Prüfung von Organfunktionen. 相似文献
43.
Using chemical separations and radiometric measurements medium-half-life irradiation products of molybdenum with 12.5 MeV deuterons were determined (90Nb, 92Nb, 95mNb, 95Nb, 96Nb, 99Mo, 95mTc, 96Tc, 99mTc) as well as thick target yields for some of them: 92Nb (0.22 μCi/μAh), 95Nb(0.05 μCi/μAh), 99Mo (64 μCi/μAh), 95mTc(0.76 μCi/μAh), 96Tc((62.5 μCi/μAh). Moreover isolation possibiities of radioactive preparations from removed worn-cut molybdenum parts of the U-120 cycletron are discussed. 相似文献
44.
Monica R. P. Rao Shital Aghav Girish Sukre Manmeet Kumar 《Journal of Dispersion Science and Technology》2014,35(2):161-167
The required hydrophilic-lipophilic balance (HLB) of an oily substance indicates the HLB of the surfactants required to prepare a stable emulsion using the oil. This study utilizes empirical method to calculate required HLB (RHLB) of Capryol 90 using surfactant blends (Span 20, Tween 20, vitamin E TPGS, Pluronic F68, Span 60, and Tween 80). The methods used were assessment of degree of creaming after centrifugation and after shelf storage for 28 days at room temperature, turbidimetric method, accelerated stability study, and droplet size analysis. The droplet size was found to be in the range of 15 to 2 µm and v/v% separation after centrifugation was found to be 0–82%. The RHLB for Capryol 90 was found to be 15. The effect of various surfactant blends was investigated. Results revealed that a blend of tocopherol polyethylene glycol succinate (TPGS) and Pluronic F68 gave the most stable emulsion for Capryol 90. 相似文献
45.
Artificial Accelerators of the Molecular Chaperone Hsp90 Facilitate Rate‐Limiting Conformational Transitions 下载免费PDF全文
Bettina K. Zierer Matthias Weiwad Martin Rübbelke Lee Freiburger Gunter Fischer Oliver R. Lorenz Michael Sattler Klaus Richter Johannes Buchner 《Angewandte Chemie (International ed. in English)》2014,53(45):12257-12262
The molecular chaperone Hsp90 undergoes an ATP‐driven cycle of conformational changes in which large structural rearrangements precede ATP hydrolysis. Well‐established small‐molecule inhibitors of Hsp90 compete with ATP‐binding. We wondered whether compounds exist that can accelerate the conformational cycle. In a FRET‐based screen reporting on conformational rearrangements in Hsp90 we identified compounds. We elucidated their mode of action and showed that they can overcome the intrinsic inhibition in Hsp90 which prevents these rearrangements. The mode of action is similar to that of the co‐chaperone Aha1 which accelerates the Hsp90 ATPase. However, while the two identified compounds influence conformational changes, they target different aspects of the structural transitions. Also, the binding site determined by NMR spectroscopy is distinct. This study demonstrates that small molecules are capable of triggering specific rate‐limiting transitions in Hsp90 by mechanisms similar to those in protein cofactors. 相似文献
46.
在医患关系十分紧张的今天,提高医生医德素养显得尤为重要。要提高医生医德素养就必须从医科学生入手,在医科学生刚进行医学教育时就加以医德教育,首先分析了医科学生医德教育现状,其次针对当今医科学生医德教育滞后提出了一些解决的方案,希望能够通过这些方法来加强医科学生医德教育。 相似文献
47.
48.
Improved Bounds for Acyclic Job Shop Scheduling 总被引:2,自引:0,他引:2
In acyclic job shop scheduling problems there are n jobs and m machines. Each job is composed of a sequence of operations to be performed on different machines. A legal schedule is one
in which within each job, operations are carried out in order, and each machine performs at most one operation in any unit
of time. If D denotes the length of the longest job, and C denotes the number of time units requested by all jobs on the most loaded machine, then clearly lb = max[C,D] is a lower bound on the length of the shortest legal schedule. A celebrated result of Leighton, Maggs, and Rao shows that
if all operations are of unit length, then there always is a legal schedule of length O(lb), independent of n and m. For the case that operations may have different lengths, Shmoys, Stein and Wein showed that there always is a legal schedule
of length , where the notation is used to suppress terms. We improve the upper bound to . We also show that our new upper bound is essentially best possible, by proving the existence of instances of acyclic job
shop scheduling for which the shortest legal schedule is of length . This resolves (negatively) a known open problem of whether the linear upper bound of Leighton, Maggs, and Rao applies to
arbitrary job shop scheduling instances (without the restriction to acyclicity and unit length operations).
Received June 30, 1998
RID="*"
ID="*" Incumbent of the Joseph and Celia Reskin Career Development Chair
RID="†"
ID="†" Research was done while staying at the Weizmann Institute, supported by a scholarship from the Minerva foundation. 相似文献
49.
Traveling salesman games 总被引:1,自引:0,他引:1
In this paper we discuss the problem of how to divide the total cost of a round trip along several institutes among the institutes visited. We introduce two types of cooperative games—fixed-route traveling salesman games and traveling salesman games—as a tool to attack this problem. Under very mild conditions we prove that fixed-route traveling salesman games have non-empty cores if the fixed route is a solution of the classical traveling salesman problem. Core elements provide us with fair cost allocations. A traveling salesman game may have an empty core, even if the cost matrix satisfies the triangle inequality. In this paper we introduce a class of matrices defining TS-games with non-empty cores. 相似文献
50.
Recently, linear programming problems with special structures have assumed growing importance in mathematical programming.
It is well known that exploiting network structures within linear programs can lead to considerable improvement of the computational
solution of large-scale linear programming problems. A linear program is said to contain an embedded network structure provided
that some subset of its constraints can be interpreted as specifying conservation of flow. If a column of the constraint matrix
has at most two non-zeros, then it leads to embedded generalized network structure and if these non-zeros are unit elements
and of opposite signs, then it leads to embedded pure network structure.
In this paper, we are concerned with algorithms for detecting embedded pure network structures within linear programs. The
network extraction methods are presented in two groups. The first group covers deletion and addition based algorithms and
the second group covers GUB based algorithms. We have extended the GUB based algorithm appearing in the second group by introducing
Markowitz merit count approach for exploiting matrix non zeros. A set of well known test problems has been used to carry out
computational experiments which show that our extensions to the GUB based algorithms give better results than the algorithms
reported earlier. 相似文献