468 research outputs found
Ectopic A-lattice seams destabilize microtubules
Natural microtubules typically include one A-lattice seam within an otherwise helically symmetric B-lattice tube. It is currently unclear how A-lattice seams influence microtubule dynamic instability. Here we find that including extra A-lattice seams in GMPCPP microtubules, structural analogues of the GTP caps of dynamic microtubules, destabilizes them, enhancing their median shrinkage rate by >20-fold. Dynamic microtubules nucleated by seeds containing extra A-lattice seams have growth rates similar to microtubules nucleated by B-lattice seeds, yet have increased catastrophe frequencies at both ends. Furthermore, binding B-lattice GDP microtubules to a rigor kinesin surface stabilizes them against shrinkage, whereas microtubules with extra A-lattice seams are stabilized only slightly. Our data suggest that introducing extra A-lattice seams into dynamic microtubules destabilizes them by destabilizing their GTP caps. On this basis, we propose that the single A-lattice seam of natural B-lattice MTs may act as a trigger point, and potentially a regulation point, for catastrophe
Islands Containing Slowly Hydrolyzable GTP Analogs Promote Microtubule Rescues
Microtubules are dynamic polymers of GTP- and GDP-tubulin that undergo stochastic transitions between growing and shrinking phases. Rescues, the conversion from shrinking to growing, have recently been proposed to be to the result of regrowth at GTP-tubulin islands within the lattice of growing microtubules. By introducing mixed GTP/GDP/GMPCPP (GXP) regions within the lattice of dynamic microtubules, we reconstituted GXP islands in vitro (GMPCPP is the slowly hydrolyzable GTP analog guanosine-5′-[(α,β)-methyleno]triphosphate). We found that such islands could reproducibly induce rescues and that the probability of rescue correlated with both the size of the island and the percentage of GMPCPP-tubulin within the island. The islands slowed the depolymerization rate of shortening microtubules and promoted regrowth more readily than GMPCPP seeds. Together, these findings provide new mechanistic insights supporting the possibility that rescues could be triggered by enriched GTP-tubulin regions and present a new tool for studying such rescue events in vitro
Universities and Pricing on Higher Education Markets
Markets and prices in higher education. When can we speak of markets, and when markets exist, how are prices set
A deterministic oscillatory model of microtubule growth and shrinkage for differential actions of short chain fatty acids.
Short chain fatty acids (SCFA), principally acetate, propionate, butyrate and valerate, are produced in pharmacologically relevant concentrations by the gut microbiome. Investigations indicate that they exert beneficial effects on colon epithelia. There is increasing interest in whether different SCFAs have distinct functions which may be exploited for prevention or treatment of colonic diseases including colorectal cancer (CRC), inflammatory bowel disease and obesity. Based on experimental evidence, we hypothesised that odd-chain SCFAs may possess anti-mitotic capabilities in colon cancer cells by disrupting microtubule (MT) structural integrity via dysregulation of β-tubulin isotypes. MT dynamic instability is an essential characteristic of MT cellular activity. We report a minimal deterministic model that takes a novel approach to explore the hypothesised pathway by triggering spontaneous oscillations to represent MT dynamic behaviour. The dynamicity parameters in silico were compared to those reported in vitro. Simulations of untreated and butyrate (even-chain length) treated cells reflected MT behaviour in interphase or untreated control cells. The propionate and valerate (odd-chain length) simulations displayed increased catastrophe frequencies and longer periods of MT-fibre shrinkage. Their enhanced dynamicity was dissimilar to that observed in mitotic cells, but parallel to that induced by MT-destabilisation treatments. Antimicrotubule drugs act through upward or downward modulation of MT dynamic instability. Our computational modelling suggests that metabolic engineering of the microbiome may facilitate managing CRC risk by predicting outcomes of SCFA treatments in combination with AMDs
Mechanochemical modeling of dynamic microtubule growth involving sheet-to-tube transition
Microtubule dynamics is largely influenced by nucleotide hydrolysis and the
resultant tubulin configuration changes. The GTP cap model has been proposed to
interpret the stabilizing mechanism of microtubule growth from the view of
hydrolysis effects. Besides, the microtubule growth involves the closure of a
curved sheet at its growing end. The curvature conversion also helps to
stabilize the successive growth, and the curved sheet is referred to as the
conformational cap. However, there still lacks theoretical investigation on the
mechanical-chemical coupling growth process of microtubules. In this paper, we
study the growth mechanisms of microtubules by using a coarse-grained molecular
method. Firstly, the closure process involving a sheet-to-tube transition is
simulated. The results verify the stabilizing effect of the sheet structure,
and the minimum conformational cap length that can stabilize the growth is
demonstrated to be two dimers. Then, we show that the conformational cap can
function independently of the GTP cap, signifying the pivotal role of
mechanical factors. Furthermore, based on our theoretical results, we describe
a Tetris-like growth style of microtubules: the stochastic tubulin assembly is
regulated by energy and harmonized with the seam zipping such that the sheet
keeps a practically constant length during growth.Comment: 23 pages, 7 figures. 2 supporting movies have not been uploaded due
to the file type restriction
Sex Segregation and Salary Structure in Academia
This article reports a study of aggregate unit salary levels, within a major research university. We analyze these salary levels, as they are influenced by unit sex composition, and modified by unit attainment levels—where unit refers to the departments, colleges and schools, and other academic divisions of the university. We investigate three central issues of sex and salary, previously overlooked in salary studies of academic employees: Do high proportions of women depress men's unit salary levels ("competition" hypothesis)? Are women's salary levels higher in male-dominated, and lower in female-dominated, units ("concentration" hypothesis)? Are men salary-compensated for working with women ("compensation" hypothesis)? The findings support none of these hypotheses. Rather, the relationship between unit sex composition and salary rests upon the connection between units' composition and attainment levels.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/69126/2/10.1177_073088848100800103.pd
On becoming (un)committed: A taxonomy and test of newcomer on-boarding scenarios
How does the bond between the newcomer and the organization develop over time? Process research on temporal patterns of newcomer's early commitment formation has been very scarce because theory and appropriate longitudinal research designs in this area are lacking. From extant research we extract three process-theoretical accounts regarding how the newcomer adjustment process evolves over time: (1) Learning to Love; (2) Honeymoon Hangover; and (3) High Match, Moderate Match, or Low Match. From these scenarios we develop a taxonomy of newcomer adjustment scenarios. Further, we empirically verify these different scenarios by examining naturally occurring "trajectory classes," which are found to display strengthening, weakening, or stabilizing of the employee-organization linkage. For this, we use a sample of 72 Ph. D. graduates whose organizational commitment history was recorded in their first 25 consecutive weeks of new employment. In closing, we discuss the theoretical and practical implications of the scenario-based approach
Energy consumption in chemical fuel-driven self-assembly
Nature extensively exploits high-energy transient self-assembly structures that are able to perform work through a dissipative process. Often, self-assembly relies on the use of molecules as fuel that is consumed to drive thermodynamically unfavourable reactions away from equilibrium. Implementing this kind of non-equilibrium self-assembly process in synthetic systems is bound to profoundly impact the fields of chemistry, materials science and synthetic biology, leading to innovative dissipative structures able to convert and store chemical energy. Yet, despite increasing efforts, the basic principles underlying chemical fuel-driven dissipative self-assembly are often overlooked, generating confusion around the meaning and definition of scientific terms, which does not favour progress in the field. The scope of this Perspective is to bring closer together current experimental approaches and conceptual frameworks. From our analysis it also emerges that chemically fuelled dissipative processes may have played a crucial role in evolutionary processes
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