39,960 research outputs found
Separase prevents genomic instability by controlling replication fork speed
Proper chromosome segregation is crucial for preserving genomic integrity, and errors in this process cause chromosome mis-segregation, which may contribute to cancer development. Sister chromatid separation is triggered by Separase, an evolutionary conserved protease that cleaves the cohesin complex, allowing the dissolution of sister chromatid cohesion. Here we provide evidence that Separase participates in genomic stability maintenance by controlling replication fork speed. We found that Separase interacted with the replication licensing factors MCM2-7, and genome-wide data showed that Separase co-localized with MCM complex and cohesin. Unexpectedly, the depletion of Separase increased the fork velocity about 1.5-fold and caused a strong acetylation of cohesin's SMC3 subunit and altered checkpoint response. Notably, Separase silencing triggered genomic instability in both HeLa and human primary fibroblast cells. Our results show a novel mechanism for fork progression mediated by Separase and thus the basis for genomic instability associated with tumorigenesis
Separase prevents genomic instability by controlling replication fork speed
Proper chromosome segregation is crucial for preserving genomic integrity, and errors in this process cause chromosome mis-segregation, which may contribute to cancer development. Sister chromatid separation is triggered by Separase, an evolutionary conserved protease that cleaves the cohesin complex, allowing the dissolution of sister chromatid cohesion. Here we provide evidence that Separase participates in genomic stability maintenance by controlling replication fork speed. We found that Separase interacted with the replication licensing factors MCM2-7, and genome-wide data showed that Separase co-localized with MCM complex and cohesin. Unexpectedly, the depletion of Separase increased the fork velocity about 1.5-fold and caused a strong acetylation of cohesin's SMC3 subunit and altered checkpoint response. Notably, Separase silencing triggered genomic instability in both HeLa and human primary fibroblast cells. Our results show a novel mechanism for fork progression mediated by Separase and thus the basis for genomic instability associated with tumorigenesis
Variability of Internally Generated Turbulence in an Estuary, from 100 Days of Continuous Observations
We present detailed observations of internally generated turbulence in a sheared, stratified natural flow, as well as an analysis of the external factors leading to its generation and temporal variability. Multi-month time series of vertical profiles of velocity, acoustic backscatter (0.5 Hz), and turbulence parameters were collected with two moored acoustic Doppler current profilers (ADCPs) in the Hudson River estuary, and estuary-long transects of water density were collected 30 times. ADCP backscatter is used for visualization of coherent turbulent structures and evaluation of surface wave biases to the turbulence measurements. Benefits of the continuous long-term turbulence record include our capturing: (1) the seasonality of turbulence due to changing riverflow, (2) hysteresis in stratification and turbulence over the fortnightly cycle of tidal range, and (3) intermittent events such as breaking internal waves. Internal mixing layers (IMLs) are defined as turbulent regions above the logarithmic velocity layer, and the bottom boundary layer (BBL) is defined as the continuously turbulent range of heights above the bed. A cross-correlation analysis reveals how IML and BBL turbulence vary with stratification and external forcing from tidal range, river flow, and winds. Turbulence in both layers is maximal at spring tide and minimal when most stratified, with one exception IML turbulence at a site with changing channel depth and width is maximal at times of maximum stratification and freshwater input
The Size Conundrum: Why Online Knowledge Markets Can Fail at Scale
In this paper, we interpret the community question answering websites on the
StackExchange platform as knowledge markets, and analyze how and why these
markets can fail at scale. A knowledge market framing allows site operators to
reason about market failures, and to design policies to prevent them. Our goal
is to provide insights on large-scale knowledge market failures through an
interpretable model. We explore a set of interpretable economic production
models on a large empirical dataset to analyze the dynamics of content
generation in knowledge markets. Amongst these, the Cobb-Douglas model best
explains empirical data and provides an intuitive explanation for content
generation through concepts of elasticity and diminishing returns. Content
generation depends on user participation and also on how specific types of
content (e.g. answers) depends on other types (e.g. questions). We show that
these factors of content generation have constant elasticity---a percentage
increase in any of the inputs leads to a constant percentage increase in the
output. Furthermore, markets exhibit diminishing returns---the marginal output
decreases as the input is incrementally increased. Knowledge markets also vary
on their returns to scale---the increase in output resulting from a
proportionate increase in all inputs. Importantly, many knowledge markets
exhibit diseconomies of scale---measures of market health (e.g., the percentage
of questions with an accepted answer) decrease as a function of number of
participants. The implications of our work are two-fold: site operators ought
to design incentives as a function of system size (number of participants); the
market lens should shed insight into complex dependencies amongst different
content types and participant actions in general social networks.Comment: The 27th International Conference on World Wide Web (WWW), 201
Group Vibrational Mode Assignments as a Broadly Applicable Tool for Characterizing Ionomer Membrane Structure as a Function of Degree of Hydration
Infrared spectra of Nafion, Aquivion, and the 3M membrane were acquired during total dehydration of fully hydrated samples. Fully hydrated exchange sites are in a sulfonate form with a CâV local symmetry. The mechanical coupling of the exchange site to a side chain ether link gives rise to vibrational group modes that are classified as CâV modes. These mode intensities diminish concertedly with dehydration. When totally dehydrated, the sulfonic acid form of the exchange site is mechanically coupled to an ether link with no local symmetry. This gives rise to Câ group modes that emerge at the expense of CâV modes during dehydration. Membrane IR spectra feature a total absence of CâV modes when totally dehydrated, overlapping Câ and CâV modes when partially hydrated, and a total absence of Câ modes when fully hydrated. DFT calculated normal mode analyses complemented with molecular dynamics simulations of Nafion with overall λ (λ_(Avg)) values of 1, 3, 10, 15 and 20 waters/exchange site, were sectioned into sub-cubes to enable the manual counting of the distribution of λ_(local) values that integrate to λ_(Avg) values. This work suggests that at any state of hydration, IR spectra are a consequence of a distribution of λ_(local) values. Bond distances and the threshold value of λ_(local), for exchange site dissociation, were determined by DFT modelling and used to correlate spectra to manually counted λ_(local) distributions
Chaperones as integrators of cellular networks: Changes of cellular integrity in stress and diseases
Cellular networks undergo rearrangements during stress and diseases. In
un-stressed state the yeast protein-protein interaction network (interactome)
is highly compact, and the centrally organized modules have a large overlap.
During stress several original modules became more separated, and a number of
novel modules also appear. A few basic functions, such as the proteasome
preserve their central position. However, several functions with high energy
demand, such the cell-cycle regulation loose their original centrality during
stress. A number of key stress-dependent protein complexes, such as the
disaggregation-specific chaperone, Hsp104, gain centrality in the stressed
yeast interactome. Molecular chaperones, heat shock, or stress proteins form
complex interaction networks (the chaperome) with each other and their
partners. Here we show that the human chaperome recovers the segregation of
protein synthesis-coupled and stress-related chaperones observed in yeast
recently. Examination of yeast and human interactomes shows that (1) chaperones
are inter-modular integrators of protein-protein interaction networks, which
(2) often bridge hubs and (3) are favorite candidates for extensive
phosphorylation. Moreover, chaperones (4) become more central in the
organization of the isolated modules of the stressed yeast protein-protein
interaction network, which highlights their importance in the de-coupling and
re-coupling of network modules during and after stress. Chaperone-mediated
evolvability of cellular networks may play a key role in cellular adaptation
during stress and various polygenic and chronic diseases, such as cancer,
diabetes or neurodegeneration.Comment: 13 pages, 3 figures, 1 glossar
NITROGEN CYCLING IN A FOREST STREAM DETERMINED BY A 15N TRACER ADDITION
Nitrogen uptake and cycling was examined using a sixâweek tracer addition of 15Nâlabeled ammonium in early spring in Walker Branch, a firstâorder deciduous forest stream in eastern Tennessee. Prior to the 15N addition, standing stocks of N were determined for the major biomass compartments. During and after the addition, 15N was measured in water and in dominant biomass compartments upstream and at several locations downstream. Residence time of ammonium in stream water (5â6 min) and ammonium uptake lengths (23â27 m) were short and relatively constant during the addition. Uptake rates of NH4 were more variable, ranging from 22 to 37 ÎŒg N·mâ2·minâ1 and varying directly with changes in streamwater ammonium concentration (2.7â6.7 ÎŒg/L). The highest rates of ammonium uptake per unit area were by the liverwort Porella pinnata, decomposing leaves, and fine benthic organic matter (FBOM), although epilithon had the highest N uptake per unit biomass N.
Nitrification rates and nitrate uptake lengths and rates were determined by fitting a nitrification/nitrate uptake model to the longitudinal profiles of 15NâNO3 flux. Nitrification was an important sink for ammonium in stream water, accounting for 19% of the total ammonium uptake rate. Nitrate production via coupled regeneration/nitrification of organic N was about oneâhalf as large as nitrification of streamwater ammonium. Nitrate uptake lengths were longer and more variable than those for ammonium, ranging from 101 m to infinity. Nitrate uptake rate varied from 0 to 29 ÎŒg·mâ2·minâ1 and was âŒ1.6 times greater than assimilatory ammonium uptake rate early in the tracer addition. A sixfold decline in instream gross primary production rate resulting from a sharp decline in light level with leaf emergence had little effect on ammonium uptake rate but reduced nitrate uptake rate by nearly 70%.
At the end of the addition, 64â79% of added 15N was accounted for, either in biomass within the 125âm stream reach (33â48%) or as export of 15NâNH4 (4%), 15NâNO3 (23%), and fine particulate organic matter (4%) from the reach. Much of the 15N not accounted for was probably lost downstream as transport of particulate organic N during a storm midway through the experiment or as dissolved organic N produced within the reach. Turnover rates of a large portion of the 15N taken up by biomass compartments were high (0.04â0.08 per day), although a substantial portion of the 15N in Porella (34%), FBOM (21%), and decomposing wood (17%) at the end of the addition was retained 75 d later, indicating relatively longâterm retention of some N taken up from water.
In total, our results showed that ammonium retention and nitrification rates were high in Walker Branch, and that the downstream loss of N was primarily as nitrate and was controlled largely by nitrification, assimilatory demand for N, and availability of ammonium to meet that demand. Our results are consistent with recent 15N tracer experiments in Nâdeficient forest soils that showed high rates of nitrification and the importance of nitrate uptake in regulating losses of N. Together these studies demonstrate the importance of 15N tracer experiments for improving our understanding of the complex processes controlling N cycling and loss in ecosystems
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Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases.
Inflammatory bowel diseases, which include Crohn's disease and ulcerative colitis, affect several million individuals worldwide. Crohn's disease and ulcerative colitis are complex diseases that are heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study's infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi'omics Database ( http://ibdmdb.org ), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases
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