226 research outputs found
Helicase processivity and not the unwinding velocity exhibits universal increase with force
Helicases, involved in a number of cellular functions, are motors that
translocate along singlestranded nucleic acid and couple the motion to
unwinding double-strands of a duplex nucleic acid. The junction between double
and single strands creates a barrier to the movement of the helicase, which can
be manipulated in vitro by applying mechanical forces directly on the nucleic
acid strands. Single molecule experiments have demonstrated that the unwinding
velocities of some helicases increase dramatically with increase in the
external force, while others show little response. In contrast, the unwinding
processivity always increases when the force increases. The differing responses
of the unwinding velocity and processivity to force has lacked explanation. By
generalizing a previous model of processive unwinding by helicases, we provide
a unified framework for understanding the dependence of velocity and
processivity on force and the nucleic acid sequence. We predict that the
sensitivity of unwinding processivity to external force is a universal feature
that should be observed in all helicases. Our prediction is illustrated using
T7 and NS3 helicases as case studies. Interestingly, the increase in unwinding
processivity with force depends on whether the helicase forces base pair
opening by direct interaction or if such a disruption occurs spontaneously due
to thermal uctuations. Based on the theoretical results, we propose that
proteins like single-strand binding proteins associated with helicases in the
replisome, may have co-evolved with helicases to increase the unwinding
processivity even if the velocity remains unaffected
Single Molecule Statistics and the Polynucleotide Unzipping Transition
We present an extensive theoretical investigation of the mechanical unzipping
of double-stranded DNA under the influence of an applied force. In the limit of
long polymers, there is a thermodynamic unzipping transition at a critical
force value of order 10 pN, with different critical behavior for homopolymers
and for random heteropolymers. We extend results on the disorder-averaged
behavior of DNA's with random sequences to the more experimentally accessible
problem of unzipping a single DNA molecule. As the applied force approaches the
critical value, the double-stranded DNA unravels in a series of discrete,
sequence-dependent steps that allow it to reach successively deeper energy
minima. Plots of extension versus force thus take the striking form of a series
of plateaus separated by sharp jumps. Similar qualitative features should
reappear in micromanipulation experiments on proteins and on folded RNA
molecules. Despite their unusual form, the extension versus force curves for
single molecules still reveal remnants of the disorder-averaged critical
behavior. Above the transition, the dynamics of the unzipping fork is related
to that of a particle diffusing in a random force field; anomalous,
disorder-dominated behavior is expected until the applied force exceeds the
critical value for unzipping by roughly 5 pN.Comment: 40 pages, 18 figure
The `Friction' of Vacuum, and other Fluctuation-Induced Forces
The static Casimir effect describes an attractive force between two
conducting plates, due to quantum fluctuations of the electromagnetic (EM)
field in the intervening space. {\it Thermal fluctuations} of correlated fluids
(such as critical mixtures, super-fluids, liquid crystals, or electrolytes) are
also modified by the boundaries, resulting in finite-size corrections at
criticality, and additional forces that effect wetting and layering phenomena.
Modified fluctuations of the EM field can also account for the `van der Waals'
interaction between conducting spheres, and have analogs in the
fluctuation--induced interactions between inclusions on a membrane. We employ a
path integral formalism to study these phenomena for boundaries of arbitrary
shape. This allows us to examine the many unexpected phenomena of the dynamic
Casimir effect due to moving boundaries. With the inclusion of quantum
fluctuations, the EM vacuum behaves essentially as a complex fluid, and
modifies the motion of objects through it. In particular, from the mechanical
response function of the EM vacuum, we extract a plethora of interesting
results, the most notable being: (i) The effective mass of a plate depends on
its shape, and becomes anisotropic. (ii) There is dissipation and damping of
the motion, again dependent upon shape and direction of motion, due to emission
of photons. (iii) There is a continuous spectrum of resonant cavity modes that
can be excited by the motion of the (neutral) boundaries.Comment: RevTex, 2 ps figures included. The presentation is completely
revised, and new sections are adde
Co-transplantation of Human Embryonic Stem Cell-derived Neural Progenitors and Schwann Cells in a Rat Spinal Cord Contusion Injury Model Elicits a Distinct Neurogenesis and Functional Recovery
Co-transplantation of neural progenitors (NPs) with Schwann cells (SCs) might be a way to overcome low rate of neuronal differentiation of NPs following transplantation in spinal cord injury (SCI) and the improvement of locomotor recovery. In this study, we initially generated NPs from human embryonic stem cells (hESCs) and investigated their potential for neuronal differentiation and functional recovery when co-cultured with SCs in vitro and co-transplanted in a rat acute model of contused SCI. Co-cultivation results revealed that the presence of SCs provided a consistent status for hESC-NPs and recharged their neural differentiation toward a predominantly neuronal fate. Following transplantation, a significant functional recovery was
observed in all engrafted groups (NPs, SCs, NPs+SCs) relative to the vehicle and control groups.
We also observed that animals receiving co-transplants established a better state as assessed with
the BBB functional test. Immunohistofluorescence evaluation five weeks after transplantation
showed invigorated neuronal differentiation and limited proliferation in the co-transplanted
group when compared to the individual hESC-NPs grafted group. These findings have
demonstrated that the co-transplantation of SCs with hESC-NPs could offer a synergistic effect,
promoting neuronal differentiation and functional recovery
Detrended Fluctuation Analysis in the prediction of type 2 diabetes mellitus in patients at risk: Model optimization and comparison with other metrics
[EN] Complexity analysis of glucose time series with Detrended Fluctuation Analysis (DFA) has been proved to be useful for the prediction of type 2 diabetes mellitus (T2DM) development. We propose a modified DFA algorithm, review some of its characteristics and compare it with other metrics derived from continuous glucose monitorization in this setting. Several issues of the DFA algorithm were evaluated: (1) Time windowing: the best predictive value was obtained including all time-windows from 15 minutes to 24 hours. (2) Influence of circadian rhythms: for 48-hour glucometries, DFA alpha scaling exponent was calculated on 24hour sliding segments (1-hour gap, 23-hour overlap), with a median coefficient of variation of 3.2%, which suggests that analysing time series of at least 24-hour length avoids the influence of circadian rhythms. (3) Influence of pretreatment of the time series through integration: DFA without integration was more sensitive to the introduction of white noise and it showed significant predictive power to forecast the development of T2DM, while the pretreated time series did not. (4) Robustness of an interpolation algorithm for missing values: The modified DFA algorithm evaluates the percentage of missing values in a time series. Establishing a 2% error threshold, we estimated the number and length of missing segments that could be admitted to consider a time series as suitable for DFA analysis. For comparison with other metrics, a Principal Component Analysis was performed and the results neatly tease out four different components. The first vector carries information concerned with variability, the second represents mainly DFA alpha exponent, while the third and fourth vectors carry essentially information related to the two "pre-diabetic behaviours" (impaired fasting glucose and impaired glucose tolerance). The scaling exponent obtained with the modified DFA algorithm proposed has significant predictive power for the development of T2DM in a high-risk population compared with other variability metrics or with the standard DFA algorithm.This study has been funded by Instituto de Salud Carlos III through the project PI17/00856 (Co-funded by the European Regional Development Fund, A way to make Europe). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Colás, A.; Vigil, L.; Vargas, B.; Cuesta Frau, D.; Varela, M. (2019). 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Altered Complexity and Correlation Properties of R-R Interval Dynamics Before the Spontaneous Onset of Paroxysmal Atrial Fibrillation. Circulation, 100(20), 2079-2084. doi:10.1161/01.cir.100.20.2079Wang, H., Naghavi, M., Allen, C., Barber, R. M., Bhutta, Z. A., Carter, A., … Coates, M. M. (2016). Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. The Lancet, 388(10053), 1459-1544. doi:10.1016/s0140-6736(16)31012-1Saudek, C. D., Derr, R. L., & Kalyani, R. R. (2006). Assessing Glycemia in Diabetes Using Self-monitoring Blood Glucose and Hemoglobin A1c. JAMA, 295(14), 1688. doi:10.1001/jama.295.14.1688Monnier, L., Colette, C., & Owens, D. R. (2008). Glycemic Variability: The Third Component of the Dysglycemia in Diabetes. Is it Important? How to Measure it? 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Diabetologia, 53(3), 435-445. doi:10.1007/s00125-009-1614-2Nathan, D. M., Davidson, M. B., DeFronzo, R. A., Heine, R. J., Henry, R. R., Pratley, R., & Zinman, B. (2007). Impaired Fasting Glucose and Impaired Glucose Tolerance: Implications for care. Diabetes Care, 30(3), 753-759. doi:10.2337/dc07-9920Ogata, H., Tokuyama, K., Nagasaka, S., Tsuchita, T., Kusaka, I., Ishibashi, S., … Yamamoto, Y. (2012). The lack of long-range negative correlations in glucose dynamics is associated with worse glucose control in patients with diabetes mellitus. Metabolism, 61(7), 1041-1050. doi:10.1016/j.metabol.2011.12.007Kohnert, K.-D. (2015). Utility of different glycemic control metrics for optimizing management of diabetes. World Journal of Diabetes, 6(1), 17. doi:10.4239/wjd.v6.i1.17GarcÃa Maset, L., González, L. B., Furquet, G. L., Suay, F. M., & Marco, R. H. (2016). Study of Glycemic Variability Through Time Series Analyses (Detrended Fluctuation Analysis and Poincaré Plot) in Children and Adolescents with Type 1 Diabetes. Diabetes Technology & Therapeutics, 18(11), 719-724. doi:10.1089/dia.2016.0208Service, F. J., O’Brien, P. C., & Rizza, R. A. (1987). Measurements of Glucose Control. Diabetes Care, 10(2), 225-237. doi:10.2337/diacare.10.2.225Goldberger, A. L., Amaral, L. A. N., Hausdorff, J. M., Ivanov, P. C., Peng, C.-K., & Stanley, H. E. (2002). Fractal dynamics in physiology: Alterations with disease and aging. Proceedings of the National Academy of Sciences, 99(Supplement 1), 2466-2472. doi:10.1073/pnas.012579499Crenier, L., Lytrivi, M., Van Dalem, A., Keymeulen, B., & Corvilain, B. (2016). Glucose Complexity Estimates Insulin Resistance in Either Nondiabetic Individuals or in Type 1 Diabetes. 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Age and gender differences in narcissism: A comprehensive study across eight measures and over 250,000 participants
Age and gender differences in narcissism have been studied often. However, considering the rich history of narcissism research accompanied by its diverging conceptualizations, little is known about age and gender differences across various narcissism measures. The present study investigated age and gender differences and their interactions across eight widely used narcissism instruments (i.e., Narcissistic Personality Inventory, Hypersensitive Narcissism Scale, Dirty Dozen, Psychological Entitlement Scale, Narcissistic Personality Disorder Symptoms from the Diagnostic and Statistical Manual of Mental Disorders, Version IV, Narcissistic Admiration and Rivalry Questionnaire-Short Form, Single-Item Narcissism Scale, and brief version of the Pathological Narcissism Inventory). The findings of Study 1 (N = 5,736) revealed heterogeneity in how strongly the measures are correlated. Some instruments loaded clearly on one of the three factors proposed by previous research (i.e., Neuroticism, Extraversion, Antagonism), while others cross-loaded across factors and in distinct ways. Cross-sectional analyses using each measure and meta-analytic results across all measures (Study 2) with a total sample of 270,029 participants suggest consistent linear age effects (random effects meta-analytic effect of r = -.104), with narcissism being highest in young adulthood. Consistent gender differences also emerged (random effects meta-analytic effect was -.079), such that men scored higher in narcissism than women. Quadratic age effects and Age × Gender effects were generally very small and inconsistent. We conclude that despite the various conceptualizations of narcissism, age and gender differences are generalizable across the eight measures used in the present study. However, their size varied based on the instrument used. We discuss the sources of this heterogeneity and the potential mechanisms for age and gender differences
Novel Escape Mutants Suggest an Extensive TRIM5α Binding Site Spanning the Entire Outer Surface of the Murine Leukemia Virus Capsid Protein
After entry into target cells, retroviruses encounter the host restriction
factors such as Fv1 and TRIM5α. While it is clear that these factors target
retrovirus capsid proteins (CA), recognition remains poorly defined in the
absence of structural information. To better understand the binding interaction
between TRIM5α and CA, we selected a panel of novel N-tropic murine
leukaemia virus (N-MLV) escape mutants by a serial passage of replication
competent N-MLV in rhesus macaque TRIM5α (rhTRIM5α)-positive cells using
a small percentage of unrestricted cells to allow multiple rounds of virus
replication. The newly identified mutations, many of which involve changes in
charge, are distributed over the outer ‘top’ surface of N-MLV CA,
including the N-terminal β-hairpin, and map up to 29 Ao apart.
Biological characterisation with a number of restriction factors revealed that
only one of the new mutations affects restriction by human TRIM5α,
indicating significant differences in the binding interaction between N-MLV and
the two TRIM5αs, whereas three of the mutations result in dual sensitivity
to Fv1n and Fv1b. Structural studies of two mutants show
that no major changes in the overall CA conformation are associated with escape
from restriction. We conclude that interactions involving much, if not all, of
the surface of CA are vital for TRIM5α binding
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