Exo1 phosphorylation inhibits exonuclease activity and prevents fork collapse in rad53 mutants independently of the 14-3-3 proteins

The S phase checkpoint is crucial to maintain genome stability under conditions that threaten DNA replication. One of its critical functions is to prevent Exo1-dependent fork degradation, and Exo1 is phosphorylated in response to different genotoxic agents. Exo1 seemed to be regulated by several post-translational modifications in the presence of replicative stress, but the specific contribution of checkpoint-dependent phosphorylation to Exo1 control and fork stability is not clear. We show here that Exo1 phosphorylation is Dun1-independent and Rad53-dependent in response to DNA damage or dNTP depletion, and in both situations Exo1 is similarly phosphorylated at multiple sites. To investigate the correlation between Exo1 phosphorylation and fork stability, we have generated phospho-mimic exo1 alleles that rescue fork collapse in rad53 mutants as efficiently as exo1-nuclease dead mutants or the absence of Exo1, arguing that Rad53-dependent phosphorylation is the mayor requirement to preserve fork stability. We have also shown that this rescue is Bmh1–2 independent, arguing that the 14-3-3 proteins are dispensable for fork stabilization, at least when Exo1 is downregulated. Importantly, our results indicated that phosphorylation specifically inhibits the 5' to 3'exo-nuclease activity, suggesting that this activity of Exo1 and not the flap-endonuclease, is the enzymatic activity responsible of the collapse of stalled replication forks in checkpoint mutantsSpanish Ministry of Economy and Competitiveness (MINECO) [FEDER-BFU2013-45182-P to C.M.C., M.S.]; University of Salamanca [KA6H/463AC01 to M.S.]; MINECO, AEI, Xunta de Galicia and FEDER [RYC-2012-10835, BFU2016-78121-P, ED431F-2016/019, ED431B-2016/016 to M.G.B.]; Junta de Castilla y León (JCyL), Program ‘Escalera de Excelencia’ [FEDER-CLU-2017-03]; JCyL Pre-doctoral Fellowship (to A.B.); MINECO Pre-Doctoral Fellowship (to E.C.M.); Xunta de Galicia Pre-doctoral Fellowship (ED481A-2018/041 to R.C.)S

Programa de rehabilitación cardíaca mediante un entrenamiento de tenis adaptado

The aims of this study were to determine the effect of a cardiac rehabilitation program, based on the adjustment of a sports modality (tennis), on differentes laboratory analysis variables (triglycerides, cholesterol,cholesterol LDL, cholesterol HDL and glucose ) And and on an exercise stress test (metabolics equivalent-METs-, time of effort, systolic pressure, dyastolic pressure, maximum cardiac frecuencia and double product). The study involved 7 patients with low risk myocardial heart attack. The ages was include between 48 and 63 years old. By the end of the program, which has lasted 3 months, triglycerides, cholesterol, exercise capacity and double product had improved significantly (p<.005 for all).Los objetivos de este estudio son evaluar los efectos de nuestro programa de rehabilitación cardiaca, basado en la adaptación de una modalidad deportiva (tenis), sobre diferentes variables del perfil lipídico (triglicéridos, colesterol, cLDL, cHDL, y glucosa) así como en la prueba de esfuerzo (MET, tiempo de esfuerzo, presión sistólica, presión diastólica, frecuencia cardíaca máxima y doble producto). Analizamos a 7 pacientes con infarto agudo de miocardio de bajo riesgo. Las edades estaban comprendidas entre los 48 y 63 años. Tras la realización del programa, que ha tenido 3 meses de duración, se han producido mejoras significativas a nivel de triglicéridos, colesterol, capacidad funcional valorada en equivalentes metabólicos y doble producto (p<.005 para todos)

A mechanism for morphogen-controlled domain growth

Many developmental systems are organised via the action of graded distributions of morphogens. In the Drosophila wing disc, for example, recent experimental evidence has shown that graded expression of the morphogen Dpp controls cell proliferation and hence disc growth. Our goal is to explore a simple model for regulation of wing growth via the Dpp gradient: we use a system of reaction-diffusion equations to model the dynamics of Dpp and its receptor Tkv, with advection arising as a result of the flow generated by cell proliferation. We analyse the model both numerically and analytically, showing that uniform domain growth across the disc produces an exponentially growing wing disc

Transverse Phase Locking for Vortex Motion in Square and Triangular Pinning Arrays

We analyze transverse phase locking for vortex motion in a superconductor with a longitudinal DC drive and a transverse AC drive. For both square and triangular arrays we observe a variety of fractional phase locking steps in the velocity versus DC drive which correspond to stable vortex orbits. The locking steps are more pronounced for the triangular arrays which is due to the fact that the vortex motion has a periodic transverse velocity component even for zero transverse AC drive. All the steps increase monotonically in width with AC amplitude. We confirm that the width of some fractional steps in the square arrays scales as the square of the AC driving amplitude. In addition we demonstrate scaling in the velocity versus applied DC driving curves at depinning and on the main step, similar to that seen for phase locking in charge-density wave systems. The phase locking steps are most prominent for commensurate vortex fillings where the interstitial vortices form symmetrical ground states. For increasing temperature, the fractional steps are washed out very quickly, while the main step gains a linear component and disappears at melting. For triangular pinning arrays we again observe transverse phase locking, with the main and several of the fractional step widths scaling linearly with AC amplitude.Comment: 10 pages, 14 postscript figure

Commensurate and Incommensurate Vortex States in Superconductors with Periodic Pinning Arrays

As a function of applied field, we find a rich variety of ordered and partially-ordered vortex lattice configurations in systems with square or triangular arrays of pinning sites. We present formulas that predict the matching fields at which commensurate vortex configurations occur and the vortex lattice orientation with respect to the pinning lattice. Our results are in excellent agreement with recent imaging experiments on square pinning arrays [K. Harada et al., Science 274, 1167 (1996)].Comment: 9 pages, 3 figures. Accepted to Physical Review

Commensurate and Incommensurate Vortex Lattice Melting in Periodic Pinning Arrays

We examine the melting of commensurate and incommensurate vortex lattices interacting with square pinning arrays through the use of numerical simulations. For weak pinning strength in the commensurate case we observe an order-order transition from a commensurate square vortex lattice to a triangular floating solid phase as a function of temperature. This floating solid phase melts into a liquid at still higher temperature. For strong pinning there is only a single transition from the square pinned lattice to the liquid state. For strong pinning in the incommensurate case, we observe a multi-stage melting in which the interstitial vortices become mobile first, followed by the melting of the entire lattice, consistent with recent imaging experiments. The initial motion of vortices in the incommensurate phase occurs by an exchange process of interstitial vortices with vortices located at the pinning sites. We have also examined the vortex melting behavior for higher matching fields and find that a coexistence of a commensurate pinned vortex lattice with an interstitial vortex liquid occurs while at higher temperatures the entire vortex lattice melts. For triangular arrays at incommensurate fields higher than the first matching field we observe that the initial vortex motion can occur through a novel correlated ring excitation where a number of vortices can rotate around a pinned vortex. We also discuss the relevance of our results to recent experiments of colloidal particles interacting with periodic trap arrays.Comment: 8 figure

Phase-Locking of Vortex Lattices Interacting with Periodic Pinning

We examine Shapiro steps for vortex lattices interacting with periodic pinning arrays driven by AC and DC currents. The vortex flow occurs by the motion of the interstitial vortices through the periodic potential generated by the vortices that remain pinned at the pinning sites. Shapiro steps are observed for fields B_{\phi} < B < 2.25B_{\phi} with the most pronouced steps occuring for fields where the interstitial vortex lattice has a high degree of symmetry. The widths of the phase-locked current steps as a function of the magnitude of the AC driving are found to follow a Bessel function in agreement with theory.Comment: 5 pages 5 postscript figure

Phase Locking, Devil's Staircases, Farey Trees, and Arnold Tongues in Driven Vortex Lattices with Periodic Pinning

Using numerical simulations, we observe phase locking, Arnold tongues, and Devil's staircases for vortex lattices driven at varying angles with respect to an underlying superconducting periodic pinning array. This rich structure should be observalble in transport measurments. The transverse $V(I)$ curves have a Devil's staircase structure, with plateaus occurring near the driving angles along symmetry directions of the pinning array. Each of the plateaus corresponds to a different dyanmical phase with a distinctive vortex structure and flow pattern.Comment: accepted to Physical Review Letter

Anisotropic vortex pinning in superconductors with a square array of rectangular submicron holes

We investigate vortex pinning in thin superconducting films with a square array of rectangular submicron holes ("antidots"). Two types of antidots are considered: antidots fully perforating the superconducting film, and "blind antidots", holes that perforate the film only up to a certain depth. In both systems, we observe a distinct anisotropy in the pinning properties, reflected in the critical current Ic, depending on the direction of the applied electrical current: parallel to the long side of the antidots or perpendicular to it. Although the mechanism responsible for the effect is very different in the two systems, they both show a higher critical current and a sharper IV-transition when the current is applied along the long side of the rectangular antidots

Dignity and psychosocial related variables in elderly advanced cancer patients

Abstract Introduction: Most cancers occur in older individuals, who are more vulnerable due to functional impairment, multiple comorbidities, cognitive impairment, and lack of socio‑familial support. These can undermine patients' sense of dignity. This study seeks to compare dignity scores in older patients with advanced cancer on sociodemographic and clinical variables and analyze the predictive value of anxiety, depression, functional limitations, and social support on dignity scores. Methods: A prospective, multicenter, observational study conducted with participation of 15 hospitals in Spain from February 2020 to October 2021. Patients with newly‑diagnosed, advanced cancer completed the dignity (PPDS), anxiety and depression (BSI), Social Support (Duke-UNC‑11), and functional limitations (EORTC‑C30) scales. Lineal regression analyses explored the effects of anxiety, depression, functional status, and social support on dignity, adjusting for sociodemographic and clinical variables. Results: A total of 180 subjects participated in this study. The results of the correlation analysis revealed that dignity correlated negatively with anxiety, depression, and sex, and positively with social support, functional status, and longer estimated survival. Thus, women, and more anxious and depressed individuals scored lower on the dignity scale, whereas patients with more social support, fewer functional limitations, and longer estimated survival scored higher. Conclusion: In conclusion, being female, having a lower educational level, lower estimated survival, depression, anxiety, less social support, and limited functionality are correlated with less dignity in the elderly with advanced cancer. It is a priority to manage both physical and psychological symptoms in patients with unresectable advanced cancer to mitigate psychological distress and increase their sense of dignit