Homologous Recombination: To Fork and Beyond

Accurate completion of genome duplication is threatened by multiple factors that hamper the advance and stability of the replication forks. Cells need to tolerate many of these blocking lesions to timely complete DNA replication, postponing their repair for later. This process of lesion bypass during DNA damage tolerance can lead to the accumulation of single-strand DNA (ssDNA) fragments behind the fork, which have to be filled in before chromosome segregation. Homologous recombination plays essential roles both at and behind the fork, through fork protection/lesion bypass and post-replicative ssDNA filling processes, respectively. I review here our current knowledge about the recombination mechanisms that operate at and behind the fork in eukaryotes, and how these mechanisms are controlled to prevent unscheduled and toxic recombination intermediates. A unifying model to integrate these mechanisms in a dynamic, replication fork-associated process is proposed from yeast results.España Gobierno (BFU2015-63698-P

Fluctuations and Instabilities of Ferromagnetic Domain Wall pairs in an External Magnetic Field

Soliton excitations and their stability in anisotropic quasi-1D ferromagnets are analyzed analytically. In the presence of an external magnetic field, the lowest lying topological excitations are shown to be either soliton-soliton or soliton-antisoliton pairs. In ferromagnetic samples of macro- or mesoscopic size, these configurations correspond to twisted or untwisted pairs of Bloch walls. It is shown that the fluctuations around these configurations are governed by the same set of operators. The soliton-antisoliton pair has exactly one unstable mode and thus represents a critical nucleus for thermally activated magnetization reversal in effectively one-dimensional systems. The soliton-soliton pair is stable for small external fields but becomes unstable for large magnetic fields. From the detailed expression of this instability threshold and an analysis of nonlocal demagnetizing effects it is shown that the relative chirality of domain walls can be detected experimentally in thin ferromagnetic films. The static properties of the present model are equivalent to those of a nonlinear sigma-model with anisotropies. In the limit of large hard-axis anisotropy the model reduces to a double sine-Gordon model.Comment: 15 pages RevTex 3.0 (twocolumn), 9 figures available on request, to appear in Phys Rev B, Dec (1994

Partial depletion of histone H4 increases homologous recombination-mediated genetic instability

DNA replication can be a source of genetic instability. Given the tight connection between DNA replication and nucleosome assembly, we analyzed the effect of a partial depletion of histone H4 on genetic instability mediated by homologous recombination. A Saccharomyces cerevisiae strain was constructed in which the expression of histone H4 was driven by the regulated tet promoter. In agreement with defective nucleosome assembly, partial depletion of histone H4 led to subtle changes in plasmid superhelical density and chromatin sensitivity to micrococcal nuclease. Under these conditions, homologous recombination between ectopic DNA sequences was increased 20-fold above the wild-type levels. This hyperrecombination was not associated with either defective repair or transcription but with an accumulation of recombinogenic DNA lesions during the S and G2/M phases, as determined by an increase in the proportion of budded cells containing Rad52-yellow fluorescent protein foci. Consistently, partial depletion of histone H4 caused a delay during the S and G2/M phases. Our results suggest that histone deposition defects lead to the formation of recombinogenic DNA structures during replication that increase genomic instability.Ministerio de Ciencia y Tecnología BMC2000-0439 SAF2003-0020

Use of personal call alarms among community-dwelling older people.

Having a fall and then lying on the floor for an hour or more is known as a ‘long lie’, which are associated with serious injury and an elevated risk of admission to hospital, long-term care, and death. Personal call alarms are designed to prevent long lies, although little is known about their use. Using cross-sectional data from the English Longitudinal Study on Ageing, this study investigated the proportion of self-reported users of personal call alarms among 3091 community-dwelling adults aged 65+ who reported difficulties of mobility or activities of daily living. The characteristics of users were then explored through logistic regressions comparing those living alone with those living with others. One hundred and eighty people self-reported using a personal call alarm (6%). Multivariate regression found the following to significantly predict personal call alarm use among both those living alone and with others: greater difficulty with activities / instrumental activities of daily living, older age, and for those living with others only: lower score on the quality of life subscale for control. Personal call alarm use may be markedly lower than the 30 per cent annual incidence of falls among community-dwelling older people. Better understanding is needed of the reasons for low usage, even amongst those at highest falls risk for whom such alarms are most likely to be beneficial

Graphical Modelling with Computer Extended Descriptive Geometry (CeDG): Description and Comparison with CAD

We present a Computer Extended Descriptive Geometry (CeDG) approach for modelling spatial geometric systems that surpasses several CAD limitations. A first concept proof has shown that the CeDG can be implemented on the dynamic geometry software (DGS) paradigm to generate parametric models based on descriptive geometric techniques. Thereliabilityandperformanceofthe CeDG approachwascomparedto CAD throughtwo study cases from the sheet metal and mechanisms design fields. The outcomes demonstrate that CeDG is able to compute the design geometrical parameters concurrently with the modelling process and to obtain planar cutouts of 3D surfaces, in situations where CAD systems can not do it. The implementation was performed in Geogebra© for CeDG and Solid Edge© 2009 for CAD, which were selected because of their cutting edge technology. As main conclusion, the CeDG approach is a Descriptive Geometry (DG) - based computer parametric graphical modelling that may complement the CAD technology with accuracy and reliability

Estudio multidisciplinar de seguimiento del peso corporal en una cohorte de pacientes en tratamiento inicial con antipsicóticos

Introduction. El aumento de peso es una de las reacciones adversas más preocupantes de los antipsicóticos atípicos por el riesgo cardiovascular que entraña, entre otros aspectos. El objetivo principal es conocer la evolución del peso e índice de masa corporal a los 6 meses asociada al tratamiento inicial con antipsicóticos en condiciones reales de uso. Métodos. Estu- dio de cohortes, multicéntrico y prospectivo. Resultados. Se ha reclutado una cohorte de 71 pacientes tratados con antipsicóticos (mediana=54 años). Un 60% de pacientes muestra un incremento de peso al finalizar el periodo de seguimiento. En los hombres (32%, mediana=37 años), se obtuvo que el peso corporal medio inicial fue 74, 9 kg (DE=15,4) y final 81,1 kg (DE=16,7); el índice masa corporal medio inicial 25, 1 kg/m2 (DE=4,2) y final 27,1 kg/m2 (DE=4,6). En las mujeres (68%, mediana=61,5 años), se obtuvo que el peso corporal medio inicial fue 61, 4 kg (DE=10,0) y final 63, 0 kg (DE=11,2); el índice masa corporal medio inicial 26, 6 kg/m2 (DE=4,9) y final 27,0 kg/m2 (DE=4,6). El aumento de 2 o más kg de peso es signi- ficativamente mayor en menores de 55 años, así como en hombres. Conclusiones. El inicio de tratamiento con un antipsicótico en condiciones reales de uso se asocia a incremento de peso e índice de masa corporal de los pacientes a los 6 meses, tanto en hombres como mujeres. Se ha constituído un grupo de investigación multidisciplinar centrado en el estudio del uso de antipsicóticos.Introduction. Weight gain is one of the most troubling adverse effects of atypical anti- psychotics due to their cardiovascular risk and other factors. The main objective is to assess possible changes of body weight and body mass index at 6 months associated with onset of antipsychotic treatment in ordinary clinical use. Methods. It's a cohort, multicentre, prospective study. Results. A cohort of 71 patients treated with antipsychotics was recruited (median=54 years). A total of 60% of patients showed an increase of body weight at the end of the follow- up period. In males (32%, median=37 years), it was obtained that mean body weight at base- line was 74, 9 kg (DE=15,4)and at 6 months 81,1 kg (DE=16,7); mean body mass index at baseline was 25,1 kg/m2 (DE=4,2) and at 6 months 27,1 kg/m2 (DE=4,6). In women (68%, median=61,5 years), it was obtained that mean body weight at baseline was 61,4 kg (DE=10,0) and at 6 months 63, 0 kg (DE=11,2); mean body mass index at baseline 26,6 kg/m2 (DE=4,9) and at 6 months 27,0 kg/m2 (DE=4,6). Increase of body weight over 2 kg was significantly higher in patients under 55 years and males. Conclusions. Onset of antipsychotic treatment in ordinary clinical use is associated with an increase of patients' body weight and body mass index at 6 months, both for men and women. A multidisciplinary research team focused on the study of antipsychotic use of has been established

Effect of implantoplasty on the elastic limit of dental implants of different diameters

Background Implantoplasty reduces both implant diameter and the thickness of its walls, subsequently reducing the ability of the implant to resist fracture in response to functional load. In combination with an increase in the crown-implant ratio due to bone loss, this could increase the lever effect, which in presence of high masticatory forces or parafunctional habits, could lead to complications such as fracture of the implant or loosening of the prosthetic screw. Objectives To determine the elastic limits of internal connection, dental implants of different designs and diameters after an implantoplasty. Materials and methods This in vitro study included 315 tapered internal connection titanium dental implants, the threads of which were removed with an industrial milling machine-for standardized implantoplasty (IMP1; n = 105)-or with the conventional approach-manually, using high-speed burs (IMP2; n = 105). The remaining 105 implants were used as controls. The final implant diameters were recorded. The quality of the newly polished surfaces was assessed by scanning electron microscopy. All implants were subjected to a mechanical pressure resistance test. A Tukey''s test for multiple comparisons was used to detect differences in the elastic limit and final implant diameters between the implant groups. Results There were statistically significant differences in the elastic limit between the IMP1, IMP2, and control groups (p < 0.05). Furthermore, the implant diameter was significantly smaller in the IMP1 and IMP2 groups (p < 0.05). Scanning electron microscopy revealed smooth implant surfaces in the IMP1 and IMP2 groups, with some titanium particles visible in the IMP1 group. Conclusions Implantoplasty significantly decreased the elastic limit of internal connection titanium dental implants, especially in those with a smaller diameter (3-3.5 mm)

Unzipping the Secrets of Amyloid Disassembly by the Human Disaggregase

Neurodegenerative diseases (NDs) are increasingly positioned as leading causes of global deaths. The accelerated aging of the population and its strong relationship with neurodegeneration forecast these pathologies as a huge global health problem in the upcoming years. In this scenario, there is an urgent need for understanding the basic molecular mechanisms associated with such diseases. A major molecular hallmark of most NDs is the accumulation of insoluble and toxic protein aggregates, known as amyloids, in extracellular or intracellular deposits. Here, we review the current knowledge on how molecular chaperones, and more specifically a ternary protein complex referred to as the human disaggregase, deals with amyloids. This machinery, composed of the constitutive Hsp70 (Hsc70), the class B J-protein DnaJB1 and the nucleotide exchange factor Apg2 (Hsp110), disassembles amyloids of α-synuclein implicated in Parkinson’s disease as well as of other disease-associated proteins such as tau and huntingtin. We highlight recent studies that have led to the dissection of the mechanism used by this chaperone system to perform its disaggregase activity. We also discuss whether this chaperone-mediated disassembly mechanism could be used to solubilize other amyloidogenic substrates. Finally, we evaluate the implications of the chaperone system in amyloid clearance and associated toxicity, which could be critical for the development of new therapies.This research was funded by MCI/AEI/FEDER, UE (grant PID2019-111068GB-I00) and by the Basque Government (grant IT1201-19). L.V.-C. is the recipient of a predoctoral fellowship from the UPV/EHU and N.O. holds a contract funded by Fundacion Biofisika Bizkaia