Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability.

Topoisomerase 3α (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult-onset mitochondrial disease resulting from bi-allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory-motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom-like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult-onset mitochondrial disease and more severe variants causing a Bloom-like syndrome with mitochondrial dysfunction in childhood.

Two type I topoisomerases maintain DNA topology in human mitochondria.

Genetic processes require the activity of multiple topoisomerases, essential enzymes that remove topological tension and intermolecular linkages in DNA. We have investigated the subcellular localisation and activity of the six human topoisomerases with a view to understanding the topological maintenance of human mitochondrial DNA. Our results indicate that mitochondria contain two topoisomerases, TOP1MT and TOP3A. Using molecular, genomic and biochemical methods we find that both proteins contribute to mtDNA replication, in addition to the decatenation role of TOP3A, and that TOP1MT is stimulated by mtSSB. Loss of TOP3A or TOP1MT also dysregulates mitochondrial gene expression, and both proteins promote transcription elongation in vitro. We find no evidence for TOP2 localisation to mitochondria, and TOP2B knockout does not affect mtDNA maintenance or expression. Our results suggest a division of labour between TOP3A and TOP1MT in mtDNA topology control that is required for the proper maintenance and expression of human mtDNA.

Controlling the topology of mammalian mitochondrial DNA.

The genome of mitochondria, called mtDNA, is a small circular DNA molecule present at thousands of copies per human cell. MtDNA is packaged into nucleoprotein complexes called nucleoids, and the density of mtDNA packaging affects mitochondrial gene expression. Genetic processes such as transcription, DNA replication and DNA packaging alter DNA topology, and these topological problems are solved by a family of enzymes called topoisomerases. Within mitochondria, topoisomerases are involved firstly in the regulation of mtDNA supercoiling and secondly in disentangling interlinked mtDNA molecules following mtDNA replication. The loss of mitochondrial topoisomerase activity leads to defects in mitochondrial function, and variants in the dual-localized type IA topoisomerase TOP3A have also been reported to cause human mitochondrial disease. We review the current knowledge on processes that alter mtDNA topology, how mtDNA topology is modulated by the action of topoisomerases, and the consequences of altered mtDNA topology for mitochondrial function and human health.

Long-term protection of HPV test in women at risk of cervical cancer.

OBJECTIVE: To evaluate the 9-year incidence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and cumulative adherence to perform a next test in a cohort of women aged 40+ years with no cervical screening cytology within a window of 5 years (underscreened women), after baseline cervical cytology and HPV tests. METHODS: In Catalonia, Spain, co-testing with cytology and HPV test has been recommended in the Public Health system since 2006 for underscreened women. In 2007, 1,594 women with underscreened criteria were identified and followed through medical records form Pathological Department. 9-year cumulative incidence of histologically confirmed CIN2+ and cumulative adherence to perform a next test were estimated using Kaplan-Meier statistics. RESULTS: Follow-up was available for 1,009 women (63.3%) resulting in 23 women with. CIN2+ (2.3%). Of them, 4 women (17%) had both tests negative at baseline (3CIN2 and 1CIN3) with cumulative incidence of CIN2+ of 0.4% (95% CI: 0.1-1.4) at 5-years and 1.3% (95% CI: 0.4-3.7) at 9-years. During the first year, the prevalence among women with both tests positive was 27.0% (95% CI: 13.0-50.6) for CIN2+. Lost to follow-up was higher among women with both tests negative compared to those with both positive tests (38.7% vs 4.2%, p-value <0.001). 40.5% of the women HPV-/cyto- had a re-screening test during the 4 years following the baseline, increasing until 53.5% during the 6 years of follow-up. CONCLUSIONS: HPV detection shows a high longitudinal predictive value at 9-year to identify women at risk to develop CIN2+. The data validate a safe extension of the 3-year screening intervals (current screening interval) to 5-year intervals in underscreened women that had negative HPV result at baseline. It is necessary to establish mechanisms to ensure screening participation and adequate follow-up for these women.

Chen's attractor exists if Lorenz repulsor exists: the Chen system is a special case of the Lorenz system.

In this paper, we show, by means of a linear scaling in time and coordinates, that the Chen system, given by x=a(y-x), y=(c-a)x+cy-xz, z=-bz+xy, is, generically (c≠0), a special case of the Lorenz system. First, we infer that it is enough to consider two parameters to study its dynamics. Furthermore, we prove that there exists a homothetic transformation between the Chen and the Lorenz systems and, accordingly, all the dynamical behavior exhibited by the Chen system is present in the Lorenz system (since the former is a special case of the second). We illustrate our results relating Hopf bifurcations, periodic orbits, invariant surfaces, and chaotic attractors of both systems. Since there has been a large literature that has ignored this equivalence, the aim of this paper is to review and clarify this field. Unfortunately, a lot of the previous papers on the Chen system are unnecessary or incorrect.

Comment on "Sil'nikov chaos of the Liu system" [Chaos 18, 013113 (2008)].

In the referenced paper, the authors use the undetermined coefficient method to prove analytically the existence of homoclinic and heteroclinic orbits in a Lorenz-like system. If the proof was correct, the existence of horseshoe chaos would be guaranteed via the Sil'nikov criterion. However, we hereby show that their demonstration is incorrect for two reasons. On the one hand, they wrongly use a symmetry the Lorenz-like system exhibits. On the other hand, they try to find structurally unstable global bifurcations by means of a series that is uniformly convergent in an open set of the parameter space: this would imply that the dynamical object they have found is structurally stable.

Efecto de la combinación pindolol-clopamida en el tratamiento de la hipertensión leve y moderada: un estudio multicéntrico / Effect of combined pindolol-clopamide in essential and moderate hypertension therapy: a multicentric study

En el presente estudio se reporta el efecto antihipertensivo de la combinación Pindolol + Clopamida vs placebo, en grupos paralelos, con distribución al azar, en un grupo de pacientes hipertensos leves y moderados que asistieron a los Servicios de Medicina Vial del Estado Carabobo. El estudio duró ocho semanas, con exámenes clínicos cada dos semanas. La dosis de Pindolol + Clopamida fue de 1 tableta (10 mg y 5 mg respectivamente). El grupo de pacientes seleccionados perteneció mayormente al sexo masculino (19 pacientes de 20 pacientes en las edades de 30 y 49 años en el grupo placebo; y 16 pacientes de 20 pacientes en las edades de 30 y 49 años en el grupo Pindolol + Clopamida). En el grupo que recibió el tratamiento activo, en el 60% de los pacientes los valores tensionales se normalizaron al final del tratamiento y en el 40% hubo reducciones apreciables, pero no alcanzaron la normalidad. En el grupo placebo apenas hubo descenso a la normalidad en el 20% de los pacientes. Nosotros concluimos que la combinación Pindolol + Clopamida es util en la terapia de la Hipertensión leve y moderada y exhibe excelente tolerancia