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Genetics and exercise: an introduction
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Claude Bouchard, Henning Wackerhage
Two important events of meiosis contribute to human genetic diversity: Independent assortment of chromosomes. Of each chromosome pair in somatic cells, gametes receive only one chromosome. Is it the mothers or fathers chromosome? This is a random process and so each spermatocyte or oocyte will have a random combination of chromosomes from maternal and paternal origins.Homologous recombination. During meiosis, before chromosomes migrate to daughter cells, chromosomes cross over and exchange equivalent segments. For instance, a crossing over may occur between maternal and paternal chromosome 3, resulting in an exchange of DNA between the two chromosomes. About 50–60 recombinations take place between all pairs of homologous chromosomes (i.e. pairs of chromosomes of maternal and paternal descent) during meiosis.
Radiotherapy Physics
Published in Debbie Peet, Emma Chung, Practical Medical Physics, 2021
Andrea Wynn-Jones, Caroline Reddy, John Gittins, Philip Baker, Anna Mason, Greg Jolliffe
The secondary standard chamber is placed in a graphite calorimeter and irradiated using a linear accelerator. The charge collected by the chamber and the temperature rise of the calorimeter are accurately measured. A current source is then used to heat the calorimeter to produce the same temperature rise the radiation produced, allowing the energy required to raise the temperature this amount to be calculated. The calibration factor of the ionisation chamber can be calculated, considering corrections including temperature and pressure (to correct for the mass of air in the chamber which is unsealed), and ion recombination. This calibration factor is valid only for a beam of the quality used to perform the calibration, and the beam quality is characterised by the ratio of the ionisations measured by an isocentric chamber at 20 cm deep to one at 10 cm deep (TPR 20/10). By performing the aforementioned procedure at different beam energies, a table is created allowing calibration factors for different qualities of beams to be interpolated.
Adenoviral Vectors for Gene Therapy of Inherited and Acquired Disorders of the Lung
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
David T. Curiel, Robert I. Garver
The details of plasmid design and common methods of use have been described in recent reviews (18,19) and therefore will not be reiterated in detail here (Fig. 1). In brief, the most widely used method involves three major steps. First, the new coding sequence with appropriate transcriptional start and stop regulatory sequences is added to a multiple cloning site within the deleted El region of a plasmid containing a portion of the left-hand (5') end of the adenovirus genome. Second, this plasmid vector containing the new coding sequence is cotransfected into 293 cells with a second plasmid that contains the entire adenovirus genome with an El deletion modified to contain a “stuffer fragment” of plasmid DNA. The stuffer fragment not only contains the plasmid origin of replication and antibiotic resistance gene for bacterial propagation, but it is sufficiently large to prevent that adenoviral DNA from being packaged into a stable viral particle. Homologous recombination occurs be tween the two plasmids so that the El region containing the coding sequence of interest replaces the plasmid stuffer within the otherwise intact genome, and the E1 proteins made by the 293 cells activate the recombinant genome replication with the result that recombinant virus is made. The third step is a series of plaque purifications with screening assays at each step to eliminate undesired wild type virus that is generated by homologous recombination between the viral sequences within 293 cells and the adenoviral plasmid with the stuffer fragment.
An introduction to the special issue of IJRB in honor of the extraordinary legacy of Professor John B. “Jack” Little in the radiation sciences
Published in International Journal of Radiation Biology, 2023
Amy Kronenberg, Edouard I. Azzam
These more difficult types of lesions are considered in the subsequent manuscript contributed by Jac Nickoloff and colleagues. Earlier in his career, Jac spent some years at the Laboratory of Radiobiology as a member of the faculty before going westward. In their article, Nickoloff and colleagues review the DNA lesions induced by radiation and focus on the cellular mechanisms that defend against these lesions. Here the focus is on the roles and mechanisms of non-homologous end joining and homologous recombination, both modes of DNA double-strand break repair, and how these pathways operate in normal and cancer cells. They discuss how the choice between these pathways is regulated during the cell cycle and by other factors, and how homologous recombination can be exploited as a target in cancer radiotherapy.
Combining inhibition of immune checkpoints and PARP: rationale and perspectives in cancer treatment
Published in Expert Opinion on Therapeutic Targets, 2022
Martina Catalano, Luigi Francesco Iannone, Federica Cosso, Daniele Generali, Enrico Mini, Giandomenico Roviello
The exchange of DNA strands between a pair of DNA segments of the double helix that have a very similar or identical sequence is defined as homologous recombination. This exchange allows one stretch of DNA double helix to act as a template to restore lost or damaged information to the other stretch. It is particularly challenging to repair DNA damage affecting both strands of the double helix that occur in somatic cells during meiosis [16]. Germline mutations in several other HR genes have been linked to tumor predisposition. The most relevant include tumor suppressors BRCA1 and BRCA2 mutations that have a key role in different stages of HR, mainly associated with familial breast and ovarian cancers [17]. However, around 20–25% of epithelial ovarian cancer patients have pathogenic variants in several genes that mostly encode for proteins involved in DDR pathways [18]. Indeed, next generation sequencing revealed that beyond BRCA1/2, mutations in HR genes, such as PALB2, RAD51, ATM, BRIP1, BARD1, and CHEK2 occurs in up to a fifth of the patients with high-grade serous ovarian cancer [18]. Failure in the HR repair system can compromise the elimination of genome mutations and increasing the risk of oncogenesis after the accumulation of DNA damage events [19].
The biology and management of dyskeratosis congenita and related disorders of telomeres
Published in Expert Review of Hematology, 2022
Hemanth Tummala, Amanda Walne, Inderjeet Dokal
Biallelic RTEL1 variants were first identified in 2013 in a subset of patients with features of HH [44,45]. An autosomal recessive founder mutation was also been reported in HH patients from two unrelated families of Ashkenazi Jewish ancestry [46]. RTEL1 functions as a helicase (Figure 3). It is critical for telomere maintenance. It also has a role in homologous recombination. Patients with biallelic RTEL1 variants usually have very short telomeres as there is impaired resolution of T-loops. However, patient cells do not have significant defects in homologous recombination, since peripheral blood lymphocytes usually have normal chromosomal breakage score following treatment with diepoxybutane or mitomycin-C [45]. These patients have very homogeneous clinical features which include global BM failure, immune deficiency, and cerebellar hypoplasia. Subsequently, it has been observed heterozygous RTEL1 variants are responsible for some cases of pulmonary fibrosis [47]. Furthermore, a subgroup of patients with a combination of MDS and liver disease are associated with heterozygous loss of function variants in RTEL1 [48].