Failure of homologous synapsis and sex-specific reproduction problems

The prophase of meiosis I ensures the correct segregation of chromosomes to each daughter cell. This includes the pairing, synapsis, and recombination of homologous chromosomes. A subset of chromosomal abnormalities, including translocation and inversion, disturbs these processes, resulting in the failure to complete synapsis. This activates the meiotic pachytene checkpoint, and the gametes are fated to undergo cell cycle arrest and subsequent apoptosis. Spermatogenic cells appear to be more vulnerable to the pachytene checkpoint, and male carriers of chromosomal abnormalities are more susceptible to infertility. In contrast, oocytes tend to bypass the checkpoint and instead generate other problems, such as chromosome imbalance that often leads to recurrent pregnancy loss in female carriers. Recent advances in genetic manipulation technologies have increased our knowledge about the pachytene checkpoint and surveillance systems that detect chromosomal synapsis. This review focuses on the consequences of synapsis failure in humans and provides an overview of the mechanisms involved. We also discuss the sexual dimorphism of the involved pathways that leads to the differences in reproductive outcomes between males and females

Cruciform extrusion propensity of human translocation-mediating palindromic AT-rich repeats

There is an emerging consensus that secondary structures of DNA have the potential for genomic instability. Palindromic AT-rich repeats (PATRRs) are a characteristic sequence identified at each breakpoint of the recurrent constitutional t(11;22) and t(17;22) translocations in humans, named PATRR22 (∼600 bp), PATRR11 (∼450 bp) and PATRR17 (∼190 bp). The secondary structure-forming propensity in vitro and the instability in vivo have been experimentally evaluated for various PATRRs that differ regarding their size and symmetry. At physiological ionic strength, a cruciform structure is most frequently observed for the symmetric PATRR22, less often for the symmetric PATRR11, but not for the other PATRRs. In wild-type E. coli, only these two PATRRs undergo extensive instability, consistent with the relatively high incidence of the t(11;22) in humans. The resultant deletions are putatively mediated by central cleavage by the structure-specific endonuclease SbcCD, indicating the possibility of a cruciform conformation in vivo. Insertion of a short spacer at the centre of the PATRR22 greatly reduces both its cruciform extrusion in vitro and instability in vivo. Taken together, cruciform extrusion propensity depends on the length and central symmetry of the PATRR, and is likely to determine the instability that leads to recurrent translocations in humans

DNA secondary structure is influenced by genetic variation and alters susceptibility to de novo translocation

<p>Abstract</p> <p><b>Background</b></p> <p>Cumulative evidence suggests that DNA secondary structures impact DNA replication, transcription and genomic rearrangements. One of the best studied examples is the recurrent constitutional t(11;22) in humans that is mediated by potentially cruciform-forming sequences at the breakpoints, palindromic AT-rich repeats (PATRRs). We previously demonstrated that polymorphisms of PATRR sequences affect the frequency of <it>de novo </it>t(11;22)s in sperm samples from normal healthy males. These studies were designed to determine whether PATRR polymorphisms affect DNA secondary structure, thus leading to variation in translocation frequency.</p> <p><b>Methods</b></p> <p>We studied the potential for DNA cruciform formation for several PATRR11 polymorphic alleles using mobility shift analysis in gel electrophoresis as well as by direct visualization of the DNA by atomic force microscopy. The structural data for various alleles were compared with the frequency of <it>de novo </it>t(11;22)s the allele produced.</p> <p><b>Results</b></p> <p>The data indicate that the propensity for DNA cruciform structure of each polymorphic allele correlates with the frequency of <it>de novo </it>t(11;22)s produced (r = 0.77, <it>P </it>= 0.01).</p> <p><b>Conclusions</b></p> <p>Although indirect, our results strongly suggest that the PATRR adopts unstable cruciform structures during spermatogenesis that act as translocation hotspots in humans.</p

The importance of central airway dilatation in patients with bronchiolitis obliterans

Background: Bronchiolitis obliterans (BO) is a clinical syndrome characterised by progressive small airway obstruction, causing significant morbidity and mortality. Central airway dilatation is one of its radiological characteristics, but little is known about the clinical and pathological associations between airway dilatation and BO. Methods: This retrospective study consecutively included patients who underwent lung transplantation due to BO at Kyoto University Hospital from 2009 to 2019. Demographic and histopathological findings of the resected lungs were compared between patients with and without airway dilatation measured by chest computed tomography (CT) at registration for lung transplantation. Results: Of a total of 38 included patients (median age, 30 years), 34 (89%) had a history of hematopoietic stem-cell transplantation, and 22 (58%) had airway dilatation based on CT. Patients with airway dilatation had a higher frequency of Pseudomonas aeruginosa isolation with greater residual volume than those without airway dilatation. Quantitative CT analysis revealed an increase in lung volume to predictive total lung capacity and a percentage of low attenuation volume <-950 HU at inspiration in association with the extent of airway dilatation. Airway dilatation on CT was associated with an increased number of bronchioles with concentric narrowing of the lumen and thickening of the subepithelium of the walls on histology. Conclusions: In patients with BO, airway dilatation may reflect increased residual volume or air trapping and pathological extent of obstructive bronchioles, accompanied by a risk of Pseudomonas aeruginosa isolation. More attention should be paid to the development of airway dilatation in the management of BO

確かな学びを創りたい ―教育実践への3つのアプローチ―

準備委員会企画シンポジウム6　　企画・司会者：青木多寿子　話題提供者：豊田弘司・秋田喜代美・向後千春　指定討論者：田中俊也・木原俊

C/Cフクゴウザイリョウ ノ チョウコウオンカ ニオケル キョウドジンセイ

Mechanical properties of carbon fiber reinforced carbon (C/C) composites, fabricated by the preformed yarn method, were studied at elevated temperature up to 2300℃ in vacuum. Various mechanical tests including tensile, flexural, interlamina shear and fracture toughness tests were carried out to evaluate temperature dependence of strength, Young\u27s modulus and fracture toughness for three kinds of laminate C/C composites with uni-directional, 0°/90° and O°/90°/±45° fiber orientations. The failure processes of C/C composites were examined mainly focused on the influence of "transverse-cracks", which bad introduced during processing

Role of Collagen Gel Droplet-Embedded Culture-Drug Sensitivity Testing (CD-DST) for Assessing the Sensitivity of Gastric Cancer to Chemotherapy Drugs Combined with Other Cancer Therapeutic Drugs

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