DNA Lesions Induced by Replication Stress Trigger Mitotic Aberration and Tetraploidy Development

During tumorigenesis, cells acquire immortality in association with the development of genomic instability. However, it is still elusive how genomic instability spontaneously generates during the process of tumorigenesis. Here, we show that precancerous DNA lesions induced by oncogene acceleration, which induce situations identical to the initial stages of cancer development, trigger tetraploidy/aneuploidy generation in association with mitotic aberration. Although oncogene acceleration primarily induces DNA replication stress and the resulting lesions in the S phase, these lesions are carried over into the M phase and cause cytokinesis failure and genomic instability. Unlike directly induced DNA double-strand breaks, DNA replication stress-associated lesions are cryptogenic and pass through cell-cycle checkpoints due to limited and ineffective activation of checkpoint factors. Furthermore, since damaged M-phase cells still progress in mitotic steps, these cells result in chromosomal mis-segregation, cytokinesis failure and the resulting tetraploidy generation. Thus, our results reveal a process of genomic instability generation triggered by precancerous DNA replication stress

BRCA1 establishes DNA damage signaling and pericentric heterochromatin of the X chromosome in male meiosis

During meiosis, DNA damage response (DDR) proteins induce transcriptional silencing of unsynapsed chromatin, including the constitutively unsynapsed XY chromosomes in males. DDR proteins are also implicated in double strand break repair during meiotic recombination. Here, we address the function of the breast cancer susceptibility gene Brca1 in meiotic silencing and recombination in mice. Unlike in somatic cells, in which homologous recombination defects of Brca1 mutants are rescued by 53bp1 deletion, the absence of 53BP1 did not rescue the meiotic failure seen in Brca1 mutant males. Further, BRCA1 promotes amplification and spreading of DDR components, including ATR and TOPBP1, along XY chromosome axes and promotes establishment of pericentric heterochromatin on the X chromosome. We propose that BRCA1-dependent establishment of X-pericentric heterochromatin is critical for XY body morphogenesis and subsequent meiotic progression. In contrast, BRCA1 plays a relatively minor role in meiotic recombination, and female Brca1 mutants are fertile. We infer that the major meiotic role of BRCA1 is to promote the dramatic chromatin changes required for formation and function of the XY body

Characterisation and evaluation of the impact of microfabricated pockets on the performance of limbal epithelial stem cells in biodegradable PLGA membranes for corneal regeneration

Scarring of the cornea affects thousands of people every year, significantly reducing the quality of life and potentially leading to corneal blindness. Although cultured limbal epithelial cells have been used to regenerate scarred corneas for more than 15 years, the culture strategies do not deliver cells under the physiological conditions they experience in vivo. One of the main characteristics of stem cells is their ability to self-renew to maintain a tissue for a lifetime. Stem cells’ unique characteristics are thought to be at least partially due to their location within enclosed protective microenvironments or niches. For corneal stem cells these are located in intricate microenvironments or niches situated within areas of the limbal region known as the Palisades of Vogt. These are located in the limbus which is the area between the cornea and sclera. In this study we introduced micropockets into biodegradable microfabricated membranes and explored the potential contribution of these structures to limbal cell migration and their ability to deliver cells to a 3D cornea model. Membranes with micropockets were characterized using SEM, OCT, light microscopy and nanoindentation. Results indicate that the micropockets enhance the migration of cells from limbal explants and cells transfer readily from the membranes to the ex vivo cornea model

Lysosome-mediated processing of chromatin in senescence

Cellular senescence is a stable proliferation arrest, a potent tumor suppressor mechanism, and a likely contributor to tissue aging. Cellular senescence involves extensive cellular remodeling, including of chromatin structure. Autophagy and lysosomes are important for recycling of cellular constituents and cell remodeling. Here we show that an autophagy/lysosomal pathway processes chromatin in senescent cells. In senescent cells, lamin A/C–negative, but strongly γ-H2AX–positive and H3K27me3-positive, cytoplasmic chromatin fragments (CCFs) budded off nuclei, and this was associated with lamin B1 down-regulation and the loss of nuclear envelope integrity. In the cytoplasm, CCFs were targeted by the autophagy machinery. Senescent cells exhibited markers of lysosomal-mediated proteolytic processing of histones and were progressively depleted of total histone content in a lysosome-dependent manner. In vivo, depletion of histones correlated with nevus maturation, an established histopathologic parameter associated with proliferation arrest and clinical benignancy. We conclude that senescent cells process their chromatin via an autophagy/lysosomal pathway and that this might contribute to stability of senescence and tumor suppression

Splenic peliosis with spontaneous splenic rupture: report of two cases

BACKGROUND: Peliosis is a rare condition characterised by multiple cyst-like, blood-filled cavities within the parenchyma of solid organs. Most commonly affecting the liver, isolated splenic peliosis is an even more unique phenomenon. Patients with the condition are often asymptomatic. However, this potentially lethal condition can present with spontaneous organ rupture. We present two such cases, discuss their management and review what is currently known in the existing literature. CASE PRESENTATION: A previously well twenty-six year old woman presented with abdominal pain following a trivial episode of coughing. A diagnosis of spontaneous splenic rupture was made following clinical and radiological examination. She underwent emergency splenectomy and made a full, uneventful recovery. Histopathological examination confirmed splenic peliosis. The second case describes an eighty six year old lady who sustained a trivial fall and developed pain in her left side. A CT confirmed splenic rupture. She became haemodynamically unstable during her admission and underwent emergency splenectomy. Histopathological examination revealed splenic peliosis. She went on to make an uneventful recovery. CONCLUSION: Splenic peliosis is very rare. It has a number of associations including immunosuppression, drug therapy and infection. Although patients are often asymptomatic, life-threatening spontaneous organ rupture may occur. If the diagnosis of peliosis is confirmed, additional investigations should be considered to detect its presence in other organs. Furthermore, the presence of the condition may be relevant if further medical or surgical intervention is planned

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幼児の発育発達の特性を縦断的研究法に基づいて,幼稚園入園時(年少)から卒園時(年長)までに定期的に運動能力を測定し,この幼児期の運動能力の発達の特性を明らかにするため検討した結果,次のような結論を得た。(1)下肢動作による,走・跳の運動能力の変化には,あまり性差がみられなかったのに対して,上肢を使用する動作による投運動能力の変化には,明らかな性差がみられた。(2)25m走と平均台歩きの直線的な走能力やバランスをともなう歩行能力は,3才児しかも比較的短時間で時間短縮が認められた。(3)発達の程度が著しくなる時期は,男女児ともに,4才から5才児であることが示唆された。(4)全体としては,どの測定項目も明らかに向上することが認められた。今後,更に研究を継続し,幼児期の運動能力の発達の特性を明らかにするとともに,園の運動遊びの教材と結びつけて丈夫な体と豊かな心とそして,すばらしい社会性の芽をはぐくんでやりたいと考えている

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幼児の発育発達の特性を縦断的研究法に基づいて,幼児期の運動能力の発達の特性を明らかにするため,1983年6月下旬から1984年10月下旬の1年間の運動能力の変化について検討した結果,次のような結論を得た。1)下肢動作による,走・跳の運動能力の変化には,あまり性差がみられなかったのに対して,上肢を使用する投の運動能力の変化には,明らかな性差がみられた。2)25m走と平均台歩きの直線的な走能力やバランスをともなう歩行能力は,比較的短期間で時間短縮が認められた。3)3才から4才児において,男児より女児の方が多くの項目に向上が認められた。また,4才から5才児では,男女児ともに,発達の程度が著しくなる時期であることが示唆された。4)全体として,どの測定項目も1年間では明らかに向上することが認められた。今後,更に研究を継続し,幼児期の運動能力の発達の特性を明らかにするとともに,園の運動遊びの教材と結びつけていきたいと考えている