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The resolution of joint molecules that link recombining sister chromatids is essential for chromosome segregation. Here, we determine the fate of unresolved recombination intermediates arising in cells lacking two nucleases required for resolution ( GEN1 –/– knockout cells depleted of MUS81). We find that intermediates persist until mitosis and form a distinct class of anaphase bridges, which we term homologous recombination ultra-fine bridges (HR-UFBs). HR-UFBs are distinct from replication stress-associated UFBs, which arise at common fragile sites, and from centromeric UFBs. HR-UFBs are processed by BLM helicase to generate single-stranded RPA-coated bridges that are broken during mitosis. In the next cell cycle, DNA breaks activate the DNA damage checkpoint response, and chromosome fusions arise by non-homologous end joining. Consequently, the cells undergo cell cycle delay and massive cell death. These results lead us to present a model detailing how unresolved recombination intermediates can promote DNA damage and chromosomal instability. Chan et al. show that unresolved recombination intermediates form a previously unappreciated type of ultra-fine bridge. These bridges are broken upon cell division, leading to chromosome breaks and instability.

Holliday junction (HJ) resolvases are necessary for the processing of persistent recombination intermediates before cell division. Their actions, however, need to be restricted to the late stages of the cell cycle to avoid the inappropriate cleavage of replication intermediates. Control of the yeast HJ resolvase, Yen1, involves phosphorylation changes that modulate its catalytic activity and nuclear import. Here, we show that GEN1, the human ortholog of Yen1, is regulated by a different mechanism that is independent of phosphorylation. GEN1 is controlled exclusively by nuclear exclusion, driven by a nuclear export signal (NES) that restricts GEN1 actions to mitosis when the nuclear membrane breaks down. Construction of a nuclear-localized version of GEN1 revealed that its premature actions partially suppress phenotypes associated with loss of BLM and MUS81, but cause elevated crossover formation. The spatial control of GEN1 therefore contributes to genome stability, by avoiding competition with non-crossover promoting repair pathways. The human Holliday junction resolvase GEN1 functions during anaphase to eliminate recombination intermediates that block proper chromosome segregation. Here, the authors demonstrate that GEN1 activity is regulated independently of its phosphorylation status and relies on its active exclusion from the nucleus.

Chromatin bridges experience significant tension due to spindle fiber pulling and cell migration. Uncontrolled breakage of chromatin bridges by actomyosin contractile forces leads to detrimental consequences. The existence of specialized mechanisms that process chromatin bridges to prevent catastrophic rupture remains uncertain. Here, we uncover a unique property of ANKLE1, a midbody-tethered endonuclease implicated in chromatin bridge processing, in sensing and responding to DNA tension and supercoiling during cell division. Using single-molecule analyses, we found that ANKLE1 specifically cuts supercoiled or mechanically stretched DNA. At higher stretching forces, ANKLE1 cleaves both strands of negatively supercoiled DNA, mirroring conditions in which stretched chromatin bridges lose histones to expose negatively supercoiled DNA. These findings show that ANKLE1 acts as a DNA tension sensor that resolves stretched chromatin bridges. Our study highlights the significance of mechanical forces in DNA bridge processing, enhances our understanding of how cells preserve genome integrity during cell division.

Chromatin bridges connecting the two segregating daughter nuclei arise from chromosome fusion or unresolved interchromosomal linkage. Persistent chromatin bridges are trapped in the cleavage plane, triggering cytokinesis delay. The trapped bridges occasionally break during cytokinesis, inducing DNA damage and chromosomal rearrangements. Recently, Caenorhabditis elegans LEM‐3 and human TREX1 nucleases have been shown to process chromatin bridges. Here, it is shown that ANKLE1 endonuclease, the human ortholog of LEM‐3, accumulates at the bulge‐like structure of the midbody via its N‐terminal ankyrin repeats. Importantly, ANKLE1−/− knockout cells display an elevated level of G1‐specific 53BP1 nuclear bodies, prolonged activation of the DNA damage response, and replication stress. Increased DNA damage observed in ANKLE1−/− cells is rescued by inhibiting actin polymerization or reducing actomyosin contractility. ANKLE1 does not act in conjunction with structure‐selective endonucleases, GEN1 and MUS81 in resolving recombination intermediates. Instead, ANKLE1 acts on chromatin bridges by priming TREX1 nucleolytic activity and cleaving bridge DNA to prevent the formation of micronuclei and cytosolic dsDNA that activate the cGAS‐STING pathway. It is therefore proposed that ANKLE1 prevents DNA damage and autoimmunity by cleaving chromatin bridges to avoid catastrophic breakage mediated by actomyosin contractile forces. Persistent chromatin bridges trapped in the spindle midzone can be broken by actomyosin forces during cytokinesis. This study shows that ANKLE1 is a midbody‐tethered endonuclease that acts directly on DNA bridges trapped in the midbody to prevent the extensive formation of micronuclei and cytosolic DNA. Therefore, ANKLE1 prevents genome instability and the activation of Cyclic GMP‐AMP synthase (cGAS) Stimulator of interferon genes (STING) immune responses.

Introduction Adolescents often feel helpless about planning their career in highly competitive societies such as Hong Kong. Relatively limited research has been conducted to examine whether being extrovert can influence adolescents’ career-related knowledge and career decision self-efficacy (CDSE). Methods: This cross-sectional study explored the relationship between extroversion, career knowledge and CDSE among 535 Hong Kong high school students based on Social Cognitive Career Theory and Trait and Factor Theory. Descriptive data analysis, correlation tests and structural equation modelling were used. Results: Study respondents displayed a low level of career knowledge and CDSE. Extroversion had a directly positive effect on CDSE ( β  = 0.219, p  < 0.001), while career knowledge significantly mediated the relationship between extroversion and CDSE ( β  = 0.185, p  < 0.001). Conclusions: This study provided a model to understand high school adolescents’ career decision self-efficacy, and empirically supported career training interventions to enhance adolescents’ self-efficacy and confidence in being more outgoing.

Genetic recombination provides an important mechanism for the repair of DNA double-strand breaks. Homologous pairing and strand exchange lead to the formation of DNA intermediates, in which sister chromatids or homologous chromosomes are covalently linked by four-way Holliday junctions (HJs). Depending on the type of recombination reaction that takes place, intermediates may have single or double HJs, and their resolution is essential for proper chromosome segregation. In mitotic cells, double HJs are primarily dissolved by the BLM helicase-TopoisomeraseIIIα-RMI1-RMI2 (BTR) complex, whereas single HJs (and double HJs that have escaped the attention of BTR) are resolved by structure-selective endonucleases known as HJ resolvases. These enzymes are ubiquitous in nature, because they are present in bacteriophage, bacteria, archaea, and simple and complex eukaryotes. The human HJ resolvase GEN1 is a member of the XPG/Rad2 family of 5′-flap endonucleases. Biochemical studies of GEN1 revealed that it cleaves synthetic DNA substrates containing a single HJ by a mechanism similar to that shown by the prototypic HJ resolvase, Escherichia coli RuvC protein, but it is unclear whether these substrates fully recapitulate the properties of recombination intermediates that arise within a physiological context. Here, we show that GEN1 efficiently cleaves both single and double HJs contained within large recombination intermediates. Moreover, we find that GEN1 exhibits a weak sequence preference for incision between two G residues that reside in a T-rich region of DNA. These results contrast with those obtained with RuvC, which exhibits a strict requirement for the consensus sequence 5 ′ − A T TT G C − 3 ′ .

The intersection of health and disaster risk reduction(DRR) has emerged in recent years as a field of critical inquiry.Health is recognized as an outcome and a goal of DRR,and the integration of both fields is essential to ensure the implementation of the Sendai Framework for Disaster Risk Reduction 2015–2030.Health Emergency and Disaster Risk Management(Health-EDRM) has emerged as an umbrella field that encompasses emergency and disaster medicine,DRR,humanitarian response,community health resilience,and health systems resilience.In September 2016,an international group of experts met in Hong Kong to assess the current status and potential of the Health-EDRM research field,a research area that these scholars characterized as underdeveloped and fragmented.Key challenges identified include research overlap,lack ofstrategic research agenda,absence of consensus regarding terminology,and limited coordination between stakeholders.The Sendai Framework provides a useful paradigm within which to shape the research field’s strategic development.The WHO Thematic Platform for Health-EDRM Research Group was established to coordinate activities,promote information-sharing,develop partnerships,and provide technical advice to strengthen the Health-EDRM research field.This group will promote the generation of robust and scientific health research to support the meaningful implementation of the Sendai Framework.

The following sections are included: Introduction Contemporary Models in the Understanding of Cancer The Biomedical Model The Biopsychosocial Model The Cognitive Behavioral Model Limitations of the Biomedical Model Theoretical Framework: The Meaning of Cancer and the Patient's Self-Interpretation The Constitutive Nature of Meaning The Relationship between Language, Emotions and Self-Interpretation Existential Situations, the Meaning of Cancer and the Patient's Self-Interpretation Understanding the Fear of Relapse among Cancer Patients Case Study: The Cancer Experience of Mr. and Mrs. Song: The Conflict between Health and Family Roles Mr. and Mrs. Song's Experience of the Disease The Self-Interpretative Meaning of Cancer Conclusion Notes

An SC spokesman told Buisness Times that [Tien Wah]'s initial public offering (IPO) is the first among several others based on the new guidelines to open for public applications. A source said that Tien Wah, after the revision, increased its share capital to RM35.01 million from RM19.99 million. The SC has raised the ceiling for second board companies' paid-up capital under its new guidelines to RM40 million, from RM20 million previously. The source said that the SC did not ask Tien Wah to revise its initial public offering, but added that as a natural consequence of the increase in the share capital, it has to revise its share price to RM1.90 per share from the initial figure of RM1.60 submitted.

Hiap Teck, through subsidiary H.T. Scaffolding Manufacturing Sdn Bhd, signed a licensing agreement yesterday with Entrepose Echafaudages to manufacture CRAB, a kind of scaffolding system, in Malaysia. Hiap Teck chairman Tan Sri Alwi Jantan said after the signing ceremony yesterday that the company has 50 to 60 per cent of the scaffolding market in Malaysia. He added that the company is working towards replacing the conventional scaffolding system. With the agreement, Hiap Teck will be manufacturing a range of CRAB products in Malaysia. However, Hiap Teck will still have to import joint components from Entrepose Echafaudages which will comprise 20 per cent of the products.