Mega-constellation satellites: Assessing their interference on ground-based astronomy

The PDF of Peter Breslin's master thesis completed for the partial fulfilment of the requirements for the master’s degree in Astronomy and Data Science at Leiden University. Thesis title: 'Mega-constellation satellites: Assessing their interference on ground-based astronomy'. For a poster presentation of this work, please see: https://doi.org/10.5281/zenodo.838091

Novel oncogenes and tumor suppressor genes in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a very deadly disease. HCC initiation and progression involve multiple genetic events, including the activation of proto-oncogenes and disruption of the function of specific tumor suppressor genes. Activation of oncogenes stimulates cell growth and survival, while loss-of-function mutations of tumor suppressor genes result in unrestrained cell growth. In this review, we summarize the new findings that identified novel proto-oncogenes and tumor suppressors in HCC over the past five years. These findings may inspire the development of novel therapeutic strategies to improve the outcome of HCC patients

The XRCC1 phosphate-binding pocket binds poly (ADP-ribose) and is required for XRCC1 function

Poly (ADP-ribose) is synthesized at DNA single-strand breaks and can promote the recruitment of the scaffold protein, XRCC1. However, the mechanism and importance of this process has been challenged. To address this issue, we have characterized the mechanism of poly (ADP-ribose) binding by XRCC1 and examined its importance for XRCC1 function. We show that the phosphate-binding pocket in the central BRCT1 domain of XRCC1 is required for selective binding to poly (ADP-ribose) at low levels of ADP-ribosylation, and promotes interaction with cellular PARP1. We also show that the phosphate-binding pocket is required for EGFP-XRCC1 accumulation at DNA damage induced by UVA laser, H2O2, and at sites of sub-nuclear PCNA foci, suggesting that poly (ADP-ribose) promotes XRCC1 recruitment both at single-strand breaks globally across the genome and at sites of DNA replication stress. Finally, we show that the phosphate-binding pocket is required following DNA damage for XRCC1-dependent acceleration of DNA single-strand break repair, DNA base excision repair, and cell survival. These data support the hypothesis that poly (ADP-ribose) synthesis promotes XRCC1 recruitment at DNA damage sites and is important for XRCC1 function

Molecular and Cellular Mechanisms of Aging in Hematopoietic Stem Cells and Their Niches

Aging drives the genetic and epigenetic changes that result in a decline in hematopoietic stem cell (HSC) functioning. Such changes lead to aging-related hematopoietic/immune impairments and hematopoietic disorders. Understanding how such changes are initiated and how they progress will help in the development of medications that could improve the quality life for the elderly and to treat and possibly prevent aging-related hematopoietic diseases. Here, we review the most recent advances in research into HSC aging and discuss the role of HSC-intrinsic events, as well as those that relate to the aging bone marrow niche microenvironment in the overall processes of HSC aging. In addition, we discuss the potential mechanisms by which HSC aging is regulated

Role of TET dioxygenases in the regulation of both normal and pathological hematopoiesis

The family of ten-eleven translocation dioxygenases (TETs) consists of TET1, TET2, and TET3. Although all TETs are expressed in hematopoietic tissues, only TET2 is commonly found to be mutated in age-related clonal hematopoiesis and hematopoietic malignancies. TET2 mutation causes abnormal epigenetic landscape changes and results in multiple stages of lineage commitment/differentiation defects as well as genetic instability in hematopoietic stem/progenitor cells (HSPCs). TET2 mutations are founder mutations (first hits) in approximately 40–50% of cases of TET2-mutant (TET2MT) hematopoietic malignancies and are later hits in the remaining cases. In both situations, TET2MT collaborates with co-occurring mutations to promote malignant transformation. In TET2MT tumor cells, TET1 and TET3 partially compensate for TET2 activity and contribute to the pathogenesis of TET2MT hematopoietic malignancies. Here we summarize the most recent research on TETs in regulating of both normal and pathogenic hematopoiesis. We review the concomitant mutations and aberrant signals in TET2MT malignancies. We also discuss the molecular mechanisms by which concomitant mutations and aberrant signals determine lineage commitment in HSPCs and the identity of hematopoietic malignancies. Finally, we discuss potential strategies to treat TET2MT hematopoietic malignancies, including reverting the methylation state of TET2 target genes and targeting the concomitant mutations and aberrant signals

Individual, occupational, and workplace correlates of occupational health and safety vulnerability in a sample of Canadian workers

Objective: To describe OH&amp;S vulnerability across a diverse sample of Canadian workers.Methods: A survey was administered to 1,835 workers employed more than 15 hrs/week in workplaces with at least five employees. Adjusted logistic models were fitted for three specific and one overall measure of workplace vulnerability developed based on hazard exposure and access to protective OH&amp;S policies and procedures, awareness of employment rights and responsibilities, and workplace empowerment.Results: More than one third of the sample experienced some OH&amp;S vulnerability. The type and magnitude of vulnerability varied by labor market sub-group. Younger workers and those in smaller workplaces experienced signficantly higher odds of multiple types of vulnerability. Temporary workers reported elevated odds of overall, awareness- and empowerment-related vulnerability, while respondents born outside of Canada had significantly higher odds of awareness vulnerability.Conclusion: Knowing how labor market sub-groups experience different types of vulnerability can inform better-tailored primary prevention interventions.<br /

Caspase-3 suppresses diethylnitrosamine-induced hepatocyte death, compensatory proliferation and hepatocarcinogenesis through inhibiting p38 activation

It is critical to understand the molecular mechanisms of hepatocarcinogenesis in order to prevent or treat hepatocellular carcinoma (HCC). The development of HCC is commonly associated with hepatocyte death and compensatory proliferation. However, the role of Caspase-3, a key apoptotic executor, in hepatocarcinogenesis is unknown. In this study, we used Caspase-3-deficient mice to examine the role of Caspase-3 in hepatocarcinogenesis in a chemical (diethylnitrosamine, DEN)-induced HCC model. We found that Caspase-3 deficiency significantly increased DEN-induced HCC. Unexpectedly, Caspase-3 deficiency increased apoptosis induced by DEN and the subsequent compensatory proliferation. Intriguingly, we discovered that Caspase-3 deficiency increased the activation of p38 with and without DEN treatment. Moreover, we demonstrated that TNFα and IL1α stimulated increased activation of p38 in Caspase-3 KO hepatocytes compared with wild-type hepatocytes. Finally, we found that inhibition of p38 by SB202190 abrogated enhanced hepatocyte death, compensatory proliferation and HCC induced by DEN in Caspase-3-deficient mice. Overall, our data suggest that Caspase-3 inhibits chemical-induced hepatocarcinogenesis by suppressing p38 activation and hepatocyte death

Tak1 is Required for the Survival of Hematopoietic Cells and Hepatocytes in Mice

Transforming growth factor beta-activated kinase 1 (TAK1), a member of the MAPKKK family, is a key mediator of proinflammatory and stress signals. Activation of TAK1 by proinflammatory cytokines and T and B cell receptors induces the nuclear localization of nuclear factor kappaB (NF-kappaB) and the activation of c-Jun N-terminal kinase (JNK)/AP1 and P38, which play important roles in mediating inflammation, immune responses, T and B cell activation, and epithelial cell survival. Here, we report that TAK1 is critical for the survival of both hematopoietic cells and hepatocytes. Deletion of TAK1 results in bone marrow (BM) and liver failure in mice due to the massive apoptotic death of hematopoietic cells and hepatocytes. Hematopoietic stem cells and progenitors were among those hematopoietic cells affected by TAK1 deletion-induced cell death. This apoptotic cell death is autonomous, as demonstrated by reciprocal BM transplantation. Deletion of TAK1 resulted in the inactivation of both JNK and NF-kappaB signaling, as well as the down-regulation of expression of prosurvival genes

Engaging Emergency Department Patients in the Creation of a Shared Decision-­Making Tool Regarding CT Scanning in Kidney Stones: Challenges to Traditional Stakeholder Engagement

Background: Every year approximately 2 million patients are seen in US EDs for suspected renal colic, and the majority receive CT scans. The objective of our study was to develop a stakeholder-informed conversation aid to help clinicians use SDM regarding CT scanning in patients with suspected renal colic. Methods: Using a published decision aid development framework, and under the direction of a multi-disciplinary Steering Committee, we engaged a diverse set of stakeholders via qualitative methods. EM clinicians, urologists, radiologists, researchers, and emergency department patients participated in focus groups and semi-structured interviews. All groups were recorded, transcribed, and analyzed in an iterative process by a four-person coding team. Emergent themes were identified and used to develop a decision aid which was iteratively refined. Results: A total of 8 interviews and 7 focus groups were conducted with 36 stakeholders (including local ED patients) The following three themes emerged: 1. Patient participants reported a desire to be involved in this decision and wanted more information regarding risks and benefits of CT scans. 2. Clinicians were comfortable diagnosing kidney stones without a CT scan, however, some felt that clinical uncertainty was a barrier to SDM. 3. All stakeholders identified strategies to facilitate this conversation such as check-lists and visual aids. Conclusion: Using stakeholder input, we developed a communication tool to facilitate an SDM conversation around the use of CT in suspected renal colic. Further testing will assess whether this tool can safely improve patient engagement and decrease low yield CT usage