Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis.

Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here, we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome patients, who are predisposed to medulloblastoma due to germline-mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma

Tephrochronology and its application: A review

Tephrochronology (from tephra, Gk ‘ashes’) is a unique stratigraphic method for linking, dating, and synchronizing geological, palaeoenvironmental, or archaeological sequences or events. As well as utilising the Law of Superposition, tephrochronology in practise requires tephra deposits to be characterized (or ‘fingerprinted’) using physical properties evident in the field together with those obtained from laboratory analyses. Such analyses include mineralogical examination (petrography) or geochemical analysis of glass shards or crystals using an electron microprobe or other analytical tools including laser-ablation-based mass spectrometry or the ion microprobe. The palaeoenvironmental or archaeological context in which a tephra occurs may also be useful for correlational purposes. Tephrochronology provides greatest utility when a numerical age obtained for a tephra or cryptotephra is transferrable from one site to another using stratigraphy and by comparing and matching inherent compositional features of the deposits with a high degree of likelihood. Used this way, tephrochronology is an age-equivalent dating method that provides an exceptionally precise volcanic-event stratigraphy. Such age transfers are valid because the primary tephra deposits from an eruption essentially have the same short-lived age everywhere they occur, forming isochrons very soon after the eruption (normally within a year). As well as providing isochrons for palaeoenvironmental and archaeological reconstructions, tephras through their geochemical analysis allow insight into volcanic and magmatic processes, and provide a comprehensive record of explosive volcanism and recurrence rates in the Quaternary (or earlier) that can be used to establish time-space relationships of relevance to volcanic hazard analysis. The basis and application of tephrochronology as a central stratigraphic and geochronological tool for Quaternary studies are presented and discussed in this review. Topics covered include principles of tephrochronology, defining isochrons, tephra nomenclature, mapping and correlating tephras from proximal to distal locations at metre- through to sub-millimetre-scale, cryptotephras, mineralogical and geochemical fingerprinting methods, numerical and statistical correlation techniques, and developments and applications in dating including the use of flexible depositional age-modelling techniques based on Bayesian statistics. Along with reference to wide-ranging examples and the identification of important recent advances in tephrochronology, such as the development of new geoanalytical approaches that enable individual small glass shards to be analysed near-routinely for major, trace, and rare-earth elements, potential problems such as miscorrelation, erroneous-age transfer, and tephra reworking and taphonomy (especially relating to cryptotephras) are also examined. Some of the challenges for future tephrochronological studies include refining geochemical analytical methods further, improving understanding of cryptotephra distribution and preservation patterns, improving age modelling including via new or enhanced radiometric or incremental techniques and Bayesian-derived models, evaluating and quantifying uncertainty in tephrochronology to a greater degree than at present, constructing comprehensive regional databases, and integrating tephrochronology with spatially referenced environmental and archaeometric data into 3-D reconstructions using GIS and geostatistics

Religious Coping and Depression: A Five-Wave Study during the COVID-19 Pandemic in Individuals with Chronic Illness and Disease

The rise of Chronic Illness and Disease (CID) globally and the increase in lifespan/survival rates among those with CID have boosted the interest on how coping, a psychosocial construct, influences rehabilitation. A relationship between coping and psychosocial adjustment has been repeatedly confirmed. Religious coping (RC), a specific emotion-focused coping act, focuses on the roles of religion in crisis, trauma, or transition. RC is part of secondary appraisals and it can take two forms: positive and negative. There is high prevalence of depression among people with CID. Coexisting depression and the COVID-19 pandemic have added significant burden on those individuals’ daily lives affecting rehabilitation outcomes. Higher-level macroanalytic models are inadequate in explaining/predicting the variability in coping behavior. PURPOSE: To examine the effects of RC on depression in individuals with CID before and during the COVID-19 pandemic. METHODS: Five waves of data were collected from a US sample. The analytic sample for this study was comprised of those with all five waves (n = 283). Three waves were collected prior to and two waves during the COVID pandemic. Participants completed the Patient Health Questionnaire–9 (depression symptoms) and the positive and negative RC subscales of the Brief RCOPE. The effects of RC on depression were examined using a linear longitudinal mixed model. The model included main of positive and negative coping and time-by-religious coping interaction effects. RESULTS: Although depression levels did not change across the five waves, on average, significant relationships were observed: a) Negative RC had a strong relationship with depression (B = 1.8, p \u3c .001) and b) there was significant time-by-positive RC interaction (B = -0.11, p = .03), suggesting that, over time, the relationship between positive RC and depression became less strong. CONCLUSION: CID can create major life stressors. Understanding which coping dispositions and strategies are most effective during the COVID-19 pandemic are central to research and practice right now. Drawing from the microanalytic level of coping (Krohne, 1993), we investigated a specific coping act in a particular context and temporal sequence. Future studies should examine why a) depression stayed stable, b) the relationship between negative RC (spiritual frictions within oneself/others/superior force) and depression remained strong, and c) the relationship between positive RC (connection with the divine, spiritual relationship with others, compassionate world view) with depression weakened during this unique global crisis

Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis.

Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here, we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome patients, who are predisposed to medulloblastoma due to germline-mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma

Scattering-Based Light-Sheet Microscopy Imaging of Human Papillomavirus-Associated Squamous Lesions of the Anal Canal: A Proof-of-Principle Study

Demand for anal cancer screening is expected to rise following the recent publication of the Anal Cancer–HSIL Outcomes Research trial, which showed that treatment of high-grade squamous intraepithelial lesions significantly reduces the rate of progression to anal cancer. While screening for human papillomavirus–associated squamous lesions in the cervix is well established and effective, this is less true for other sites in the lower anogenital tract. Current anal cancer screening and prevention rely on high-resolution anoscopy with biopsies. This procedure has a steep learning curve for providers and may cause patient discomfort. Scattering-based light-sheet microscopy (sLSM) is a novel imaging modality with the potential to mitigate these challenges through real-time, microscopic visualization of disease-susceptible tissue. Here, we report a proof-of-principle study that establishes feasibility of dysplasia detection using an sLSM device. We imaged 110 anal biopsy specimens collected prospectively at our institution's dysplasia clinic (including 30 nondysplastic, 40 low-grade squamous intraepithelial lesion, and 40 high-grade squamous intraepithelial lesion specimens) and found that these optical images are highly interpretable and accurately recapitulate histopathologic features traditionally used for the diagnosis of human papillomavirus–associated squamous dysplasia. A reader study to assess diagnostic accuracy suggests that sLSM images are noninferior to hematoxylin and eosin images for the detection of anal dysplasia (sLSM accuracy = 0.87; hematoxylin and eosin accuracy = 0.80; P = .066). Given these results, we believe that sLSM technology holds great potential to enhance the efficacy of anal cancer screening by allowing accurate sampling of diagnostic tissue at the time of anoscopy. While the current imaging study was performed on ex vivo biopsy specimens, we are currently developing a handheld device for in vivo imaging that will provide immediate microscopic guidance to high-resolution anoscopy providers.6 month embargo; first published 12, April 2024This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Die Wohnungsmaerkte Dortmund und Saarbruecken: ein Strukturvergleich ; Text-Teil

Available from Bibliothek des Instituts fuer Weltwirtschaft, ZBW, Duesternbrook Weg 120, D-24105 Kiel C 165160 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman