PARENTS AND COMMUNITY, AND SCHOOL: A GENERAL OVERVIEW

This Canadian Journal of Educational Administration and Policy special issue, “Parent and Community Participation in Educational Improvement,” was inspired by the recognition of the ecological nature of schools; participative approaches to educational improvement, educational policy development, and school decision-making have become commonplace. It is, however, one matter to theoretically and/or philosophically accept parents and the larger community as contributors to educational goals, and rather quite another to enunciate this Zeitgeist of collaboration, partnership, or authentic engagement in mutually beneficial ways. In other words, this special issue is premised on the assumption that an academic exploration of parent and community engagement in education is required to strengthen the discourse beyond an uncontested and romanticized rhetoric of school community

Characterization of the promoter region of a variant of the ß-subunit of the human farnesyltransferase

Die humane Farnesyltransferase steht im Fokus intensiver onkologischer und anderer pathophysiologischer Forschung. Das Enzym überträgt eine Farnesylgruppe auf Proteine, wodurch sich diese an die Zellmembran anheften und so ihre Funktion innerhalb von Signalkaskaden wahrnehmen können. Hemmstoffe der Farnesyltransferase zeigten zwar im Tiermodell große Erfolge, ihr Einsatz bei Malignomen des Menschen verlief allerdings bislang wenig erfolgreich. Um eine Optimierung zu erreichen sind weitere Erkenntnisse über die Regulation und Funktion der Farnesyltransferase essentiell. Das Enzym besteht aus einer α- und einer ß-Untereinheit. Bachmann et al. konnten zeigen, dass neben der bekannten FNTB-F1-Variante, mindestens vier weitere Varianten der ß-Untereinheit existieren. Da über die Regulation dieser Varianten bislang nichts bekannt ist, war das Ziel dieser Arbeit die Promotorregion einer dieser Varianten zu charakterisieren (FNTB-F2). Es wurde ein Bereich von ca. 2000 bp vor dem Translationsstartpunkt der FNTB-F2-Variante als Promotorregion der FNTB-F2-Variante identifiziert. Dieser Bereich weist signifikante basale Promotoraktivität in HEK-293-Zellen auf, wobei der Hauptaktivitätsbereich auf einen DNA-Abschnitt von ca. 300 bp unmittelbar vor dem Translationsstartpunkt lokalisiert werden konnte. Die Kernpromotorregion umfasst einen Bereich von ca. 500 bp vor dem Translationsstartpunkt. Diese Region ist essentiell für die basale Promotoraktivität. In dieser Region befinden sich sechs promotortypische Elemente und der experimentell ermittelte Haupttranskriptionsstartpunkt ist direkt am Beginn dieses Bereiches lokalisiert (zwischen -519 und -488 bp). Der Transkriptionsfaktor HNF1α wurde als regulatorischer Faktor der FNTB-F2-Variante identifiziert. Von 12 in silico vorhergesagten HNF1α-Bindungsstellen innerhalb der untersuchten FNTB-F2-Promotorregion konnten drei Bindungsstellen bei -402/-426, -972/-996 und -979/-1003 mittels EMSA bestätigt werden. Unter Stimulation mit diesem Faktor zeigte sich zudem in HEK-293-Zellen eine bis zu 7-fache Erhöhung der Promotoraktivität. Es gelang die Beschreibung des FNTB-F2-Promotors und die Identifizierung sowie anschließende Evaluierung des funktionellen Einflusses des spezifischen Transkriptionsfaktors HNF1α auf die Promotoraktivität. Die Ergebnisse können als Grundlage für weitere klinische Forschungen dienen. Insbesondere aufgrund der gezeigten relevanten Abhängigkeit der FNTB-F2-Promotoraktivität vom Transkriptionsfaktor HNF1α könnte in Zukunft auch bei weiteren Erkrankungen Hinweise für eine mögliche Bedeutsamkeit der FNTB-F2-Variante aufgedeckt werden. Ähnlich wie dies in dieser Arbeit bereits für den MODY Diabetes, Typ 3 aufgezeigt werden konnte.The human farnesyltransferase is in focus of intensive cancer- and other pathophysiological research. The enzyme transfers a farnesyl group to proteins, allowing these proteins to anchor to cellular membranes and carrying out their function within signal cascades. Inhibitors of the farnesyltransferase showed great success in animal models but the treatment of human malignant tumors has so far been of little success. In order to achieve an optimization, further knowledge about regulation and function of the farnesyltransferase is essential. The enzyme consist of an α-and a ß-subunit. Bachmann et al. were able to demonstrate that there are at least four orther variants of the ß-subunit in addition to the already known variant F1. Currently, nothing is known about the regulation of these variants. Therefore, the aim of this study was to characterize the promoter region of one of these variants (FNTB-F2). A DNA region of 2000 bp upstream of the translation initiation site was identified as promoter region of the FNTB-F2 variant. This region exhibits significant basal promoter activity in HEK-293 cells. A sequence of 300 bp upstream of the translation initiation site comprises the main activity. The core promoter region is localized 500 bp upstream the translation initiation site. This region is essential for basal promoter activity. This region contains six typical promoter elements and the main transcription start site is localized at the beginning of this region (between -519 and -488 bp). The transcription factor HNF1α was identified as a regulative factor of the FNTB-F2 variant. In silico analyses predicted twelve putative binding sites in the investigated FNTB-F2 promoter region. EMSA experiments verified three of this binding sites (-402/-426, -972/-996, -979/-1003). By stimulation with HNF1α the promoter activity could be increased seven times. The FNTB-F2 promoter was identified and the influence of the specific transcription factor HNF1α on the promoter activity was evaluated. These findings could be used for further clinical research. Especially, because of the demonstrated relevant dependency of the FNTB-F2 promoter activity from the transcription factor HNF1α, future studies may demonstrate a relevant meaning of the FNTB-F2 variant for other diseases. This was already demonstrated in this study for MODY diabetes Type 3

Leukemic stem cells and therapy resistance in acute myeloid leukemia

A major obstacle in the treatment of acute myeloid leukemia (AML) is refractory disease or relapse after achieving remission. The latter arises from a few therapy-resistant cells within minimal residual disease (MRD). Resistant cells with long-term self-renewal capacity that drive clonal outgrowth are referred to as leukemic stem cells (LSC). The cancer stem cell concept considers LSC as relapse-initiating cells residing at the top of each genetically defined AML subclone forming epigenetically controlled downstream hierarchies. LSC display significant phenotypic and epigenetic plasticity, particularly in response to therapy stress, which results in various mechanisms mediating treatment resistance. Given the inherent chemotherapy resistance of LSC, targeted strategies must be incorporated into first-line regimens to prevent LSC-mediated AML relapse. The combination of venetoclax and azacitidine is a promising current strategy for the treatment of AML LSC. Nevertheless, the selection of patients who would benefit either from standard chemotherapy or venetoclax + azacitidine treatment in first-line therapy has yet to be established and the mechanisms of resistance still need to be discovered and overcome. Clinical trials are currently underway that investigate LSC susceptibility to first-line therapies. The era of single-cell multi-omics has begun to uncover the complex clonal and cellular architectures and associated biological networks. This should lead to a better understanding of the highly heterogeneous AML at the inter- and intra-patient level and identify resistance mechanisms by longitudinal analysis of patients’ samples. This review discusses LSC biology and associated resistance mechanisms, potential therapeutic LSC vulnerabilities and current clinical trial activities

Clonal hematopoiesis landscape in frequent blood donors

Donor blood saves lives, yet the potential impact of recurrent large-volume phlebotomy on donor health and hematopoietic stem cells (HSCs) remains largely unexplored. In our study, we conducted a comprehensive screening of 217 older male volunteer donors with a history of extensive blood donation (>100 lifetime donations) to investigate the phenomenon of clonal hematopoiesis (CH). No significant difference in the overall incidence of CH was found in frequent donors (FDs) compared with sporadic donors (<10 lifetime donations; 212 donors). However, upon deeper analysis of mutations in DNMT3A, the most commonly affected gene in CH, we observed distinct mutational patterns between the FD and age/sex-matched control donor cohorts. Functional analysis of FD-enriched DNMT3A variants examined in CRISPR-edited human HSCs demonstrated their competitive outgrowth potential upon stimulation with erythropoietin (EPO), a hormone that increases in response to blood loss. In contrast, clones harboring leukemogenic DNMT3A R882 mutations increase upon stimulation with interferon gamma. Through concurrent mutational and immunophenotypic profiling of primary samples at single-cell resolution, a myeloid bias of premalignant R882 mutant HSCs was found, whereas no significant lineage bias was observed in HSCs harboring EPO-responsive DNMT3A variants. The latter exhibited preferential erythroid differentiation when persistent erythropoietic stress was applied to CRISPR-edited human HSC xenografts. Our data demonstrate a nuanced, ongoing Darwinian evolution at the somatic stem cell level, with EPO identified as a novel environmental factor that favors HSCs carrying certain DNMT3A mutations

Clonal hematopoiesis with <i>DNMT3A</i> and <i>PPM1D</i> mutations impairs regeneration in autologous stem cell transplant recipients

Clonal hematopoiesis (CH) is an age-related condition driven by stem and progenitor cells harboring recurrent mutations linked to myeloid neoplasms. Currently, potential effects on hematopoiesis, stem cell function and regenerative potential under stress conditions are unknown. We performed targeted DNA sequencing of 457 hematopoietic stem cell grafts collected for autologous stem cell transplantation (ASCT) in myeloma patients and correlated our findings with high-dimensional longitudinal clinical and laboratory data (26,510 data points for blood cell counts/serum values in 25 days around transplantation). We detected CHrelated mutations in 152 patients (33.3%). Since many patients (n=54) harbored multiple CH mutations in one or more genes, we applied a non-negative matrix factorization (NMF) clustering algorithm to identify genes that are commonly co-mutated in an unbiased approach. Patients with CH were assigned to one of three clusters (C1-C3) and compared to patients without CH (C0) in a gene specific manner. To study the dynamics of blood cell regeneration following ASCT, we developed a time-dependent linear mixed effect model to validate differences in blood cell count trajectories amongst different clusters. The results demonstrated that C2, composed of patients with DNMT3A and PPM1D single and co-mutated CH, correlated with reduced stem cell yields and delayed platelet count recovery following ASCT. Also, the benefit of maintenance therapy was particularly strong in C2 patients. Taken together, these data indicate an impaired regenerative potential of hematopoietic stem cell grafts harboring CH with DNMT3A and PPM1D mutations

Large-Scale Cortical Functional Organization and Speech Perception across the Lifespan

Aging is accompanied by substantial changes in brain function, including functional reorganization of large-scale brain networks. Such differences in network architecture have been reported both at rest and during cognitive task performance, but an open question is whether these age-related differences show task-dependent effects or represent only task-independent changes attributable to a common factor (i.e., underlying physiological decline). To address this question, we used graph theoretic analysis to construct weighted cortical functional networks from hemodynamic (functional MRI) responses in 12 younger and 12 older adults during a speech perception task performed in both quiet and noisy listening conditions. Functional networks were constructed for each subject and listening condition based on inter-regional correlations of the fMRI signal among 66 cortical regions, and network measures of global and local efficiency were computed. Across listening conditions, older adult networks showed significantly decreased global (but not local) efficiency relative to younger adults after normalizing measures to surrogate random networks. Although listening condition produced no main effects on whole-cortex network organization, a significant age group x listening condition interaction was observed. Additionally, an exploratory analysis of regional effects uncovered age-related declines in both global and local efficiency concentrated exclusively in auditory areas (bilateral superior and middle temporal cortex), further suggestive of specificity to the speech perception tasks. Global efficiency also correlated positively with mean cortical thickness across all subjects, establishing gross cortical atrophy as a task-independent contributor to age-related differences in functional organization. Together, our findings provide evidence of age-related disruptions in cortical functional network organization during speech perception tasks, and suggest that although task-independent effects such as cortical atrophy clearly underlie age-related changes in cortical functional organization, age-related differences also demonstrate sensitivity to task domains

ARIA digital anamorphosis : Digital transformation of health and care in airway diseases from research to practice

Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe