Epitaxy of hexagonal ABO3_3 quantum materials

Hexagonal $AB$O$_3$ oxides ($A$, $B$ = cation) are a rich materials class for realizing novel quantum phenomena. Their hexagonal symmetry, oxygen trigonal bipyramid coordination and quasi-two dimensional layering give rise to properties distinct from those of the cubic $AB$O$_3$ perovskites. As bulk materials, most of the focus in this materials class has been on the rare earth manganites, $R$MnO$_3$ ($R$ = rare earth); these materials display coupled ferroelectricity and antiferromagnetic order. In this review, we focus on the thin film manifestations of the hexagonal $AB$O$_3$ oxides. We cover the stability of the hexagonal oxides and substrates which can be used to template the hexagonal structure. We show how the thin film geometry not only allows for further tuning of the bulk-stable manganites but also the realization of metastable hexagonal oxides such as the $R$FeO$_3$ that combine ferroelectricity with weak ferromagnetic order. The thin film geometry is a promising platform to stabilize additional metastable hexagonal oxides to search for predicted high-temperature superconductivity and topological phases in this materials class.Comment: The following article has been accepted by Applied Physics Review

Predictors of student mask mandate policies in United States school districts during the COVID-19 pandemic

IntroductionAlthough factors such as urbanicity, population demographics, and political affiliation have been linked with COVID-19 masking behavior and policy in community settings, little work has investigated factors associated with school mask policies. We sought to characterize United States state and school district student COVID-19 masking policies during the 2021–22 school year and determine predictors of these mandates at four time points, including before and after federal guidance relaxed school mask recommendations in February 2022.MethodsStudent mask policies for US states and the District of Columbia, as well as a sample of 56 districts were categorized as prohibited, recommended, or required in September 2021, November 2021, January 2022, and March 2022 based on the Johns Hopkins eSchool+ Initiative School Reopening Tracker. Changes in policies over time were characterized. Generalized estimating equations and logistic regression were used to evaluate whether political affiliation of governor, urbanicity, economic disadvantage, and race/ethnic composition of district students, and county-level COVID-19 incidence predicted the presence of a district mask mandate at any time point and at all four time points.ResultsState and district policies changed over time. Districts that implemented student mandates at any point were more likely to be in states with Democratic governors (AOR: 5.52; 95% CI: 2.23, 13.64) or in non-rural areas (AOR: 8.20; 95% CI: 2.63, 25.51). Districts that retained mask mandates at all four time points were more likely to have Democratic governors (AOR: 5.39; 95% CI: 2.69, 10.82) and serve a smaller proportion of economically disadvantaged students (AOR: 0.97; 95% CI: 0.95, 0.99). Districts serving a larger proportion of students from minoritized racial/ethnic groups were more likely to have mask mandates at any or all timepoints. Notably, county-level COVID-19 prevalence was not related to the presence of a mask mandate at any or all time points. By March 2022, no factors were significantly associated with district mask policy.DiscussionPolitical, geographic, and demographic characteristics predicted the likelihood of student mask mandates in the 2021–22 school year. Public health promotion messages and policy must account for variation in these factors, potentially through centralized and consistent messaging and unbiased, trustworthy communication

Regulation of PTEN Inhibition by the Pleckstrin Homology Domain of P-REX2 During Insulin Signaling and Glucose Homeostasis

Insulin activation of phosphoinositide 3-kinase (PI3K) signaling regulates glucose homeostasis through the production of phosphatidylinositol 3,4,5-trisphosphate (PIP3). The dual-specificity phosphatase and tensin homolog deleted on chromosome 10 (PTEN) blocks PI3K signaling by dephosphorylating PIP3, and is inhibited through its interaction with phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 (P-REX2). The mechanism of inhibition and its physiological significance are not known. Here, we report that P-REX2 interacts with PTEN via two interfaces. The pleckstrin homology (PH) domain of P-REX2 inhibits PTEN by interacting with the catalytic region of PTEN, and the inositol polyphosphate 4-phosphatase domain of P-REX2 provides high-affinity binding to the postsynaptic density-95/Discs large/zona occludens-1-binding domain of PTEN. P-REX2 inhibition of PTEN requires C-terminal phosphorylation of PTEN to release the P-REX2 PH domain from its neighboring diffuse B-cell lymphoma homology domain. Consistent with its function as a PTEN inhibitor, deletion of Prex2 in fibroblasts and mice results in increased Pten activity and decreased insulin signaling in liver and adipose tissue. Prex2 deletion also leads to reduced glucose uptake and insulin resistance. In human adipose tissue, P-REX2 protein expression is decreased and PTEN activity is increased in insulin-resistant human subjects. Taken together, these results indicate a functional role for P-REX2 PH-domain-mediated inhibition of PTEN in regulating insulin sensitivity and glucose homeostasis and suggest that loss of P-REX2 expression may cause insulin resistance

Early experience with targeted therapy as a first-line adjuvant treatment for pediatric low-grade glioma.

OBJECTIVE: Pediatric low-grade gliomas (pLGGs) frequently exhibit dysregulation of the mitogen-activated protein kinase (MAPK) pathway. Targeted therapies, including mutant BRAF inhibitors (dabrafenib) and MEK inhibitors (trametinib), have shown promise in patients in whom conventional chemotherapy has failed. However, few studies have investigated the use of targeted therapy as a first-line treatment for pLGG. Here, the authors reviewed their institutional experience with using a personalized medicine approach to patients with newly diagnosed pLGGs. METHODS: All pediatric patients at the authors\u27 institution who had been treated with dabrafenib or trametinib for pLGG without first receiving conventional chemotherapy or radiation were retrospectively reviewed. Demographic, clinical, and radiological data were collected. RESULTS: Eight patients underwent targeted therapy as a first-line treatment for pLGG. Five patients had a BRAF alteration (1 with a BRAFV600E mutation, 4 with a KIAA1549:BRAF fusion), and 3 patients had an NF1 mutation. One of the 8 patients was initially treated with dabrafenib, and trametinib was added later. Seven patients were initially treated with trametinib; of these, 2 later transitioned to dual therapy, whereas 5 continued with trametinib monotherapy. Six patients (75%) demonstrated a partial response to therapy during their treatment course, whereas stable disease was identified in the remaining 2 patients (25%). One patient experienced mild disease progression after completing a course of trametinib monotherapy, but ultimately stabilized after a period of close observation. Another patient experienced tumor progression while on dabrafenib, but subsequently responded to dual therapy with dabrafenib and trametinib. The most common adverse reactions to targeted therapy were cutaneous toxicity (100%) and diarrhea (50%). CONCLUSIONS: Targeted therapies have the potential to become a standard treatment option for pLGG due to their favorable toxicity profile and oral route of administration. This case series provides preliminary evidence that targeted therapies can induce an early disease response as a first-line adjuvant treatment; however, large-scale studies are required to assess long-term durability and safety

Making Room for Zoom in Focus Group Methods: Opportunities and Challenges for Novice Researchers (During and Beyond COVID-19)

Als die COVID-19-Pandemie über die Welt hereinbrach, waren viele Menschen gezwungen, sich auf online-basierte Routinen einzustellen, darunter auch qualitative Forscher*innen, die nach alternativen Möglichkeiten zur Erhebung aussagekräftiger Daten suchten. Während Fokusgruppen traditionell Face to Face durchgeführt werden, bieten Fortschritte bei Online-Videokonferenzanwendungen neue Methoden zur Datenerhebung, die jedoch bisher nur selten untersucht wurden. In diesem Artikel berichten wir über die Erfahrungen von 12 Doktorand*innen mit der Durchführung von Fokusgruppen unter Verwendung von Zoom im Rahmen eines Kurses zu qualitativen Interviewmethoden. Wir reflektieren Chancen und Herausforderungen, die wir als Moderator*innen und Teilnehmer*innen bei der Nutzung von Zoom erlebten z.B. bei der Vorbereitung oder in Bezug auf Rapport, die Einbindung anderer digitaler Tools und von Internetverbindungen. Zusammenfassend lässt sich sagen, dass die Durchführung von Online-Fokusgruppen unter Verwendung von Zoom insgesamt eine positive Erfahrung war und mit Face-to-Face-Fokusgruppen vergleichbar ist. Möglichkeiten der Teilnehmer*innenrekrutierung, die Sicherheitsmerkmale von Zoom und die Nutzung von Zoom und allgemeiner neuen Technologien sollten auch jenseits der Pandemie weiter erforscht werden.As the COVID-19 pandemic swept through the world, it forced many people to adapt to an online-based routine, including qualitative researchers looking for alternative ways to collect meaningful data. While focus groups are traditionally conducted in-person, advances with online videoconferencing applications present a new method to collect data, however, few studies have explored this. In this article we present 12 doctoral students' experiences with conducting focus groups using the videoconferencing application Zoom during a qualitative methods course on interviewing methods. Through this self-study qualitative analysis, participants reflected on the opportunities and challenges experienced as both moderators and participants using Zoom including: preparation, rapport, incorporating other digital tools, and internet connectivity. In conclusion, doing focus groups online using Zoom was a positive experience overall and comparable to in-person focus groups for collecting qualitative data, despite the introduction of technology. More research on participant recruitment, new technology, Zoom's security features, and Zoom's use outside of a pandemic should be further explored

Impact of hypercapnia on alveolar Na+-transport : Establishing a system for ENaC-protein detection

Acute respiratory distress syndrome is a life threatening condition triggered by a variety of pulmonary and extrapulmonary causes, that is characterized by pulmonary edema and subsequently impaired gas exchange. Due to lung protective ventilation strategies, its treatment is often associated with systemic accumulation of CO2, a condition termed permissive hypercapnia. Recent studies report a negative effect of CO2 on alveolar fluid clearance, a process mediated by its two key elements the Na+,K+-ATPase and epithelial Na+-channels (ENaCs). A reduced activity of the Na+,K+-ATPase during hypercapnia has already been demonstrated, but regulation of ENaC has never been directly linked to CO2. Many molecular signaling events that are activated during hypercapnia are known to regulate ENaC function, so the present study aimed to generate and subsequently apply techniques to investigate a possible contribution of ENaC to the reduction of alveolar epithelial fluid transport upon hypercapnia. ENaC function was studied in H441 cells by Ussing chamber experiments which revealed no significant regulation during short term hypercapnia, but a clear reduction of ENaC function during sustained hypercapnia. To identify the signaling mechanism on the molecular level, epitope-tagged human ENaC constructs for the α-, β- and γ-subunit were cloned and initially expressed in A549 cells. Exposition to hypercapnia up to 4 hours did not significantly reduce cell surface expression of the ENaC-subunits, but after 24 hours, a significant decrease of β-ENaC was observed. Since the molecular sizes of α- and γ-ENaC expressed in A549 cells were differing from previously published studies, transfection of ENaC was continued in other cells. H441 cells are commonly used for ENaC studies, so their transfection was established, yielding an efficiency of about 60 %. The molecular sizes of transfected ENaC subunits matched the pattern that was expected, but expression levels were evanescent and too low for further experiments. Since ENaC detection in these two cell lines remained problematic, a novel methodology was applied. Since the primary site of ENaC expression in the lung are epithelial cells, rat primary alveolar epithelial cells type II were used as recipients for ENaC plasmids. Non-viral transfection of ATII cells has been inefficient in the past, but during the present study a protocol was generated to efficiently deliver nucleic acids to exactly this cell type. ENaC expression was largely increased in ATII cells, compared to the cell lines used, indicating that established system might be extremely useful for further studies involving ENaC turnover. Thus, a new and highly relevant, non-viral transfection technique for primary alveolar epithelial type II cells was established, providing ground-breaking opportunities for future pulmonary research.Das Atemnotsyndrom des Erwachsenen ist eine lebensbedrohliche Erkrankung, ausgelöst durch eine Reihe von Faktoren, die direkt oder indirekt auf die Lunge einwirken . Charakteristisch für dieses Syndrom sind pulmonare Ödeme und daraus resultierend ein eingeschränkter Gasaustausch. Die daher benötigte künstliche Beatmung führt im Zuge von protektiven Beatmungsstrategien oft zu einer systemischen Anreicherung von CO2 (Hyperkapnie). Einige Studien zeigen, dass erhöhte CO2-Level den Flüssigkeitstransport der Lunge einschränken. Dieser aktive Prozess wird maßgeblich durch zwei Komponenten, die Na+,K+-ATPase und epitheliale Na+-Kanäle (ENaCs), kontrolliert. Eine Beeinträchtigung der Na+,K+-ATPase durch CO2 gezeigt, für ENaCs ist dies bislang nicht bekannt. Einige bekannte Regulatoren von ENaCs werden jedoch während Hyperkapnie aktiviert. Das Ziel der vorliegenden Arbeit war, Methoden zu etablieren und anzuwenden, die einen möglichen Einfluss von CO2 auf ENaC zeigen. Funktionelle Versuche wurden an H441-Zellen mit Ussing-Kammer-Messungen durchgeführt. Während akuter Hyperkapnie konnte keine signifikante Regulation von ENaC nachgewiesen werden, jedoch war die ENaC-Funktion bei anhaltender Hyperkapnie deutlich verringert. Um die Signalwege auf molekularer Ebene zu untersuchen, wurde die α-, β- und γ- Untereinheit des humanen ENaC kloniert, genetisch modifiziert und in A549 Zellen überexprimiert. Nach bis zu vierstündiger Hyperkapnie erfolgte keine Regulation von ENaC, jedoch wurde nach 24 Stunden eine deutlich verminderte Menge β-ENaC in der Zellmembran nachgewiesen. Da die Größen von α- und γ-ENaC von den bisher publizierten abwichen, wurden weitere Versuche in H441 Zellen durchgeführt. Die Transfektion dieser Zelllinie wurde etabliert und erreichte eine Effizienz von ungefähr 60 %. Die posttranslationale Regulation der α- und γ-Untereinheiten, insbesondere die proteolytische Aktivierung funktionierten wie in der Literatur beschrieben, jedoch waren die Expressionslevel zu gering für weitere Versuche. In der Lunge werden ENaCs überwiegend in epithelialen Zellen exprimiert. Diese Zellen konnten bisher jedoch nicht effizient transfiziert werden, ohne Viren einzusetzen. In der vorliegenden Arbeit wurde jedoch eine effiziente Methode zur Transfektion von primären epithelialen Zellen der Ratte erarbeitet. Die Expression von transfizierten ENaC-Untereinheiten war in diesen Zellen deutlich erhöht, weswegen die Etablierung dieses Systems ausschlaggebend für weitere Versuche ist. Die vorliegende Arbeit beschreibt daher zum ersten Mal die nicht-virale, effiziente Transfektion von primären alveolaren Zellen und liefert damit ein bedeutendes neues Werkzeug für die Lungenforschung

The Impact of Realistic Age Structure in Simple Models of Tuberculosis Transmission

Background : Mathematical models of tuberculosis (TB) transmission have been used to characterize disease dynamics, investigate the potential effects of public health interventions, and prioritize control measures. While previous work has addressed the mathematical description of TB natural history, the impact of demography on the behaviour of TB models has not been assessed. Methods : A simple model of TB transmission, with alternative assumptions about survivorship, is used to explore the effect of age structure on the prevalence of infection, disease, basic reproductive ratio and the projected impact of control interventions. We focus our analytic arguments on the differences between constant and exponentially distributed lifespans and use an individual-based model to investigate the range of behaviour arising from realistic distributions of survivorship. Results : The choice of age structure and natural (non-disease related) mortality strongly affects steady-state dynamics, parameter estimation and predictions about the effectiveness of control interventions. Since most individuals infected with TB develop an asymptomatic latent infection and never progress to active disease, we find that assuming a constant mortality rate results in a larger reproductive ratio and an overestimation of the effort required for disease control in comparison to using more realistic age-specific mortality rates. Conclusions : Demographic modelling assumptions should be considered in the interpretation of models of chronic infectious diseases such as TB. For simple models, we find that assuming constant lifetimes, rather than exponential lifetimes, produces dynamics more representative of models with realistic age structure