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Targeting prostaglandin E2 receptor 2 in Schwann cells inhibits inflammatory pain but not inflammation
Get PDFAnalgesia by non-steroidal anti-inflammatory drugs (NSAIDs) is ascribed to inhibition of prostaglandin (PG) biosynthesis and ensuing inflammation. However, NSAIDs have life-threatening side effects, and inhibition of inflammation delays pain resolution. Decoupling the mechanisms underlying PG-evoked pain vs. protective inflammation would facilitate pain treatment. Herein, we reveal that selective silencing of the PGE2 receptor 2 (EP2) in Schwann cells via adeno-associated viral vectors abrogates the indomethacin-sensitive component of pain-like responses in mice elicited by inflammatory stimuli without affecting inflammation. In human Schwann cells and in mice, EP2 activation and optogenetic stimulation of adenylyl cyclase evokes a plasma membrane-compartmentalized cyclic adenosine monophosphate (cAMP) signal that, via A-kinase anchor protein-associated protein kinase A, sustains inflammatory pain-like responses, but does not delay their resolution. Thus, an unforeseen and druggable EP2 receptor in Schwann cells, via specific cAMP nanodomains, encodes PGE2-mediated persistent inflammatory pain but not PG-dependent protective inflammation
Interlocked 2D Covalent Organic Frameworks from Overcrowded Nodes
Get PDFA challenging aspect in the synthesis of covalent organic frameworks (COFs) that goes beyond the framework’s structure and topology is interpenetration, where two or more independent frameworks are mechanically interlocked with each other. Such interpenetrated or interlocked frameworks are commonly found in three-dimensional (3D) COFs with large pores. However, interlocked two-dimensional (2D) COFs are rarely seen in the literature, as 2D COF layers typically crystallize in stacks that maximize stabilization through π-stacking. The few interlocked 2D COFs described to date have been derived from monomers with aryl groups arranged perpendicularly. Herein, we report an interlocked 2D COF derived from a new class of monomers constituted of sterically overcrowded polycyclic aromatic hydrocarbons. The formation of such an interlocked structure is ascribed to the presence and the bulkiness of the substituents that directly interfere with interlayer π-stacking. The microscopy, gas sorption, spectroscopic, and charge transport characterization are consistent with the absence of π-stacking, as imposed by the interlocked architecture. This work evidences how the use of overcrowded aromatic systems as monomers can generate mechanically interlocked 2D COFs, offering new avenues for the design of COFs with unconventional topologies
Neuroinflammation in Alzheimer disease
No full textIncreasing evidence points to a pivotal role of immune processes in the pathogenesis of Alzheimer disease, which is the most prevalent neurodegenerative and dementia-causing disease of our time. Multiple lines of information provided by experimental, epidemiological, neuropathological and genetic studies suggest a pathological role for innate and adaptive immune activation in this disease. Here, we review the cell types and pathological mechanisms involved in disease development as well as the influence of genetics and lifestyle factors. Given the decade-long preclinical stage of Alzheimer disease, these mechanisms and their interactions are driving forces behind the spread and progression of the disease. The identification of treatment opportunities will require a precise understanding of the cells and mechanisms involved as well as a clear definition of their temporal and topographical nature. We will also discuss new therapeutic strategies for targeting neuroinflammation, which are now entering the clinic and showing promise for patients
Reporting Guideline for Therapeutic Immersive Virtual Reality Interventions: International eDelphi Study (INVIRTUE)
Get PDFWith the rising adoption of virtual reality (VR) in health care, research publications on the topic are increasing rapidly. Guidance on reporting VR interventions is limited, which risks misinterpretation of findings, inappropriate data synthesis in reviews and meta-analyses, and reduced reproducibility. This could also result in possible misuse of VR interventions and might hinder further implementation in clinical practice. The aim of this study was to develop a reporting guideline for therapeutic, immersive VR interventions using head-mounted displays in scientific publications. To reach this aim, we intended to achieve expert consensus on key items and categories for reporting these interventions. We conducted a three-round, modified, online Delphi study with a validation meeting to develop a VR intervention reporting guideline. Participants were international experts in therapeutic VR research, working as academic or industrial researchers. Convenience, purposive, and snowball sampling were used to recruit participants. Consensus was defined a priori as ≥75% agreement on each reporting item and category. Of the 280 invited experts, 61 participants (22%) completed all three rounds of this Delphi study. Participants (32 females [52%]) had an average of 6 years’ experience with VR research and diverse backgrounds in VR research settings and disciplines. The final consensus-based VR intervention reporting guideline consists of 16 reporting items divided into six categories (i.e., theory, content, deployment, development, safety, and context). The INVIRTUE intervention reporting guideline provides a framework for describing therapeutic VR interventions. Using this tool may enhance the uniformity and completeness of VR intervention reporting and support study replicability and scientific progress. The reporting guideline will also facilitate efficient empirical comparison across existing VR interventions and ultimately contribute to the appropriate use and effective implementation of therapeutic VR in clinical practice
The Lyman α emitter bispectrum as a probe of reionization morphology
Get PDFLy α emitters (LAEs) have now been discovered out to redshift z = 13, and are valuable probes of the reionization historyat redshifts beyond the reach of other currently available tracers. Most inferences of the neutral hydrogen fraction from LAEobservations rely on one-point and two-point statistics like the luminosity function and the power spectrum. We present herean analysis of the bispectrum of high-redshift LAEs and demonstrate its sensitivity to the epoch of reionization. We use theSherwood-Relics suite of cosmological hydrodynamical simulations post-processed with the GPU-based radiative transfer codeATON-HE to generate realistic LAE mock cataloguesfor a wide range of reionization models, varying the ionization history and thesource populations, including contributions of active galactic nucleus (AGN) to hydrogen reionization. We demonstrate that thebispectrum provides greater sensitivity than the power spectrum to both the timing and spatial morphology of reionization. Usingreduced-χ2 analysis we furthershow that the bispectrum also responds more strongly to variations in source population and AGNcontribution, apparently more efficiently capturing morphological features missed by two-point statistics. The redshift evolutionof the bispectrum reflects the increased clustering of ionizing sources at earlier epochs. The sensitivity of the bispectrum topeculiar velocities underscores the importance of velocity corrections in comparisons to observations. Our findings demonstratethat the LAE bispectrum is a powerful higher order statistic for probing reionization through current and future LAE surveysusing telescopes such as Subaru and James Webb Space Telescope
Perinatal Experiences of Black Women During COVID-19: A Qualitative Study Guided by the Public Health Critical Race Praxis
No full textPregnancy during the COVID-19 pandemic presented unique challenges for all women; however, the experiences of Black women were particularly affected by intersecting processes and systems such as race, class, gender, socioeconomic status, and healthcare access. The objective of this study was to explore the perinatal experiences of Black women amidst the COVID-19 pandemic. This was a qualitative study. Inclusion criteria were self-identification as a Black woman aged 18–49; experienced at least one pregnancy from March 2020 to May 2023; received at least one dose of COVID-19 vaccine during the perinatal period; and residence in Greater Philadelphia. Interviews (n = 22) were conducted by trained researchers and were audio-recorded and transcribed verbatim, and analyzed inductively. Participants were incentivized for their time. The average age of the participants was 33.5 (±6.2) years. Of 28 pregnancies, 22 resulted in live births, two ended in miscarriages, two in abortions, and two participants were pregnant during data collection. Three main themes were identified: (1) emotional impact of COVID-19; (2) experiences of COVID-19 illness during pregnancy and postpartum; and (3) impact of COVID-19 mitigation measures on perinatal experiences. The perinatal experiences of Black women during the COVID-19 pandemic revealed critical gaps in our maternal healthcare system. Hence, culturally sensitive and targeted crisis preparedness and readiness strategies, such as community-led response teams, for minority groups during health crises like the COVID-19 pandemic, are warranted
Continuous and algebraic domains in univalent foundations
Get PDFWe develop the theory of continuous and algebraic domains in constructive and predicative univalent foundations, building upon our earlier work on basic domain theory in this setting. That we work predicatively means that we do not assume Voevodsky's propositional resizing axioms. Our work is constructive in the sense that we do not rely on excluded middle or the axiom of (countable) choice. To deal with size issues and give a predicatively suitable definition of continuity of a dcpo, we follow Johnstone and Joyal's work on continuous categories. Adhering to the univalent perspective, we explicitly distinguish between data and property. To ensure that being continuous is a property of a dcpo, we turn to the propositional truncation, although we explain that some care is needed to avoid needing the axiom of choice. We also adapt the notion of a domain-theoretic basis to the predicative setting by imposing suitable smallness conditions, analogous to the categorical concept of an accessible category. All our running examples of continuous dcpos are then actually examples of dcpos with small bases which we show to be well behaved predicatively. In particular, such dcpos are exactly those presented by small ideals. As an application of the theory, we show that Scott's D∞ model of the untyped λ-calculus is an example of an algebraic dcpo with a small basis. Our work is formalised in the Agda proof assistant and its ability to infer universe levels has been invaluable for our purposes
Evidence informed policy? The Australian Education Research Organisation’s borrowed knowledge-rich curriculum dispositif
Get PDF'Knowledge-richness' is now being promoted in Australia by the Australian Education Research Organisation (AERO). Knowledge richness is part of a curriculum dispositif which sutures together methods drawn from cognitive science, a subject driven approach and performance based summative assessment. Based heavily on the English instantiation of knowledge-richness, the dispositif potentially heralds radical changes in the Australian curriculum and the ways in which it is taught. A discourse analysis of AERO's A knowledge rich approach to curriculum design (2024) report shows (1) a politics of omissions, a (2) a politics of definition and (3) a politics of evidence. I argue that we might expect better from a national evidence body but that surfacing alternative understandings of knowledge-richness opens space for important debates about a more socially just national curriculum
Green synthesis of NaP1 zeolite from MSWI fly ash and silica-rich solid waste with superior Cu(II) removal efficiency
Get PDFMicrowave hydrothermal treatment provides a promising strategy for detoxifying and valorizing municipal solid waste solid waste incineration fly ash (MSWI-FA) into zeolite materials. However, the intrinsically low Si/Al ratio of MSWI-FA often results in reduced zeolite purity. To address this issue, an alkali fusion-assisted microwave hydrothermal method was developed to synthesize NaP1 zeolite directly from MSWI-FA, employing silica-rich solid waste as an eco-friendly alternative to conventional sodium silicate (Na2SiO3). The resultant MSWI-FA-based zeolite (IFA-NaP1) was comprehensively evaluated for its Cu(II) adsorption characteristics. Among the silica-rich solid waste investigated (i.e., silica fume, rice husk ash, and waste glass), silica fume-derived IFA-NaP1 exhibits the most favorable properties, achieving a cation exchange capacity of 2.46 meq∙g−1, 11% higher than that of its Na2SiO3-based counterpart. Mechanistic analysis reveals distinctive silica source-dependent pathways: Na2SiO3 induces multinuclear competition and sequential transformations, whereas silica fume enables a direct sequential transformation. Leaching assessments of IFA-NaP1 confirm its effective immobilization of Pb, Zn, and Cd, with Cr and Cu levels remaining within regulatory thresholds. The silica fume-derived IFA-NaP1 synthesized at 140 °C exhibits superior Cu(II) removal, achieving a maximum adsorption capacity of 123 mg∙g−1, 13% higher than Na2SiO3-derived material. Thermodynamic analysis shows Cu(II) adsorption is endothermic and entropy-driven, involving mechanisms such as electrostatic attraction, ion exchange, silyl radical reduction, surface complexation, and precipitation. This work highlights a sustainable strategy for converting MSWI-FA into efficient zeolite adsorbents, advancing hazardous waste detoxification and heavy metal remediation
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