4,137 research outputs found

    Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

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    Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

    Combined Nutrition and Exercise Interventions in Community Groups

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    Diet and physical activity are two key modifiable lifestyle factors that influence health across the lifespan (prevention and management of chronic diseases and reduction of the risk of premature death through several biological mechanisms). Community-based interventions contribute to public health, as they have the potential to reach high population-level impact, through the focus on groups that share a common culture or identity in their natural living environment. While the health benefits of a balanced diet and regular physical activity are commonly studied separately, interventions that combine these two lifestyle factors have the potential to induce greater benefits in community groups rather than strategies focusing only on one or the other. Thus, this Special Issue entitled ‚ÄúCombined Nutrition and Exercise Interventions in Community Groups‚ÄĚ is comprised of manuscripts that highlight this combined approach (balanced diet and regular physical activity) in community settings. The contributors to this Special Issue are well-recognized professionals in complementary fields such as education, public health, nutrition, and exercise. This Special Issue highlights the latest research regarding combined nutrition and exercise interventions among different community groups and includes research articles developed through five continents (Africa, Asia, America, Europe and Oceania), as well as reviews and systematic reviews

    Effects of municipal smoke-free ordinances on secondhand smoke exposure in the Republic of Korea

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    ObjectiveTo reduce premature deaths due to secondhand smoke (SHS) exposure among non-smokers, the Republic of Korea (ROK) adopted changes to the National Health Promotion Act, which allowed local governments to enact municipal ordinances to strengthen their authority to designate smoke-free areas and levy penalty fines. In this study, we examined national trends in SHS exposure after the introduction of these municipal ordinances at the city level in 2010.MethodsWe used interrupted time series analysis to assess whether the trends of SHS exposure in the workplace and at home, and the primary cigarette smoking rate changed following the policy adjustment in the national legislation in ROK. Population-standardized data for selected variables were retrieved from a nationally representative survey dataset and used to study the policy action‚Äôs effectiveness.ResultsFollowing the change in the legislation, SHS exposure in the workplace reversed course from an increasing (18% per year) trend prior to the introduction of these smoke-free ordinances to a decreasing (‚ąí10% per year) trend after adoption and enforcement of these laws (ő≤2‚ÄČ=‚ÄČ0.18, p-value‚ÄČ=‚ÄČ0.07; ő≤3‚ÄČ=‚ÄČ‚ąí0.10, p-value‚ÄČ=‚ÄČ0.02). SHS exposure at home (ő≤2‚ÄČ=‚ÄČ0.10, p-value‚ÄČ=‚ÄČ0.09; ő≤3‚ÄČ=‚ÄČ‚ąí0.03, p-value‚ÄČ=‚ÄČ0.14) and the primary cigarette smoking rate (ő≤2‚ÄČ=‚ÄČ0.03, p-value‚ÄČ=‚ÄČ0.10; ő≤3‚ÄČ=‚ÄČ0.008, p-value‚ÄČ=‚ÄČ0.15) showed no significant changes in the sampled period. Although analyses stratified by sex showed that the allowance of municipal ordinances resulted in reduced SHS exposure in the workplace for both males and females, they did not affect the primary cigarette smoking rate as much, especially among females.ConclusionStrengthening the role of local governments by giving them the authority to enact and enforce penalties on SHS exposure violation helped ROK to reduce SHS exposure in the workplace. However, smoking behaviors and related activities seemed to shift to less restrictive areas such as on the streets and in apartment hallways, negating some of the effects due to these ordinances. Future studies should investigate how smoke-free policies beyond public places can further reduce the SHS exposure in ROK

    Estimating the number of people living with dementia at different stages of the condition in India: A Delphi process

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    Introduction Numerous studies have previously estimated the dementia prevalence in India. However, as these estimates use different methodologies and sampling strategies, generating definitive prevalence estimates can be difficult. Methods A Delphi process involving eight clinical and academic experts provided prevalence estimates of dementia within India, split by sex and age. The experts were also asked to estimate the number of people potentially living at different stages of the condition. A priori criteria were used to ascertain the point in which consensus was achieved. Results Our consensus estimates generated a dementia prevalence of 2.8% (95% CI = 1.9 to 3.6) for those aged 60¬†years and above in India. Consensus was achieved across age and sex prevalence estimates, with the exception of one (females aged 60‚Äď64). Our experts estimated that 42.9% of people living with dementia in India had a mild severity. Conclusions The findings indicate that there could be approximately 3.9 million people living with dementia in India, of which 1.7 million could be living with dementia of mild severity. Such estimates can better help researchers and policy makers to estimate the true cost and impact of dementia in India and can inform resource allocation decisions

    The Role of Preprocessing for Word Representation Learning in Affective Tasks

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    Affective tasks, including sentiment analysis, emotion classification, and sarcasm detection have drawn a lot of attention in recent years due to a broad range of useful applications in various domains. The main goal of affect detection tasks is to recognize states such as mood, sentiment, and emotions from textual data (e.g., news articles or product reviews). Despite the importance of utilizing preprocessing steps in different stages (i.e., word representation learning and building a classification model) of affect detection tasks, this topic has not been studied well. To that end, we explore whether applying various preprocessing methods (stemming, lemmatization, stopword removal, punctuation removal and so on) and their combinations in different stages of the affect detection pipeline can improve the model performance. The are many preprocessing approaches that can be utilized in affect detection tasks. However, their influence on the final performance depends on the type of preprocessing and the stages that they are applied. Moreover, the preprocessing impacts vary across different affective tasks. Our analysis provides thorough insights into how preprocessing steps can be applied in building an effect detection pipeline and their respective influence on performance

    An Exploration of the Relationship Between Disability Status Disclosure, Accommodation Use, and Student Success: Curricular and Co-Curricular Implications

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    Colleges and universities rely on the individualized accommodation process to ensure access for students with disabilities, however, there is ample evidence that educational inequity is pervasive. This study used a critical and comparative quantitative methodology (n=6,500) to investigate data from a large urban community college, analyzing the relationship between final grades and accommodation eligibility and use across academic disciplines and curricular modalities (in-person vs. on-line) to identify implications for the academic success of students with disabilities. Results indicate disability inequity varies across racial identity groups and racial inequity persists across disability status groups. Results also indicate that accommodation may be most impactful for students with lower cumulative grade point averages, students taking courses at the 100 level, students taking online courses, and students taking courses in disciplines such as math. There appear to be benefits to a connection with Disability Services even when students do not notify faculty of their eligibility for accommodation. Recommendations include the inclusion of disability as a demographic within institutional reporting; professional development for faculty, staff, and student leaders that goes beyond compliance to address implications of the intersections of gender, race, identity, and disability; and inclusion of disabled student voices to improve access and inclusion throughout curricular and co-curricular programs and activities

    Biographical Lexicon of Public Health

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    Biographical Lexicon of Public Healt

    Rational development of stabilized cyclic disulfide redox probes and bioreductive prodrugs to target dithiol oxidoreductases

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    Countless biological processes allow cells to develop, survive, and proliferate. Among these, tightly balanced regulatory enzymatic pathways that can respond rapidly to external impacts maintain dynamic physiological homeostasis. More specifically, redox homeostasis broadly affects cellular metabolism and proliferation, with major contributions by thiol/disulfide oxidoreductase systems, in particular, the Thioredoxin Reductase Thioredoxin (TrxR/Trx) and the Glutathione Reductase-Glutathione-Glutaredoxin (GR/GSH/Grx) systems. These cascades drive vital cellular functions in many ways through signaling, regulating other proteins' activity by redox switches, and by stoichiometric reductant transfers in metabolism and antioxidant systems. Increasing evidence argues that there is a persistent alteration of the redox environment in certain pathological states, such as cancer, that heavily involve the Trx system: upregulation and/or overactivity of the Trx system may support or drive cancer progression, making both TrxR and Trx promising targets for anti-cancer drug development. Understanding the biochemical mechanisms and connections between certain redox cascades requires research tools that interact with them. The state-of-the-art genetic tools are mostly ratiometric reporters that measure reduced:oxidized ratios of selected redox pairs or the general thiol pool. However, the precise cellular roles of the central oxidoreductase systems, including TrxR and Trx, remain inaccessible due to the lack of probes to selectively measure turnover by either of these proteins. However, such probes would allow measuring their effective reductive activity apart from expression levels in native systems, including in cells, animals, or patient samples. They are also of high interest to identify chemical inhibitors for TrxR/Trx in cells and to validate their potential use as anti-cancer agents (to date, there is no selective cellular Trx inhibitor, and most known TrxR inhibitors were not comprehensively evaluated considering selectivity and potential off-targets). However, small molecule redox imaging tools are underdeveloped: their protein specificity, spectral properties, and applicability remain poorly precedented. This work aimed to address this opportunity gap and develop novel, small molecule diagnostic and therapeutic tools to selectively target the Trx system based on a modular trigger cargo design: artificial cyclic disulfide substrates (trigger) for oxidoreductases are tethered to molecular agents (cargo) such that the cargo‚Äôs activity is masked and is re-established only through reduction by a target protein. The rational design of these novel reduction sensors to target the cell's strongest disulfide-reducing enzymes was driven by the following principles: (i) cyclic disulfide triggers with stabilized ring systems were used to gain low reduction potentials that should resist reduction except by the strongest cellular reductases, such as Trx; and (ii) the cyclic topology also offers the potential for kinetic reversibility that should select for dithiol-type redox proteins over the cellular monothiol background. Creating imaging agents based on such two-component designs to selectively measure redox protein activity in native cells required to combine the correct trigger reducibility, probe activation kinetics, and imaging modalities and to consider the overall molecular architecture. The major prior art in this field has applied cyclic 5-membered disulfides (1,2 dithiolanes) as substrates for TrxR in a similar way to create such tools. However, this motif was described elsewhere as thermodynamically instable and was due to widely used for dynamic covalent cascade reactions. By comparing a novel 1,2 dithiolane-based probe to the state-of-the-art probes, including commercial TrxR sensors, by screening a conclusive assay panel of cellular TrxR modulations, I clarified that 1,2 dithiolanes are not selective substrates for TrxR in biological settings (Nat Commun 2022). Instead, aiming for more stable ring systems and thus more robust redox probes, during this work, I developed bicyclic 6 membered disulfides (piperidine fused 1,2 dithianes) with remarkably low reduction potentials. I showed that molecular probes using them as reduction sensors can be mostly processed by thioredoxins while being stable against reduction by GSH. The thermodynamically stabilized decalin like topology of the cis-annelated 1,2 dithianes requires particularly strong reductants to be cleaved. They also select for dithiol type redox proteins, like Trx, based on kinetic reversibility and offer fast cyclization due to the preorganization by annelation (JACS 2021). This work further expanded the system‚Äôs modularity with structural cores based on piperazine-fused 1,2 dithianes with the two amines allowing independent derivatization. Diagnostic tools using them as reduction sensors proved equally robust but with highly improved activation kinetics and were thus cellularly activated. Cellular studies evolved that they are substrates for both Trxs and their protein cousins Grxs, so measuring the cellular dithiol protein pool rather than solely Trx activity (preprint 2023). Finally, a trigger based on a slightly adapted reduction sensor, a desymmetrized 1,2 thiaselenane, was designed for selective reduction by TrxR‚Äôs selenol/thiol active site, then combined with a precipitating large Stokes‚Äô shift fluorophore and a solubilizing group, to evolve the first selective probe RX1 to measure cellular TrxR activity, which even allowed high throughput inhibitor screening (Chem 2022). The central principle of this work was further advanced to therapeutic prodrugs based on the duocarmycin cargo (CBI) with tunable potency (JACS Au 2022) that can be used to create off-to-on therapeutic prodrugs. Such CBI prodrugs employing stabilized 1,2 dichalcogenide triggers proved to be cytotoxins that depend on Trx system activity in cells. They could further be exploited for cell-line dependent reductase activity profiling by screening their redox activation indices, the reduction-dependent part of total prodrug activation, in 177 cell lines. Beyond that, these prodrugs were well-tolerated in animals and showed anti-cancer efficacy in vivo in two distinct mouse tumor models (preprint 2022). Taken together, I introduced unique monothiol-resistant reducible motifs to target the cellular Trx system with chemocompatible units for each for TrxR and Trx/Grx, where the cyclic nature of the dichalcogenides avoids activation by GSH. By using them with distinct molecular cargos, I developed novel selective fluorescent reporter probes; and introduced a new class of bioreductive therapeutic constructs based on a common modular design. These were either applied to selectively measure cellular reductase activity or to deliver cytotoxic anti cancer agents in vivo. Ongoing work aims to differentiate between the two major redox effector proteins Trx and Grx, requiring additional layers of selectivity that may be addressed by tuned molecular recognition. The flexible use of various molecular cargos allows harnessing the same cellular redox machinery by either probes or prodrugs. This allows predictive conclusions from diagnostics to be directly translated into therapy and offers great potential for future adaptation to other enzyme classes and therapeutic venues.Die zellul√§re Redox-Hom√∂ostase h√§ngt von Thiol/Disulfid-Oxidoreduktasen ab, die den Stoffwechsel, die Proliferation und die antioxidative Antwort von Zellen beeinflussen. Die wichtigsten Netzwerke sind die Thioredoxin Reduktase-Thioredoxin (TrxR/Trx) und Glutathion Reduktase-Glutathion-Glutaredoxin (GR/GSH/Grx) Systeme, die √ľber Redox-Schalter in Substratproteinen lebenswichtige zellul√§re Funktionen steuern und so an der Redox-Regulation und -Signal√ľbertragung beteiligt sind. Persistente Ver√§nderungen des Redoxmilieus in pathologischen Zust√§nden, wie z. B. bei Krebs, sind in hohem Ma√üe mit dem Trx-System verbunden. Eine Hochregulierung und/oder √úberaktivit√§t des Trx-Systems, die bei vielen Krebsarten auftreten, unterst√ľtzt zudem das Fortschreiten des Krebswachstums, was TrxR/Trx zu vielversprechenden Zielproteinen f√ľr die Entwicklung neuer Krebsmedikamente macht. Um die biochemischen Prozesse dahinter zu erforschen, sind spezielle Techniken zur Visualisierung und Messung enzymatischer Aktivit√§t n√∂tig. Die hierzu geeigneten, meist genetischen Sensoren messen ratiometrisch das Verh√§ltnis reduzierter/oxidierter Spezies in zellul√§rem Umfeld oder spezifisch ausgew√§hlte Redoxpaare. Die weitere Erforschung der exakten Funktion von TrxR/Trx und deren Substrate ist jedoch durch mangelnde Nachweismethoden limitiert. Diese sind au√üerdem zur Validierung chemischer Hemmstoffe f√ľr TrxR/Trx in Zellen und deren potenziellen Verwendung als Krebsmittel von gro√üem Interesse. Bislang gibt es keinen selektiven zellul√§ren Trx-Inhibitor und potenzielle Off-Target-Effekte der bekannten TrxR-Inhibitoren wurden nicht abschlie√üend bewertet. Ziel dieser Arbeit ist die Entwicklung niedermolekularer, diagnostischer und therapeutischer Werkzeuge, die selektiv auf das Trx-System abzielen und auf einem modularen Trigger-Cargo Design basieren. Hierzu werden zyklische Disulfid-Substrate (Trigger) f√ľr Oxidoreduktasen so mit molekularen Wirkstoffen (Cargo) verkn√ľpft, dass dabei die Wirkstoffaktivit√§t maskiert, und erst nach Reduktion durch ein Zielprotein wiederhergestellt wird. Diese neuartigen, synthetischen Reduktionssensoren basieren auf den folgenden Grundprinzipien: (i) Zyklische Disulfide sind thermodynamisch stabilisiert und k√∂nnen nur durch die st√§rksten Reduktasen gespalten werden; und (ii) die zyklische Topologie erm√∂glicht die kinetische Reversibilit√§t der zwei Thiol-Disulfid-Austauschreaktionen, die eine erste Reaktion mit Monothiolen, wie z. B. GSH, sofort umkehrt und so eine vollst√§ndige Reduktion verhindert. Die meisten fr√ľheren Arbeiten auf diesem Gebiet verwendeten ein zyklisches, f√ľnfgliedriges Disulfid (1,2 Dithiolan) als Substrat f√ľr TrxR. Das gleiche Strukturmotiv wurde jedoch an anderer Stelle als thermodynamisch instabil beschrieben und aufgrund dieser Eigenschaft explizit f√ľr dynamische Kaskadenreaktionen verwendet. Deshalb vergleicht diese Arbeit zu Beginn einen neuen 1,2 Dithiolan basierten fluorogenen Indikator mit bestehenden, z. T. kommerziellen, Redox Sonden f√ľr TrxR in einer Reihe von Zellkultur-Experimenten unter Modulation der zellul√§ren TrxR Aktivit√§t und stellt so einen Widerspruch in der Literatur klar: 1,2 Dithiolane eignen sich nicht als selektive Substrate f√ľr TrxR, da sie labil sowohl gegen die Reduktion durch andere Redoxproteine, als auch gegen den Monothiol Hintergrund in Zellen sind (Nat. Commun. 2022). Als alternatives Strukturmotiv wird in dieser Arbeit ein bizyklisches sechsgliedriges Disulfid (anneliertes 1,2 Dithian) etabliert. Durch sein niedriges Reduktionspotenzial, also seine hohe Resistenz gegen Reduktion, werden molekulare Sonden basierend auf diesem 1,2 Dithian als Reduktionssensor fast ausschlie√ülich von Trx aktiviert, nicht aber von TrxR oder GSH (JACS 2021). Dieses Kernmotiv bestimmt dabei die Reduzierbarkeit, und damit die Enzymspezifit√§t, durch seine zyklische Natur und die Annelierung, auch unter Verwendung unterschiedlicher Farb-/Wirkstoffe. Auf dieser Grundlage konnte die molekulare Struktur durch einen weiteren Modifikationspunkt f√ľr die flexible Verwendung weiterer funktioneller Einheiten erg√§nzt werden. Obwohl zellul√§re Studien ergaben, dass diese neuartigen 1,2 Dithian Einheiten in Zellen sowohl Trx als auch das strukturell verwandte Grx adressieren, sind die daraus resultierenden diagnostischen Molek√ľle wertvoll, um den katalytischen Umsatz zellul√§rer Dithiol-Reduktasen, der sogenannten Trx Superfamilie, selektiv anzuzeigen (Preprint 2023). Beg√ľnstigt durch das modulare Molek√ľldesign stellt diese Arbeit zudem das erste Reportersystem RX1 zum selektiven Nachweis der TrxR-Aktivit√§t in Zellen vor. Es basiert auf der Verwendung eines zyklischen, unsymmetrischen Selenenylsulfid-Sensors (1,2 Thiaselenan), der selektiv von dem einzigartigen Selenolat der TrxR angegriffen wird, und dadurch letztlich nur von TrxR reduziert werden kann. RX1 eignete sich zudem f√ľr eine Hochdurchsatz-Validierung bestehender TrxR Inhibitoren und unterstreicht dadurch den kommerziellen Nutzen derartiger Diagnostika (Chem 2022). Das zentrale Trigger-Cargo Konzept dieser Arbeit wurde f√ľr therapeutische Zwecke weiterentwickelt und nutzt dabei den einzigartigen Wirkmechanismus der Duocarmycin-Naturstoffklasse (CBI) (JACS Au 2022) zur Entwicklung reduktiv aktivierbarer Therapeutika. CBI Prodrugs basierend auf stabilisierten Redox-Schaltern (1,2 Dithiane f√ľr Trx; 1,2 Thiaselenan f√ľr TrxR) reagierten signifikant auf TrxR-Modulation in Zellen. Sie wurden dar√ľber hinaus durch das Referenzieren ihrer Aktivit√§t gegen√ľber nicht-reduzierbaren Kontrollmolek√ľle f√ľr die Erstellung zelllinienabh√§ngiger Profile der Reduktaseaktivit√§t in 177 Zelllinien genutzt. Schlie√ülich waren diese neuen Krebsmittel im Tiermodell gut vertr√§glich und zeigten in zwei verschiedenen Mausmodellen eine krebshemmende Wirkung (Preprint 2022b). Zusammenfassend pr√§sentiert diese Dissertation monothiol-resistente reduzierbare Trigger-Einheiten f√ľr das zellul√§re Trx-System zur Entwicklung neuartiger, selektiver Reporter-Sonden, sowie eine neue Klasse reduktiv aktivierbarer Krebsmittel auf Basis eines adaptierbaren Trigger-Cargo Designs. Diese fanden entweder zur selektiven Messung zellul√§rer Proteinaktivit√§t oder zum Einsatz als Antikrebsmittel Verwendung. Es wurden chemokompatible Motive sowohl f√ľr TrxR als auch f√ľr Trx/Grx identifiziert, wobei deren zyklische Natur eine Aktivierung durch GSH verhindert. Eine weitere Differenzierung zwischen den beiden Redox-Proteinen Trx und Grx und anderen Proteinen der Trx-Superfamilie erfordert eine zus√§tzliche Ebene der Selektierung, z. B. durch molekulare Erkennung, und ist Gegenstand laufender Arbeiten. Die flexible Verwendung verschiedener molekularer Wirkstoffe erm√∂glicht dabei die ‚ÄěPipeline-Entwicklung‚Äú von Diagnostika und Therapeutika, die von der zellul√§ren Redox-Maschinerie analog umgesetzt werden, und dadurch Schlussfolgerungen aus der Diagnostik direkt auf eine Therapie √ľbertragbar machen. Dies birgt gro√ües Potenzial f√ľr k√ľnftige Entwicklungen bei einer potenziellen √úbertragung des modularen Konzepts auf andere Enzymklassen und therapeutische Einsatzgebiete

    Making Connections: A Handbook for Effective Formal Mentoring Programs in Academia

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    This book, Making Connections: A Handbook for Effective Formal Mentoring Programs in Academia, makes a unique and needed contribution to the mentoring field as it focuses solely on mentoring in academia. This handbook is a collaborative institutional effort between Utah State University’s (USU) Empowering Teaching Open Access Book Series and the Mentoring Institute at the University of New Mexico (UNM). This book is available through (a) an e-book through Pressbooks, (b) a downloadable PDF version on USU’s Open Access Book Series website), and (c) a print version available for purchase on the USU Empower Teaching Open Access page, and on Amazon
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