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Site-selective protein-protein coupling has long been a goal of chemical biology research. In recent years, that goal has been realized to varying degrees through a number of techniques, including the use of tyrosinase-based coupling strategies. Early publications utilizing tyrosinase from Agaricus bisporus(abTYR) showed the potential to convert tyrosine residues into ortho-quinone functional groups, but this enzyme is challenging to produce recombinantly and suffers from some limitations in substrate scope. Initial screens of several tyrosinase candidates revealed that the tyrosinase from Bacillus megaterium (megaTYR) is an enzyme that possesses a broad substrate tolerance. We use the expanded substrate preference as a starting point for protein design experiments and show that single point mutants of megaTYR are capable of activating tyrosine residues in various sequence contexts. We leverage this new tool to enable the construction of protein trimers via a charge-directed sequential activation of tyrosine residues (CDSAT).

The high-altitude lakes of the Altiplano–Puna Plateau in the Central Andes commonly have large radiocarbon reservoir effects. This, combined with the general scarcity of terrestrial organic matter, makes obtaining a reliable and accurate chronological model based on radiocarbon ages a challenge. As a result, age–depth models based on radiocarbon dating are often constructed by correcting for the modern reservoir effect, but commonly without consideration of spatial and possible temporal variations of reservoir ages within the lake and across the basin. In order to get a better constraint on the spatial variability of the radiocarbon reservoir effects, we analyse 14C ages of modern terrestrial and aquatic plants from the El Peinado basin in the southern Puna Plateau, which hosts Laguna del Peinado fed by hydrothermal springs. The oldest 14C ages of modern samples (> 18 000 and > 26 000 BP) were found in hot springs discharging into the lake, likely resulting from the input of 14C-depleted carbon from old groundwater and 14C-free magmatic CO2. In the littoral and central part of Laguna del Peinado, 14C ages of modern samples were several thousand years younger (> 13 000 and > 12 000 BP) compared to the inflowing waters as a result of CO2 exchange with the atmosphere. Altogether, our findings reveal a spatial variability of up to 14 000 14C years of the modern reservoir effect between the hot springs and the northern part of the Peinado lake basin. Temporal changes of reservoir effects in sediment records are more difficult to quantify, but 14C ages from a short core from Laguna del Peinado may suggest temporal reservoir age variations of a few thousand years. This study has implications for accurate 14C-based chronologies for palaeoclimate studies in the Altiplano–Puna Plateau and similar settings. Our results highlight the need to consider spatial and likely also temporal variations in the reservoir effects when constructing age–depth models.

Abstract Background Aim of the current study was the assessment of risk classes according to a previously established system to classify the anamnesis-related risk of complications and of oral diseases in a cohort of patients attending the dental student course for dental preventive measures. Methods Patients attending the student course between April 2020 and December 2021 were included. To assess the medical history, a specific anamnesis tool was used, which included the classification of different potential anamneis-related risks originating from general diseases, medications or lifestyle factors into a low, moderate or high risk of complications and/or risk of oral diseases. Thereby, the risk of complications was defined as the increaeed probability of harm during dental measures (professional tooth cleaning, invasive dental treatment or any kind of manipulation, which may cause a bacteremia), e.g. infectious endocarditis. On the other hand, the risk of oral diseases was an increaeed probability of development and/or progression of oral diseases like caries, periodontitis or mucosal diseases. Those risk classes were subsequently analyzed under consideration of age and gender. Results 858 patients, with a mean age of 50.48 ± 20.72 [median: 52.0] years, and a nearly balanced gender distribution (50.8% female and 49.2% male) were included. In the overall cohort, the risk of complications related with dental measures was low in 38.3%, moderate in 42.4% and high in 19.3% of participants. The risk of oral diseases was low in 33.1%, moderate in 37.2% and high in 29.7% of participants. Both, the risk of complications and the risk of oral diseases increased with patients’ age (p

(1) Background: This conceptual paper departs from the background of how Higher Education represents a critical component of the continuation of Western civilisation and culture. Specifically, the paper addresses the knowledge gap of what an emphasis on the outcome/impact does to pedagogy at Western universities. (2) Methods: Methodologically the paper subdivides the educational process into four discrete phases as to reflect upon whom and on what premises the pedagogy happens (teaching, research, funding, and curriculum formation). (3) Research findings: The presented argument suggests that universities can focus on educating students for its own sake or as means to an end. The current impact agenda prioritizes achieving specific goals at the expense of exploratory research, leading to a different definition of research success. This could result in only end-goal-focused individuals being successful and the curriculum being changed to align with their impact ambitions, the unintended consequence being that Higher Education stops being a genuine mechanism for education and instead becomes inadvertent indoctrination. (4) Conclusions: Only by having student benefit as the primary focus of pedagogy (process view) can the inter-generational feedback loop be safeguarded, regardless of how noble other sentiments may appear to be for related practical purposes (end-product view).

Abstract Urbanization and inequalities are two of the major policy themes of our time, intersecting in large cities where social and economic inequalities are particularly pronounced. Large scale street-level images are a source of city-wide visual information and allow for comparative analyses of multiple cities. Computer vision methods based on deep learning applied to street images have been shown to successfully measure inequalities in socioeconomic and environmental features, yet existing work has been within specific geographies and have not looked at how visual environments compare across different cities and countries. In this study, we aim to apply existing methods to understand whether, and to what extent, poor and wealthy groups live in visually similar neighborhoods across cities and countries. We present novel insights on similarity of neighborhoods using street-level images and deep learning methods. We analyzed 7.2 million images from 12 cities in five high-income countries, home to more than 85 million people: Auckland (New Zealand), Sydney (Australia), Toronto and Vancouver (Canada), Atlanta, Boston, Chicago, Los Angeles, New York, San Francisco, and Washington D.C. (United States of America), and London (United Kingdom). Visual features associated with neighborhood disadvantage are more distinct and unique to each city than those associated with affluence. For example, from what is visible from street images, high density poor neighborhoods located near the city center (e.g., in London) are visually distinct from poor suburban neighborhoods characterized by lower density and lower accessibility (e.g., in Atlanta). This suggests that differences between two cities is also driven by historical factors, policies, and local geography. Our results also have implications for image-based measures of inequality in cities especially when trained on data from cities that are visually distinct from target cities. We showed that these are more prone to errors for disadvantaged areas especially when transferring across cities, suggesting more attention needs to be paid to improving methods for capturing heterogeneity in poor environment across cities around the world.

This position paper argues that creative writing can be a fruitful tool for cultural responsiveness in secondary education and calls for creative writing to be viewed as a more natural part of language teachers’ culturally responsive pedagogical repertoire. The integration of creative writing exercises in culturally responsive language arts education may rouse a strengthened voice, benefit cultural literacy, engender the discovery and exploration of individual funds of knowledge, enhance relational competence, and bring about the critical crafting of and engagement with cultural representations. These arguments are convergent with the view that teaching, in order to be culturally responsive, should originate from students’ funds of knowledge, taking both subject content and relational aspects into consideration – and this paper proposes that creative writing is uniquely positioned to facilitate these aims.

Resumo Objetivo: O mindset digital pode ser definido como um conjunto de comportamentos individuais relacionados ao grau de aderência às transformações digitais. Nesse contexto, o objetivo da presente pesquisa foi, após revisão de literatura sobre o tema, responder à seguinte questão: “É possível mensurar o mindset digital de profissionais por meio de uma escala elaborada para o contexto das organizações brasileiras?”. Originalidade/valor: A digitalização das organizações passou a ser o centro da transformação dos negócios. No entanto, um dos fatores muitas vezes negligenciado no processo de transição é o desenvolvimento no nível micro-organizacional. Os profissionais variam no nível de interesse, no conhecimento e na capacidade de inovar. Para guiar o planejamento e desenvolvimento de uma cultura de aprendizagem digital, uma medida para identificar os perfis individuais de mindset digital seria essencial, mas tal ferramenta ainda não era encontrada na literatura brasileira. Design/metodologia/abordagem: A partir da literatura sobre estruturas cognitivas e a transformação digital, foi proposto um construto multidimensional de mindset digital. Elaboraram-se itens para a mensuração do grau de maturidade do construto, descrito por meio de três perfis digitais (open mind, transformador e empreendedor) e um analógico. A escala foi submetida a 574 profissionais de empresas brasileiras para análise fatorial exploratória. Resultados: A escala de mindset digital apresentou bons indícios de validade, sendo confirmadas, na presente amostra, as dimensões de mindset relacionadas ao meio digital (alfas de Cronbach entre 0,85 e 0,62). / Abstract Purpose: The digital mindset can be defined as a set of individual behaviors related to the degree of adherence to digital transformations. After reviewing the literature on the subject, this research’s objective was to answer the following question: “Is it possible to measure the digital mindset of employees through a scale designed for the context of Brazilian organizations?”. Originality/value: The digitization of organizations has become the center of business transformation. However, one of the often-overlooked factors in the transition process is developed at the micro-organizational level. Collaborators vary in interest, knowledge, and ability to innovate. A measure to identify individual digital mindset profiles would be essential to guide the planning and development of a digital learning culture mindset. Still, such a tool was not yet found in the Brazilian literature. Design/methodology/approach: A multidimensional digital mindset construct was proposed based on the literature on cognitive structures and digital transformation mindset. Items were prepared to measure the degree of maturity of the construct, described through three digital profiles (open mind, transformer, and entrepreneur) and an analog profile. The scale was submitted to 574 professionals from Brazilian companies for exploratory factor analysis. Findings: The digital mindset scale showed signs of validity, confirming, in the present sample, the mindset dimensions related to the digital environment (Cronbach’s alphas between 0.85 and 0.62).

BackgroundDigital media-use disorders (DMUD) in adolescents are a rising phenomenon associated with psychological distress, comorbid mental disorders, and high burden on affected families. Since the ICD-11 introduced criteria for gaming disorder, these can now be transferred to describe additional DMUD associated with social media platforms and streaming services. Most evidence for effective treatments comes from cognitive-behavioral therapy (CBT). However, interventions based on theoretical models for adolescents and their parents are widely missing, leading to a significant clinical gap.MethodsRes@t digital (Resource-Strengthening Training for Adolescents with Problematic Digital-Media Use and their Parents) is the app-based translation of the first model-based digital intervention for adolescents with DMUD and their parents based on CBT. It comprises separate but content-related modules for adolescents (Res@t–A) and parents (Res@t–P), applying multimodal techniques. The effectiveness of Res@t will be evaluated within a multicenter cluster-randomized controlled evaluator-blinded pre–post follow-up trial with the waitlist control group (CG). In addition to the Res@t program in the intervention group, both groups will receive treatment as usual within primary child and adolescent psychiatric/psychotherapeutic healthcare. The primary outcome addresses DMUD symptom reduction after 10 weeks. Secondary outcomes are related to a reduction in psychological and family-related problems and an increase in parental self-efficacy. All outcomes will be assessed using standardized self-report measures. A total of 1,334 participating adolescent–parent dyads from a large clinical network throughout Germany are planned to be included in the primary analyses based on an intention-to-treat approach, applying linear mixed models.DiscussionAssuming superiority of Res@t over the control condition, the intervention has the potential to provide evidence-based treatment for a significant number of help-seeking families, supporting local healthcare structures and resources. It is a promising program for practicable implementation and flexible use in different settings.Clinical trial registrationhttps://drks.de, DRKS00031043.

Abstract Collaborative approaches to conservation management are critical to respond to the ongoing biodiversity crisis. However, local community involvement in many conservation actions is lacking, especially within translocation and reintroduction programs. Similarly, rapid integration of genetic information into collaborative programs with local communities is rarely conducted. Here, we describe a community‐based and collaborative reintroduction program for a threatened Australian freshwater fish, the southern pygmy perch (Nannoperca australis). We integrate on‐the‐ground translocation efforts by volunteers from local communities, captive breeding by a private aquarium business, and genetic analyses done by a research institution to provide a holistic framework for the reintroduction of southern pygmy perch. We evaluated genetic diversity, population structure, relatedness, and inbreeding across the duration of the reintroduction program using data from neutral and adaptive genomic markers. This allowed us to assess the ability of such a program to minimize inbreeding and retain genomic variation, and to promote adaptive potential of the reintroduced population. While genetic variation for the source populations was very low, we found no decrease in genetic diversity or increase in inbreeding across the program. These genetic findings support the efforts made by local communities and will further inform future reintroductions as part of a collaborative conservation framework. We expand on our empirical case study by describing a theoretical framework for integrating conservation genomics research with community‐led conservation management programs and identifying the benefits of such a collaboration. Our study highlights the importance of multifaceted and integrated conservation management approaches to effectively protect and manage threatened species.

As visible and knowledgeable experts who constantly collect, analyze and disseminate information about the future prospects of publicly listed firms, financial analysts fulfill an important information brokerage and monitoring function for investors. By providing investment advice, financial analysts also influence the demand for a firm’s stock and thus its price. Executives pay close attention to financial analysts’ earnings forecasts and recommendations, so much so that they are frequently criticized for excessive focus on their forecasts at the expense of the long-term interests of the firm. But while research on analysts in strategic management is steadily growing, we lack a coherent understanding of the extent and nature of analysts’ diverse influences on executives’ and investors’ decision-making, and the context in which analysts operate. This is largely due to the fragmentation of the literature and the absence of prior reviews or meta-analyses of the topic. By organizing, synthesizing and analyzing extant research efforts on analysts in the various domains of strategic management research, we aim to advance our knowledge on the influence of analysts on firms and investors. Further, we hope that our analyses and recommendations help further increase research coverage on this important organizational stakeholder.

Historically, efforts to improve academic climate have been siloed-many efforts involve the collection of data to understand issues affecting diversity at an institutional level, while others prioritize recruitment and retention of historically marginalized groups. Few initiatives, however, effectively combine the two in order to create concrete action plans to eliminate structural barriers that hinder the retention of minorities in STEM. In this Editorial, we present the history and details of a collaborative effort to improve the academic climate of the Department of Chemistry at University of California, Berkeley. This initiative began in 2016 as a graduate student-led, grassroots movement to develop a method to assess the department's academic climate. Over the past several years-and with support from stakeholders at all levels-it has grown into a department-wide effort to systematically collect data, exchange ideas, and implement goal-oriented interventions to make our academic community more inclusive. With the recent development of a five-year strategic plan and funding increase to provide financial support for student-led programs, we have institutionalized a method to maintain the initiative's momentum. Here, we share our approaches, insights, and perspectives from community members who have shaped this movement. We also provide advice to help other academic communities determine a practical path toward affecting positive cultural change.

Ongoing efforts to improve diversity in science, technology, engineering, and mathematics (STEM) primarily manifest as attempts to recruit more women and individuals from historically marginalized groups. Yet, these efforts fail to repair the specific, systemic issues within academic communities that hinder diverse individuals from persisting and thriving in STEM. Here, we present the results of a quantitative, multiyear effort to make the academic climate of an R1 STEM department more inclusive. We use a student-led, department-specific, faculty-supported initiative to assess and improve the climate of the Department of Chemistry at the University of California, Berkeley, as a case study. Our results provide quantitative evidence that community discussions grounded in our own data, alongside cooperative community efforts to address the issues present in those data, are effective methods for driving positive change. Longitudinal assessment of our academic climate from 2018 to 2020 via annual department-wide surveys indicates that these interventions have succeeded in shifting the perception of our academic climate. This study confirms the positive outcomes of having a practical, sustainable, and data-driven framework for affecting change within a graduate community.

The generalized S-X[superscript 2]-test is a test of item fit for items with polytomous responses format. The test is based on a comparison of the observed and expected number of responses in strata defined by the test score. In this article, we make four contributions. We demonstrate that the performance of the generalized S-X[superscript 2]-test depends on how sparse cells are pooled. We propose alternative implementations of the test within the framework of limited information testing. We derive the distribution of the S-X[superscript 2]-residuals that can be used for post hoc analyses. We suggest a diagnostic plot that visualizes the form of the misfit. The performance of the alternative implementations is investigated in a simulation study. The simulation study suggests that the alternative implementations are capable of controlling the Type-I error rate well and have high power. An empirical application concludes this article.

Mechanistic information about how gaseous ions are formed from charged droplets has been difficult to establish because direct observation of nanodrops in a size range relevant to gaseous macromolecular ion formation by optical or traditional mass spectrometry methods is challenging owing to their small size and heterogeneity. Here, the mass and charge of individual aqueous nanodrops between 1-10 MDa (15-32 nm diameter) with ∼50-300 charges are dynamically monitored for 1 s using charge detection mass spectrometry. Discrete losses of minimally solvated singly charged ions occur, marking the first direct observation of ion emission from aqueous nanodrops in late stages of droplet evaporation relevant to macromolecular ion formation in native mass spectrometry. Nanodrop charge depends on the identity of constituent ions, with pure water nanodrops charged slightly above the Rayleigh limit and aqueous solutions containing alkali metal ions charged progressively below the Rayleigh limit with increasing cation size. MS2 capsid ions (∼3.5 MDa; ∼27 nm diameter) are more highly charged from aqueous ammonium acetate than from its biochemically preferred, 100 mM NaCl/10 mM Na phosphate solution, consistent with ion emission reducing the nanodrop and resulting capsid charge. The extent of charging indicates that the capsid partially collapses inside the nanodrops prior to the charging and formation of the dehydrated gaseous ions. These results demonstrate that ion emission can affect macromolecular charging and that conformational changes to macromolecular structure can occur in nanodrops prior to the formation of naked gaseous ions.

Gelotophobia (the fear of being laughed at) is an individual difference variable that relates to a particular set of emotional reactions, behaviors, and processes towards laughter and ridicule that are potentially detrimental to learning processes. We extend the research of gelotophobia to the educational domain by exploring the direct effect of gelotophobia on willingness to communicate (WTC) and second-language (L2) achievement. We hypothesized that communication anxiety might have an indirect effect on the relation between gelotophobia and WTC and L2 achievement. A sample of 483 Iranian high school students completed measures of gelotophobia, WTC, and communication anxiety. The results of structural equation modeling indicated that gelotophobia was negatively related to both L2 achievement and WTC. Further, communication anxiety showed the expected indirect effect on the gelotophobia-WTC association. Finally, we incorporated teacher-ratings of students' gelotophobia and found that (a) the accuracy of teachers' impressions was comparatively low and (b) that higher accuracy was associated with better L2 achievement. We argue that because of fear of anticipated derision in performance situations such as speaking an L2, gelotophobic L2 learners might adopt a withdrawal strategy by avoiding the social situation altogether. Hence, L2 teachers should be aware that not all students enjoy humor and laughter, and they are recommended to use humor judiciously without laughing at students, and to adapt to students' engagement and perceptions of laughter., Author(s): Elyas Barabadi [sup.1] , Kay Brauer [sup.2] , René T. Proyer [sup.2] , Mohsen Rahmani Tabar [sup.1] Author Affiliations: (1) grid.488432.1, 0000 0004 5935 1577, University of Bojnord, , [...]

Abstract Transcranial Direct Current Stimulation (tDCS) is a non-invasive neuromodulation technique with a wide variety of clinical and research applications. As increasingly acknowledged, its effectiveness is subject dependent, which may lead to time consuming and cost ineffective treatment development phases. We propose the combination of electroencephalography (EEG) and unsupervised learning for the stratification and prediction of individual responses to tDCS. A randomized, sham-controlled, double-blind crossover study design was conducted within a clinical trial for the development of pediatric treatments based on tDCS. The tDCS stimulation (sham and active) was applied either in the left dorsolateral prefrontal cortex or in the right inferior frontal gyrus. Following the stimulation session, participants performed 3 cognitive tasks to assess the response to the intervention: the Flanker Task, N-Back Task and Continuous Performance Test (CPT). We used data from 56 healthy children and adolescents to implement an unsupervised clustering approach that stratify participants based on their resting-state EEG spectral features before the tDCS intervention. We then applied a correlational analysis to characterize the clusters of EEG profiles in terms of participant’s difference in the behavioral outcome (accuracy and response time) of the cognitive tasks when performed after a tDCS-sham or a tDCS-active session. Better behavioral performance following the active tDCS session compared to the sham tDCS session is considered a positive intervention response, whilst the reverse is considered a negative one. Optimal results in terms of validity measures was obtained for 4 clusters. These results show that specific EEG-based digital phenotypes can be associated to particular responses. While one cluster presents neurotypical EEG activity, the remaining clusters present non-typical EEG characteristics, which seem to be associated with a positive response. Findings suggest that unsupervised machine learning can be successfully used to stratify and eventually predict responses of individuals to a tDCS treatment.

Abstract The utility of spatial immunobiomarker quantitation in prognostication and therapeutic prediction is actively being investigated in triple-negative breast cancer (TNBC). Here, with high-plex quantitative digital spatial profiling, we map and quantitate intraepithelial and adjacent stromal tumor immune protein microenvironments in systemic treatment-naïve (female only) TNBC to assess the spatial context in immunobiomarker-based prediction of outcome. Immune protein profiles of CD45-rich and CD68-rich stromal microenvironments differ significantly. While they typically mirror adjacent, intraepithelial microenvironments, this is not uniformly true. In two TNBC cohorts, intraepithelial CD40 or HLA-DR enrichment associates with better outcomes, independently of stromal immune protein profiles or stromal TILs and other established prognostic variables. In contrast, intraepithelial or stromal microenvironment enrichment with IDO1 associates with improved survival irrespective of its spatial location. Antigen-presenting and T-cell activation states are inferred from eigenprotein scores. Such scores within the intraepithelial compartment interact with PD-L1 and IDO1 in ways that suggest prognostic and/or therapeutic potential. This characterization of the intrinsic spatial immunobiology of treatment-naïve TNBC highlights the importance of spatial microenvironments for biomarker quantitation to resolve intrinsic prognostic and predictive immune features and ultimately inform therapeutic strategies for clinically actionable immune biomarkers.

BACKGROUND: Studies across the globe generally reported increased mortality risks associated with particulate matter with aerodynamic diameter [less than or equal to]2.5 [micro]m (P[M.sub.2.5]) exposure with large heterogeneity in the magnitude of reported associations and the shape of concentration-response functions (CRFs). We aimed to evaluate the impact of key study design factors (including confounders, applied exposure model, population age, and outcome definition) on P[M.sub.2.5] effect estimates by harmonizing analyses on three previously published large studies in Canada [Mortality-Air Pollution Associations in Low Exposure Environments (MAPLE), 1991-2016], the United States (Medicare, 2000-2016), and Europe [Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE), 2000-2016] as much as possible. METHODS: We harmonized the study populations to individuals 65+ years of age, applied the same satellite-derived P[M.sub.2.5] exposure estimates, and selected the same sets of potential confounders and the same outcome. We evaluated whether differences in previously published effect estimates across cohorts were reduced after harmonization among these factors. Additional analyses were conducted to assess the influence of key design features on estimated risks, including adjusted covariates and exposure assessment method. A combined CRF was assessed with meta-analysis based on the extended shape-constrained health impact function (eSCHIF). RESULTS: More than 81 million participants were included, contributing 692 million person-years of follow-up. Hazard ratios and 95% confidence intervals (CIs) for all-cause mortality associated with a 5-[micro]g/[m.sup.3] increase in P[M.sub.2.5] were 1.039 (1.032, 1.046) in MAPLE, 1.025 (1.021, 1.029) in Medicare, and 1.041 (1.014, 1.069) in ELAPSE. Applying a harmonized analytical approach marginally reduced difference in the observed associations across the three studies. Magnitude of the association was affected by the adjusted covariates, exposure assessment methodology, age of the population, and marginally by outcome definition. Shape of the CRFs differed across cohorts but generally showed associations down to the lowest observed P[M.sub.2.5] levels. A common CRF suggested a monotonically increased risk down to the lowest exposure level. https://doi.org/10.1289/EHP12141, Introduction Ambient particulate matter (PM) pollution has been identified as a leading risk factor for global disease burden. (1) Evaluating the risks attributable to PM with aerodynamic diameter [less than [...]