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The de novo design of small molecule-binding proteins has seen exciting recent progress; however, high-affinity binding and tunable specificity typically require laborious screening and optimization after computational design. We developed a computational procedure to design a protein that recognizes a common pharmacophore in a series of poly(ADP-ribose) polymerase-1 inhibitors. One of three designed proteins bound different inhibitors with affinities ranging from

The continual emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) poses a major challenge to vaccines and antiviral therapeutics due to their extensive evasion of immunity. Aiming to develop potent and broad-spectrum anticoronavirus inhibitors, we generated A1-(GGGGS)7-HR2m (A1L35HR2m) by introducing an angiotensin-converting enzyme 2 (ACE2)-derived peptide A1 to the N terminus of the viral HR2-derived peptide HR2m through a long flexible linker, which showed significantly improved antiviral activity. Further cholesterol (Chol) modification at the C terminus of A1L35HR2m greatly enhanced the inhibitory activities against SARS-CoV-2, SARS-CoV-2 VOCs, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV) pseudoviruses, with IC50 values ranging from 0.16 to 5.53 nM. A1L35HR2m-Chol also potently inhibits spike-protein-mediated cell-cell fusion and the replication of authentic Omicron BA.2.12.1, BA.5, and EG.5.1. Importantly, A1L35HR2m-Chol distributed widely in respiratory tract tissue and had a long half-life (>10 h) in vivo. Intranasal administration of A1L35HR2m-Chol to K18-hACE2 transgenic mice potently inhibited Omicron BA.5 and EG.5.1 infection both prophylactically and therapeutically.

Cyber-wisdom is the ability to know and do the right thing at the right time, when using digital technologies, and is a concept that is gaining attention from educators. Whilst the theory and practice of cyber-wisdom education is established, to date there has been no attempt to investigate how the virtue of cyber-wisdom might be measured. This is a lacuna as it limits future research in the area, including, in particular, proximal evaluations of cyber-wisdom interventions. This article introduces a new four-component measure of cyber-wisdom, which is relevant to how the virtue may be cultivated in practice via formal education and the teaching of what is generally referred to as digital citizenship education. The measure was piloted with 1,331 13--16 year-olds. The findings provide initial evidence that cyber-wisdom literacy, reasoning, reflection, and motivation can be measured. This study provides preliminary validation of cyber-wisdom sub-measures that might be used in evaluations of educational interventions that seek to help children and adolescents live with wisdom in the digital age.

Evidence to date indicates that compassion and empathy are health-enhancing qualities. Research points to interventions and practices involving compassion and empathy being beneficial, as well as being salient outcomes of contemplative practices such as mindfulness. Advancing the science of compassion and empathy requires that we select measures best suited to evaluating effectiveness of training and answering research questions. The objective of this scoping review was to 1) determine what instruments are currently available for measuring empathy and compassion, 2) assess how and to what extent they have been validated, and 3) provide an online tool to assist researchers and program evaluators in selecting appropriate measures for their settings and populations. A scoping review and broad evidence map were employed to systematically search and present an overview of the large and diverse body of literature pertaining to measuring compassion and empathy. A search string yielded 19,446 articles, and screening resulted in 559 measure development or validation articles reporting on 503 measures focusing on or containing subscales designed to measure empathy and/or compassion. For each measure, we identified the type of measure, construct being measured, in what context or population it was validated, response set, sample items, and how many different types of psychometrics had been assessed for that measure. We provide tables summarizing these data, as well as an open-source online interactive data visualization allowing viewers to search for measures of empathy and compassion, review their basic qualities, and access original citations containing more detail. Finally, we provide a rubric to help readers determine which measure(s) might best fit their context.

There is a dearth of studies exploring how younger children engage in civic life, what may be expected of them given their age, and what instruments may be used to capture their levels of civic engagement. Addressing these questions, this article presents key findings from a pilot study that aimed to create a validated instrument designed to measure the civic engagement of primary school children. Based on a survey administered to 655 primary school children aged 9-11 across England, this article focuses on the new measure that was specifically designed, and then tested and validated through both exploratory and confirmatory analyses. The findings validate a tripartite measure of civic engagement that assesses the civic attitudes, actions and awareness of 9-11-year-olds. This measure was found to be both practical and efficient in its administration, and it has been shown to be easily comprehensible by this age group. This new measure addresses an important gap in the literature on civic engagement in children, providing researchers with a validated tool to effectively measure civic engagement in 9-11-year-olds. The findings have implications for both researchers and educators interested in designing and evaluating interventions aimed at promoting civic engagement among younger children.

Pestalotioid fungi were isolated in pure culture from symptomatic plants of Callistemon laevis, C. viminalis, Luma apiculata (marketed as “Myrtus luma”), Myrtus communis subsp. tarentina, and M. communis var. microphylla (M. communis ’Microphylla’), showing twig canker, dieback and defoliation. The isolates were identified to species by ITS, tef1 and tub2 sequences, which revealed the presence of six species of Neopestalotiopsis (N. camelliae-oleiferae, N. hispanica, N. iberica, N. rosae, N. rosicola, and N. zakeelii) and one species of Pestalotiopsis (P. biciliata). While most species were isolated only once or twice, the majority of isolates belonged to N. rosae (13) and N. hispanica (8). Pathogenicity was investigated by pathogenicity tests on all hosts, which confirmed the pathogenicity of all Neopestalotiopsis species on at least some of the hosts tested, while P. biciliata did not cause any disease symptoms. Neopestalotiopsis hispanica and N. rosae caused symptoms in all hosts of the present study, while the other Neopestalotiopsis species tested showed no symptoms on Luma apiculata.

Objective: Self-report symptom inventories are commonly used in adult ADHD assessment, and research indicates they should be interpreted with caution. This study investigated one self-report symptom inventory for adult ADHD in a clinical sample. Method: Archival data were used to evaluate diagnostic utility of the Conners Adult ADHD Rating Scale--Self-Report: Long Version (CAARS-S:L) in a sample of 122 adults seeking ADHD assessment. Results: Overall, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) estimates for the ADHD Index and other CAARS-S:L scales demonstrated weak accuracy. Anxiety and depression were the most common diagnoses present when a false positive on the ADHD Index was observed. PPV and specificity for the ADHD Index were higher in males compared to females. Conclusion: The CAARS-S:L may be useful for screening purposes in some cases, but should not be the main method used for diagnostic purposes. Clinical implications of findings are discussed.

The promise of community benefit from health data linked at scale is often missing the perspective of communities themselves. This paper outlines a recent project on developing a peer research and public engagement methodology to build community-designed linked and open wellbeing data hubs. Drawing on action research and appreciative inquiry, we aimed to develop a novel method to engage community on the use of linked local data. In Spring 2023 we recruited and trained 15 community researchers in Widnes, UK to co-design and run a project on what feeling well meant for their community. We trained our community researchers in listening skills, methods, and data concepts. Over Summer 2023, they interviewed over 200 of their fellow residents. We then ran three design workshops to analyse their findings and co-design a data and community insights hub with local policymakers and voluntary sector representatives. Through repeated, comparative semi-structured interviews we tracked the community researchers’ progress. We used thematic analysis to explore the benefits and challenges at each stage of the project: recruitment, training, and field work. Benefits ranged from the practical value of capacity building through the research training to the key role of confidence in how community researchers perceived their own success during the project. Challenges ranged from more esoteric concepts like managing expectations of impact to practical concerns around diversity and interview recruitment. Overall, the project evidenced the value of peer research methodologies in involving public in data science both for the participants but also to wider community.

BackgroundIn obstructive hypertrophic cardiomyopathy (HOCM), disopyramide is used in patients who remain symptomatic despite β-blockers or verapamil. However, effectiveness of disopyramide therapy has not been clearly established due to inconsistent definition of responders and the insufficient length of follow-ups reported in literature. To address these shortcomings, we have conducted a retrospective analysis from detailed databases with long follow-up, from two HCM Referral Centers.Methods62 symptomatic HOCM patients (43% women, age 52 ± 14 years) with left ventricular (LV) outflow tract gradient (LVOTG) ≥ 50 mmHg at rest or during provocation, were recruited from two Italian Centers. Disopyramide was added as second-line therapy in the patients in whom symptoms persisted despite classic pharmacologic treatment. Patients in NYHA class > II at baseline who reached NYHA class II or I, and patients in NYHA class II at baseline who reached NYHA class I or symptoms stabilization were defined as responders.ResultsAt follow-up, (mean 4.4 years, IQR 1.1–6.6 years), 47 patients (76%) were responders, whereas 15 (24%) were no-responders. Responders showed larger LV diastolic volume index (LVEDVi) at baseline as compared to no-responders (61 ± 14 vs. 49 ± 16 ml, respectively, p = 0.018), and, at follow-up, reached lower LVOTG than no-responders (43 ± 32 vs. 66 ± 28 mmHg, respectively, p = 0.013), with a LVOTG

Abstract Quantitative computed tomography (QCT)-based in silico models have demonstrated improved accuracy in predicting hip fractures with respect to the current gold standard, the areal bone mineral density. These models require that the femur bone is segmented as a first step. This task can be challenging, and in fact, it is often almost fully manual, which is time-consuming, operator-dependent, and hard to reproduce. This work proposes a semi-automated procedure for femur bone segmentation from CT images. The proposed procedure is based on the bone and joint enhancement filter and graph-cut algorithms. The semi-automated procedure performances were assessed on 10 subjects through comparison with the standard manual segmentation. Metrics based on the femur geometries and the risk of fracture assessed in silico resulting from the two segmentation procedures were considered. The average Hausdorff distance (0.03 ± 0.01 mm) and the difference union ratio (0.06 ± 0.02) metrics computed between the manual and semi-automated segmentations were significantly higher than those computed within the manual segmentations (0.01 ± 0.01 mm and 0.03 ± 0.02). Besides, a blind qualitative evaluation revealed that the semi-automated procedure was significantly superior (p

Abstract Did cultures change shortly after, and in response to, the COVID-19 outbreak? If so, then in what way? We study these questions for a set of macro-cultural dimensions: collectivism/individualism, duty/joy, traditionalism/autonomy, and pro-fertility/individual-choice norms. We also study specific perceptions and norms like perceived threats to society (e.g. immigration) and hygiene norms. We draw on Evolutionary Modernization Theory, Parasite Stress Theory, and the Behavioural Immune System, and existing evidence, to make an overarching prediction: the COVID-19 pandemic should increase collectivism, duty, traditionalism, conformity (i.e. pro-fertility), and outgroup prejudice. We derive specific hypotheses from this prediction and use survey data from 29,761 respondents, in 55 cities and 43 countries, collected before (April–December 2019) and recently after the emergence of COVID-19 (March–July 2020) to test them. We exploit variation in disease intensity across regions to test potential mechanisms behind any changes. The macro-cultural dimensions remained stable. In contrast, specific perceptions and norms related to the pandemic changed: norms of hygiene substantially increased as did perceived threats related to disease. Taken together, our findings imply that macro-cultural dimensions are primarily stable while specific perceptions and norms, particularly those related to the pandemic, can change rapidly. Our findings provide new evidence for theories of cultural change and have implications for policy, public health, daily life, and future trajectories of our societies.

Abstract The immediate, direct effects of the COVID-19 pandemic on the United States population are substantial. Millions of people were affected by the pandemic: many died, others did not give birth, and still others could not migrate. Research that has examined these individual phenomena is important, but fragmented. The disruption of mortality, fertility, and migration jointly affected U.S. population counts and, consequently, future population structure. We use data from the United Nations World Population Prospects and the cohort component projection method to isolate the effect of the pandemic on U.S. population estimates until 2060. If the pandemic had not occurred, we project that the population of the U.S. would have 2.1 million (0.63%) more people in 2025, and 1.7 million (0.44%) more people in 2060. Pandemic-induced migration changes are projected to have a larger long-term effect on future population size than mortality, despite comparable short-term effects.

Abstract Neuromodulation by means of vagus nerve stimulation (VNS) therapy, reduces seizure frequency and improves quality of life in subjects with drug‐resistant epilepsy (DRE), yet its molecular mechanism remains unclear. This study investigates the impact of chronic VNS on lipid bioactive metabolites and fatty acids (FA) in the plasma and red blood cells of seven subjects with DRE. By measuring expression levels of peroxisome proliferator‐activated receptor α (PPARα) and sirtuin1 (SIRT1) genes—key regulators in energy and lipid metabolism—and lipid profiles before and after various stages of VNS, this study identifies potential mechanisms by which VNS may reduce seizure frequency. Blood samples collected before VNS device implantation, after acute VNS stimulus, and following gradual intensity increments up to therapeutic levels revealed that VNS increases SIRT1 and PPARα expression and erythrocyte concentrations of PPARα ligands. Additionally, we observe reduced de novo lipogenesis biomarkers in erythrocytes, indicating that VNS may influence systemic lipid and energy metabolism. Our findings suggest that VNS could enhance neuronal function by modulating energy metabolism, thus potentially reducing seizure frequency in subjects with DRE. Future research targeting SIRT1 and PPARα may provide innovative therapeutic strategies for managing DRE. Plain Language Summary: The exact mechanism of VNS is still unknown. This study investigated the effects of VNS Therapy on energetic metabolism, suggesting possible novel biomarkers for DRE subjects and neuromodulation therapies.

BackgroundHeterogeneous mental health outcomes during the COVID-19 pandemic are documented in the general population. Such heterogeneity has not been systematically assessed in youth with autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDD). To identify distinct patterns of the pandemic impact and their predictors in ASD/NDD youth, we focused on pandemic-related changes in symptoms and access to services.MethodsUsing a naturalistic observational design, we assessed parent responses on the Coronavirus Health and Impact Survey Initiative (CRISIS) Adapted For Autism and Related neurodevelopmental conditions (AFAR). Cross-sectional AFAR data were aggregated across 14 European and North American sites yielding a clinically well-characterized sample of N = 1275 individuals with ASD/NDD (age = 11.0 ± 3.6 years; n females = 277). To identify subgroups with differential outcomes, we applied hierarchical clustering across eleven variables measuring changes in symptoms and access to services. Then, random forest classification assessed the importance of socio-demographics, pre-pandemic service rates, clinical severity of ASD-associated symptoms, and COVID-19 pandemic experiences/environments in predicting the outcome subgroups.ResultsClustering revealed four subgroups. One subgroup-broad symptom worsening only (20%)-included youth with worsening across a range of symptoms but with service disruptions similar to the average of the aggregate sample. The other three subgroups were, relatively, clinically stable but differed in service access: primarily modified services (23%), primarily lost services (6%), and average services/symptom changes (53%). Distinct combinations of a set of pre-pandemic services, pandemic environment (e.g., COVID-19 new cases, restrictions), experiences (e.g., COVID-19 Worries), and age predicted each outcome subgroup.LimitationsNotable limitations of the study are its cross-sectional nature and focus on the first six months of the pandemic.ConclusionsConcomitantly assessing variation in changes of symptoms and service access during the first phase of the pandemic revealed differential outcome profiles in ASD/NDD youth. Subgroups were characterized by distinct prediction patterns across a set of pre- and pandemic-related experiences/contexts. Results may inform recovery efforts and preparedness in future crises; they also underscore the critical value of international data-sharing and collaborations to address the needs of those most vulnerable in times of crisis.

Educationalists', researchers', and policy makers' work on children's digital resilience has marginalised the role of the broader context within which digital resilience is constituted, experienced and derived. We aimed to address this lacuna by exploring how pre-teen's digital resilience operates as a dynamic socio-ecological process. Addressing this aim, we employed participatory methods and thematically analysed eight focus groups with children aged 8-12 years (n = 59) and 20 telephone interviews with parents/carers and teachers of 8-12-year-olds and internet safety experts to examine this issue. We used purposive sampling and collected data over three months (January-March 2020). Our analysis constructed a matrix of main themes, constituent, and cross-cutting sub-themes. By placing this within a socio-ecological framework, we illustrate how pre-teens' digital resilience operates within and across differing four levels (individual, home, community and societal) and four domains (learning, recognising, managing, and recovery). The paper advances the literature by illustrating how children can be supported to build and show digital resilience within and across different levels and domains. It is argued that digital resilience should be re-conceptualised as a collective endeavour involving children at an individual level, parents/carers within home environments, youth workers, civil society, teachers, and schools at a community level, along with governments, policymakers, and the education system and internet corporations at a societal level. We conclude by providing practice and research recommendations guiding those supporting children to facilitate opportunities to thrive online.

IntroductionLong COVID involves debilitating symptoms, many of which mirror those observed with dysautonomia, and care must be taken with rehabilitation for autonomic dysfunction to avoid post-exertional malaise/post-exertional symptom exacerbation. Resonant breathing (breathing slowly at a defined rate of breaths per minute) requires less exertion and can potentially improve autonomic function. The objective of this work was to report on the impact of a resonant breathing program on self-reported symptoms and wellbeing in people with Long COVID.MethodsA retrospective analysis of de-identified data was completed in a convenience sample of people with Long COVID, who participated in the Meo Health (formerly known as Stasis HP) resonant breathing program. Participants completed baseline and follow up surveys.ResultsData were available for 99 participants. Most measures of symptoms and wellbeing improved at follow up, with the largest differences per participant seen in sense of wellness (47.3%, p

Una delle questioni emerse nel corso della 18° Legislatura italiana riguarda il ruolo delle associazioni dei magistrati nel processo di conferimento degli incarichi direttivi e semidirettivi. È opinione diffusa che il modello emerso dalle riforme del periodo 2005-2007 abbia favorito forme di carrierismo interne alla magistratura, lontane dal modello delineato dalla Costituzione del 1948. L’articolo analizza gli snodi problematici della disciplina delle nomine giudiziarie “prima” e “dopo” la l. n. 71 del 2022. Nelle conclusioni presenta una proposta, de iure condendo, che mira a insignire le associazioni dei magistrati di un ruolo formale nel procedimento di conferimento degli incarichi dirigenziali.

Purpose: Standardization of x-ray cabinet irradiator dose, geometry, and calibration reporting is an ongoing process. Multi-tube designs have been introduced into the preclinical market and give a theoretical benefit but have not been widely assessed for use in preclinical irradiation conditions. The aim of this study was to report our experience commissioning a dual x-ray source cabinet irradiator (CIXD, Xstrahl Limited, United Kingdom) and assess the dose distribution for various experimental conditions. Methods and Materials: Half-value layer (HVL) measurement, profile measurements, and output calibration were performed using a calibrated ion chamber. Constancy measurements were performed twice daily over 2 weeks to assess output fluctuations. Film measurements were completed using solid water to assess percent depth dose and homogeneity within the field and within variable thicknesses of solid water and phosphate-buffered saline solution. Film measurements were repeated for various arrangements of petri dishes filled with phosphate-buffered saline or water and in a 3D-printed mouse phantom. Results: The x-ray tubes had a measured in-air output of 1.27 Gy/min. The HVL was 1.7 mm Cu. The upper and lower tubes both exhibited the heel effect, but when operated simultaneously, the effect was reduced. Ion chamber measurements revealed a 15% dose inhomogeneity within the tray area (18 × 18 cm2). Film measurements in the petri dishes indicated minor nonuniformities in the arrangements of the experimental apparatus. Measurements from the mouse phantom with film agreed with ion chamber measurements for various phantom placements and orientations. Conclusions: X-ray cell culture and animal irradiation with dual tube cabinet irradiation is efficient and robust when using established dosimetric tools to confirm output and homogeneity. The conditions assumed for calibrations are often not maintained during experiments. We have confirmed that inhomogeneities are present for single-tube use; however, they are reduced with simultaneous tube use. Additional dosimetric monitoring should be performed for each unique irradiation setup.

Human Papilloma Virus (HPV) is considered one of the most common sexually transmitted infections and has been shown to play an important role in the pathogenesis of squamous cell carcinomas (SCC) of the cervix and head and neck. Manifestations of HPV infections can be manifold, ranging from asymptomatic infections to benign or potentially malignant lesions to intraepithelial neoplasms and invasive carcinomas. The heterogeneity of clinical manifestations from HPV infection depends on the interactions between the viral agent and the host, a direct consequence of the ability on the part of HPV is to remain silent and to evade and convey the action of the host immune system. The oral mucosa represents one of the tissues for which HPV has a distinct tropism and is frequently affected by infection. While much information is available on the role that HPV infection plays in the development of SCC in the oral cavity, there is less information on asymptomatic infections and benign HPV-induced oral lesions. Therefore, the purpose of this review is to analyze, in light of current knowledge, the early clinical and bio-humoral prognostic features related to the risk of HPV malignant transformation, focusing on subclinical conditions, benign lesions, and the correlation between oral infection and infection in other districts. The data show that the main risk associated with HPV infection is related to malignant transformation of lesions. Although HPV-driven OPSCC is associated with a better prognosis than non-HPV-driven OPSCC, primary prevention and early detection of the infection and affected genotype are essential to reduce the risk of malignant neoplastic complications and improve the prognosis.

Abstract FGF19 hormone has pleiotropic metabolic functions, including the modulation of insulin sensitivity, glucose/lipid metabolism and energy homeostasis. On top of its physiological metabolic role, FGF19 has been identified as a potentially targetable oncogenic driver, notably in hepatocellular carcinoma (HCC). Nevertheless, FGF19 remained an attractive candidate for treatment of metabolic disease, prompting the development of analogs uncoupling its metabolic and tumor-promoting activities. Using pre-clinical mice models of somatic mutation driven HCC, we assessed the oncogenicity of FGF19 in combination with frequent HCC tumorigenic alterations: p53 inactivation, CTNNB1 mutation, CCND1 or MYC overexpression. Our data revealed a strong oncogenic cooperation between FGF19 and MYC. Most importantly, we show that this oncogenic synergy is conserved with a FGF19-analog Aldafermin (NGM282), designed to solely mimic the hormone’s metabolic functions. In particular, even a short systemic treatment with recombinant proteins triggered rapid appearance of proliferative foci of MYC-expressing hepatocytes. The fact that FGF19 analog Aldafermin is not fully devoid of the hormone’s oncogenic properties raises concerns in the context of its potential use for patients with damaged, mutation-prone liver.