Discovery of a cell-active chikungunya virus nsP2 protease inhibitor using a covalent fragment-based screening approach.

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has been responsible for numerous large-scale outbreaks in the last twenty years. Currently, there are no FDA-approved therapeutics for any alphavirus infection. CHIKV non-structural protein 2 (nsP2), which contains a cysteine protease domain, is essential for viral replication, making it an attractive target for a drug discovery campaign. Here, we optimized a CHIKV nsP2 protease (nsP2pro) biochemical assay for the screening of a 6,120-compound cysteine-directed covalent fragment library. Using a 50% inhibition threshold, we identified 153 hits (2.5% hit rate). In dose-response follow up, RA-0002034, a covalent fragment that contains a vinyl sulfone warhead, inhibited CHIKV nsP2pro with an IC 50 of 58 ± 17 nM, and further analysis with time-dependent inhibition studies yielded a k inact /K I of 6.4 × 10 3 M -1 s -1 . LC-MS/MS analysis determined that RA-0002034 covalently modified the catalytic cysteine in a site-specific manner. Additionally, RA-0002034 showed no significant off-target reactivity against a panel of cysteine proteases. In addition to the potent biochemical inhibition of CHIKV nsP2pro activity and exceptional selectivity, RA-0002034 was tested in cellular models of alphavirus infection and effectively inhibited viral replication of both CHIKV and related alphaviruses. This study highlights the discovery and characterization of the chemical probe RA-0002034 as a promising hit compound from covalent fragment-based screening for future development toward a CHIKV or pan-alphavirus therapeutic. Significance Statement: Chikungunya virus is one of the most prominent and widespread alphaviruses and has caused explosive outbreaks of arthritic disease. Currently, there are no FDA-approved drugs to treat disease caused by chikungunya virus or any other alphavirus-caused infection. Here, we report the discovery of a covalent small molecule inhibitor of chikungunya virus nsP2 protease activity and viral replication of four diverse alphaviruses. This finding highlights the utility of covalent fragment screening for inhibitor discovery and represents a starting point towards the development of alphavirus therapeutics targeting nsP2 protease.

The Prevalence of Financial Conflict of Interest Disclosures by Endovascular Specialists on X (Twitter).

PURPOSE: Evaluate conflicts of interest (COI) among interventional radiologists and related specialties who mention specific devices or companies on the social media (SoMe) platform X, formerly Twitter. MATERIALS & METHODS: 13,809 posts between 10/7/2021 and 12/31/2021 on X were evaluated. Posts by US interventional radiologists and related specialties that mentioned a specific device or company were identified. A positive COI was defined as receiving a payment from the device manufacturer or company within 36 months prior to posting. The CMS Open Payment database was used to identify financial payments. The prevalence and value of COIs were assessed and compared between posts mentioning a device or company and a paired control group using descriptive statistics and chi-squared tests and independent t-tests. RESULTS: Eighty posts containing the mention of 100 specific devices or companies were evaluated. COIs were present in 53% (53/100). When mentioning a specific device or product, 40% interventional radiologists had a COI, neurosurgeons 62%. Physicians who mentioned a specific device or company were 3.7 times more likely to have a positive COI relative to the paired control group (53/100 vs 14/100, p<0.001). Of the 31 physicians with a COI, the median physician received $2,270. None of the positive COIs were disclosed. CONCLUSION: Physicians posting on SoMe about a specific device or company are more likely to have a financial COI than authors of posts not mentioning a specific device or company. No disclosure of any COIs were present in the posts, limiting followers ability to weigh potential bias.

Subjective Causes for Failure to Return to Sport After Anterior Cruciate Ligament Reconstruction: A Systematic Review and Meta-analysis.

CONTEXT: While current literature has explored the outcomes of athletes who return to sport (RTS) after anterior cruciate ligament (ACL) injuries, less is known about the outcomes of those who are unsuccessful in returning to sport. OBJECTIVE: To determine the rate of athletes who did not RTS after primary ACL reconstruction (ACLR) and to identify the specific subjective reasons for failure to RTS. DATA SOURCES: A comprehensive search of the PubMed/MEDLINE, Scopus, and Web of Science databases was conducted through April 2021. STUDY SELECTION: Eligible studies included those explicitly reporting the rate of failure for RTS after ACLR as well as providing details on reasons for athletes' inability to return; 31 studies met the inclusion criteria. STUDY DESIGN: Systematic review and meta-analysis. LEVEL OF EVIDENCE: Level 2 to 4. DATA EXTRACTION: The reasons for failure to RTS referred to in our study are derived from those established previously in the studies included. Data were collected on the number of athletes, mean age, mean follow-up time, type of sport played, failure to RTS rate, and specific reasons for failure to return. RESULTS: The weighted rate of failure to RTS after ACLR was 25.5% (95% CI, 19.88-31.66). The estimated proportion of psychosocial-related reasons cited for failure to RTS was significantly greater than knee-related reasons for failure RTS (55.4% vs 44.6%, P < 0.01). The most cited reason for failure to RTS was fear of reinjury (33.0%). CONCLUSION: This study estimates the rate of failure to RTS after ACLR to be 25.5%, with the majority of athletes citing fear of reinjury as the major deterrent for returning to sports. We highlight how factors independent of surgical outcomes may impact an athlete's ability to return to play given that the predominant reason for no RTS after ACLR was unrelated to the knee.

A meta-analysis of the effect of visiting zoos and aquariums on visitors' conservation knowledge, beliefs, and behavior.

Zoos and aquariums are well placed to connect visitors with the issues facing biodiversity globally and many deliver interventions that seek to influence visitors' beliefs and behaviors with respect to conservation. However, despite primary studies evaluating the effect of such interventions, the overall effect of engaging with zoos and the factors that influence this effect remain unclear. We conducted a systematic review to investigate the effect of zoo-led interventions on knowledge, beliefs (attitudes, intentions, self-efficacy, and social norms), and behavior among zoo visitors. These outcomes were identified using the Theory of Planned Behavior as a theoretical lens. We identified and described the nature of zoo-led interventions in 56 studies and used the behavior change technique (BCT) taxonomy to identify 6 specific BCTs used in interventions to date. Multilevel meta-analyses revealed a small to medium positive effect of engaging with zoo-led interventions on outcomes (d+  = 0.40, 95% confidence interval = 0.28-0.51). Specifically, visitors were more knowledgeable about conservation issues, held more favorable attitudes toward conservation, and reported being more likely to act for the benefit of biodiversity. No evidence of publication bias was present. Effect sizes were, however, heterogeneous and subgroup analyses revealed that the nature of the intervention or type of outcome did not explain this variance. Larger effects were, however, found in studies conducted at a single institution relative to research at multiple institutions and studies that used within-participant designs relative to between-participant designs. Taken together, these findings demonstrate how behavior change frameworks can be used to describe zoo-led interventions and supports the assertion that zoos and aquariums can promote changes in beliefs and behaviors that may help protect biodiversity.

Metaanálisis del efecto de la visita a acuarios y zoológicos sobre el conocimiento, creencias y comportamientos de conservación de los visitantes © 2024 by John Wiley & Sons, Inc. Resumen Los zoológicos y los acuarios están bien posicionados para conectar a los visitantes con temas mundiales de biodiversidad y varios cuentan con intervenciones que buscan influir las creencias y el comportamiento de los visitantes con respecto a la conservación. Sin embargo, con todo y los estudios primarios que evalúan el efecto de dichas intervenciones, aún no está claro el efecto general de participar en los zoológicos y los factores que influyen sobre este efecto. Realizamos una revisión sistemática para investigar el efecto de las intervenciones en los zoológicos sobre el conocimiento, creencias (actitud, intención, autosuficiencia y normas sociales) y comportamiento de sus visitantes. Usamos la teoría del comportamiento planeado como lente teórico para identificar los resultados. Identificamos y describimos la naturaleza de las intervenciones en los zoológicos en 56 estudios y usamos la taxonomía de las técnicas de modificación de conducta (TMC) para identificar seis TMC específicas que se usan hoy en día en dichas intervenciones. Los metaanálisis multinivel revelaron un efecto positivo de pequeño a mediano sobre los resultados causado por la participación en las intervenciones de los zoológicos (d+ = 0.40, 95% CI = 0.28 - 0.51). En específico, los visitantes fueron más conocedores sobre los temas de conservación, tuvieron actitudes más favorables hacia la conservación y reportaron tener mayor probabilidad de actuar en beneficio de la biodiversidad. No hubo evidencias de sesgos en las publicaciones. Sin embargo, el tamaño de los efectos fue heterogéneo y el análisis de los subgrupos reveló que la naturaleza de la intervención o el tipo de resultados no explicaban esta varianza. A pesar de esto, encontramos efectos más grandes en los estudios realizados en una sola institución en relación con la investigación realizada en varias instituciones y los estudios que usaron diseños intraparticipantes en relación a los que usaron diseños interparticipantes. Nuestra revisión demuestra cómo los marcos de modificación conductual pueden usarse para describir las intervenciones en los zoológicos y acuarios y respalda la aseveración de que estas instituciones pueden promover cambios en las creencias y el comportamiento que pueden ayudar a proteger la biodiversidad.

Longitudinal clustering of health behaviours and their association with multimorbidity in older adults in England: A latent class analysis.

BACKGROUND: Health-risk behaviours such as smoking, unhealthy nutrition, alcohol consumption, and physical inactivity (termed SNAP behaviours) are leading risk factors for multimorbidity and tend to cluster (i.e. occur in specific combinations within distinct subpopulations). However, little is known about how these clusters change with age in older adults, and whether and how cluster membership is associated with multimorbidity. METHODS: Repeated measures latent class analysis using data from Waves 4-8 of the English Longitudinal Study of Ageing (ELSA; n = 4759) identified clusters of respondents with common patterns of SNAP behaviours over time. Disease status (from Wave 9) was used to assess disorders of eight body systems, multimorbidity, and complex multimorbidity. Multinomial and binomial logistic regressions were used to examine how clusters were associated with socio-demographic characteristics and disease status. FINDINGS: Seven clusters were identified: Low-risk (13.4%), Low-risk yet inactive (16.8%), Low-risk yet heavy drinkers (11.4%), Abstainer yet inactive (20.0%), Poor diet and inactive (12.9%), Inactive, heavy drinkers (14.5%), and High-risk smokers (10.9%). There was little evidence that these clusters changed with age. People in the clusters characterised by physical inactivity (in combination with other risky behaviours) had lower levels of education and wealth. People in the heavy drinking clusters were predominantly male. Compared to other clusters, people in the Low-risk and Low-risk yet heavy drinkers had a lower prevalence of all health conditions studied. In contrast, the Abstainer but inactive cluster comprised mostly women and had the highest prevalence of multimorbidity, complex multimorbidity, and endocrine disorders. High-risk smokers were most likely to have respiratory disorders. CONCLUSIONS: Health-risk behaviours tend to be stable as people age and so ought to be addressed early. We identified seven clusters of older adults with distinct patterns of behaviour, socio-demographic characteristics and multimorbidity prevalence. Intervention developers could use this information to identify high-risk subpopulations and tailor interventions to their behaviour patterns and socio-demographic profiles.

Random variation drives a critical bias in the comparison of healthcare-associated infections.

OBJECTIVE: To evaluate random effects of volume (patient days or device days) on healthcare-associated infections (HAIs) and the standardized infection ratio (SIR) used to compare hospitals. DESIGN: A longitudinal comparison between publicly reported quarterly data (2014-2020) and volume-based random sampling using 4 HAI types: central-line-associated bloodstream infections, catheter-associated urinary tract infections, Clostridioides difficile infections, methicillin-resistant Staphylococcus aureus infections. METHODS: Using 4,268 hospitals with reported SIRs, we examined relationships of SIRs to volume and compared distributions of SIRs and numbers of reported HAIs to the outcomes of simulated random sampling. We included random expectations into SIR calculations to produce a standardized infection score (SIS). RESULTS: Among hospitals with volumes less than the median, 20%-33% had SIRs of 0, compared to 0.3%-5% for hospitals with volumes higher than the median. Distributions of SIRs were 86%-92% similar to those based on random sampling. Random expectations explained 54%-84% of variation in numbers of HAIs. The use of SIRs led hundreds of hospitals with more infections than either expected at random or predicted by risk-adjusted models to rank better than other hospitals. The SIS mitigated this effect and allowed hospitals of disparate volumes to achieve better scores while decreasing the number of hospitals tied for the best score. CONCLUSIONS: SIRs and numbers of HAIs are strongly influenced by random effects of volume. Mitigating these effects drastically alters rankings for HAI types and may further alter penalty assignments in programs that aim to reduce HAIs and improve quality of care.

Population-based real-world registry study to evaluate clinical outcomes of chronic graft-versus-host disease.

INTRODUCTION: Chronic graft-versus-host disease (cGVHD) is a serious immune-mediated complication after allogeneic haematopoietic stem cell transplantation (HSCT), but in patients with malignancy, cGVHD development is associated with superior survival. Lack of reliable biomarkers and clinical underreporting means there is insufficient understanding of cGVHD clinical outcomes and balance between cGVHD treatment and maintaining beneficial graft-versus-tumour effects. METHODS: We performed a Swedish population-wide registry study following patients who underwent allogeneic HSCT 2006-2015. cGVHD status was retrospectively classified using a real-world method based on the timing and extent of systemic immunosuppressive treatment. RESULTS: cGVHD incidence among patients surviving ≥6 months post-HSCT (n = 1246) was 71.9%, significantly higher than previously reported. 5-year overall survival in patients surviving ≥6 months post-HSCT was 67.7%, 63.3%, and 65.3%, in non-, mild, and moderate-severe cGVHD, respectively. Non-cGVHD patients had a mortality risk almost five-fold higher compared to moderate-severe cGVHD patients 12-months post-HSCT. Moderate-severe cGVHD patients had greater healthcare utilization compared with mild and non cGVHD patients. CONCLUSION: cGVHD incidence was high among HSCT survivors. Non-cGVHD patients had higher mortality during the first 6 months of follow-up; however, moderate-severe cGVHD patients had more comorbidities and healthcare utilization. This study highlights the urgent need for new treatments and real-time methods to monitor effective immunosuppression after HSCT.

Elucidation of the genetic causes of bicuspid aortic valve disease.

AIMS: The present study aims to characterize the genetic risk architecture of bicuspid aortic valve (BAV) disease, the most common congenital heart defect. METHODS AND RESULTS: We carried out a genome-wide association study (GWAS) including 2236 BAV patients and 11 604 controls. This led to the identification of a new risk locus for BAV on chromosome 3q29. The single nucleotide polymorphism rs2550262 was genome-wide significant BAV associated (P = 3.49 × 10-08) and was replicated in an independent case-control sample. The risk locus encodes a deleterious missense variant in MUC4 (p.Ala4821Ser), a gene that is involved in epithelial-to-mesenchymal transformation. Mechanistical studies in zebrafish revealed that loss of Muc4 led to a delay in cardiac valvular development suggesting that loss of MUC4 may also play a role in aortic valve malformation. The GWAS also confirmed previously reported BAV risk loci at PALMD (P = 3.97 × 10-16), GATA4 (P = 1.61 × 10-09), and TEX41 (P = 7.68 × 10-04). In addition, the genetic BAV architecture was examined beyond the single-marker level revealing that a substantial fraction of BAV heritability is polygenic and ∼20% of the observed heritability can be explained by our GWAS data. Furthermore, we used the largest human single-cell atlas for foetal gene expression and show that the transcriptome profile in endothelial cells is a major source contributing to BAV pathology. CONCLUSION: Our study provides a deeper understanding of the genetic risk architecture of BAV formation on the single marker and polygenic level.

Halide Chemistry in Tin Perovskite Optoelectronics: Bottlenecks and Opportunities.

Tin halide perovskites (Sn HaPs) are the top lead-free choice for perovskite optoelectronics, but the oxidation of perovskite Sn2+ to Sn4+ remains a key challenge. However, the role of inconspicuous chemical processes remains underexplored. Specifically, the halide component in Sn HaPs (typically iodide) has been shown to play a key role in dictating device performance and stability due to its high reactivity. Here we describe the impact of native halide chemistry on Sn HaPs. Specifically, molecular halogen formation in Sn HaPs and its influence on degradation is reviewed, emphasising the benefits of iodide substitution for improving stability. Next, the ecological impact of halide products of Sn HaP degradation and its mitigation are considered. The development of visible Sn HaP emitters via halide tuning is also summarised. Lastly, halide defect management and interfacial engineering for Sn HaP devices are discussed. These insights will inspire efficient and robust Sn HaP optoelectronics.

Can behavior change techniques be delivered via short text messages?

Despite significant advancements in behavioral science it is unclear whether behavior change techniques (or BCTs) can be delivered to large numbers of people in a cost-effective and reliable way. The current study investigated whether it is possible to reliably deliver BCTs using short text messages. Short text messages were designed to deliver each of the 93 BCTs specified in the BCT taxonomy v1. Following initial coding and refinement by the team, a Delphi study with a panel of 15 experts coded which BCT each short text message was designed to deliver and also rated whether they were likely to be understood by recipients and easily converted to target different behaviors. After two iterations, the experts correctly assigned 66 of the 93 messages to the BCT that they were designed to deliver and indicated that these messages were likely to be easy to apply to a range of behaviors and understood by recipients. Experts were not able to identify which BCT 27 of the messages were designed to deliver and it was notable that some clusters of BCTs (e.g., "Goals and planning") were easier to deliver via short text messages than other clusters (e.g., "Scheduled consequences"). The findings suggest that short text messages can be a reliable way to deliver many, but not all, BCTs. The implications of the current study are discussed with respect to the delivery of specific BCTs and clusters of the taxonomy, as well as the need to test the acceptability of interventions delivered via short messages and the impact of messages on behavior.

Identifying ways to support people to make changes to their behavior is central to many of the grand challenges facing science and society. Ninety-three unique behavior change techniques (BCTs) have been identified; however, it is hard to reliably deliver these techniques to large populations in an efficient and cost-effective way. We developed a list of short text messages to deliver each of the 93 BCTs to promote cycling. Fifteen experts agreed that 66 of the messages delivered their intended BCT and that these messages would be easily understood by people and be easily modified to target different behaviors.

Exploring attitudes towards more sustainable dentistry among adults living in the UK.

Introduction Despite evidence that public pressure can promote sustainability in various domains (for example, retail and travel), no research has considered the public's attitudes towards sustainability in dentistry.Methods A questionnaire was developed to measure attitudes towards sustainable dentistry among adults living in the UK and their willingness to make compromises to reduce the impact of their dental treatment on the environment. In total, 344 adults completed the questionnaire that also measured pro-environmental identity and concern, general willingness to make compromises for the environment, and the tendency to engage in ecological behaviours.Results Participants reported positive attitudes towards sustainable dentistry, and were willing to compromise their time, convenience and durability of their dental treatment, as well as pay more, to reduce the impact of their dental work on the environment. Participants were not willing to compromise their health or the aesthetics of their teeth. There was also evidence that participants' current oral health shaped their attitudes towards sustainable dentistry, such that better oral health was associated with more positive attitudes towards more sustainable dentistry.Conclusions Given that public pressure can be a significant driver of change, these findings provide valuable insight into the kind of compromises that may be accepted by the public in order to improve the sustainability of dental services.

The integrin ligand SVEP1 regulates GPCR-mediated vasoconstriction via integrins α9ß1 and α4ß1.

BACKGROUND AND PURPOSE: Vascular tone is regulated by the relative contractile state of vascular smooth muscle cells (VSMCs). Several integrins directly modulate VSMC contraction by regulating calcium influx through L-type voltage-gated Ca2+ channels (VGCCs). Genetic variants in ITGA9, which encodes the α9 subunit of integrin α9ß1, and SVEP1, a ligand for integrin α9ß1, associate with elevated blood pressure; however, neither SVEP1 nor integrin α9ß1 has reported roles in vasoregulation. We determined whether SVEP1 and integrin α9ß1 can regulate VSMC contraction. EXPERIMENTAL APPROACH: SVEP1 and integrin binding were confirmed by immunoprecipitation and cell binding assays. Human induced pluripotent stem cell-derived VSMCs were used in in vitro [Ca2+ ]i studies, and aortas from a Svep1+/- knockout mouse model were used in wire myography to measure vessel contraction. KEY RESULTS: We confirmed the ligation of SVEP1 to integrin α9ß1 and additionally found SVEP1 to directly bind to integrin α4ß1. Inhibition of SVEP1, integrin α4ß1 or α9ß1 significantly enhanced [Ca2+ ]i levels in isolated VSMCs to Gαq/11 -vasoconstrictors. This response was confirmed in whole vessels where a greater contraction to U46619 was seen in vessels from Svep1+/- mice compared to littermate controls or when integrin α4ß1 or α9ß1 was inhibited. Inhibition studies suggested that this effect was mediated via VGCCs, PKC and Rho A/Rho kinase dependent mechanisms. CONCLUSIONS AND IMPLICATIONS: Our studies reveal a novel role for SVEP1 and the integrins α4ß1 and α9ß1 in reducing VSMC contractility. This could provide an explanation for the genetic associations with blood pressure risk at the SVEP1 and ITGA9 loci.

Variation in the Reporting of Elective Surgeries and Its Influence on Patient Safety Indicators.

BACKGROUND: US hospital safety is routinely measured via Patient Safety Indicators (PSIs). Receiving a score for most PSIs requires a minimum number of qualifying cases to meet specific criteria; for example, whether an admission was elective. Because admission type is determined by hospitals' internal policies, the study team suspected that hospitals may be exempted from elective-based PSI scores as a result of their internal admission classification policies. METHODS: Multiple regression was combined with machine learning to analyze Medicare inpatient claims data reported by 3,484 hospitals during the 2015-2017 PSI measurement period. The researchers examined the average percentage of elective admissions across surgical diagnosis-related groups (DRGs) (average percent elective [APE]) in relation to hospital characteristics, surgical claims volumes, and numbers and types of surgical DRGs. This study asked whether hospitals with exceptionally low APE shared particular characteristics, reported claims for similar DRGs, or were disproportionately exempted from elective-based PSIs. RESULTS: Cross-validated multiple regression explained 73.9% of variation in APE among hospitals and identified surgical claims volume and 16 surgical DRGs as consistently important variables. However, the exceptionally low APE of 96 hospitals could not be explained by surgical claims volume, surgical DRGs among claims, or hospital characteristics. These outliers were disproportionately exempt from elective-based PSI scores. CONCLUSION: Some hospitals may have classified admissions in a way that exempted them from elective-based PSI scores. Transparency into admission classification policies is needed to ensure fair and reliable use of PSIs when ranking hospitals and adjusting payments. Alternatively, PSIs may need modifications to rely on externally validated criteria.

Whole blood transcriptomic profiling identifies molecular pathways related to cardiovascular mortality in heart failure.

AIMS: Chronic heart failure (CHF) is a systemic syndrome with a poor prognosis and a need for novel therapies. We investigated whether whole blood transcriptomic profiling can provide new mechanistic insights into cardiovascular (CV) mortality in CHF. METHODS AND RESULTS: Transcriptome profiles were generated at baseline from 944 CHF patients from the BIOSTAT-CHF study, of whom 626 survived and 318 died from a CV cause during a follow-up of 21 months. Multivariable analysis, including adjustment for cell count, identified 1153 genes (6.5%) that were differentially expressed between those that survived or died and strongly related to a validated clinical risk score for adverse prognosis. The differentially expressed genes mainly belonged to five non-redundant pathways: adaptive immune response, proteasome-mediated ubiquitin-dependent protein catabolic process, T-cell co-stimulation, positive regulation of T-cell proliferation, and erythrocyte development. These five pathways were selectively related (RV coefficients >0.20) with seven circulating protein biomarkers of CV mortality (fibroblast growth factor 23, soluble ST2, adrenomedullin, hepcidin, pentraxin-3, WAP 4-disulfide core domain 2, and interleukin-6) revealing an intricate relationship between immune and iron homeostasis. The pattern of survival-associated gene expression matched with 29 perturbagen-induced transcriptome signatures in the iLINCS drug-repurposing database, identifying drugs, approved for other clinical indications, that were able to reverse in vitro the molecular changes associated with adverse prognosis in CHF. CONCLUSION: Systematic modelling of the whole blood protein-coding transcriptome defined molecular pathways that provide a link between clinical risk factors and adverse CV prognosis in CHF, identifying both established and new potential therapeutic targets.

Hereditary retinoblastoma iPSC model reveals aberrant spliceosome function driving bone malignancies.

The RB1 gene is frequently mutated in human cancers but its role in tumorigenesis remains incompletely defined. Using an induced pluripotent stem cell (iPSC) model of hereditary retinoblastoma (RB), we report that the spliceosome is an up-regulated target responding to oncogenic stress in RB1-mutant cells. By investigating transcriptomes and genome occupancies in RB iPSC­derived osteoblasts (OBs), we discover that both E2F3a, which mediates spliceosomal gene expression, and pRB, which antagonizes E2F3a, coregulate more than one-third of spliceosomal genes by cobinding to their promoters or enhancers. Pharmacological inhibition of the spliceosome in RB1-mutant cells leads to global intron retention, decreased cell proliferation, and impaired tumorigenesis. Tumor specimen studies and genome-wide TCGA (The Cancer Genome Atlas) expression profile analyses support the clinical relevance of pRB and E2F3a in modulating spliceosomal gene expression in multiple cancer types including osteosarcoma (OS). High levels of pRB/E2F3a­regulated spliceosomal genes are associated with poor OS patient survival. Collectively, these findings reveal an undiscovered connection between pRB, E2F3a, the spliceosome, and tumorigenesis, pointing to the spliceosomal machinery as a potentially widespread therapeutic vulnerability of pRB-deficient cancers.

Using social cognition models to understand why people, such as perfectionists, struggle to respond with self-compassion.

Responding with self-compassion to lapses in goal pursuit helps people to achieve their goals, yet evidence suggests that some people struggle to respond with self-compassion. The current research proposes that social cognition models such the Theory of Planned Behaviour and the Prototype Willingness Model could explain why some people, such as those high in perfectionistic concerns, struggle to respond with self-compassion. We therefore conducted a pre-registered prospective study that measured participants' beliefs about self-compassion, difficulties enacting self-compassionate responding, perfectionistic concerns, and then tested their ability to be self-compassionate in response to a recalled and future lapse. The results showed that participants were less likely to respond with self-compassion to lapses if they held negative beliefs about self-compassion and experienced difficulties enacting self-compassion. Participants high in perfectionistic concerns were more likely to have negative beliefs about self-compassion and experience difficulties enacting self-compassion. Together, these findings provide evidence that social cognition models can be used to understand self-compassionate responding and identify why some people struggle to respond with self-compassion to goal lapses.

Targeting epigenetic modulators using PROTAC degraders: Current status and future perspective.

Epigenetic modulators perform critical functions in gene expression for rapid adaption to external stimuli and are prevalent in all higher-order organisms. The establishment of a link between dysregulation of epigenetic processes and disease pathogenesis, particularly in cancer, has led to much interest in identifying drug targets. This prompted the development of small molecule inhibitors, primarily in haematological malignancies. While there have been epigenetic-targeting drugs to receive FDA approval for the treatment of cancers, many suffer from limited applicability, toxicity and the onset of drug resistance, as our understanding of the biology remains incomplete. The recent advent of genome-wide RNAi and CRISPR screens has shed new light on loss of specific proteins causing vulnerabilities of specific cancer types, highlighting the potential for exploiting synthetic lethality as a therapeutic approach. However, small molecule inhibitors have largely been unable to recapitulate phenotypic effects observed using genome-wide knockdown approaches. This mechanistic disconnect and gap are set to be addressed by targeted protein degradation. Degraders such as PROTACs targeting epigenetic proteins recapitulate CRISPR mediated genetic knockdown at the post-translational level and therefore can better exploit target druggability. Here, we review the current landscape of epigenetic drug discovery, the rationale behind and progress made in the development of PROTAC degraders, and look at future perspectives for the field.

Molecular Weight Tuning of Organic Semiconductors for Curved Organic-Inorganic Hybrid X-Ray Detectors.

Curved X-ray detectors have the potential to revolutionize diverse sectors due to benefits such as reduced image distortion and vignetting compared to their planar counterparts. While the use of inorganic semiconductors for curved detectors are restricted by their brittle nature, organic-inorganic hybrid semiconductors which incorporated bismuth oxide nanoparticles in an organic bulk heterojunction consisting of poly(3-hexylthiophene-2,5-diyl) (P3HT) and [6,6]-phenyl C71 butyric acid methyl ester (PC70 BM) are considered to be more promising in this regard. However, the influence of the P3HT molecular weight on the mechanical stability of curved, thick X-ray detectors remains less well understood. Herein, high P3HT molecular weights (>40 kDa) are identified to allow increased intermolecular bonding and chain entanglements, resulting in X-ray detectors that can be curved to a radius as low as 1.3 mm with low deviation in X-ray response under 100 repeated bending cycles while maintaining an industry-standard dark current of <1 pA mm-2 and a sensitivity of ≈ 0.17 µC Gy-1 cm-2 . This study identifies a crucial missing link in the development of curved detectors, namely the importance of the molecular weight of the polymer semiconductors used.

Do people choose the same strategies to regulate other people's emotions as they choose to regulate their own?

How do people choose how to regulate others' emotional responses? We extended previous work on how the intensity of an emotional situation influences which strategies people choose to regulate their emotions (i.e., intrapersonal emotion regulation choice) to also consider the effect of intensity on which strategies people choose to regulate other people's emotions (i.e., interpersonal emotion regulation choice). Studies 1a and 1b found that the intensity of the emotional situation influenced whether participants chose distraction or reappraisal in both intrapersonal and interpersonal regulation contexts, but also that the effect of intensity differed between the contexts (participants choose reappraisal more frequently for others in intense situations than for themselves). However, this difference was stronger (or only found) when participants helped the other person to control their emotions first. Two further studies examined whether differences in perceived intensity (Study 2) and/or the anticipated effort or effectiveness of the strategies (Study 3) could explain the difference between intrapersonal and interpersonal contexts. Together, the findings suggest that the regulation strategies that people choose depend on the intensity of the emotional situation, the target of regulation, and whether people choose how to regulate their own emotions before choosing how to regulate another person's emotions, with preliminary evidence that differences between intrapersonal and interpersonal emotion regulation choice may be associated with differences in the anticipated effort and effectiveness of regulation between these contexts. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Phosphorene Nanoribbon-Augmented Optoelectronics for Enhanced Hole Extraction.

Phosphorene nanoribbons (PNRs) have been widely predicted to exhibit a range of superlative functional properties; however, because they have only recently been isolated, these properties are yet to be shown to translate to improved performance in any application. PNRs show particular promise for optoelectronics, given their predicted high exciton binding energies, tunable bandgaps, and ultrahigh hole mobilities. Here, we verify the theorized enhanced hole mobility in both solar cells and space-charge-limited-current devices, demonstrating the potential for PNRs improving hole extraction in universal optoelectronic applications. Specifically, PNRs are demonstrated to act as an effective charge-selective interlayer by enhancing hole extraction from polycrystalline methylammonium lead iodide (MAPbI3) perovskite to the poly(triarylamine) semiconductor. Introducing PNRs at the hole-transport/MAPbI3 interface achieves fill factors above 0.83 and efficiencies exceeding 21% for planar p-i-n (inverted) perovskite solar cells (PSCs). Such efficiencies are typically only reported for single-crystalline MAPbI3-based inverted PSCs. Methylammonium-free PSCs also benefit from a PNR interlayer, verifying applicability to architectures incorporating mixed perovskite absorber layers. Device photoluminescence and transient absorption spectroscopy are used to demonstrate that the presence of the PNRs drives more effective carrier extraction. Isolation of the PNRs in space-charge-limited-current hole-only devices improves both hole mobility and conductivity, demonstrating applicability beyond PSCs. This work provides primary experimental evidence that the predicted superlative functional properties of PNRs indeed translate to improved optoelectronic performance.