Immunization with a peptide mimicking lipoteichoic acid induces memory B cells in BALB/c mice.

BACKGROUND: There is an urgent clinical need for developing novel immunoprophylaxis and immunotherapy strategies against Staphylococcus aureus (S. aureus). In our previous work, immunization with a tetra-branched multiple antigenic peptide, named MAP2-3 that mimics lipoteichoic acid, a cell wall component of S. aureus, successfully induced a humoral immune response and protected BALB/c mice against S. aureus systemic infection. In this study, we further investigated whether vaccination with MAP2-3 can elicit immunologic memory. METHODS: BALB/c mice were immunized with MAP2-3 five times. After one month of the last vaccination, mice were challenged with heat-killed S. aureus via intraperitoneal injection. After a 7-day inoculation, the percentage of plasma cells, memory B cells, effector memory T cells, and follicular helper T cells were detected by flow cytometry. The levels of IL-6, IL-21, IL-2, and IFN-γ were measured by real-time PCR and ELISA. Flow cytometry results were compared by using one-way ANOVA or Mann-Whitney test, real-time PCR results were compared by using one-way ANOVA, and ELISA results were compared by using one-way ANOVA or student's t-test. RESULTS: The percentage of plasma cells and memory B cells in the spleen and bone marrow from the MAP2-3 immunized mice was significantly higher than that from the control mice. The percentage of effector memory T cells in spleens and lymphoid nodes as well as follicular helper T cells in spleens from the MAP2-3 immunized mice were also higher. Moreover, the levels of IL-6 and IL-21, two critical cytokines for the development of memory B cells, were significantly higher in the isolated splenocytes from immunized mice after lipoteichoic acid stimulation. CONCLUSIONS: Immunization with MAP2-3 can efficiently induce memory B cells and memory T cells.

Passenger Gene Coamplifications Create Collateral Therapeutic Vulnerabilities in Cancer.

DNA amplifications in cancer do not only harbor oncogenes. We sought to determine whether passenger coamplifications could create collateral therapeutic vulnerabilities. Through an analysis of >3,000 cancer genomes followed by the interrogation of CRISPR-Cas9 loss-of-function screens across >700 cancer cell lines, we determined that passenger coamplifications are accompanied by distinct dependency profiles. In a proof-of-principle study, we demonstrate that the coamplification of the bona fide passenger gene DEAD-Box Helicase 1 (DDX1) creates an increased dependency on the mTOR pathway. Interaction proteomics identified tricarboxylic acid (TCA) cycle components as previously unrecognized DDX1 interaction partners. Live-cell metabolomics highlighted that this interaction could impair TCA activity, which in turn resulted in enhanced mTORC1 activity. Consequently, genetic and pharmacologic disruption of mTORC1 resulted in pronounced cell death in vitro and in vivo. Thus, structurally linked coamplification of a passenger gene and an oncogene can result in collateral vulnerabilities. SIGNIFICANCE: We demonstrate that coamplification of passenger genes, which were largely neglected in cancer biology in the past, can create distinct cancer dependencies. Because passenger coamplifications are frequent in cancer, this principle has the potential to expand target discovery in oncology. This article is featured in Selected Articles from This Issue, p. 384.

Elimusertib has Antitumor Activity in Preclinical Patient-Derived Pediatric Solid Tumor Models.

The small-molecule inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), elimusertib, is currently being tested clinically in various cancer entities in adults and children. Its preclinical antitumor activity in pediatric malignancies, however, is largely unknown. We here assessed the preclinical activity of elimusertib in 38 cell lines and 32 patient-derived xenograft (PDX) models derived from common pediatric solid tumor entities. Detailed in vitro and in vivo molecular characterization of the treated models enabled the evaluation of response biomarkers. Pronounced objective response rates were observed for elimusertib monotherapy in PDX, when treated with a regimen currently used in clinical trials. Strikingly, elimusertib showed stronger antitumor effects than some standard-of-care chemotherapies, particularly in alveolar rhabdomysarcoma PDX. Thus, elimusertib has strong preclinical antitumor activity in pediatric solid tumor models, which may translate to clinically meaningful responses in patients.

The executive functions among patients with an initial Glasgow coma scale score of 15.

Executive functions (EF) were the critical neuropsychological functions linked to long-term adaptation. Given the heterogeneous prognosis trajectories of mild traumatic brain jury (mTBI), the mildest TBI may not always be benign in the chronic stage. The present study explored the long-term EF in patients with chronic complicated mTBI and a Glasgow Coma Scale (GCS) score of 15. Fifty patients with complicated mTBI and GCS scores of 15 and 35 control participants were recruited in this study. Medical records were retrospectively analyzed, and neuropsychological assessments and subjective measures examined the neuropsychological functions. Compared with healthy controls, complicated mTBI patients with a GCS score of 15 performed significantly worse on most EF assessments, including longer reaction time (RT) and poor cognitive flexibility and abstract reasoning performances. Patients also reported more EF problems and lower quality of life (QoL) than healthy controls. Females and those with subdural hematoma (SDH) had significantly longer reaction times (RT) on executive attention tests. This study found that complicated mTBI with a GCS score of 15 had incomplete recovery of EF, even in the chronic stage. We suggest that early neuropsychological assessment and rehabilitation should be arranged for such patients.

The impact of neuropsychological functions on self-care/self-management of type 2 diabetes in middle-aged people: a scoping review and meta-analysis.

INTRODUCTION: This study aimed to investigate the impact of neuropsychological functions on self-care/self-management in middle-aged individuals with type 2 diabetes (T2DM). AREAS COVERED: A comprehensive literature search was conducted from January 2012 to April 2023 across multiple databases. Ten articles were included in the scoping review, and 3 articles were included in the meta-analysis. The findings consistently indicated an association between reduced neuropsychological functions and poor self-care/self-management in this population. Memory functions, executive functions, and other domains were found to be significantly related to self-care/self-management, including diet management, exercise, blood glucose monitoring, and foot care. EXPERT OPINION: This study highlights the importance of considering neuropsychological factors in understanding and improving diabetes management outcomes. The findings underscore the need for comprehensive neuropsychological assessments and the development of targeted interventions to address specific vulnerable domains. Future research should focus on elucidating underlying mechanisms, addressing methodological inconsistencies, and exploring the effectiveness of interventions targeting neuropsychological impairments. Incorporating technology and personalized approaches into diabetes management can enhance self-care/self-management and clinical outcomes in individuals with T2DM.

Correlation Among Workplace Burnout, Resilience, and Well-Being in Nursing Staff: A Cross-Sectional Study in Taiwan.

BACKGROUND: Because nurses often work in medical environments characterized by high workloads and high levels of stress and pressure, they are particularly vulnerable to workplace burnout and their well-being may suffer. Related studies on burnout, resilience, and well-being have focused primarily on teachers, social workers, and students, with few studies addressing the situation faced by nursing staff. It is important to understand the factors affecting the well-being of nursing staff. PURPOSE: This study explores the status quo and correlations among nursing-staff demographic characteristics, workplace burnout, well-being-related resilience, and the predictive factors of well-being in nurses. METHODS: A cross-sectional, descriptive, correlational research design and purposive sampling were used in this study. Nursing staff who had worked for more than 6 months at a medical center in central Taiwan were recruited as participants, with data from 289 participants collected. A structured questionnaire was used to collect data on demographic characteristics, workplace burnout, resilience, and well-being. RESULTS: The average scores for workplace burnout, resilience, and well-being were 40.40/(0- to 100-point scale), 26.79/(10- to 50-point scale), and 43.25/(24- to 96-point scale), respectively. The result of the regression analysis explained about 51.6% of the variance in well-being. Furthermore, resilience (28.4%), self-perceived health (14.3%), workplace burnout (4.5%), exercise frequency (1.8%), job title (1.2%), interpersonal pressure relief resilience (0.9%), and marital status (0.5%) were other important predictive factors of well-being in the participants. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Medical institutions should provide appropriate resilience-enhancing countermeasures to reduce workplace burnout as well as pay greater attention to the exercise frequency, self-perceived health, job title, and marital status of their nurses to help them achieve physical, mental, and overall well-being.

Sex differences in children's cognitive functions and phthalates exposure: a meta-analysis.

BACKGROUND: Phthalates exposure might affect children's intelligence development. This study aimed to determine (1) whether sex and age affect cognitive function and (2) whether sex differences in cognitive performance are wider with higher phthalate concentrations. METHODS: Data were collected from PubMed (1998-2022), PROQUEST (1997-2022), and SpringerLink (1995-2022). The study followed the PRISMA process. The included articles were followed by PECO framework. The GRADE applied to assess the certainty of evidence. Of 2422 articles obtained, nine were selected using inclusion criteria. The random-effects model was used to estimate the pooled effects. RESULTS: Our meta-regression indicated a significant difference between sex differences with age at phthalate concentration assessment (ß = -0.25; 95% CI = -0.47, -0.03) and MEHP concentration (ß = -0.20; 95% CI = -0.37, -0.03). CONCLUSIONS: The limitation of the current article is it only provides information on intelligence level rather than other aspects of cognitive function. Thus, the sequelae of phthalate exposure on attention and executive function are still unclear. Our analysis shows significant difference between sex differences in cognitive function scores associated with age at phthalate concentration assessment. Girls might be more resilient in cognitive function at a younger age or during lower concentrations of phthalates metabolites. IMPACT: This is the first meta-analysis to evaluate the pooled estimates of sex differences in objective cognitive functions among children with phthalate exposure. The female might be a protective factor when exposed to toxic plasticizers while the concentration is low. This study captures the possible role of sex in cognitive functioning and plasticizer exposure through a meta-analysis of children's sex, cognitive scores, and plasticizer exposure.

Neuropsychological Impairments in Patients With Post-traumatic Epilepsy: A Scoping Review.

OBJECTIVES: To date, the research on the prognosis of the neuropsychological function of patients with post-traumatic seizure (PTE) is sparse. This study aimed to systematically map the literature's extent, range, and characteristics regarding PTE and neuropsychological impairments. METHODS: A systematic literature search was conducted in CINAHL, Cochrane, Embase, Medline, PubMed, Scopus, Web of Science, and ScienceDirect databases. The search terms were related to PTE and neuropsychological impairments. RESULTS: This scoping review included seven studies, two of which examined the impact of PTE on neuropsychological outcomes. Among the three studies that used neuropsychological assessments, attention/concentration, and memory were the most frequently assessed domains. Only one study reported a significant difference between PTE and non-PTE patients. The cognitive rating scale findings in the other four studies were similar, indicating that patients with PTE performed worse than those without PTE. CONCLUSIONS: The results of this review suggest that patients with PTE may have neuropsychological function impairments. More attention needs to be paid to older patients and those with higher brain injury and seizure severity. Additional investigation is necessary to determine the clinical characteristics of TBI and PTE and elucidate the relations between PTE and specific neuropsychological domains.

Twelve tips for co-production of online learning.

In the digital age, experts in digital learning tools, or learning technologists (LTs), play an increasingly important role in the creation and delivery of online learning in health professions education. However, their expertise in the selection, curation and implementation of digital tools is often underutilized due to imbalanced relationships and lack of effective collaboration between faculty and LTs. Here, we describe how the co-production model can be applied to build equal and synergistic partnerships between faculty and LTs, so as to optimize the use of digital affordances and enhance online learning.

Multi-scale dissection of wing transparency in the clearwing butterfly Phanus vitreus.

Optical transparency is rare in terrestrial organisms, and often originates through loss of pigmentation and reduction in scattering. The coloured wings of some butterflies and moths have repeatedly evolved transparency, offering examples of how they function optically and biologically. Because pigments are primarily localized in the scales that cover a colourless wing membrane, transparency has often evolved through the complete loss of scales or radical modification of their shape. Whereas bristle-like scales have been well documented in glasswing butterflies, other scale modifications resulting in transparency remain understudied. The butterfly Phanus vitreus achieves transparency while retaining its scales and exhibiting blue/cyan transparent zones. Here, we investigate the mechanism of wing transparency in P. vitreus by light microscopy, focused ion beam milling, microspectrophotometry and optical modelling. We show that transparency is achieved via loss of pigments and vertical orientation in normal paddle-like scales. These alterations are combined with an anti-reflective nipple array on portions of the wing membrane being more exposed to light. The blueish coloration of the P. vitreus transparent regions is due to the properties of the wing membrane, and local scale nanostructures. We show that scale retention in the transparent patches might be explained by these perpendicular scales having hydrophobic properties.

Parallel sequencing of extrachromosomal circular DNAs and transcriptomes in single cancer cells.

Extrachromosomal DNAs (ecDNAs) are common in cancer, but many questions about their origin, structural dynamics and impact on intratumor heterogeneity are still unresolved. Here we describe single-cell extrachromosomal circular DNA and transcriptome sequencing (scEC&T-seq), a method for parallel sequencing of circular DNAs and full-length mRNA from single cells. By applying scEC&T-seq to cancer cells, we describe intercellular differences in ecDNA content while investigating their structural heterogeneity and transcriptional impact. Oncogene-containing ecDNAs were clonally present in cancer cells and drove intercellular oncogene expression differences. In contrast, other small circular DNAs were exclusive to individual cells, indicating differences in their selection and propagation. Intercellular differences in ecDNA structure pointed to circular recombination as a mechanism of ecDNA evolution. These results demonstrate scEC&T-seq as an approach to systematically characterize both small and large circular DNA in cancer cells, which will facilitate the analysis of these DNA elements in cancer and beyond.

Profile identification and characterization of risk perceptions and preventive behaviors during the COVID-19 pandemic: A latent profile analysis.

In a public health crisis, communication plays a vital role in making sure policies and recommendations from the government level get disseminated accurately to its people and is only considered as effective when the public accepts, supports, complies to, and engages in policies or behaves as per governments' recommendations. Adopting the multivariate audience segmentation strategy for health communication, this study uses a data-driven analytical method to (1) identify audience segments of public health crisis communication in Singapore based on knowledge, risk perception, emotional responses, and preventive behaviors; and (2) characterize each audience segment according to demographic factors, personality traits, information processing styles, and health information preferences. Results (N = 2033) from a web-based questionnaire executed in August 2021 have identified three audience segments: the less-concerned (n = 650), the risk-anxious (n = 142), and the risk-majority (n = 1,241). This study offers insights to how audiences of public health crisis communication perceive, process, and respond to information directed to them during the pandemic, thereby informing policy makers to tailor more targeted public health communication interventions in promoting positive attitude and behavior change.

5S management improves the service quality in the outpatient-emergency pharmacy: from management process optimisation to staff capacity enhancement.

OBJECTIVE: As a high-efficiency demanding department in a hospital, the outpatient pharmacy has a great need for quality improvement to provide superior medical service for patients. Little is known about the application of 5S management in a hospital pharmacy department. The aim of this study was to evaluate the impacts of 5S management on pharmaceutical service quality and staff capacity in the outpatient-emergency pharmacy. METHODS: We carried out a 5S project in the outpatient-emergency pharmacy at a local hospital that involved processes including waste elimination, workplace standardisation, and optimisation of workflow and staff quality, and then evaluated the effects of the project. RESULTS: The equipment and items in the outpatient-emergency pharmacy were sorted. All the drugs were categorised and put in order. The redesigned workspace and standardised workflow during the project improved the accuracy and efficiency of drug dispensing. The satisfaction rate of patients regarding the pharmaceutical service quality in the outpatient-emergency pharmacy was elevated, as well as the satisfaction rate of pharmacists about their work experiences. The optimisation of objective conditions also stimulated a positive working attitude and professional ability promotion of pharmacists in the outpatient-emergency pharmacy. CONCLUSIONS: In this study, the 5S management method has proven useful for quality and efficiency improvement in the outpatient-emergency pharmacy, and could be generalised to other departments in a hospital, which provides further evidence of the advantages of the Lean tool in healthcare system management.

Factors Related to the Continuity of Care and Self-Management of Patients with Type 2 Diabetes Mellitus: A Cross-Sectional Study in Taiwan.

BACKGROUND: Most diabetic patients suffer from chronic diseases affecting their self-management status. This study aims to explore the relationship between the CoC and the self-management of patients with Type 2 Diabetes Mellitus (T2DM) and analyze the predictive factors affecting their self-management. METHODS: Structured questionnaires were used for data collection. Convenient sampling was adopted to recruit inpatients diagnosed with T2DM in the endocrine ward of a medical hospital in central Taiwan. RESULTS: A total of 160 patients were recruited. The average age of the patients is 66.60 ± 14.57 years old. Among the four dimensions of the self-management scale, the average score of the problem-solving dimension was the highest, and that of the self-monitoring of blood glucose was the lowest. The analysis results showed that the overall regression model could explain 20.7% of the total variance in self-management. CONCLUSIONS: Healthcare providers should attach importance to the CoC of T2DM patients and encourage patients to maintain good interaction with healthcare providers during their hospitalization. It is recommended to strengthen CoC for patients with diabetes who are single or with low educational levels in clinical practice to enhance their blood glucose control and improve diabetes self-management.

Therapeutic targeting of ATR in alveolar rhabdomyosarcoma.

Despite advances in multi-modal treatment approaches, clinical outcomes of patients suffering from PAX3-FOXO1 fusion oncogene-expressing alveolar rhabdomyosarcoma (ARMS) remain dismal. Here we show that PAX3-FOXO1-expressing ARMS cells are sensitive to pharmacological ataxia telangiectasia and Rad3 related protein (ATR) inhibition. Expression of PAX3-FOXO1 in muscle progenitor cells is not only sufficient to increase sensitivity to ATR inhibition, but PAX3-FOXO1-expressing rhabdomyosarcoma cells also exhibit increased sensitivity to structurally diverse inhibitors of ATR. Mechanistically, ATR inhibition leads to replication stress exacerbation, decreased BRCA1 phosphorylation and reduced homologous recombination-mediated DNA repair pathway activity. Consequently, ATR inhibitor treatment increases sensitivity of ARMS cells to PARP1 inhibition in vitro, and combined treatment with ATR and PARP1 inhibitors induces complete regression of primary patient-derived ARMS xenografts in vivo. Lastly, a genome-wide CRISPR activation screen (CRISPRa) in combination with transcriptional analyses of ATR inhibitor resistant ARMS cells identifies the RAS-MAPK pathway and its targets, the FOS gene family, as inducers of resistance to ATR inhibition. Our findings provide a rationale for upcoming biomarker-driven clinical trials of ATR inhibitors in patients suffering from ARMS.

Effects of Twenty Hours of Neurofeedback-Based Neuropsychotherapy on the Executive Functions and Achievements among ADHD Children.

Objective. Neurofeedback can reduce ADHD symptoms; however, current programs are relatively long, with fewer concerns about executive function (EF). The present study aimed to investigate a 20-hour combined computerized training neurofeedback program. Methods. Fifty ADHD children were randomly assigned to either the experimental group (EXP) or the wait-list control group (CON), who took training after the post-tests. The EF measures were the Tower of London (ToL), Wisconsin Card Sorting Test (WCST), and Comprehensive Nonverbal Attention Test (CNAT). SNAP-IV and questionnaires reported by parents constituted the behavioral measures. Two-way repeated-measures ANOVA and bootstrapping dependent t-tests were also used. Results. The F-tests revealed the interaction effects on ADHD symptoms and math scores. The EXP had increased the ToL scores, decreased the error and perseverative error rates on WCST, as well as the dysexecutive index on CNAT in the t-test. Conclusions. The training effects were related to behavioral symptoms and functions, EFs, and generalized achievement performances. We suggest that future studies could apply to different patients and examine the maintenance of the program.

Frontal Beta Activity in the Meta-Intention of Children With Attention Deficit Hyperactivity Disorder.

Children with attention deficit hyperactivity disorder (ADHD) have high theta and low beta activity in the frontal lobe. The higher the theta/beta ratio, the lower the level of central nervous system (CNS) cortical arousal. However, there is seldom evidence between electroencephalograms (EEGs) and the patient's intentionality to regulate the cortical activity of executive attention tasks. We investigated whether children with ADHD intended to improve their performance in executive attention tasks and whether that increased their brain activity. Fifty-one children with ADHD (ADHD) and 51 typical developing (TD) children were investigated using focused attention (FA) and search attention (SA) tasks and a simultaneous EEG. The children were then regrouped as faster (ADHD-F, TD-F) and slower (ADHD-S, TD-S) depending on reaction time (RT). Quantitative EEGs of frontal lobe theta and beta activity at frontal F3, F4, and Fz were used. Twenty-eight (54.9%) ADHD children were regrouped as ADHD-S and 14 (27.5%) as TD-S. The ADHD-S group, however, had poorer FA and SA performance than the other 3 groups did: fewer correct answers, more frequent impulsive and missing errors, and higher RT variations. There were no significant differences in theta activity, but the TD-S group had higher beta activity than the ADHD-S group did. We conclude that the ADHD-F and ADHD-S groups had different attention processes. beta activity did not increase in the ADHD-S group, and their executive attention performance in the FA and SA tests was poor. It seems ADHD-S had poor meta-intention function. The frontal beta activity might be a feasible training target of neurofeedback in ADHD-S patients.

Enhancer hijacking determines extrachromosomal circular MYCN amplicon architecture in neuroblastoma.

MYCN amplification drives one in six cases of neuroblastoma. The supernumerary gene copies are commonly found on highly rearranged, extrachromosomal circular DNA (ecDNA). The exact amplicon structure has not been described thus far and the functional relevance of its rearrangements is unknown. Here, we analyze the MYCN amplicon structure using short-read and Nanopore sequencing and its chromatin landscape using ChIP-seq, ATAC-seq and Hi-C. This reveals two distinct classes of amplicons which explain the regulatory requirements for MYCN overexpression. The first class always co-amplifies a proximal enhancer driven by the noradrenergic core regulatory circuit (CRC). The second class of MYCN amplicons is characterized by high structural complexity, lacks key local enhancers, and instead contains distal chromosomal fragments harboring CRC-driven enhancers. Thus, ectopic enhancer hijacking can compensate for the loss of local gene regulatory elements and explains a large component of the structural diversity observed in MYCN amplification.

Clinicopathological Characteristics and Prognostic Factors of Patients with Gastric Cancer Accompanying Neuroendocrine Differentiation (NEDGC).

AIM: Gastric carcinoma with neuroendocrine differentiation (NEDGC) is a relatively rare pathologic diagnosis in clinical practice, which has no specific guidelines or treatment recommendations yet. In this study, we aim to investigate the clinicopathological characteristics and prognostic factors of this disease. PATIENTS AND METHODS: We retrospectively analyzed clinicopathological data from a series of 82 NEDGC patients who underwent surgery for gastrectomy at Huashan Hospital Fudan University between January 2007 and December 2018. Furthermore, a series of 50 cases were used to analyze 3-year overall survival (OS). RESULTS: Ages of the patients ranged from 26 to 83 years (M:F, 4.8:1). The majority of patients suffered from some symptoms (97.6%), as the most common one was abdominal pain (48.8%). Most of the tumors were ≥5 cm (53.7%), in the lower part of the stomach (47.5%), and with advanced T (87.8% ≥T3) and N (67.1% ≥N1) stage. As to the neuroendocrine markers, Syn showed a slight advantage on sensitivity than CgA (79.3 and 75.6%, respectively). The 3-year OS was 54%. Advanced T stage (≥T3) of the primary tumor, positive lymphovascular invasion (LVI), large tumor size (5.5cm), high neutrophil-to-lymphocyte ratio (NLR, 2.51), and low prealbumin level (173.87 mg/L) were associated with inferior OS based on the univariate analysis. Low preoperative hemoglobin level (113.87g/L), laparoscopic-assisted gastrectomy, and advanced N stage (N3) were three independent risk factors for 3-year OS of NEDGC patients in both univariate and multivariate analysis. CONCLUSION: The TN staging system for gastric adenocarcinoma also has a prognostic value for NEDGC patients, while N3 stage works as an independent predictor of patients' survival. Since most of the NEDGC patients were in advanced stage, proper indications to perform operative laparoscopy should be selected.

Umpolung Difunctionalization of Carbonyls via Visible-Light Photoredox Catalytic Radical-Carbanion Relay.

The combination of photoredox catalysis with the Wolff-Kishner (WK) reaction allows the difunctionalization of carbonyl groups by a radical-carbanion relay sequence (photo-Wolff-Kishner reaction). Photoredox initiated radical addition to N-sulfonylhydrazones yields α-functionalized carbanions following the WK-type mechanism. With sulfur-centered radicals, the carbanions are further functionalized by reaction with electrophiles including CO2 and aldehydes, whereas CF3 radical addition furnishes a wide range of gem-difluoroalkenes through ß-fluoride elimination of the generated α-CF3 carbanions. More than 80 substrate examples demonstrate the broad applicability of this reaction sequence. A series of investigations including radical inhibition, deuterium labeling, fluorescence quenching, cyclic voltammetry, and control experiments support the proposed radical-carbanion relay mechanism.