The distribution of sediment microplastics assemblages is driven by location and hydrodynamics, not sediment characteristics, in the Gulf of Maine, USA.

Microplastics (MP) are found in marine sediments across the globe, but we are just beginning to understand their spatial distribution and assemblages. In this study, we quantified MP in Gulf of Maine, USA sediments. MP were extracted from 20 sediment samples, followed by polymer identification using Raman spectroscopy. We detected 27 polymer types and 1929 MP kg-1 wet sediment, on average. Statistical analyses showed that habitat, hydrodynamics, and station proximity were more important drivers of MP assemblages than land use or sediment characteristics. Stations closer to one another were more similar in their MP assemblages, tidal rivers had higher numbers of unique plastic polymers than open water or embayment stations, and stations closer to shore had higher numbers of MP. There was little evidence of relationships between MP assemblages and land use, sediment texture, total organic carbon, or contaminants.

Where the rubber meets the road: Emerging environmental impacts of tire wear particles and their chemical cocktails.

About 3 billion new tires are produced each year and about 800 million tires become waste annually. Global dependence upon tires produced from natural rubber and petroleum-based compounds represents a persistent and complex environmental problem with only partial and often-times, ineffective solutions. Tire emissions may be in the form of whole tires, tire particles, and chemical compounds, each of which is transported through various atmospheric, terrestrial, and aquatic routes in the natural and built environments. Production and use of tires generates multiple heavy metals, plastics, PAH's, and other compounds that can be toxic alone or as chemical cocktails. Used tires require storage space, are energy intensive to recycle, and generally have few post-wear uses that are not also potential sources of pollutants (e.g., crumb rubber, pavements, burning). Tire particles emitted during use are a major component of microplastics in urban runoff and a source of unique and highly potent toxic substances. Thus, tires represent a ubiquitous and complex pollutant that requires a comprehensive examination to develop effective management and remediation. We approach the issue of tire pollution holistically by examining the life cycle of tires across production, emissions, recycling, and disposal. In this paper, we synthesize recent research and data about the environmental and human health risks associated with the production, use, and disposal of tires and discuss gaps in our knowledge about fate and transport, as well as the toxicology of tire particles and chemical leachates. We examine potential management and remediation approaches for addressing exposure risks across the life cycle of tires. We consider tires as pollutants across three levels: tires in their whole state, as particulates, and as a mixture of chemical cocktails. Finally, we discuss information gaps in our understanding of tires as a pollutant and outline key questions to improve our knowledge and ability to manage and remediate tire pollution.

A deep learning model of tumor cell architecture elucidates response and resistance to CDK4/6 inhibitors.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have revolutionized breast cancer therapy. However, <50% of patients have an objective response, and nearly all patients develop resistance during therapy. To elucidate the underlying mechanisms, we constructed an interpretable deep learning model of the response to palbociclib, a CDK4/6i, based on a reference map of multiprotein assemblies in cancer. The model identifies eight core assemblies that integrate rare and common alterations across 90 genes to stratify palbociclib-sensitive versus palbociclib-resistant cell lines. Predictions translate to patients and patient-derived xenografts, whereas single-gene biomarkers do not. Most predictive assemblies can be shown by CRISPR-Cas9 genetic disruption to regulate the CDK4/6i response. Validated assemblies relate to cell-cycle control, growth factor signaling and a histone regulatory complex that we show promotes S-phase entry through the activation of the histone modifiers KAT6A and TBL1XR1 and the transcription factor RUNX1. This study enables an integrated assessment of how a tumor's genetic profile modulates CDK4/6i resistance.

Growth signaling autonomy in circulating tumor cells aids metastatic seeding.

Self-sufficiency (autonomy) in growth signaling, the earliest recognized hallmark of cancer, is fueled by the tumor cell's ability to "secrete-and-sense" growth factors (GFs); this translates into cell survival and proliferation that is self-sustained by autocrine/paracrine secretion. A Golgi-localized circuitry comprised of two GTPase switches has recently been implicated in the orchestration of growth signaling autonomy. Using breast cancer cells that are either endowed or impaired (by gene editing) in their ability to assemble the circuitry for growth signaling autonomy, here we define the transcriptome, proteome, and phenome of such an autonomous state, and unravel its role during cancer progression. We show that autonomy is associated with enhanced molecular programs for stemness, proliferation, and epithelial-mesenchymal plasticity. Autonomy is both necessary and sufficient for anchorage-independent GF-restricted proliferation and resistance to anticancer drugs and is required for metastatic progression. Transcriptomic and proteomic studies show that autonomy is associated, with a surprising degree of specificity, with self-sustained epidermal growth factor receptor (EGFR)/ErbB signaling. Derivation of a gene expression signature for autonomy revealed that growth signaling autonomy is uniquely induced in circulating tumor cells (CTCs), the harshest phase in the life of tumor cells when it is deprived of biologically available epidermal growth factor (EGF). We also show that autonomy in CTCs tracks therapeutic response and prognosticates outcome. These data support a role for growth signaling autonomy in multiple processes essential for the blood-borne dissemination of human breast cancer.

Tunable Electrochemical Entropy through Solvent Ordering by a Supramolecular Host.

An aqueous electrochemically controlled host-guest encapsulation system demonstrates a large and synthetically tunable redox entropy change. Electrochemical entropy is the basis for thermally regenerative electrochemical cycles (TRECs), which utilize reversible electrochemical processes with large molar entropy changes for thermogalvanic waste-heat harvesting and electrochemical cooling, among other potential applications. A supramolecular host-guest system demonstrates a molar entropy change of 4 times that of the state-of-the-art aqueous TREC electrolyte potassium ferricyanide. Upon encapsulation of a guest, water molecules that structurally resemble amorphous ice are displaced from the host cavity, leveraging a change in the degrees of freedom and ordering of the solvent rather than the solvation of the redox-active species to increase entropy. The synthetic tunability of the host allows rational optimization of the system's ΔS, showing a range of -51 to -101 cal mol-1 K-1 (-2.2 to -4.4 mV K-1) depending on ligand and metal vertex modifications, demonstrating the potential for rational design of high-entropy electrolytes and a new strategy to overcome theoretical limits on ion solvation reorganization entropy.

Enabling mothers of young children in a low SES area to co-design the support they are seeking for the adoption of healthy behaviours.

AIMS: There is a need for interventions that meet the needs of low socioeconomic status (SES) groups, to encourage the adoption of healthy diets and physical activity, in line with current public health guidance. This qualitative research used co-production, a method which actively involves the relevant community, to identify and describe public health interventions to support a group of mothers of young children living in a low SES area. METHODS: A group of 20 mothers took part in three in-depth qualitative interviews to discuss in detail the type of support that would be of value to them for the adoption and maintenance of healthy behaviours. The mothers were subsequently invited to take part in a public engagement project, a community-based self-help group. RESULTS: Four themes explained the principles of interventions that would be of value in supporting the mothers with the adoption of healthy behaviours, namely, a community-based self-help group, support for the whole family and support in the home and influencing the environment. These were then further developed into two types of intervention (1) learning for self-help and family care, which encompassed the first three learning-based themes and (2) community of support, which covered influencing the environment and the experience of the community-based self-help group. CONCLUSION: Co-production enabled a group of mothers of young children, from a low SES area, to describe the type of support that would help them with the establishment and maintenance of healthy lifestyle behaviours. A community-based self-help group warrants further research.

Using eRNA/eDNA metabarcoding to detect community-level impacts of nanoplastic exposure to benthic estuarine ecosystems.

Plastic particles are ubiquitous in marine systems and fragment into smaller pieces, such as nanoplastics (NPs). The effects of NPs on marine organisms are of growing concern but are not well understood. Marine sediments act as a sink for many contaminants, like microplastics, and are rich habitats for benthic micro- and meiofauna which are ecologically-important components of marine food webs; however, little is known about the sensitivities of specific organisms to NPs or the effects on community diversity and composition. Utilizing molecular methods, such as metabarcoding of environmental DNA/RNA, allows for the rapid and comprehensive detection of microscopic organisms via high-throughput sequencing to assess adverse effects at the community level. The objective of this study was to use a metabarcoding approach to investigate the effects of NPs on benthic micro- and meiofaunal community diversity. Mesocosms were created with sediment cores collected from the Narrow River estuary (Rhode Island, USA) and exposed to 900 nm diameter weathered polystyrene beads at concentrations of 0.1, 1, 10, or 100 mg/kg dry weight in sediment for two weeks. Following exposure, RNA and DNA were co-extracted from the sediment, RNA was reverse-transcribed, 18S and COI markers were PCR-amplified, and amplicons were sequenced on an Illumina MiSeq. Using the 18S marker and eRNA template, increases to α-diversity and significant differences to ß-diversity were observed in the highest NP exposures relative to the control. Observed differences in community composition were driven by the differential abundance of several types of protists and arthropods. Significant dose-dependent shifts in composition were observed in ß-diversity Jaccard and Unweighted-Unifrac metrics with the 18S marker using the RNA template. To our knowledge, this is the first demonstration of a dose-response relationship for NPs at a community level, and it highlights the value of using community-level endpoints to assess environmental impacts of nanoparticles.

Assessment of filter subsampling and extrapolation for quantifying microplastics in environmental samples using Raman spectroscopy.

A common method for characterizing microplastics (MPs) involves capturing the plastic particles on a filter after extraction and isolation from the sediment particles. Microplastics captured on the filter are then scanned with Raman spectroscopy for polymer identification and quantification. However, scanning the whole filter manually using Raman analysis is a labor-intensive and time-consuming process. This study investigates a subsampling method for Raman spectroscopic analysis of microplastics (operationally defined here as 45-1000 µm in size) present in sediments and isolated onto laboratory filters. The method was evaluated using spiked MPs in deionized water and two environmentally contaminated sediments. Based on statistical analyses, we found quantification of a sub-fraction of 12.5 % of the filter in a wedge form was optimal, efficient, and accurate for estimating the entire filter count. The extrapolation method was then used to assess microplastic contamination in sediments from different marine regions of the United States.

The influence of complex matrices on method performance in extracting and monitoring for microplastics.

Previous studies have evaluated method performance for quantifying and characterizing microplastics in clean water, but little is known about the efficacy of procedures used to extract microplastics from complex matrices. Here we provided 15 laboratories with samples representing four matrices (i.e., drinking water, fish tissue, sediment, and surface water) each spiked with a known number of microplastic particles spanning a variety of polymers, morphologies, colors, and sizes. Percent recovery (i.e., accuracy) in complex matrices was particle size dependent, with ∼60-70% recovery for particles >212 µm, but as little as 2% recovery for particles <20 µm. Extraction from sediment was most problematic, with recoveries reduced by at least one-third relative to drinking water. Though accuracy was low, the extraction procedures had no observed effect on precision or chemical identification using spectroscopy. Extraction procedures greatly increased sample processing times for all matrices with the extraction of sediment, tissue, and surface water taking approximately 16, 9, and 4 times longer than drinking water, respectively. Overall, our findings indicate that increasing accuracy and reducing sample processing times present the greatest opportunities for method improvement rather than particle identification and characterization.

Transcriptomic and immunophenotypic characterization of two cases of adamantinoma-like Ewing sarcoma of the thyroid gland.

INTRODUCTION: Adamantinoma-like Ewing sarcoma (ALES) is a rare aggressive malignancy occasionally diagnosed in the thyroid gland. ALES shows basaloid cytomorphology, expresses keratins, p63, p40, frequently CD99, and harbours the t(11;22) EWSR1::FLI1 translocation. There is debate on whether ALES resembles more sarcoma or carcinoma. METHODS: We performed RNA sequencing from two ALES cases and compared findings with skeletal Ewing's sarcomas and nonneoplastic thyroid tissue. ALES was investigated by in situ hybridization (ISH) for high-risk human papillomavirus (HPV) DNA and immunohistochemistry for the following antigens: keratin 7, keratin 20, keratin 5, keratins (AE1/AE3 and CAM5.2), CD45, CD20, CD5, CD99, chromogranin, synaptophysin, calcitonin, thyroglobulin, PAX8, TTF1, S100, p40, p63, p16, NUT, desmin, ER, FLI1, INI1, and myogenin. RESULTS: An uncommon EWSR1::FLI transcript with retained EWSR1 exon 8 was detected in both ALES cases. Regulators of EWSR1::FLI1 splicing (HNRNPH1, SUPT6H, SF3B1) necessary for production of a functional fusion oncoprotein, as well as 53 genes (including TNNT1, NKX2.2) activated downstream to the EWSR1::FLI1 cascade, were overexpressed. Eighty-six genes were uniquely overexpressed in ALES, most of which were related to squamous differentiation. Immunohistochemically, ALES strongly expressed keratins 5, AE1/AE3 and CAM5.2, p63, p40, p16, and focally CD99. INI1 was retained. The remaining immunostains and HPV DNA ISH were negative. CONCLUSION: Comparative transcriptomic profiling reveals overlapping features of ALES with skeletal Ewing's sarcoma and an epithelial carcinoma, as evidenced by immunohistochemical expression of keratin 5, p63, p40, CD99, the transcriptome profile, and detection of EWSR1::FLI1 fusion transcript by RNA sequencing.

Reduced digestion of circulating genomic DNA in systemic sclerosis patients with the DNASE1L3 R206C variant.

OBJECTIVES: Polymorphism in a coding region of deoxyribonuclease I-like III (DNASE1L3), causing amino acid substitution of Arg-206 to Cys (R206C), is a robustly replicated heritable risk factor for SSc and other autoimmune diseases. DNASE1L3 is secreted into the circulation, where it can digest genomic DNA (gDNA) in apoptosis-derived membrane vesicles (AdMVs). We sought to determine the impact of DNASE1L3 R206C on digestion of circulating gDNA in SSc patients and healthy controls (HCs). METHODS: The ability of DNASE1L3 to digest AdMV-associated gDNA was tested in vitro. The effect of R206C substitution on extracellular secretion of DNASE1L3 was determined using a transfected cell line and primary monocyte-derived dendritic cells from SSc patients. Plasma samples from SSc patients and HCs with DNASE1L3 R206C or R206 wild type were compared for their ability to digest AdMV-associated gDNA. The digestion status of endogenous gDNA in plasma samples from 123 SSc patients and 74 HCs was determined by measuring the proportion of relatively long to short gDNA fragments. RESULTS: The unique ability of DNASE1L3 to digest AdMV-associated gDNA was confirmed. Extracellular secretion of DNASE1L3 R206C was impaired. Plasma from individuals with DNASE1L3 R206C had reduced ability to digest AdMV-associated gDNA. The ratio of long: short gDNA fragments was increased in plasma from SSc patients with DNASE1L3 R206C, and this ratio correlated inversely with DNase activity. CONCLUSION: Our results confirm that circulating gDNA is a physiological DNASE1L3 substrate and show that its digestion is reduced in SSc patients with the DNASE1L3 R206C variant.

Topical Review of Hobbies and Cognitive Health.

BACKGROUND: Establishing preventive measures to improve cognitive health of the growing older adult population is a public health priority. Though, the links between low-cost non-pharmacologist interventions that target activities like hobbies and cognitive health remain unclear. OBJECTIVE: We conducted a topical review of extant literature to characterize prior findings in context and identify potential research opportunities. METHODS: Search criteria was conducted with search terms "Hobbies and Dementia", "Hobbies and Cognitive Health," "Leisure Activities and Dementia," and "Leisure Activities and Cognitive Health". From the initial 383 articles, 25 articles were selected for review by using broad inclusion and exclusion criteria. RESULTS: Of the 25 articles included in this review, 19 were longitudinal cohort, 1 was a retrospective cohort, 2 were case-control, and 3 were cross-sectional. These studies classified hobbies as leisure activities that were cognitive/intellectual, cultural, religious, social, gardening, traveling, or physical. These studies were conducted in the United States (9), United Kingdom (3), Sweden (3), France (5), Finland (1), Korea (1), Japan (2), and China (1). The associations of different types of hobbies with dementia from these studies were not consistent. Inconsistencies could be due to limitations of study design, lack of standardized methods, sample diversity, and differences in factors like social/cultural environment across the study populations. CONCLUSION: This review examined existing evidence for the association between engagement in different types of hobbies and dementia and identified key knowledge gaps and promising approaches for future research.

Comparison of two procedures for microplastics analysis in sediments based on an interlaboratory exercise.

Microplastics (MP) are distributed throughout ecosystems and settle into sediments where they may threaten benthic communities; however, methods for quantifying MP in sediments have not been standardized. This study compares two methods for analyzing MP in sediments, including extraction and identification, and provides recommendations for improvement. Two laboratories processed sediment samples using two methods, referred to as "core" and "augmentation", and identified particles with visual microscopy and spectroscopy. Using visual microscopy, the augmentation method yielded mean recoveries (78%) significantly greater than the core (47%) (p = 0.03), likely due to the use of separatory funnels in the former. Spectroscopic recovery of particles was lower at 42 and 54% for the core and augmentation methods, respectively. We suspect the visual identification recoveries are overestimations from erroneous identification of non-plastic materials persisting post-extraction, indicating visual identification alone is not an accurate method to identify MP, particularly in complex matrices like sediment. However, both Raman and FTIR proved highly accurate at identifying recovered MP, with 96.7% and 99.8% accuracy, respectively. Low spectroscopic recovery of spiked particles indicates that MP recovery from sediments is lower than previously assumed, and MP may be more abundant in sediments than current analyses suggest. To our knowledge, likely due to the excessive time/labor-intensity associated with MP analyses, this is the first interlaboratory study to quantify complete method performance (extraction, identification) for sediments, with regards to capabilities and limitations. This is essential as regulatory bodies move toward long-term environmental MP monitoring.

Environmental RNA as a Tool for Marine Community Biodiversity Assessments.

Microscopic organisms are often overlooked in traditional diversity assessments due to the difficulty of identifying them based on morphology. Metabarcoding is a method for rapidly identifying organisms where Environmental DNA (eDNA) is used as a template. However, legacy DNA is problematically detected from organisms no longer in the environment during sampling. Environmental RNA (eRNA), which is only produced by living organisms, can also be collected from environmental samples and used for metabarcoding. The aim of this study was to determine differences in community composition and diversity between eRNA and eDNA templates for metabarcoding. Using mesocosms containing field-collected communities from an estuary, RNA and DNA were co-extracted from sediment, libraries were prepared for two loci (18S and COI), and sequenced using an Illumina MiSeq. Results show a higher number of unique sequences detected from eRNA in both markers and higher α-diversity compared to eDNA. Significant differences between eRNA and eDNA for all ß-diversity metrics were also detected. This study is the first to demonstrate community differences detected with eRNA compared to eDNA from an estuarine system and illustrates the broad applications of eRNA as a tool for assessing benthic community diversity, particularly for environmental conservation and management applications.

Acute syphilitic posterior placoid chorioretinitis as the presenting symptom of syphilis in an immunocompetent patient.

Purpose: To report the case of an immunocompetent 62-year old woman with acute syphilitic posterior placoid chorioretinitis. Observations: The patient presented with sudden, painless vision loss in the left eye (OS) four months after self-resolving decreased vision in the right eye (OD) which was incorrectly attributed to ischemic optic neuropathy. At the time of presentation, visual acuity (VA) was hand motion OS and 20/30 OD. The dilated fundus exam demonstrated a flat, yellow-white macular lesion, deep to the retinal vasculature with a temporal, curvilinear demarcation line OS and was unremarkable OD. Trace vitreous cells and veils OS were observed. Optical coherence tomography demonstrated loss of photoreceptor layers. Rapid plasma reagin and fluorescent treponemal antibody absorption were positive. The patient was treated with intravenous penicillin and prednisolone acetate drops with resolution of vitreous cells and return of VA. Conclusions and Importance: Acute syphilitic posterior placoid chorioretinitis can be the single presenting symptom in syphilis. It is imperative for ophthalmologists to consider this relatively uncommon manifestation of syphilis in the differential in immunocompetent patients presenting with unsuspecting histories and perplexing vision loss.

Exercise and colorectal cancer survival: an updated systematic review and meta-analysis.

PURPOSE: The benefit of exercise to colorectal cancer patients has been advocated. However, comparative data to quantify the survival benefit is lacking. The aim of this review was to assess the effect of exercise on colorectal cancer survival. METHODS: An up-to-date systematic review was performed on the available literature between 2000 and 2021 on PubMed, EMBASE, Medline, and Cochrane Library databases. All studies reporting on the impact of exercise and colorectal cancer outcomes in patients treated for non-metastatic colorectal cancer were analysed. The main outcome measures were the overall survival (OS), cancer specific survival (CSS) and disease free survival (DFS). RESULTS: A total of 13 prospective observational studies were included, accounting for 19,135 patients. Compared to negligible physical activity, overall survival (OS) was significantly increased for both moderate and highest activity group (HR 0.82, 95% CI: 0.74-0.90, p < 0.001 and HR 0.64, 0.56-0.72, p < 0.001 respectively). This was also reflected in cancer specific survival (CSS) analysis, but not disease-free survival (DFS) analysis. CONCLUSION: Exercise was associated with an increased in overall survival after a colorectal cancer resection. This would support the promotion of exercise interventions amongst colorectal cancer patients.

Temporal Dynamics of Subclinical Malaria in Different Transmission Zones of Myanmar.

Countries in the Greater Mekong Subregion have committed to eliminate Plasmodium falciparum malaria by 2025. Subclinical malaria infections that can be detected by highly sensitive polymerase chain reaction (PCR) testing in asymptomatic individuals represent a potential impediment to this goal, although the extent to which these low-density infections contribute to transmission is unclear. To understand the temporal dynamics of subclinical malaria in this setting, a cohort of 2,705 participants from three epidemiologically distinct regions of Myanmar was screened for subclinical P. falciparum and P. vivax infection using ultrasensitive PCR (usPCR). Standard rapid diagnostic tests (RDTs) for P. falciparum were also performed. Individuals who tested positive for malaria by usPCR were followed for up to 12 weeks. Regression analysis was performed to estimate whether the baseline prevalence of infection and the count of repeated positive tests were associated with demographic, behavioral, and clinical factors. At enrollment, the prevalence of subclinical malaria infection measured by usPCR was 7.7% (1.5% P. falciparum monoinfection, 0.3% mixed P. falciparum and P. vivax, and 6.0% P. vivax monoinfection), while P. falciparum prevalence measured by RDT was just 0.2%. Prevalence varied by geography and was higher among older people and in those with outdoor exposure and travel. No difference was observed in either the prevalence or count of subclinical infection by time of year, indicating that even in low-endemicity areas, a reservoir of subclinical infection persists year-round. If low-density infections are shown to represent a significant source of transmission, identification of high-risk groups and locations may aid elimination efforts.

Adopting and maintaining a healthy lifestyle in low SES families: How the experience of motherhood shapes responses to dietary and physical activity public health guidance.

BACKGROUND: Public health guidance and associated interventions seek to bring about change in diet and physical activity behaviours to improve life expectancy and healthy life expectancy in the population. Low socioeconomic status (SES) groups suffer from reduced life/healthy life expectancy compared with the population as a whole. This in-depth qualitative study, investigates the lives and experiences of mothers with young children living in a low SES area in a London (UK) borough, to understand the context in which current public health guidance on diet and physical activity is received and viewed, and how this understanding could be used to inform the development of public health guidance and interventions for this group. METHODS: The mothers (n = 20), were recruited from a Surestart Centre, Children's Centres and through the local branch of a national charity. The mothers took part in a series of three in depth interviews over two years (2016-2017). Thematic analysis was used to generate an iterative set of codes informing an understanding of motherhood, diet and physical activity. RESULTS: Motherhood was found to be a major factor for understanding and interpreting how women in low SES areas respond to public health guidance on diet and physical activity. The mothers were well informed about dietary guidance, considered that provision of healthy food was critical to the mothering role, but found it difficult to implement the guidance in their own lives. In contrast, physical activity was not seen as integral to the mothering role, although it was acknowledged that it played a part in ensuring that the mothers remained healthy enough to fulfil all their duties. Constrained by the ethic of care, and a lack of material and time resources, the mothers prioritised their family's health above their own. This study, enabled the mothers to articulate ideas for interventions that would be supportive of a healthy lifestyle and of practical application in their busy lives. CONCLUSIONS: Mothers from this low SES area responded differently to the public health guidance on diet and on physical activity. Whilst providing and modelling a healthy diet was seen as an essential part of the mother's role, participating in leisure based physical activity was problematic, and unless carefully framed, could be perceived as selfish behaviour, inappropriate for the "good" mother.

Source of Rate Acceleration for Carbocation Cyclization in Biomimetic Supramolecular Cages.

The results of quantum chemical and molecular dynamics calculations reveal that polyanionic gallium-based cages accelerate cyclization reactions of pentadienyl alcohols as a result of substrate cage interactions, preferential binding of reactive conformations of substrate/H3O+ pairs, and increased substrate basicity. However, the increase in basicity dominates. Experimental structure-activity relationship studies in which the metal vertices and overall charge of the cage are varied confirm the model derived via calculations.