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Meritocracy continues to dominate conventional thinking in the postmodern West. Yet, recently, an increasing number of critics have highlighted how meritocracy has gone wrong. One such critic is Daniel Markovits, author of The Meritocracy Trap. In this article, we highlight the major themes of Markovits’s book, identify how the ideology of meritocracy has infiltrated kinesiology and sport, and then propose how to reconceptualize and redirect kinesiology toward a more humane and morally sound discipline, which can avoid the pitfalls of the meritocracy trap. Most notably, we propose that kinesiology should (a) recognize the frailty and temporality of humans, (b) embrace the wide middle of human skill performance capabilities, (c) value mid-level jobs and occupations such as physical education teaching and YMCA and/or city recreation department positions, and (d) redefine what counts as success.

In 2019, 254 samples were collected from five aquifer systems to evaluate perfluoroalkyl and polyfluoroalkyl substance (PFAS) occurrence in groundwater used as a source of drinking water in the eastern United States. The samples were analyzed for 24 PFAS, major ions, nutrients, trace elements, dissolved organic carbon (DOC), volatile organic compounds (VOCs), pharmaceuticals, and tritium. Fourteen of the 24 PFAS were detected in groundwater, with 60 and 20% of public-supply and domestic wells, respectively, containing at least one PFAS detection. Concentrations of tritium, chloride, sulfate, DOC, and manganese + iron; percent urban land use within 500 m of the wells; and VOC and pharmaceutical detection frequencies were significantly higher in samples containing PFAS detections than in samples with no detections. Boosted regression tree models that consider 57 chemical and land-use variables show that tritium concentration, distance to the nearest fire-training area, percentage of urban land use, and DOC and VOC concentrations are the top five predictors of PFAS detections, consistent with the hydrologic position, geochemistry, and land use being important controls on PFAS occurrence in groundwater. Model results indicate that it may be possible to predict PFAS detections in groundwater using existing data sources.

Purpose: Physical education teachers often report feeling isolated due to being the only specialist in a building. Professional learning communities (PLCs) are spaces where individuals who hold shared goals come together to build connections, allowing educators to feel connected, valued, and empowered. The authors sought to explore the shared values created by a PLC and the process through which that value emerged. Method: The authors facilitated a PLC for eight physical education teachers within one midsized school district and collected interview and meeting audio data to explore the process and outcomes of the PLC. Results: Coding using a Value Creation Framework revealed themes of building common ground, support for big and small problems of practice, and an increased connection with other school faculty. Discussion: Teachers were able to build a supportive network where ideas could be traded, partner support was provided, and problems of practice were discussed.

The ancient city of Gabii—an Italian polity of the first millennium BC and a peer to early Rome—has often been presented as an example of urban decline, a counterpoint to Rome's rise from a collection of hilltop huts to a Mediterranean hegemon. Here the authors draw on the results from recent excavations at Gabii that challenge such simplistic models of urban history. Diachronic evidence documenting activity at the site over the course of 1400 years highlights shifting values and rhythms materialised in the maintenance, transformation and abandonment of different urban components. This complex picture of adaptation and resilience provides a model of ancient urbanism that calls into question outdated narratives of urban success and failure.

Mouse models of CLN3 Batten disease, a rare lysosomal storage disorder with no cure, have improved our understanding of CLN3 biology and therapeutics through their ease of use and a consistent display of cellular pathology. However, the translatability of murine models is limited by disparities in anatomy, body size, life span, and inconsistent, subtle behavior deficits that can be difficult to detect in CLN3 mutant mouse models, limiting their utility in preclinical studies. Here we present a longitudinal characterization of a novel miniswine model of CLN3 disease that recapitulates the most common human pathogenic variant, an exon 7-8 deletion (CLN3Δex7/8). Progressive pathology and neuron loss is observed in various regions of the CLN3Δex7/8 miniswine brain and retina. Additionally, mutant miniswine present with vision impairment and motor abnormalities, similar to deficits seen in human patients. Taken together, the CLN3Δex7/8 miniswine model shows consistent and progressive Batten disease pathology and behavioral impairment mirroring clinical presentation, demonstrating its value in studying the role of CLN3 and safety/efficacy of novel disease modifying therapeutics.

CLN2 Batten disease is a lysosomal disorder in which pathogenic variants in CLN2 lead to reduced activity in the enzyme tripeptidyl peptidase 1. The disease typically manifests around 2 to 4 years of age with developmental delay, ataxia, seizures, inability to speak and walk, and fatality between 6 and 12 years of age. Multiple Cln2 mouse models exist to better understand the etiology of the disease; however, these models are unable to adequately recapitulate the disease due to differences in anatomy and physiology, limiting their utility for therapeutic testing. Here, we describe a new CLN2

Microtubule-stabilizing agents (MSAs) are a class of compounds used in the treatment of triple-negative breast cancer (TNBC), a subtype of breast cancer where chemotherapy remains the standard-of-care for patients. Taxanes like paclitaxel and docetaxel have demonstrated efficacy against TNBC in the clinic, however new classes of MSAs need to be identified due to the rise of taxane resistance in patients. (−)-Zampanolide is a covalent microtubule stabilizer that can circumvent taxane resistance in vitro but has not been evaluated for in vivo antitumor efficacy. Here, we determine that (−)-zampanolide has similar potency and efficacy to paclitaxel in TNBC cell lines, but is significantly more persistent due to its covalent binding. We also provide the first reported in vivo antitumor evaluation of (−)-zampanolide where we determine that it has potent and persistent antitumor efficacy when delivered intratumorally. Future work on zampanolide to further evaluate its pharmacophore and determine ways to improve its systemic therapeutic window would make this compound a potential candidate for clinical development through its ability to circumvent taxane-resistance mechanisms.

As the bacterial multidrug resistance crisis continues, membrane-active antimicrobial peptides are being explored as an alternate treatment to conventional antibiotics. In contrast to antimicrobial peptides, which function by a nonspecific membrane disruption mechanism, here we describe a series of transmembrane (TM) peptides that are designed to act as drug efflux inhibitors by aligning with and out-competing a conserved TM4-TM4 homodimerization motif within bacterial small multidrug resistance proteins. The peptides contain two terminal tags: a C-terminal lysine tag to direct the peptides toward the negatively charged bacterial membrane, and an uncharged N-terminal sarcosine (N-methyl-glycine) tag to promote membrane insertion. While effective at inhibiting efflux activity, ostensibly through their designed mechanism of action, the impact of the peptides on the bacterial inner membrane remains undetermined. To evaluate the extant peptide-membrane interactions, we performed a series of biophysical measurements. Circular dichroism spectroscopy and Trp fluorescence showed that the peptides insert into the membrane generally in helical form. Interestingly, differential scanning calorimetry of the peptides added to bacterial-like membranes (POPE:POPG 3:1) revealed the peptides' ability to demix the POPE and POPG lipids, creating two pools, one of which is likely a peptide-POPG conglomerate, and the other a POPE-rich component where the native POPG content has been depleted. However, dye leakage assays confirmed that these events occur without causing significant membrane disruption both in vitro and in vivo, indicating that the peptides can target the small multidrug resistance TM4-TM4 motif without nonspecific membrane disruption. In related studies, DiOC

Determining the viral load and infectivity of SARS-CoV-2 in macroscopic respiratory droplets, bioaerosols, and other bodily fluids and secretions is important for identifying transmission modes, assessing risks and informing public health guidelines. Here we show that viral load of SARS-CoV-2 Ribonucleic Acid (RNA) in participants’ naso-pharyngeal (NP) swabs positively correlated with RNA viral load they emitted in both droplets >10 $$\upmu \hbox {m}$$ μ m and bioaerosols $$\upmu \hbox {m}$$ μ m directly captured during the combined expiratory activities of breathing, speaking and coughing using a standardized protocol, although the NP swabs had $$\approx$$ ≈ 10$$^3\times$$ 3 × more RNA on average. By identifying highly-infectious individuals (maximum of 18,000 PFU/mL in NP), we retrieved higher numbers of SARS-CoV-2 RNA gene copies in bioaerosol samples (maximum of 4.8$${\times }10^{5}$$ × 10 5 gene copies/mL and minimum cycle threshold of 26.2) relative to other studies. However, all attempts to identify infectious virus in size-segregated droplets and bioaerosols were negative by plaque assay (0 of 58). This outcome is partly attributed to the insufficient amount of viral material in each sample (as indicated by SARS-CoV-2 gene copies) or may indicate no infectious virus was present in such samples, although other possible factors are identified.

Poor ionic conductivity of the catalyst-binding, sub-micrometer-thick ionomer layers in energy conversion and storage devices is a huge challenge. However, ionomers are rarely designed keeping in mind the specific issues associated with nanoconfinement. Here, we designed nature-inspired ionomers (calix-2) having hollow, macrocyclic, calix[4]arene-based repeat units with precise, sub-nanometer diameter. In ≤100 nm-thick films, the in-plane proton conductivity of calix-2 was up to 8 times higher than the current benchmark ionomer Nafion at 85% relative humidity (RH), while it was 1-2 orders of magnitude higher than Nafion at 20-25% RH. Confocal laser scanning microscopy and other synthetic techniques allowed us to demonstrate the role of macrocyclic cavities in boosting the proton conductivity. The systematic self-assembly of calix-2 chains into ellipsoids in thin films was evidenced from atomic force microscopy and grazing incidence small-angle X-ray scattering measurements. Moreover, the likelihood of alignment and stacking of macrocyclic units, the presence of one-dimensional water wires across this macrocycle stacks, and thus the formation of long-range proton conduction pathways were suggested by atomistic simulations. We not only did see an unprecedented improvement in thin-film proton conductivity but also saw an improvement in proton conductivity of bulk membranes when calix-2 was added to the Nafion matrices. Nafion-calix-2 composite membranes also took advantage of the asymmetric charge distribution across calix[4]arene repeat units collectively and exhibited voltage-gating behavior. The inclusion of molecular macrocyclic cavities into the ionomer chemical structure can thus emerge as a promising design concept for highly efficient ion-conducting and ion-permselective materials for sustainable energy applications.

CLN3 Batten disease is a rare pediatric neurodegenerative lysosomal disorder caused by biallelic disease-associated variants inWe performed an exhaustive metabolomic screen using serum samples from a novel minipig model of CLN3 Batten disease and validated findings inCLN3 pig serum samples from 4 ages exhibited large elevations in 4 glycerophosphodiester species: glycerophosphoinositol (GPI), glycerophosphoethanolamine (GPE), glycerophosphocholine (GPC), and glycerophosphoserine (GPS). GPI and GPE exhibited the largest elevations, with similar elevations found inGPE and GPI could have utility as biomarkers of CLN3 disease status. GPI, in particular, shows consistent elevations across a diverse cohort of individuals with CLN3. This raises the potential to use these biomarkers as a blood-based diagnostic test or as an efficacy measure for disease-modifying therapies.

Combustion-generated particles are typically non-spherical (soot aggregates) and sometimes mixed with organic compounds (e.g. in vehicle emissions). The effective density, dynamic shape factor, and volatile mixing of particles are widely studied using aerosol instruments that measure the particle mobility diameter, aerodynamic diameter, and mass. In theory, any of these three physical properties can be obtained from a combination of the other two. In the present study, a tandem arrangement of aerodynamic aerosol classifier (AAC; measuring aerodynamic diameter), differential mobility analyzer (DMA; measuring mobility diameter), optional catalytic stripper (CS), and centrifugal particle mass analyzer (CPMA; measuring particle mass) was used to study the effective density, dynamic shape factor, and volatile mixing of non-spherical non-homogenous particles. In terms of mass, the vast majority of the particles were purely semi-volatile mixed with soot with and without semi-volatile coating. The effective density of polydisperse non-stripped particles was relatively constant (indicating nearly spherical particles), while that of polydisperse stripped particles decreased from ~1200 to ~800 kg/m³ as the particle size increased (indicating a compact structure). The effective density of monodisperse particles, measured by DMA-CPMA, AAC-DMA, and AAC-CPMA methods, was consistent within the measurement uncertainty; however, the latter method had larger discrepancy with the other two methods, particularly for non-spherical particles. The dynamic shape factor, measured by AAC-CPMA and DMA-CPMA methods, increased with the mobility diameter, a trend also supported by electron micrographs. The volatile mass fraction of particles decreased as their mobility diameter increased, with smaller particles having volatile mass fraction of ~20%. This result was further confirmed by chemical characterization of size-selected particles, proving the robustness of online aerosol measurements.

Batten disease is unique among lysosomal storage disorders for the early and profound manifestation in the central nervous system, but little is known regarding potential neuron-specific roles for the disease-associated proteins. We demonstrate substantial overlap in the protein interactomes of three transmembrane Batten proteins (CLN3, CLN6, and CLN8), and that their absence leads to synaptic depletion of key partners (i.e., SNAREs and tethers) and altered synaptic SNARE complexing in vivo, demonstrating a novel shared etiology.

PurposeThe solid tumor microenvironment (TME) drives T cell dysfunction and inhibits the effectiveness of immunotherapies such as chimeric antigen receptor-based T cell (CAR T) cells. Early data has shown that modulation of T cell metabolism can improve intratumoral T cell function in preclinical models. Experimental DesignWe evaluated GPC3 expression in human normal and tumor tissue specimens. We developed and evaluated BOXR1030, a novel CAR T therapeutic co-expressing glypican-3 (GPC3)-targeted CAR and exogenous glutamic-oxaloacetic transaminase 2 (GOT2) in terms of CAR T cell function both in vitro and in vivo. ResultsExpression of tumor antigen GPC3 was observed by immunohistochemical staining in tumor biopsies from hepatocellular carcinoma, liposarcoma, squamous lung cancer, and Merkel cell carcinoma patients. Compared to control GPC3 CAR alone, BOXR1030 (GPC3-targeted CAR T cell that co-expressed GOT2) demonstrated superior in vivo efficacy in aggressive solid tumor xenograft models, and showed favorable attributes in vitro including an enhanced cytokine production profile, a less-differentiated T cell phenotype with lower expression of stress and exhaustion markers, an enhanced metabolic profile and increased proliferation in TME-like conditions. ConclusionsTogether, these results demonstrated that co-expression of GOT2 can substantially improve the overall antitumor activity of CAR T cells by inducing broad changes in cellular function and phenotype. These data show that BOXR1030 is an attractive approach to targeting select solid tumors. To this end, BOXR1030 will be explored in the clinic to assess safety, dose-finding, and preliminary efficacy (NCT05120271). Statement of Translational RelevanceChimeric antigen receptor-based T cell (CAR T) therapeutics have revolutionized the field of oncology. Despite early successes targeting hematological malignancies, substantial challenges limit application of CAR T therapy in solid tumors, in part due to the suppressive tumor microenvironment which drives T cell exhaustion and metabolic dysfunction. Glutamic-oxaloacetic transaminase 2 (GOT2) is a mitochondrial enzyme in glutamine metabolism and contributes to cellular redox balance. Glypican-3 (GPC3) is an oncofetal tumor antigen with restricted expression on normal tissues and high prevalence in several solid tumors. We describe BOXR1030, a novel CAR T therapeutic co-expressing GPC3-targeted CAR and exogenous GOT2. Compared to T cells expressing CAR alone, BOXR1030 T cells demonstrated superior in vivo efficacy and have favorable attributes including enhanced cytokine production, a less-differentiated phenotype with lower expression of exhaustion markers, and an enhanced metabolic profile. These data support BOXR1030 as a potential treatment to explore in select solid tumor indications.

11010 Background: Oncology is a vast and fast-paced field. Fellows must expend significant effort to learn and stay updated. Up-to-date learning tools covering core oncology content in a digestible manner are lacking. Additionally, passive lectures are common in oncology, while constructivist approaches that may improve learning are rare. Therefore, we piloted updatable online modules (“scaffolds”) as a learning tool for oncology fellows. Methods: Author SB, a University of California, San Francisco (UCSF) solid-tumor oncologist, designed 12 scaffolds (breast, non-small cell lung, small cell lung, head/neck, salivary/thyroid, upper gastrointestinal, lower gastrointestinal, germ cell, bladder/renal/adrenal, prostate, melanoma, and sarcoma) using Google Slides between 12/2018 and 6/2019. The scaffolds included bullet points and tables/figures synthesized from the ASCO self-evaluation program textbook’s solid tumor chapters and the National Comprehensive Cancer Network (NCCN) guidelines. We emailed scaffold links to all UCSF and Stanford oncology fellows in 2019-2020, including instructions for fellows to update the scaffolds without exceeding 20 slides per scaffold, 5 lines per slide, or 7 words per line. The scaffolds were reintroduced to new fellows at the beginning of each academic year. SB audited to ensure no erroneous information was added. In December 2021 we reviewed updates tracked in Google Slides and conducted one UCSF and one Stanford focus group with four 1st-3rd year fellows each. Results: Between 7/2019 and 12/2021, fellows made 60 updates to the scaffolds, with a mean of 5 updates per scaffold ranging from new trials to changes in management. During the same period, the auditor made 9 updates and found no erroneous fellow updates. Fellow updates occasionally exceeded specified limits, requiring correction. Content analysis revealed that fellows considered the scaffolds to be accessible and succinct learning tools that 1) addressed a dearth of similar resources, 2) served as effective preparation for clinical work and examinations, 3) provided structured information for rapid review, and 4) made subsequent interactions with complex resources such as NCCN guidelines easier. Barriers to fellows updating the scaffolds included lack of ownership and low confidence in judgment regarding appropriate updates. Conclusions: In this two-institution pilot, oncology fellows used and subsequently updated online scaffolds in a constructivist fashion. This model has the potential to fill a crucial gap in available learning resources and can be applied to other specialties. Assigning scaffolds to fellows with faculty mentorship may facilitate ownership and bolster fellow confidence in updating these tools. Individual institutions may update their own versions of the scaffolds to align with institution-specific needs.

11011 Background: For new fellows, learning clinical oncology represents an enormous challenge. Few data support specific didactic approaches. The senior author (TPJ) developed a novel curriculum, emphasizing deliberate practice as part of a design grounded in Ericsson’s “expert performance approach”. These noon conferences are case based with a focus on key clinical trials and NCCN guidelines. In comparison to didactics given directly by faculty, these conferences are primarily presented by a senior teaching fellow with an invited faculty member adding additional commentary as an “expert discussant”. We surveyed fellows to assess perception of efficacy and also created a board style test to evaluate knowledge gains. Methods: The curriculum began in 2020. After one year, we surveyed fellows with a five-point likert scale survey to quantify their perception of the curriculum. In 2022, we created a pair of 18-question lung cancer specific board style tests for the five teaching sessions on lung cancer. Prior to the first conference, the pre-test was sent to fellows electronically; after the final lecture the other 18-question test was sent out. Differences in the overall cohort’s test score were examined via a paired student t-test. Results: On the 2021 survey, 59% of fellows responded (17 of 29). Of the respondents, 83% attended at least half of the lectures (14 of 17). When asked to compare this conference series to traditional lecture-based series, 59% (10 of 17) agreed with the statement that "this series is one of the very best I've encountered" and all said it was at least “better than average.” 94% of respondents (16 of 17) said the series equipped them for clinical practice to either a “significant” or “remarkable” degree. 94% of respondents (16 of 17) agreed the conferences helped them learn to “think like oncologists.” For the five session lung cancer block, fellows reported attending an average of 3.6 ± 1.4 sessions (n = 13). On the 18-question pre-test (n = 19), the average score ± one standard deviation was 73% ± 15%. For the post-test (n = 13), the average was 68% ± 17% (p = 0.48). Conclusions: We developed a novel curriculum to replace traditional didactics. Fellows perceived the curriculum to be exceptionally strong as compared to traditional lecture series, felt it prepared them well for practice, and said it taught them to think like oncologists. Pre/post knowledge assessments did not show an improvement in knowledge. Distribution to larger numbers of fellows–especially early learners–may better power a study to detect improvements in learning.