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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.

Mutations in CLN3 lead to photoreceptor cell loss in CLN3 disease, a lysosomal storage disorder characterized by childhood-onset vision loss, neurological impairment, and premature death. However, how CLN3 mutations cause photoreceptor cell death is not known. Here, we show that CLN3 is required for phagocytosis of photoreceptor outer segment (POS) by retinal pigment epithelium (RPE) cells, a cellular process essential for photoreceptor survival. Specifically, a proportion of CLN3 in human, mouse, and iPSC-RPE cells localized to RPE microvilli, the site of POS phagocytosis. Furthermore, patient-derived CLN3 disease iPSC-RPE cells showed decreased RPE microvilli density and reduced POS binding and ingestion. Notably, POS phagocytosis defect in CLN3 disease iPSC-RPE cells could be rescued by wild-type CLN3 gene supplementation. Altogether, these results illustrate a novel role of CLN3 in regulating POS phagocytosis and suggest a contribution of primary RPE dysfunction for photoreceptor cell loss in CLN3 disease that can be targeted by gene therapy., CLN3 disease is characterised by childhood-onset vision loss and premature death. Using patient-derived retinal cells, the authors show that CLN3 is required for retinal pigment epithelium (RPE) cell structure, microvilli and phagocytosis of photoreceptor outer segments that are essential for vision. They further suggest that gene-therapy targeting RPE cells can be effective for CLN3 disease.

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.

CLN3 Batten disease is an autosomal recessive, neurodegenerative, lysosomal storage disease caused by mutations in CLN3, which encodes a lysosomal membrane protein(1–3). There are no disease-modifying treatments for this disease that affects up to 1 in 25,000 births, has an onset of symptoms in early childhood and typically is fatal by 20–30 years of life(4–7). Most patients with CLN3 Batten have a deletion encompassing exons 7 and 8 (CLN3(Δex7/8)), creating a reading frame-shift(7,8). Here we demonstrate that mice with this deletion can be effectively treated using an antisense oligonucleotide (ASO) that induces exon skipping to restore the open reading frame. A single treatment of neonatal mice with an exon 5-targeted ASO-induced robust exon skipping for more than a year, improved motor coordination, reduced histopathology in Cln3(Δex7/8) mice and increased survival in a new mouse model of the disease. ASOs also induced exon skipping in cell lines derived from patients with CLN3 Batten disease. Our findings demonstrate the utility of ASO-based reading-frame correction as an approach to treat CLN3 Batten disease and broaden the therapeutic landscape for ASOs in the treatment of other diseases using a similar strategy.

CLN3 Batten disease (CLN3 disease) is a pediatric lysosomal storage disorder that presents with progressive blindness, motor and cognitive decline, seizures, and premature death. CLN3 disease results from mutations in CLN3 with the most prevalent mutation, a 966 bp deletion spanning exons 7–8, affecting ~ 75% of patients. Mouse models with complete Cln3 deletion or Cln3Δex7/8 mutation have been invaluable for learning about both the basic biology of CLN3 and the underlying pathological changes associated with CLN3 disease. These models, however, vary in their disease presentation and are limited in their utility for studying the role of nonsense mediated decay, and as a consequence, in testing nonsense suppression therapies and read-through compounds. In order to develop a model containing a disease-causing nonsense point mutation, here we describe a first-of-its-kind Cln3Q352X mouse model containing a c.1054C > T (p.Gln352Ter) point mutation. Similar to previously characterized Cln3 mutant mouse lines, this novel model shows pathological deficits throughout the CNS including accumulation of lysosomal storage material and glial activation, and has limited perturbation in behavioral measures. Thus, at the molecular and cellular level, this mouse line provides a valuable tool for testing nonsense suppression therapies or read through compounds in CLN3 disease in the future.

Background Dogs with protein-losing nephropathy (PLN) are treated with antiplatelet drugs for thromboprophylaxis but no standardized method exists to measure drug response. It is also unknown if clopidogrel metabolite concentrations [CM] differ between healthy and PLN dogs. Objectives Assess response to aspirin or clopidogrel in PLN dogs using platelet aggregometry (PA) and compare [CM] between healthy and PLN dogs. Animals Six healthy and 14 PLN dogs. Methods Platelet aggregometry using adenosine diphosphate (ADP), arachidonic acid (AA), and saline was performed in healthy dogs at baseline and 1-week postclopidogrel administration to identify responders or nonresponders. A decrease of ≥60% for ADP or ≥30% for AA at 1 or 3 hours postpill was used to define a responder. At 1 and 3 hours postclopidogrel, [CM] and PA were measured in healthy and PLN dogs. Platelet aggregometry was performed in PLN dogs at baseline, 1, 6, and 12 weeks after clopidogrel or aspirin administration. Results In PLN dogs receiving clopidogrel, PA differed from baseline at all time points for ADP but not for AA at any time point. Most dogs responded at 1 or both time points except for 1 dog that showed no response. For PLN dogs receiving aspirin, no differences from baseline were observed at any time point for either ADP or AA. No differences in [CM] were found at either time point between healthy and PLN dogs. Conclusions and clinical importance Platelet aggregometry may represent an objective method to evaluate response to clopidogrel or aspirin treatment and PLN dogs appear to metabolize clopidogrel similarly to healthy dogs.

Reinvestigation of mycothiazole (1) revealed picomolar potency (IC50 = 0.00016, 0.00027, 0.00035 μM) against pancreatic, (PANC-1), liver (HepG2), and colon (HCT-116) tumor cell lines. Reevaluation of 1 provided [α]D data indicating Vanuatu specimens of C. mycofijiensis contain the 8S enantiomer of 1 and not the 8R configuration previously reported. Semisynthesis provided 8-O-acetylmycothiazole (2), 8-oxomycothiazole (8), mycothiazole nitrosobenzene derivatives (MND1, MND2: 9a, 9b), and MND3 (10) with IC50 = 0.00129, >1.0, >1.0, >1.0, >1.0 μM, respectively, against PANC-1 cell lines. These results highlight the significance of the penta-2,4-dien-1-ol residue as a key structural feature of 1 required for its cytotoxicty against tumor cell lines.

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.

As neurons establish extensive connections throughout the central nervous system, the transport of cargo along the microtubule network of the axon is crucial for differentiation and homeostasis. Specifically, building blocks such as membrane and cytoskeletal components, organelles, transmembrane receptors, adhesion molecules, and peptide neurotransmitters all require proper transport to the presynaptic compartment. Here, we identify a novel complex regulating vesicular endoplasmic reticulum transport in neurites, composed of CLN6: an ER-associated protein of relatively unknown function implicated in CLN6-Batten disease; CRMP2: a tubulin binding protein important in regulating neurite microtubule dynamics; and KLC4: a classic transport motor protein. We show that this “CCK” complex allows ER-derived vesicles to migrate to the distal end of the axon, aiding in proper neurite outgrowth and arborization. In the absence of CLN6, the CCK complex does not function effectively, leading to reduced vesicular transport, stunted neurite outgrowth, and deficits in CRMP2 binding to other protein partners. Treatment with a CRMP2 modulating compound, lanthionine ketimine ester, partially restores these deficits in CLN6-deficient mouse neurons, indicating that stabilization of CRMP2 interacting partners may prove beneficial in lieu of complete restoration of the CCK complex. Taken together, these findings reveal a novel mechanism of ER-derived vesicle transport in the axon and provide new insights into therapeutic targets for neurodegenerative disease.

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 aberrant synaptic SNARE dynamics in vivo, demonstrating a novel shared etiology.

Most Americans receive their drinking water from publicly supplied sources, a large portion of it from groundwater. Mapping these populations consistently and at a high resolution is important for understanding where the resource is used and needs to be protected. The results show that 269 million people are supplied by public supply, 107 million are supplied by groundwater and 162 million are supplied by surface water. The population using public supply drinking water was mapped in two ways: the census enhanced method (CEM) evenly distributes the population across populated census blocks, and the urban land-use enhanced method (ULUEM) distributes the population only to certain urban land use designations. In addition, a two-dimensional polygon dataset was created for the conterminous U.S. that identifies 177 unique Hydrogeologic Mapping Units (HMUs) with similar hydrogeologic characteristics. The HMUs do not overlap, but they can delineate areas where stacked hydrogeologic regions (HRs) contribute drinking water from below the surface. HRs are waterbearing geologic regions identified as either a principal aquifers (PA) or secondary hydrogeologic regions (SHR). Within each HMU, the wells were used to determine the proportion of each HR that is providing groundwater to the HMU. In 63% of the HMUs, a single HR is providing water to the public supply wells located within it, while the rest of the HMUs show that the wells are tapping up to a maximum of four stacked HRs. In total, groundwater from 108 HRs provide drinking water for public supply, six of which provide more than 50% of the groundwater used for public supply drinking water. The aquifer serving the largest number of equivalent people (>17 million) is the glacial aquifer. The HR providing the greatest number of people per km2 is the Biscayne aquifer in Florida at nearly 453 people per km2.