Purpose: Racial inequality in school discipline is an important challenge facing educational stakeholders. There is little research on how educators exercise discretion in navigating the disciplinary ...process from perceived misbehavior to disciplinary consequences. Research Methods/Approach: This study draws primarily on semistructured interviews with district leaders, school administrators, and teachers in an urban emergent district in the southeastern United States to examine how principals, assistant principals, and teachers relate to and interact with each other in determining students' disciplinary consequences. Findings: The findings illustrate the variation of administrators' disciplinary philosophies across interventionist, interactionalist, and noninterventionist tendencies. Relationships and interactions among school leaders and teachers are a major component of the organizational dynamics underlying how perceived misbehavior is handled in schools. School-level decisions about the generation and adjudication of office discipline referrals are the product of interactional patterns and relationships among adults in schools that partly shape discretion and accountability in disciplinary decisions. The findings unearth two key tensions--disciplinary philosophical tensions and discretion and accountability for office discipline referrals tensions--among district leaders, school administrators, and teachers navigating referrals and further disciplinary consequences. Implications: More intensive on-the-job support for both school leaders and teachers is needed to reduce racial inequality in suspensions. Developing the professional capacity of teachers and school leaders through mentoring, coaching, and professional development is crucial to replacing exclusionary discipline with nonpunitive practices. Districts ought to prioritize supporting school leaders in developing and expanding their professional capacity, who in turn support teachers in addressing school discipline challenges.
Chimeric antigen receptor (CAR) T cell therapy has been successful in clinical trials against hematological cancers, but has experienced challenges in the treatment of solid tumors. One of the main ...difficulties lies in a paucity of tumor-specific targets that can serve as CAR recognition domains. We therefore focused on developing VHH-based, single-domain antibody (nanobody) CAR T cells that target aspects of the tumor microenvironment conserved across multiple cancer types. Many solid tumors evade immune recognition through expression of checkpoint molecules, such as PD-L1, that down-regulate the immune response. We therefore targeted CAR T cells to the tumor microenvironment via the checkpoint inhibitor PD-L1 and observed a reduction in tumor growth, resulting in improved survival. CAR T cells that target the tumor stroma and vasculature through the EIIIB⁺ fibronectin splice variant, which is expressed by multiple tumor types and on neovasculature, are likewise effective in delaying tumor growth. VHH-based CAR T cells can thus function as antitumor agents for multiple targets in syngeneic, immunocompetent animal models. Our results demonstrate the flexibility of VHH-based CAR T cells and the potential of CAR T cells to target the tumor microenvironment and treat solid tumors.
We use a tetrahedral color space to describe and analyze male plumage color variation and evolution in a clade of New World buntings—CyanocompsaandPasserina(Aves: Cardinalidae). The Goldsmith color ...space models the relative stimulation of the four retinal cones, using the integrals of the product of plumage reflectance spectra and cone sensitivity functions. A color is represented as a vector defined by the relative stimulation of the four cone types—ultraviolet, blue, green, and red. Color vectors are plotted in a tetrahedral, or quaternary, plot with the achromatic point at the origin and the ultraviolet/violet channel along theZ‐axis. Each color vector is specified by the spherical coordinates θ, φ, andr. Hue is given by the angles θ and φ. Chroma is given by the magnitude ofr, the distance from the achromatic origin. Color vectors of all distinct patches in a plumage characterize the plumage color phenotype. We describe the variation in color space occupancy of male bunting plumages, using various measures of color contrast, hue contrast and diversity, and chroma. Comparative phylogenetic analyses using linear parsimony (in MacClade) and generalized least squares (GLS) models (in CONTINUOUS) with a molecular phylogeny of the group document that plumage color evolution in the clade has been very dynamic. The single best‐fit GLS evolutionary model of plumage color variation over the entire clade is a directional change model with no phylogenetic correlation among species. However, phylogenetic innovations in feather color production mechanisms—derived pheomelanin and carotenoid expression in two lineages—created new opportunities to colonize novel areas of color space and fostered the explosive differentiation in plumage color. Comparison of the tetrahedral color space of Goldsmith with that of Endler and Mielke demonstrates that both provide essentially identical results. Evolution of avian ultraviolet/violet opsin sensitivity in relation to chromatic experience is discussed.
Physical and psychological changes during menopause can be especially tumultuous for autistic people: difficulties with sensory sensitivity and daily functioning may be exacerbated. Through ...individual interviews, we examined the language used by seven peri- or post-menopausal autistic people to construct their experiences, and to consider the implications for their wellbeing and identities. Our analysis, which utilised thematic decomposition, yielded three discursive themes. The theme “Uncertainty about Changes” addressed how limited awareness and understanding of menopause combined with difficulties recognising internal states. However, with “Growing Self-Awareness and Self-Care”, some participants made conscious efforts to resist negative societal constructions of both autism and menopause. The theme “Navigating Support Options” addressed the interpersonal and systemic barriers participants faced when seeking support. There is a need for accessible information for autistic people experiencing menopause, and greater professional awareness.
Being one of the main proteins in the human body and many animal species, albumin plays a decisive role in the transport of various ions—electrically neutral and charged molecules—and in maintaining ...the colloidal osmotic pressure of the blood. Albumin is able to bind to almost all known drugs, as well as many nutraceuticals and toxic substances, largely determining their pharmaco- and toxicokinetics. Albumin of humans and respective representatives in cattle and rodents have their own structural features that determine species differences in functional properties. However, albumin is not only passive, but also an active participant of pharmacokinetic and toxicokinetic processes, possessing a number of enzymatic activities. Numerous experiments have shown esterase or pseudoesterase activity of albumin towards a number of endogeneous and exogeneous esters. Due to the free thiol group of Cys34, albumin can serve as a trap for reactive oxygen and nitrogen species, thus participating in redox processes. Glycated albumin makes a significant contribution to the pathogenesis of diabetes and other diseases. The interaction of albumin with blood cells, blood vessels and tissue cells outside the vascular bed is of great importance. Interactions with endothelial glycocalyx and vascular endothelial cells largely determine the integrative role of albumin. This review considers the esterase, antioxidant, transporting and signaling properties of albumin, as well as its structural and functional modifications and their significance in the pathogenesis of certain diseases.
The kynurenine pathway of tryptophan degradation contributes to the differentiation of T lymphocytes, thereby influencing immune system activity, tolerance, and inflammation.The rate-limiting enzyme ...of the kynurenine pathway in immune cells, indoleamine 2,3-dioxygenase (IDO), has been considered to be a therapeutic target in cancer although clinical trials of IDO inhibitors have largely failed.The aryl hydrocarbon receptor (AHR) is thought to be the principal receptor through which kynurenine signals, although kynurenic acid is also a ligand for G protein-coupled receptor 35.Indoles, generated by commensal microbes, also serve as AHR agonists and therefore are likely to influence immune homeostasis as well as anticancer immunity.
Lymphocytes maturing in the thymus (T cells) are key factors in adaptive immunity and the regulation of inflammation. The kynurenine pathway of tryptophan metabolism includes several enzymes and compounds that can modulate T cell function, but manipulating these pharmacologically has not achieved the expected therapeutic activity for the treatment of autoimmune disorders and cancer. With increasing knowledge of other pathways interacting with kynurenines, the expansion of screening methods, and the application of virtual techniques to understanding enzyme structures and mechanisms, details of interactions between kynurenines and other pathways are being revealed. This review surveys some of these alternative approaches to influence T cell function indirectly via the kynurenine pathway and summarizes the most recent work on the development of compounds acting directly on the kynurenine pathway.
Checkpoint blockade immunotherapies can be extraordinarily effective, but might benefit only the minority of patients whose tumors are pre-infiltrated by T cells. Here, using lung adenocarcinoma ...mouse models, including genetic models, we show that autochthonous tumors that lacked T cell infiltration and resisted current treatment options could be successfully sensitized to host antitumor T cell immunity when appropriately selected immunogenic drugs (e.g., oxaliplatin combined with cyclophosphamide for treatment against tumors expressing oncogenic Kras and lacking Trp53) were used. The antitumor response was triggered by direct drug actions on tumor cells, relied on innate immune sensing through toll-like receptor 4 signaling, and ultimately depended on CD8+ T cell antitumor immunity. Furthermore, instigating tumor infiltration by T cells sensitized tumors to checkpoint inhibition and controlled cancer durably. These findings indicate that the proportion of cancers responding to checkpoint therapy can be feasibly and substantially expanded by combining checkpoint blockade with immunogenic drugs.
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•Kras/Trp53 mutant tumors lack CD8+ T cells and resist chemo- and immunotherapies•Immunogenic chemotherapy elicits tumor T cell infiltration and controls cancer growth•Tumor control requires CD8+ T cells, TLR4+ cells, and drug actions on cancer cells•T cell influx sensitizes tumors to checkpoint inhibition and durably controls cancer
There is an urgent need to expand the proportion of patients that respond to immune checkpoint therapy. Using clinically relevant genetic mouse models and a combination of immunogenic drugs to trigger T cell infiltration into tumors, Pittet and colleagues are able to make unresponsive tumors sensitive to checkpoint blockade therapy.
Abstract
Aims
The alcohol abstinence challenge ‘Dry January’ continues to grow, but there is a lack of knowledge of how Dry January participants compare to the general population. There is also a ...need to determine whether benefits experienced by Dry January participants are unique to that group or are also observed among other people.
Methods
We conducted a prospective cohort study using online questionnaires in early January, February and August 2019. We compared 1192 Dry January participants and 1549 adult drinkers who did not attempt to abstain from alcohol. Key outcomes were self-rated physical health, psychological well-being (Warwick–Edinburgh Mental Well-Being Scale), control over drinking (Drink Refusal Self-Efficacy Scale (DRSE)) and alcohol intake (Alcohol Use Disorders Identification Test–Consumption (AUDIT-C) subscale). Baseline differences in demographic and alcohol consumption variables were included as covariates in between-group analyses.
Results
Dry January participants had higher SES, poorer well-being, higher AUDIT-C scores and less control over their drinking than the general population. Beneficial changes in health, WEMWBS, DRSE and AUDIT-C observed among people completing Dry January were not observed among other adult drinkers.
Conclusions
Dry January appears to attract people who are heavier drinkers than the general population and who are more concerned about their alcohol intake. Completion of Dry January is associated with short- and longer-term benefits to well-being that are not observed in the general population.
This study explored whether participation in temporary alcohol abstinence challenges conveys health benefits not observed in the general population. This was done via a 7-month prospective study comparing 1192 ‘Dry January’ participants to 1549 non-participants. Completion of Dry January is associated with health benefits not observed in the general population.
The SARS-CoV-2 beta coronavirus is the etiological driver of COVID-19 disease, which is primarily characterized by shortness of breath, persistent dry cough, and fever. Because they transport oxygen, ...red blood cells (RBCs) may play a role in the severity of hypoxemia in COVID-19 patients. The present study combines state-of-the-art metabolomics, proteomics, and lipidomics approaches to investigate the impact of COVID-19 on RBCs from 23 healthy subjects and 29 molecularly diagnosed COVID-19 patients. RBCs from COVID-19 patients had increased levels of glycolytic intermediates, accompanied by oxidation and fragmentation of ankyrin, spectrin beta, and the N-terminal cytosolic domain of band 3 (AE1). Significantly altered lipid metabolism was also observed, in particular, short- and medium-chain saturated fatty acids, acyl-carnitines, and sphingolipids. Nonetheless, there were no alterations of clinical hematological parameters, such as RBC count, hematocrit, or mean corpuscular hemoglobin concentration, with only minor increases in mean corpuscular volume. Taken together, these results suggest a significant impact of SARS-CoV-2 infection on RBC structural membrane homeostasis at the protein and lipid levels. Increases in RBC glycolytic metabolites are consistent with a theoretically improved capacity of hemoglobin to off-load oxygen as a function of allosteric modulation by high-energy phosphate compounds, perhaps to counteract COVID-19-induced hypoxia. Conversely, because the N-terminus of AE1 stabilizes deoxyhemoglobin and finely tunes oxygen off-loading and metabolic rewiring toward the hexose monophosphate shunt, RBCs from COVID-19 patients may be less capable of responding to environmental variations in hemoglobin oxygen saturation/oxidant stress when traveling from the lungs to peripheral capillaries and vice versa.
In their roles as major adhesion receptors, integrins signal across the plasma membrane in both directions. Recent structural and cell biological data suggest models for how integrins transmit ...signals between their extracellular ligand binding adhesion sites and their cytoplasmic domains, which link to the cytoskeleton and to signal transduction pathways. Long-range conformational changes couple these functions via allosteric equilibria.
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