Clonal dynamics underlying the skewed CD4/CD8 ratio of mouse thymocytes revealed by TCR-independent barcoding

T cell differentiation in the thymus generates CD4+ helper and cytotoxic CD8+ cells as the two principal T cell lineages. Curiously, at the end of this complex selection process, CD4+ cells invariably outnumber CD8+ cells. Here, we examine the dynamics of repertoire formation and the emergence of the skewed CD4/CD8 ratio using high-resolution endogenous CRISPR/Cas9 barcoding that indelibly marks immature T cells at the DN2/DN3 pre-TCR stage. In wild-type mice, greater clone size of CD4+ cells and an intrinsically greater probability of Tcr β clonotypes for pMHCII interactions are major contributors to the skewed CD4/CD8 ratio. Clonal perturbations of thymocyte differentiation following the precocious expression of a rearranged iNKT invariant TCR α chain are due to loss of Tcr β clonotypes from the CD4 lineage-committed pre-selection repertoire. The present barcoding scheme offers a novel means to examine the clonal dynamics of lymphocyte differentiation orthogonal to that using TCR clonotypes

Developmental dynamics of two bipotent thymic epithelial progenitor types

T cell development in the thymus is essential for cellular immunity and depends on the organotypic thymic epithelial microenvironment. In comparison with other organs, the size and cellular composition of the thymus are unusually dynamic, as exemplified by rapid growth and high T cell output during early stages of development, followed by a gradual loss of functional thymic epithelial cells and diminished naive T cell production with age. Single-cell RNA sequencing (scRNA-seq) has uncovered an unexpected heterogeneity of cell types in the thymic epithelium of young and aged adult mice; however, the identities and developmental dynamics of putative pre- and postnatal epithelial progenitors have remained unresolved. Here we combine scRNA-seq and a new CRISPR–Cas9-based cellular barcoding system in mice to determine qualitative and quantitative changes in the thymic epithelium over time. This dual approach enabled us to identify two principal progenitor populations: an early bipotent progenitor type biased towards cortical epithelium and a postnatal bipotent progenitor population biased towards medullary epithelium. We further demonstrate that continuous autocrine provision of Fgf7 leads to sustained expansion of thymic microenvironments without exhausting the epithelial progenitor pools, suggesting a strategy to modulate the extent of thymopoietic activity

Axial Involvement in Psoriatic Arthritis cohort (AXIS): the protocol of a joint project of the Assessment of SpondyloArthritis international Society (ASAS) and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).

BACKGROUND: Involvement of the axial skeleton (sacroiliac joints and spine) is a relatively frequent manifestation associated with psoriatic skin disease, mostly along with involvement of peripheral musculoskeletal structures (peripheral arthritis, enthesitis, dactylitis), which are referred to as psoriatic arthritis (PsA). Data suggest that up to 30% of patients with psoriasis have PsA. Depending on the definition used, the prevalence of axial involvement varies from 25% to 70% of patients with PsA. However, there are currently no widely accepted criteria for axial involvement in PsA.Objective: The overarching aim of the Axial Involvement in Psoriatic Arthritis (AXIS) study is to systematically evaluate clinical and imaging manifestations indicative of axial involvement in patients with PsA and to develop classification criteria and a unified nomenclature for axial involvement in PsA that would allow defining a homogeneous subgroup of patients for research. DESIGN: Prospective, multicenter, multinational, cross-sectional study. METHODS AND ANALYSES: In this multicenter, multinational, cross-sectional study, eligible patients [adult patients diagnosed with PsA and fulfilling Classification Criteria for Psoriatic Arthritis (CASPAR) with musculoskeletal symptom duration of ⩽10 years not treated with biological or targeted synthetic disease-modifying anti-rheumatic drugs] will be recruited prospectively. They will undergo study-related clinical and imaging examinations. Imaging will include radiography and magnetic resonance imaging examinations of sacroiliac joints and spine. Local investigators will evaluate for the presence of axial involvement based on clinical and imaging information which will represent the primary outcome of the study. In addition, imaging will undergo evaluation by central review. Finally, the central clinical committee will determine the presence of axial involvement based on all available information. ETHICS: The study will be performed according to the ethical principles of the Declaration of Helsinki and International Council for Harmonisation Good Clinical Practice guidelines. The study protocol will be approved by the individual Independent Ethics Committee / Institutional Review Board of participating centers. Written informed consent will be obtained from all included patients.Registration: ClinicalTrials.gov ID: NCT04434885

Axial Involvement in Psoriatic Arthritis cohort (AXIS): the protocol of a joint project of the Assessment of SpondyloArthritis international Society (ASAS) and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).

BACKGROUND: Involvement of the axial skeleton (sacroiliac joints and spine) is a relatively frequent manifestation associated with psoriatic skin disease, mostly along with involvement of peripheral musculoskeletal structures (peripheral arthritis, enthesitis, dactylitis), which are referred to as psoriatic arthritis (PsA). Data suggest that up to 30% of patients with psoriasis have PsA. Depending on the definition used, the prevalence of axial involvement varies from 25% to 70% of patients with PsA. However, there are currently no widely accepted criteria for axial involvement in PsA.Objective: The overarching aim of the Axial Involvement in Psoriatic Arthritis (AXIS) study is to systematically evaluate clinical and imaging manifestations indicative of axial involvement in patients with PsA and to develop classification criteria and a unified nomenclature for axial involvement in PsA that would allow defining a homogeneous subgroup of patients for research. DESIGN: Prospective, multicenter, multinational, cross-sectional study. METHODS AND ANALYSES: In this multicenter, multinational, cross-sectional study, eligible patients [adult patients diagnosed with PsA and fulfilling Classification Criteria for Psoriatic Arthritis (CASPAR) with musculoskeletal symptom duration of ⩽10 years not treated with biological or targeted synthetic disease-modifying anti-rheumatic drugs] will be recruited prospectively. They will undergo study-related clinical and imaging examinations. Imaging will include radiography and magnetic resonance imaging examinations of sacroiliac joints and spine. Local investigators will evaluate for the presence of axial involvement based on clinical and imaging information which will represent the primary outcome of the study. In addition, imaging will undergo evaluation by central review. Finally, the central clinical committee will determine the presence of axial involvement based on all available information. ETHICS: The study will be performed according to the ethical principles of the Declaration of Helsinki and International Council for Harmonisation Good Clinical Practice guidelines. The study protocol will be approved by the individual Independent Ethics Committee / Institutional Review Board of participating centers. Written informed consent will be obtained from all included patients.Registration: ClinicalTrials.gov ID: NCT04434885

Axial Involvement in Psoriatic Arthritis cohort (AXIS): the protocol of a joint project of the Assessment of SpondyloArthritis international Society (ASAS) and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)

Background: Involvement of the axial skeleton (sacroiliac joints and spine) is a relatively frequent manifestation associated with psoriatic skin disease, mostly along with involvement of peripheral musculoskeletal structures (peripheral arthritis, enthesitis, dactylitis), which are referred to as psoriatic arthritis (PsA). Data suggest that up to 30% of patients with psoriasis have PsA. Depending on the definition used, the prevalence of axial involvement varies from 25% to 70% of patients with PsA. However, there are currently no widely accepted criteria for axial involvement in PsA.Objective: The overarching aim of the Axial Involvement in Psoriatic Arthritis (AXIS) study is to systematically evaluate clinical and imaging manifestations indicative of axial involvement in patients with PsA and to develop classification criteria and a unified nomenclature for axial involvement in PsA that would allow defining a homogeneous subgroup of patients for research.Design: Prospective, multicenter, multinational, cross-sectional study.Methods and analyses: In this multicenter, multinational, cross-sectional study, eligible patients [adult patients diagnosed with PsA and fulfilling Classification Criteria for Psoriatic Arthritis (CASPAR) with musculoskeletal symptom duration of <= 10 years not treated with biological or targeted synthetic disease-modifying anti-rheumatic drugs] will be recruited prospectively. They will undergo study-related clinical and imaging examinations. Imaging will include radiography and magnetic resonance imaging examinations of sacroiliac joints and spine. Local investigators will evaluate for the presence of axial involvement based on clinical and imaging information which will represent the primary outcome of the study. In addition, imaging will undergo evaluation by central review. Finally, the central clinical committee will determine the presence of axial involvement based on all available information.Ethics: The study will be performed according to the ethical principles of the Declaration of Helsinki and International Council for Harmonisation Good Clinical Practice guidelines. The study protocol will be approved by the individual Independent Ethics Committee / Institutional Review Board of participating centers. Written informed consent will be obtained from all included patients.Pathophysiology and treatment of rheumatic disease

Brain Imaging of Pain

The brain is the principal processor of internal and external sensory experiences including pain. Pain is a multidimensional experience influenced by complex interactions among multiple processes including nociception (the afferent neural activity transmitting sensory information about noxious stimuli), cognitive appraisals (expectation, attention), and emotional aspects (affect)

Factors influencing engineering students’ decisions to cheat by type of assessment

Academic dishonesty (cheating) has been prevalent on college campuses for decades, and the percentage of students reporting cheating varies by college major. This study, based on a survey of 643 undergraduate engineering majors at 11 institutions, used two parallel hierarchical multiple regression analyses to predict the frequency of cheating on exams and the frequency of cheating on homework based on eight blocks of independent variables: demographics, pre-college cheating behavior, co-curricular participation, plus five blocks organized around Ajzen’s Theory of Planned Behavior (moral obligation not to cheat, attitudes about cheating, evaluation of the costs and benefits of cheating, perceived social pressures to cheat or not to cheat, and perceived effectiveness of academic dishonesty policies). The final models significantly predict 36% of the variance in “frequency of cheating on exams” and 14% of the variance in “frequency of cheating on homework”. Students don’t see cheating as a single construct and their decisions to cheat or not to cheat are influenced differently depending on the type of assessment. Secondary findings are that a student’s conviction that cheating is wrong no matter what the circumstances is a strong deterrent to cheating across types of assessment and that a student who agrees that he/she would cheat in order to alleviate stressful situations is more likely to cheat on both exams and homework.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42694/1/11162_2006_Article_9010.pd

The primary structure of the Pol-RFamide neuropeptide precursor protein from the hydromedusa Polyorchis penicillatus indicates a novel processing proteinase activity.

Neuropeptides containing the C-terminal sequence Arg-Phe-NH2 (RFamide) occur throughout the Animal Kingdom and are abundant in evolutionarily 'old' nervous systems such as those of cnidarians. From the hydromedusa Polyorchis penicillatus we have previously isolated two neuropeptides, Pol-RFamide I (<Glu-Leu-Leu-Gly-Gly-Arg-Phe-NH2) and Pol-RFamide II (<Glu-Trp-Leu-Lys-Gly-Arg-Phe-NH2). Here we describe the cloning of a common precursor protein for these peptides from P. penicillatus. The precursor protein contains one copy of Pol-RFamide I, 11 copies of Pol-RFamide II and one putative neuropeptide sequence. The Pol-RFamide I sequence is flanked by pairs of basic residues (Arg-Lys). At the C-termini of all Pol-RFamide II sequences, single basic residues (Arg) occur. Paired and single basic residues are established sites for post-translational precursor cleavage. At the N-termini of the Pol-RFamide II sequences, however, basic residues are lacking and, instead, either single Asp (in eight cases) or single Asn residues (in three cases) occur. This means that processing must take place at Asp and/or Asn residues. This is firm evidence for the presence of one or more unconventional processing enzymes. The first type of processing enzyme could be an endoproteinase or aminopeptidase hydrolysing at the C-terminal side of Asp residues. Proteolytic cleavage at acidic amino acid residues has previously been inferred from other cnidarian neuropeptide precursors. The second type of processing enzyme could be an endoproteinase or aminopeptidase hydrolysing at the C-terminal side of Asn residues