Tissue determinants of the human T cell receptor repertoire.

98% of T cells reside in tissues, yet nearly all human T cell analyses are performed from peripheral blood. We single-cell sequenced 5.7 million T cells from ten donors' autologous blood and tonsils and sought to answer key questions about T cell receptor biology previously unanswerable by smaller-scale experiments. We identified distinct clonal expansions and distributions in blood compared to tonsils, with surprisingly low (1-7%) clonal sharing. These few shared clones exhibited divergent phenotypes across bodily sites. Analysis of antigen-specific CD8 T cells revealed location as a main determinant of frequency, phenotype, and immunodominance. Finally, diversity estimates from the tissue recalibrates current repertoire diversity estimates, and we provide a refined estimate of whole-body repertoire. Given the tissue-restricted nature of T cell phenotypes, functions, differentiation, and clonality revealed by this dataset, we conclude that tissue analyses are crucial for accurate repertoire analysis and monitoring changes after perturbing therapies.

From Rhetoric to Action: Justice, Equity, Diversity, and Inclusion in Coordinated Specialty Care for Early Psychosis.

Attention to inclusivity and equity in health research and clinical practice has grown in recent years; however, coordinated specialty care (CSC) for early psychosis lags in efforts to improve equity despite evidence of ongoing disparities and inequities in CSC care. This Open Forum argues that marginalization and disparities in early psychosis research and clinical care are interrelated, and the authors provide suggestions for paths forward. Commitment to equity and justice demands recentering the perspectives of those most affected by early psychosis services and investing in the integration of historically excluded perspectives across all aspects of practice, policy, and research.

Cis-regulatory evolution of the recently expanded Ly49 gene family.

Comparative genomics has revealed the rapid expansion of multiple gene families involved in immunity. Members within each gene family often evolved distinct roles in immunity. However, less is known about the evolution of their epigenome and cis-regulation. Here we systematically profile the epigenome of the recently expanded murine Ly49 gene family that mainly encode either inhibitory or activating surface receptors on natural killer cells. We identify a set of cis-regulatory elements (CREs) for activating Ly49 genes. In addition, we show that in mice, inhibitory and activating Ly49 genes are regulated by two separate sets of proximal CREs, likely resulting from lineage-specific losses of CRE activity. Furthermore, we find that some Ly49 genes are cross-regulated by the CREs of other Ly49 genes, suggesting that the Ly49 family has begun to evolve a concerted cis-regulatory mechanism. Collectively, we demonstrate the different modes of cis-regulatory evolution for a rapidly expanding gene family.

Symptom contributors to quality of life in schizophrenia: Exploratory factor and network analyses.

Individuals with schizophrenia and other associated disorders experience significant disturbance to their quality of life (QoL) due to a multitude of co-occurring symptoms. Popular evidence-based practices (EBPs) devote significant effort to reduce positive symptomatology in order to prevent relapse, while emerging research posits that other symptoms (cognitive deficits, negative and affective symptoms) are more indicative of QoL disturbance. This study sought to examine the impact of symptom constructs on QoL and attempt to infer directionality of influence via network analysis. A total of 102 recovery phase adult outpatients with schizophrenia spectrum disorders were assessed on positive, negative, and affective symptomatology, in addition to QoL and cognitive abilities. Exploratory factor analysis and network analysis were performed to identify associations and infer directed influence between symptom constructs, and a directed acyclic graph was constructed to observe associations between symptom domains and QoL. Factor analysis results indicated that individual measures align with their respective symptom constructs. Strong factor correlations were found between QoL and the negative and affective symptom constructs, with weaker associations found between positive symptoms and cognition. Visualization of the network structure illustrated QoL as the central cluster of the network, and examination of the weighted edges found the strongest connectivity between QoL, negative symptomatology, and affective symptoms. More severe negative and affective symptoms were most directly linked with poorer QoL and may prove to be integral in attaining positive outcomes in schizophrenia treatment. Incorporation of psychosocial treatments in addition to pharmacotherapy may prove effective in targeting negative and affective symptoms.

Promoting skill use in skill enhanced cognitive behavioral therapy: A case example.

Cognitive behavioral therapy (CBT) appears to achieve its effects at least in part by fostering the development of CBT skills. In an effort to leverage CBT skill development, our group developed and tested a skill-enhanced version of CBT (CBT-SE) in a recent trial. In this paper, we describe our work with a client who participated in a 12-week course of CBT-SE as part of that trial. Although homework is a critical aspect of CBT, the greater emphasis on skill development in CBT-SE means that homework is even more central. This client's course of treatment illustrates the potential benefits of a strong focus on skill development and the use of specific homework assignments to foster mastery and ongoing use of CBT skills. The client developed CBT skills at a rapid pace early in treatment and exhibited enduring symptom reductions. The experience of this client reinforces the value of a focus on CBT skills and highlights strategies for fostering skill development. Given the evidence in support of the therapeutic value of CBT skills and the well-established benefits of homework assignment, we encourage use of skill enhancing procedures, including in-session procedures and assignments that help clients develop and maintain ongoing skill use.

High-Temperature Intrinsic Defect Chemistry of Li8PbO6 Ceramic Breeding Material.

Understanding the intrinsic defect chemistry of tritium breeder materials proposed for use in future fusion reactors is imperative, as certain defects may act as traps leading to retention of tritium in the ceramic matrix. In this paper, we use combined density functional theory simulations with simple thermodynamics to explore the intrinsic defect chemistry of octalithium plumbate (Li8PbO6) as a function of both temperature and oxygen partial pressure. Importantly, we consider vibrational contributions to the energies of the reference states used in the calculations of the defect formation energies. Our results indicate that including these temperature effects can modify the predicted defect chemistry for materials at a high temperature. For Li8PbO6, the defect chemistry is predicted to be dominated by the VLi-1 defect, which will likely act as a trap for tritium. The charge compensating mechanism is predicted to change as a function of the conditions, with the Lii+1 interstitial defect providing compensation at low temperatures and the VO2+ vacancy defect occurring close to the Li2O saturation limit.

Extrafollicular IgD-CD27-CXCR5-CD11c- DN3 B cells infiltrate inflamed tissues in autoimmune fibrosis and in severe COVID-19.

Although therapeutic B cell depletion dramatically resolves inflammation in many diseases in which antibodies appear not to play a central role, distinct extrafollicular pathogenic B cell subsets that accumulate in disease lesions have hitherto not been identified. The circulating immunoglobulin D (IgD)-CD27-CXCR5-CD11c+ DN2 B cell subset has been previously studied in some autoimmune diseases. A distinct IgD-CD27-CXCR5-CD11c- DN3 B cell subset accumulates in the blood both in IgG4-related disease, an autoimmune disease in which inflammation and fibrosis can be reversed by B cell depletion, and in severe COVID-19. These DN3 B cells prominently accumulate in the end organs of IgG4-related disease and in lung lesions in COVID-19, and double-negative B cells prominently cluster with CD4+ T cells in these lesions. Extrafollicular DN3 B cells may participate in tissue inflammation and fibrosis in autoimmune fibrotic diseases, as well as in COVID-19.

Vindicating pollyanna? An experimental test of cognitive restructuring and positive thinking interventions.

OBJECTIVE: Despite its considerable potential, psychotherapy research has made limited use of small-scale experimental study designs to test intervention components. This study employs such a design to test the immediate effects on emotional experience of two approaches to changing negative thoughts, cognitive restructuring and fostering positive thinking. Cognitive restructuring draws on the strategies core to cognitive behavioral therapies. Fostering positive thinking has also received attention, though less so as a psychological intervention. METHOD: We tested the benefits of these strategies over a brief interval by randomizing 230 participants to complete a worksheet introducing one of the two strategies. Participants reported their skills prior to exposure to these worksheets and affect was assessed immediately prior to and following use of worksheets. RESULTS: Participants' negative affect reduced following both strategies. Conditions did not differ significantly in affect change. Analysis of potential moderators showed that, among those with higher levels of cognitive behavioral therapy skills, the positive thinking condition produced greater gains in positive affect than the cognitive restructuring condition. CONCLUSIONS: These results indicate that both forms of brief interventions promote reductions in negative affect. Positive thinking interventions, which are not focused on the accuracy of one's thinking, appear to be particularly effective in promoting positive affect.

Thermodynamics and phase stability of Li8XO6octalithium ceramic breeder materials (X= Pb, Ce, Ge, Zr, Sn).

Octalithium ceramics with their high stoichiometric concentration of lithium offer exceptionally high tritium breeding ratios in comparison with other candidate breeder materials for tokamak fusion reactors, this is especially true with incorporation of a neutron multiplier into the crystal structures. Although, there are concerns surrounding the stability of these materials at operational temperatures. Therefore in this paper, we explore the thermodynamic properties of a selection of candidate octalithium ceramics in low and high temperature regimes (0-1200 K) using density functional perturbation theory. Enthalpies as well as Gibbs formation energies were used to distinguish candidates which may or may not be susceptible to degradation.

Accommodation of helium in PuO2±x and the role of americium.

The high alpha-activity of plutonium dioxide (PuO2) results in significant ingrowth of radiogenic helium (He) in the aged material. To safely store/dispose PuO2 or use in applications such as space exploration, the impact of He accumulation needs to be understood. In this work, defect energies obtained using a density functional theory (DFT) + U + D3 scheme are used in a point defect model constructed for PuO2 to predict the method of He incorporation within the PuO2 lattice. The simulations predict that the preferred incorporation site for He in PuO2 is a plutonium vacancy, however, the point defect model indicates that helium will be accommodated as an interstitial irrespective of He concentration and across a wide stoichiometric range. By considering the charge imbalance that arises due to incorporation of Am3+ ions it is shown that He accommodation in oxygen vacancy sites will dominate in PuO2-x as the material ages.

The therapeutic alliance and dropout in cognitive behavioral therapy of depression.

Identifying predictors of dropout is an important step in improving treatment outcomes. The alliance is the most frequently studied psychotherapy process variable, but its relation to dropout in cognitive behavioral therapy (CBT) of depression is not well understood.We evaluated the alliance at session one as reported by clients and therapists as predictors of dropout among 126 clients with major depressive disorder participating in CBT for depression.Over a similar time period, those who dropped out experienced less symptom change than those who did not. Client, but not therapist reported alliance was related to reduced risk for dropout. This relation remained significant even when clients' pre-treatment predictions of the alliance were included as a covariate. Concurrent use of medication did not moderate the alliance-dropout relation.Our findings are consistent with alliance being an important contributor to risk of dropout in CBT for depression. Future research should investigate intervention strategies that might promote the alliance as a means of reducing dropout.

Framing an intervention as focused on one's strength: Does framing enhance therapeutic benefit?

INTRODUCTION: A capitalization approach to enhancing client skills in cognitive behavioral interventions is focused on enhancing skills that represent relative strengths. This approach may bolster outcomes because the targeted skills are those that clients can most effectively use to recover from negative moods. Alternatively, the benefits might be due to client attitudes about these skills, such as their confidence that they can use these skills effectively. METHODS: In an unselected sample of 616 undergraduates, we randomized to one of two brief interventions (a cognitive or mindfulness intervention) and one of two framing conditions (framing the intervention as focusing on a relative strength or a weakness), resulting in four conditions. Participants were then asked to use the skill targeted in their intervention to recover from a sad mood induction. RESULTS: Framing conditions did not differ on expectations of benefit from sustained use of an intervention but did differ on mood recovery. Participants told that the intervention focused on a strength recovered more quickly following the mood induction. There was no difference between the skill interventions. DISCUSSION: Our finding suggests intervention framing positively contributes to the effects of strengths focused treatments, though perhaps not by enhancing treatment expectations.

Using Socratic Questioning to promote cognitive change and achieve depressive symptom reduction: Evidence of cognitive change as a mediator.

Socratic questioning has long been thought to play a critical role in cognitive behavioral therapy (CBT) for depression. Though use of Socratic questioning is theorized to achieve symptom reduction by promoting cognitive change, research has yet to investigate this pathway. In a sample of 123 clients participating in CBT for depression, we tested cognitive change as a mediator of the relation between Socratic questioning and symptom change in early treatment sessions. We found evidence of a significant indirect effect, consistent with cognitive change mediating the effect of Socratic questioning on change in depressive symptoms. Further analyses showed that pre-treatment CBT skills moderated the effect of Socratic questioning on cognitive change, with this relationship being stronger for clients who started treatment with lower CBT skills. These findings provide support for the view that Socratic questioning contributes to therapeutic gains in CBT through cognitive change. This study also provides initial evidence to suggest the use of Socratic questioning is particularly important for clients who begin treatment with particularly low CBT skills.

When Are Therapists' Efforts to Bring about Cognitive Change Effective? Considering Interpersonal Vulnerabilities as Contextual Factors.

We examined interpersonal variables as moderators of the relation between therapists' use of cognitive change (CC) strategies and CC in a sample of 125 adults who participated in cognitive behavioral therapy for depression. We measured self-reported maladaptive personality characteristics, interpersonal problems, and social skills at intake. Observers rated therapist adherence to cognitive methods for the first five sessions. Patients reported in-session CC following each session. Cognitive methods predicted greater CC. The relation between cognitive methods and CC was moderated by maladaptive personality traits; this relation was stronger for patients with greater maladaptive personality traits. We encourage future research investigating moderators of therapist interventions of putative therapeutic mechanisms.

Who Benefits From a Cognitive vs. Behavioral Approach to Treating Depression? A Pilot Study of Prescriptive Predictors.

Although experts have suggested ways that cognitive behavioral therapy (CBT) of depression might be personalized for individual clients, there has been little empirical examination of this issue. We examine cognitive behavioral skills and vulnerabilities (i.e., dysfunctional thinking, behavioral inactivation, and avoidance) as potential prescriptive predictors to cognitive vs. behavioral interventions. Forty-two adults with major depressive disorder were randomized to eight weeks of cognitive-only (n = 21) or behavioral-only (n = 21) individual psychotherapy. Clients completed pre-treatment measures of cognitive and behavioral skills and vulnerabilities. Dropout rates were comparable across treatments (21% overall). Treatment outcomes did not differ significantly between treatments (g = .13). Cognitive skills were associated with superior outcomes in the behavioral-only treatment, but additional analyses suggested general skillfulness (i.e., the tendency to have high scores across cognitive and behavioral assessments), rather than cognitive skills per se, predicted a larger response to behavioral interventions. Similarly, behavioral avoidance of social and non-social domains were associated with worse outcomes in the behavioral-only treatment, indicating that behavioral approaches yield less positive outcomes for clients high in behavioral avoidance. If replicated, the results of this pilot study suggest ways that a cognitive behavioral therapist could select intervention strategies to suit individual clients and thereby improve treatment outcomes.

Evolving Defect Chemistry of (Pu,Am)O2±x.

The ß decay of 241Pu to 241Am results in a significant ingrowth of Am during the interim storage of PuO2. Consequently, the safe storage of the large stockpiles of separated Pu requires an understanding of how this ingrowth affects the chemistry of PuO2. This work combines density functional theory (DFT) defect energies and empirical potential calculations of vibrational entropies to create a point defect model to predict how the defect chemistry of PuO2 evolves due to the incorporation of Am. The model predicts that Am occupies Pu sites in (Pu,Am)O2±x in either the +III or +IV oxidation state. High temperatures, low oxygen-to-metal (O/M) ratios, or low Am concentrations favor Am in the +III oxidation state. Am (+III) exists in (Pu,Am)O2±x as the negatively charged (AmPu 1-) defect, requiring charge compensation from holes in the valence band, thereby increasing the conductivity of the material compared to Am-free PuO2. Oxygen vacancies take over as the charge compensation mechanism at low O/M ratios. In (Pu,Am)O2±x , hypo- and (negligible) hyperstoichiometry is found to be provided by the doubly charged oxygen vacancy (VO 2+) and singly charged oxygen interstitial (Oi 1-), respectively.

B1a and B2 cells are characterized by distinct CpG modification states at DNMT3A-maintained enhancers.

The B1 and B2 lineages of B cells contribute to protection from pathogens in distinct ways. The role of the DNA CpG methylome in specifying these two B-cell fates is still unclear. Here we profile the CpG modifications and transcriptomes of peritoneal B1a and follicular B2 cells, as well as their respective proB cell precursors in the fetal liver and adult bone marrow from wild-type and CD19-Cre Dnmt3a floxed mice lacking DNMT3A in the B lineage. We show that an underlying foundational CpG methylome is stably established during B lineage commitment and is overlaid with a DNMT3A-maintained dynamic methylome that is sculpted in distinct ways in B1a and B2 cells. This dynamic DNMT3A-maintained methylome is composed of novel enhancers that are closely linked to lineage-specific genes. While DNMT3A maintains the methylation state of these enhancers in both B1a and B2 cells, the dynamic methylome undergoes a prominent programmed demethylation event during B1a but not B2 cell development. We propose that the methylation pattern of DNMT3A-maintained enhancers is determined by the coincident recruitment of DNMT3A and TET enzymes, which regulate the developmental expression of B1a and B2 lineage-specific genes.

Melanins as Sustainable Resources for Advanced Biotechnological Applications.

Melanins are a class of biopolymers that are widespread in nature and have diverse origins, chemical compositions, and functions. Their chemical, electrical, optical, and paramagnetic properties offer opportunities for applications in materials science, particularly for medical and technical uses. This review focuses on the application of analytical techniques to study melanins in multidisciplinary contexts with a view to their use as sustainable resources for advanced biotechnological applications, and how these may facilitate the achievement of the United Nations Sustainable Development Goals.

The defect chemistry of non-stoichiometric PuO2±x.

An increased knowledge of the chemistry of PuO2 is imperative for the design of procedures to store, dispose, or make use of PuO2. In this work, point defect concentrations in PuO2 are determined by combining density functional theory (DFT) defect energies and empirical potential calculations of vibrational entropies. The obtained defect concentrations are expressed as a function of temperature and oxygen partial pressure and used to calculate non-stoichiometry in PuO2±x. The results show that the defect chemistry of PuO2 is dominated by oxygen vacancies and interstitials. Hypo-stoichiometric PuO2-x is accommodated by both the uncharged oxygen vacancy and positively charged oxygen vacancy at small values of x, with increasingly dominant with increasing x. The negatively charged oxygen interstitial (O2-i) is found to accommodate hyper-stoichiometry (PuO2+x), but reluctance to form hyper-stoichiometric PuO2+x is observed, with oxygen interstitials present only in very low concentrations irrespective of conditions. The small degree of hyper-stoichiometry found is favoured by low temperatures.

Atomistic Simulation of Water Incorporation and Mobility in Bombyx mori Silk Fibroin.

Bombyx mori silk fibroin (SF) is a biopolymer that can be processed into materials with attractive properties (e.g., biocompatibility and degradability) for use in a multitude of technical and medical applications (including textiles, sutures, drug delivery devices, tissue scaffolds, etc.). Utilizing the information from experimental and computational SF studies, a simplified SF model has been produced (alanine-glycine [Ala-Gly] n crystal structure), enabling the application of both molecular dynamic and density functional theory techniques to offer a unique insight into SF-based materials. The secondary structure of the computational model has been evaluated using Ramachandran plots under different environments (e.g., different temperatures and ensembles). In addition, the mean square displacement of water incorporated into the SF model was investigated: the diffusion coefficients, activation energies, most and least favorable positions of water, and trajectory of water diffusion through the SF model are obtained. With further computational study and in combination with experimental data, the behavior/degradation of SF (and similar biomaterials) can be elucidated. Consequently, greater control of the aforementioned technologies may be achieved and positively affect their potential applications.