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Human aging is associated with an increased frequency of somatic mutations in hematopoietic cells. Several of these recurrent mutations, including those in the gene encoding the epigenetic modifier enzyme TET2, promote expansion of the mutant blood cells. This clonal hematopoiesis correlates with an increased risk of atherosclerotic cardiovascular disease. We studied the effects of the expansion of Tet2-mutant cells in atherosclerosis-prone, low-density lipoprotein receptor–deficient (Ldlr –/–) mice. We found that partial bone marrow reconstitution with TET2-deficient cells was sufficient for their clonal expansion and led to a marked increase in atherosclerotic plaque size. TET2-deficient macrophages exhibited an increase in NLRP3 inflammasome–mediated interleukin-1β secretion. An NLRP3 inhibitor showed greater atheroprotective activity in chimeric mice reconstituted with TET2-deficient cells than in nonchimeric mice. These results support the hypothesis that somatic TET2 mutations in blood cells play a causal role in atherosclerosis.

Background The management of schizophrenia is evolving towards a more comprehensive model based on functional recovery. The concept of functional recovery goes beyond clinical remission and encompasses multiple aspects of the patient’s life, making it difficult to settle on a definition and to develop reliable assessment criteria. In this consensus process based on a panel of experts in schizophrenia, we aimed to provide useful insights on functional recovery and its involvement in clinical practice and clinical research. Methods After a literature review of functional recovery in schizophrenia, a scientific committee of 8 members prepared a 75-item questionnaire, including 6 sections: (I) the concept of functional recovery (9 items), (II) assessment of functional recovery (23 items), (III) factors influencing functional recovery (16 items), (IV) psychosocial interventions and functional recovery (8 items), (V) pharmacological treatment and functional recovery (14 items), and (VI) the perspective of patients and their relatives on functional recovery (5 items). The questionnaire was sent to a panel of 53 experts, who rated each item on a 9-point Likert scale. Consensus was achieved in a 2-round Delphi dynamics, using the median (interquartile range) scores to consider consensus in either agreement (scores 7–9) or disagreement (scores 1–3). Items not achieving consensus in the first round were sent back to the experts for a second consideration. Results After the two recursive rounds, consensus was achieved in 64 items (85.3%): 61 items (81.3%) in agreement and 3 (4.0%) in disagreement, all of them from section II (assessment of functional recovery). Items not reaching consensus were related to the concepts of functional recovery (1 item, 1.3%), functional assessment (5 items, 6.7%), factors influencing functional recovery (3 items, 4.0%), and psychosocial interventions (2 items, 5.6%). Conclusions Despite the lack of a well-defined concept of functional recovery, we identified a trend towards a common archetype of the definition and factors associated with functional recovery, as well as its applicability in clinical practice and clinical research.

In this paper we study the performance in e+e- collisions of classical e+e- jet reconstruction algorithms, longitudinally invariant algorithms and the recently proposed Valencia algorithm. The study includes a comparison of perturbative and non-perturbative jet energy corrections and the response under realistic background conditions. Several algorithms are benchmarked with a detailed detector simulation at s=3 TeV. We find that the classical e+e- algorithms, with or without beam jets, have the best response, but they are inadequate in environments with non-negligible background. The Valencia algorithm and longitudinally invariant kt algorithms have a much more robust performance, with a slight advantage for the former.

Background Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation of the joints, leading to bone erosion and joint dysfunction. Despite the recent successes of disease-modifying anti-rheumatic drugs (DMARDs), there is still clinical need for understanding the development and molecular etiology of RA. Wnts are developmental morphogens whose roles in adult pathology are poorly characterized. Wnt5a is a member of the non-canonical family of Wnts that modulates a wide range of cell processes, including differentiation, migration, and inflammation. Wnt5a has been implicated as a possible contributor to arthritis and it is upregulated in synovial fibroblasts from RA patients. Methods We investigated the role of endogenous Wnt5a in RA. Tamoxifen-inducible, Wnt5a knockout (Wnt5a cKO) mice and littermate controls were monitored for arthritis development and joint pathology using the K/BxN serum transfer-induced arthritis (STIA) model. To explore a role of Wnt5a in osteoclast fusion, bone marrow-derived monocytes (BMDMs) were differentiated in vitro. Results Wnt5a cKO mice were resistant to arthritis development compared to control littermates as assessed by ankle thickness and histologic measurements. Some parameters of inflammation were reduced in the Wnt5a cKO mice, including the extent of polymononuclear cell infiltration and extra-articular inflammation. Wnt5a cKO mice also exhibited less cartilage destruction and a reduction in osteoclast activity with concomitant reduction in tartrate-resistant acid phosphatase ( TRAP ), cathepsin K ( CTSK ), macrophage colony-stimulating factor  ( MCSF ), matrix metalloproteinase ( MMP ) 2 and MMP9 in the arthritic joints. Treatment of BMDMs with Wnt5a enhanced osteoclast fusion and increased the expression of dendrocyte-expressed seven transmembrane protein ( DCSTAMP ) and MMP9 , that are necessary for osteoclast formation and activity. Conclusions These data suggest that Wnt5a modulates the development of arthritis by promoting inflammation and osteoclast fusion, and provide the first mouse genetic evidence of a role for endogenous Wnt5a in autoimmune disease.

Clonal hematopoiesis, a condition in which acquired somatic mutations in hematopoietic stem cells lead to the outgrowth of a mutant hematopoietic clone, is associated with a higher risk of hematological cancer and a growing list of nonhematological disorders, most notably atherosclerosis and associated cardiovascular disease. However, whether accelerated atherosclerosis is a cause or a consequence of clonal hematopoiesis remains a matter of debate. Some studies support a direct contribution of certain clonal hematopoiesis-related mutations to atherosclerosis via exacerbation of inflammatory responses, whereas others suggest that clonal hematopoiesis is a symptom rather than a cause of atherosclerosis, as atherosclerosis or related traits may accelerate the expansion of mutant hematopoietic clones. Here we combine high-sensitivity DNA sequencing in blood and noninvasive vascular imaging to investigate the interplay between clonal hematopoiesis and atherosclerosis in a longitudinal cohort of healthy middle-aged individuals. We found that the presence of a clonal hematopoiesis-related mutation confers an increased risk of developing de novo femoral atherosclerosis over a 6-year period, whereas neither the presence nor the extent of atherosclerosis affects mutant cell expansion during this timeframe. These findings indicate that clonal hematopoiesis unidirectionally promotes atherosclerosis, which should help translate the growing understanding of this condition into strategies for the prevention of atherosclerotic cardiovascular disease in individuals exhibiting clonal hematopoiesis. Use of a longitudinal study design allows for more precise analysis of the interplay between clonal hematopoiesis and atherosclerotic disease, finding that whereas clonal hematopoiesis confers an increased risk of atherosclerosis, the reverse is not the case, arguing for a unidirectional effect of clonal hematopoiesis on atherosclerosis.

Sequencing studies demonstrate a strong clinical association between clonal haematopoiesis driven by acquired mutations and atherosclerotic disease. Previous research supports the idea that this association reflects a direct contribution of some clonal haematopoiesis-related mutations to atherosclerosis. Now, mathematical modelling suggests that atherosclerosis could instead accelerate clonal haematopoiesis.

Background Elevated glycated hemoglobin (HbA1c) is associated with a higher burden of subclinical atherosclerosis (SA). However, the association with SA of earlier insulin resistance markers is poorly understood. The study assessed the association between the homeostatic model assessment of insulin resistance index (HOMA-IR) and SA in addition to the effect of cardiovascular risk factors (CVRFs) in individuals with normal HbA1c. Methods A cohort of 3,741 middle-aged individuals from the Progression of Early Subclinical Atherosclerosis (PESA) study with basal HbA1c < 6.0% (< 42 mmol/mol) and no known CV disease underwent extensive imaging (multiterritorial vascular ultrasound and coronary artery calcium score, CACS) to assess the presence, burden, and extent of SA. Results Individuals with higher HOMA-IR values had higher rates of CVRFs. HOMA-IR showed a direct association with the multiterritorial extent of SA and CACS (p < 0.001) and with global plaque volume measured by 3-dimensional vascular ultrasound (p < 0.001). After adjusting for key CVRFs and HbA1c, HOMA-IR values ≥ 3 were associated with both the multiterritorial extent of SA (odds ratio 1.41; 95%CI: 1.01 to 1.95, p = 0.041) and CACS > 0 (odds ratio 1.74; 95%CI: 1.20 to 2.54, p = 0.004), as compared with the HOMA-IR < 2 (the reference HOMA-IR category). In a stratified analysis, this association remained significant in individuals with a low-to-moderate SCORE2 risk estimate (75.6% of the cohort) but not in high-risk individuals. Conclusions The use of HOMA-IR identified low-risk individuals with a higher burden of SA, after adjusting for the effects of key traditional CVRFs and HbA1c. HOMA-IR is a simple measure that could facilitate earlier implementation of primary CV prevention strategies in clinical practice.

The purpose of this investigation was to design and validate a multidimensional scale with the potential to measure perceived discrimination in different stigmatized groups. The study was carried out in Spain with a sample of 1,016 participants belonging to five stigmatized groups: Latin American immigrants, Romanian immigrants, people with HIV, gays and lesbians. Confirmatory factor analysis validated the existence of four dimensions in the scale: blatant group discrimination, subtle group discrimination, blatant individual discrimination, and subtle individual discrimination. In accordance with the literature, the scale presents positive relations with the stigma consciousness scale (Pinel in J Pers Soc Psychol 76:114–128, 1999) and negative relations with two measures of psychological well-being, affect balance and self-acceptance. Likewise, the results indicate that the perception of subtle individual discrimination is more negatively associated with participants' psychological well-being.

A new method to measure the top-quark mass in high energetic hadron collisions is presented. We use theoretical predictions calculated at next-to-leading order accuracy in quantum chromodynamics to study the (normalized) differential distribution of the cross section with respect to its invariant mass . The sensitivity of the method to the top-quark mass together with the impact of various theoretical and experimental uncertainties has been investigated and quantified. The new method allows for a complementary measurement of the top-quark mass parameter and has a high potential to become competitive in precision with respect to established approaches. Furthermore we emphasize that in the proposed method the mass parameter is uniquely defined through one-loop renormalization.