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AbstractThis study explored whether adolescents’ introspection increased while engaged in a mindfulness-based intervention (MBI). Using a quasi-experimental design, the researchers identified high school students (n = 13) with elevated levels of anxiety to participate in an 11-week, multiphase MBI. Participants’ introspection ability was assessed by comparing self-reported levels and observed percentage of time calm as recorded by a neurofeedback (NFB) device three times a week during the program. Using general linear modeling, results indicated a significant interaction effect with moderate effect sizes between self-reported scores by phase on NFB scores, F(2, 407)=4.12, p = 0.017 and a significant interaction between sex and self-reported scores on NFB scores overall, F(1, 407)=5.05, p = 0.025. Female participants appeared to have increased introspection compared to males. Results support the use of MBIs to foster introspection in adolescents. The MBI with an NFB device appeared to improve introspection, a key factor in accurate self-report.

Phenotypic and transcriptional profiling of regulatory T (Treg) cells at homeostasis reveals that T cell receptor activation promotes Tregcells with an effector phenotype (eTreg) characterized by the production of interleukin-10 and expression of the inhibitory receptor PD-1. At homeostasis, blockade of the PD-1 pathway results in enhanced eTregcell activity, whereas during infection with Toxoplasmagondii, early interferon-γ upregulates myeloid cell expression of PD-L1 associated with reduced Tregcell populations. In infected mice, blockade of PD-L1, complete deletion of PD-1 or lineage-specific deletion of PD-1 in Tregcells prevents loss of eTregcells. These interventions resulted in a reduced ratio of pathogen-specific effector T cells: eTregcells and increased levels of interleukin-10 that mitigated the development of immunopathology, but which could compromise parasite control. Thus, eTregcell expression of PD-1 acts as a sensor to rapidly tune the pool of eTregcells at homeostasis and during inflammatory processes.

Cryptosporidium is an enteric pathogen and a prominent cause of diarrheal disease worldwide. Control of Cryptosporidium requires CD4+ T cells, but how protective CD4+ T cell responses are generated is poorly understood. Here, Cryptosporidium parasites that express MHCII-restricted model antigens were generated to understand the basis for CD4+ T cell priming and effector function. These studies revealed that parasite-specific CD4+ T cells are primed in the draining mesenteric lymph node but differentiate into Th1 cells in the gut to provide local parasite control. Although type 1 conventional dendritic cells (cDC1s) were dispensable for CD4+ T cell priming, they were required for CD4+ T cell gut homing and were a source of IL-12 at the site of infection that promoted local production of IFN-γ. Thus, cDC1s have distinct roles in shaping CD4+ T cell responses to an enteric infection: first, to promote gut homing from the mesLN, and second, to drive effector responses in the intestine.

The intestinal parasite, Cryptosporidium, is a major contributor to global child mortality and causes opportunistic infection in immune deficient individuals. Innate resistance to Cryptosporidium, which specifically invades enterocytes, is dependent on the production of IFN-γ, yet whether enterocytes contribute to parasite control is poorly understood. In this study, utilizing a mouse-adapted strain of C. parvum, we show that epithelial-derived IL-18 synergized with IL-12 to stimulate innate lymphoid cell (ILC) production of IFN-γ required for early parasite control. The loss of IFN-γ-mediated STAT1 signaling in enterocytes, but not dendritic cells or macrophages, antagonized early parasite control. Transcriptional profiling of enterocytes from infected mice identified an IFN-γ signature and enrichment of the anti-microbial effectors IDO, GBP, and IRG. Deletion experiments identified a role for Irgm1/m3 in parasite control. Thus, enterocytes promote ILC production of IFN-γ that acts on enterocytes to restrict the growth of Cryptosporidium.

ON AUGUST 13, 1891, AT A REMOTE SPOT HIGH IN THE PAMIR MOUNTAINS in Central Asia, British explorer Francis Younghusband opened the doors of his tent to see 20 Russian […]

Objective. To measure the sagittal alignment of the tibial tubercle through the sagittal tibial tubercle–trochlear groove (sTTTG) distance in patients with and without patellar chondral lesions. Design. Patients treated with patellofemoral cartilage restoration or repair procedures were retrospectively reviewed (group 1; N= 17). A control group of patients (group 2; N= 20) undergoing partial meniscectomy with normal patellar cartilage was included. An asymptomatic patellar chondrosis group (group 3; N= 15) was identified as patients undergoing partial meniscectomy with patellar cartilage wear. The sTTTG was measured on the preoperative axial T2magnetic resonance imaging (MRI) sequence. The first point was the nadir of the anterior trochlear cartilage, and the second point was the anterior tibial tubercle. A line was drawn between these points, perpendicular to the posterior condylar axis. Comparisons were made between the 3 groups using analysis of variance testing with Bonferroni corrections. Significance was defined as P< 0.05. Results. The mean sTTTG was significantly more posterior in group 1 (5.9 ± 5.5 mm posterior to the trochlear groove) relative to group 2 (0.8 ± 5.3 mm posterior; P= 0.018). The mean value for group 3 (2.7 ± 5.3 mm posterior) fell between group 1 and 3 but was not significantly different from group 1 (P= 0.31) or group 2 (P= 0.89). There were no significant differences with regards to sulcus angle, Caton-Deschamps Index, TTTG, or knee flexion angle on the MRI scan. Conclusions. A more posteriorly positioned tibial tubercle was observed in patients with patellar cartilage lesions relative to those with intact patellar cartilage. Intermediate positioning was observed in patients with asymptomatic patellar chondral wear. Level of Evidence. Level 3 diagnostic study.

Purpose Evaluate the ability of patients to return to work (RTW) following arthroscopic meniscal allograft transplantation (MAT) for meniscal deficiency.Methods Consecutive patients undergoing MAT were retrospectively reviewed at a minimum of 2 years postoperatively. Patients completed a subjective work questionnaire, Visual Analogue Scale for pain, Single Assessment Numerical Evaluation, and satisfaction.Results Forty-seven patients who were employed within 3 years prior to surgery (average age: 30.2 ± 6.9 years) were contacted at an average of 3.5 ± 0.9 years postoperatively. Forty-six patients (97.8%) returned to work by 2.7 ± 2.6 months postoperatively, and 44 patients (93.6%) returned to the same level of occupational intensity. Patients who held sedentary, light, medium, or high intensity occupations were able to RTW at a rate of 100.0%, 100.0%, 88.9%, and 85.7% (P= 0.4) by 1.1 ± 1.0 months, 2.5 ± 2.5 months, 3.5 ± 3.2 months, and 4.3 ± 2.8 months (P= 0.3) postoperatively. Thirty-eight patients (80.9%) were at least somewhat satisfied, and 43 patients (91.5%) would still have the operation if presented the opportunity. No patient underwent revision MAT or conversion to arthroplasty.Conclusion In patients with painful meniscal deficiency, MAT provides a high rate of RTW (97.8%) by 2.7 ± 2.6 months postoperatively. However, some patients may be unable to return to their previous level of occupational intensity. Although statistically insignificant, patients with higher intensity occupations may have a lower rate and longer duration until RTW than those with less physically demanding occupations. Information regarding RTW is imperative for appropriately managing postoperative expectations.

Purpose Patients with isolated medial compartment osteoarthritis and varus deformity may undergo high tibial osteotomy (HTO) to reduce the contact pressure in the medial compartment. The purpose of this investigation is (1) examine the timeline of return to work (RTW) following HTO and (2) evaluate RTW stratified by occupational intensity.Methods Consecutive patients undergoing HTO were reviewed retrospectively at a minimum of 2-years postoperatively. Patients completed a subjective work questionnaire, a visual analogue scale for pain, Single Assessment Numerical Evaluation, and a satisfaction questionnaire.Results Thirty-eight patients were included at an average of 9.0 ± 3.3 years postoperatively. Thirty-seven patients (average age 43.4 ± 7.8 years, 91.9% with a Kellgren-Lawrence grade of III/IV) were employed within 3 years prior to surgery. Eighteen patients (48.6%) underwent subsequent surgery with 14 patients (37.8%) receiving a salvage knee arthroplasty at an average of 6.1 ± 3.5 years following HTO. Thirty-five patients (94.5%) returned to work at an average of 2.9 ± 2.0 months. The rate of RTW for sedentary, light, moderate, and heavy duties were 87.5%, 100%, 100%, and 93.3%, respectively, while the duration until RTW was 1.0 months, 1.1 months, 2.4 months, and 3.3 months, respectively.Conclusion In a young and active population with osteoarthritis or varus deformity, an HTO allows patients to return to work; however, patients with high-intensity occupations may be absent from work longer than those with lesser physically demanding occupations. HTO is not a definitive treatment option as nearly 40% of patients underwent knee arthroplasty by 6.1 years postoperatively.Level of Evidence IV, case series.

Abstract:This article proposes the use of Adlerian theory to guide adventure therapy (AT), an active intervention that uses experiential techniques to foster client growth. Important Adlerian concepts identified in this paper include phenomenology, teleology, choice, superiority, social interest, and lifestyle with further discussion into Adlerian theory as a guiding theory of counseling. Also explored is the use of Adlerian theory to conceptualize AT participants and facilitate activities. Specific AT techniques like challenge by choice, full-value contract, adventure wave, risk, and adventure activities are identified. Finally, this article concludes by exploring how Adlerian theory can guide culturally responsive AT practice.

The solutions found by neural networks to solve a task are often inscrutable. We have little insight into why a particular structure emerges in a network. By reverse engineering neural networks from dynamical principles, Dubreuil, Valente et al. show how neural population structure enables computational flexibility.

While CD19-directed chimeric antigen receptor (CAR) T cells can induce remission in patients with B cell acute lymphoblastic leukemia (ALL), a large subset relapse with CD19−disease. Like CD19, CD22 is broadly expressed by B-lineage cells and thus serves as an alternative immunotherapy target in ALL. Here we present the composite outcomes of two pilot clinical trials (NCT02588456and NCT02650414) of T cells bearing a 4-1BB-based, CD22-targeting CAR in patients with relapsed or refractory ALL. The primary end point of these studies was to assess safety, and the secondary end point was antileukemic efficacy. We observed unexpectedly low response rates, prompting us to perform detailed interrogation of the responsible CAR biology. We found that shortening of the amino acid linker connecting the variable heavy and light chains of the CAR antigen-binding domain drove receptor homodimerization and antigen-independent signaling. In contrast to CD28-based CARs, autonomously signaling 4-1BB-based CARs demonstrated enhanced immune synapse formation, activation of pro-inflammatory genes and superior effector function. We validated this association between autonomous signaling and enhanced function in several CAR constructs and, on the basis of these observations, designed a new short-linker CD22 single-chain variable fragment for clinical evaluation. Our findings both suggest that tonic 4-1BB-based signaling is beneficial to CAR function and demonstrate the utility of bedside-to-bench-to-bedside translation in the design and implementation of CAR T cell therapies.

This article introduces the Seshat: Global History Databank, its potential, and its methodology. Seshat is a databank containing vast amounts of quantitative data buttressed by qualitative nuance for a large sample of historical and archaeological polities. The sample is global in scope and covers the period from the Neolithic Revolution to the Industrial Revolution. Seshat allows scholars to capture dynamic processes and to test theories about the co-evolution (or not) of social scale and complexity, agriculture, warfare, religion, and any number of such Big Questions. Seshat is rapidly becoming a massive resource for innovative cross-cultural and cross-disciplinary research. Seshat is part of a growing trend to use comparative historical data on a large scale and contributes as such to a growing consilience between the humanities and social sciences. Seshat is underpinned by a robust and transparent workflow to ensure the ever growing dataset is of high quality.

Osteochondral lesions of the talus (OLT) involve the subchondral bone and the overlying articular cartilage. Various surgical treatments for these lesions are available, such as bone marrow stimulation (BMS), autologous osteochondral grafting, and fixation of an osteochondral fragment. Treatment choice depends on the condition of the lesion, which includes lesion size, morphology, location, and the presence of cysts. Among the surgical procedures available to date, in situfixation of the osteochondral fragment has the advantage of restoring the articular surface while preserving the native hyaline cartilage and its subchondral bone. Fixation for OLT has been shown to be clinically successful for the treatment of both acute and chronic lesions. Moreover, the indication for osteochondral fragment fixation is expanding as recent studies have found good clinical outcomes in relatively small-sized lesions. The present article describes the current evidence on fixation for acute and chronic OLT.

Cryptosporidiumcauses debilitating diarrheal disease in patients with primary and acquired defects in T cell function.However, it has been a challenge to understand how this infection generates T cell responses and how they mediate parasite control. Here, Cryptosporidiumwas engineered to express a parasite effector protein (MEDLE-2) that contains the major histocompatibility complex-I restricted SIINFEKL epitope which is recognized by T cell receptor transgenic OT-I(OVA-TCR-I) clusters of differentiation (CD)8+T cells. These modified parasites induced expansion of endogenous SIINFEKL-specific and OT-I CD8+T cells that were a source of interferon-gamma (IFN-γ) that could restrict growth of Cryptosporidium. This T cell response was dependent on the translocation of the effector and similar results were observed with another secreted parasite effector (rhoptry protein 1). Although infection and these translocated effector proteins are restricted to intestinal epithelial cells, type 1 conventional dendritic cells were required to generate CD8+T cell responses to these model antigens. These data sets highlight Cryptosporidiumeffectors as potential targets of the immune system and suggest that crosstalk between enterocytes and type 1 conventional dendritic cells is crucial for CD8+T cell responses to Cryptosporidium.

Introduction: The management of periprosthetic joint infections (PJI) of the lower limb is challenging, and evidence-based recommendations are lacking. The present clinical investigation characterized the pathogens diagnosed in patients who underwent revision surgery for  PJI of total hip arthroplasty (THA) and total knee arthroplasty (TKA). Methods: The present study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). The institutional databases of the RWTH University Medical Centre of Aachen, Germany, were accessed. The OPS (operation and procedure codes) 5–823 and 5–821 and the ICD (International Statistical Classification of Diseases and Related Health Problems) codes T84.5, T84.7 or T84.8 were used. All patients with PJI of a previous THA and TKA who underwent revision surgery were retrieved and included for analysis. Results: Data from 346 patients were collected (181 THAs and 165 TKAs). 44% (152 of 346 patients) were women. Overall, the mean age at operation was 67.8 years, and the mean BMI was 29.2 kg/m2. The mean hospitalization length was 23.5 days. 38% (132 of 346) of patients presented a recurrent infection. Conclusion: PJI remain a frequent cause for revisions after total hip and knee arthroplasty. Preoperative synovial fluid aspiration was positive in 37%, intraoperative microbiology was positive in 85%, and bacteraemia was present in 17% of patients. Septic shock was the major cause of in-hospital mortality. The most common cultured pathogens were Staph. epidermidis, Staph. aureus, Enterococcus faecalis, and Methicillin-resistant Staph aureus (MRSA). An improved understanding of PJI pathogens is important to plan treatment strategies and guide the choice of empirical antibiotic regimens in patients presenting with septic THAs and TKAs.

Exploring Television Acting, Tom Cantrell and Christopher Hogg (eds) (2018) London: Continuum, 206 pp., ISBN 9781474248587, h/bk, £75Technicolored: Reflections on Race in the Time of TV, Ann DuCille (2018) Durham: Duke University Press, 352 pp., ISBN 9781478000396, h/bk, $104.95; p/bk, $27.95

Cartilage defects commonly occur in young, active patients and can be debilitating injuries with patients experiencing significant pain and swelling. Clinical diagnosis is made using a combination of patient history, physical exam, imaging, and diagnostic arthroscopy. In patients who have failed conservative measures such as physical therapy, tolerable lifestyle modification, and injection treatments, surgical options exist including microfracture, autologous chondrocyte implantation, osteochondral autograft transfer, or osteochondral allograft transplantation. In this article, we present the diagnosis, indications, surgical technique, and reported outcomes for the treatment of cartilage defects with both osteochondral autograft transfer and osteochondral allograft transplantation. [ABSTRACT FROM AUTHOR]

The treatment of articular cartilage defects can be a challenging problem in clinical decision making. In recent years, there has been increasing interest in and utilization of biologically active injections either as an alternative or adjunct to surgical treatment. Additionally, indications for biologic therapies continue to evolve. This chapter provides a broad overview of the current science, techniques, and other considerations associated with injectable biologic treatment options for articular cartilage defects. In turn, platelet-rich plasma, bone marrow aspirate concentrate, adipose-derived mesenchymal stem cells, and amniotic membrane-derived tissue will be discussed. [ABSTRACT FROM AUTHOR]

Context: Shoulder pain and dysfunction are common, with patients presenting complaints to both primary and orthopaedic physicians. History and physical examination remain essential to creating a differential diagnosis, even as noninvasive imaging has improved.Evidence Acquisition: Literature was obtained through keyword searches based on the pathology in question (eg, rotator cuff) and the keywords physical examinationusing PubMed from January 1, 1980, through September 20, 2017. Additional evidence was obtained through screening references from articles identified through the PubMed searches.Study Design: Clinical review.Level of Evidence: Level 3.Results: A total of 7817 articles were screened for relevance. Several physical examination maneuvers have been described for each specific pathology. The Neer sign has a 75% sensitivity for subacromial impingement (SAI), while the Hawkins-Kennedy test has an 80% sensitivity. The painful arc test has an 80% specificity for SAI. The apprehension test has a hazard ratio of 2.96 for anterior shoulder instability. The Jobe test has a sensitivity of 52.6% and a specificity of 82.4% for full-thickness supraspinatus tears, confirmed on arthroscopy. The lag sign is highly sensitive and specific for combined full-thickness supraspinatus and infraspinatus tears at 97% and 93%, respectively. The Speed test has a sensitivity of 54% and specificity of 81% for biceps pathology. The anterior slide test and O’Brien active compression test have been described for superior labrum anterior posterior tears with inconsistent reliability. The cross-body adduction test has a sensitivity of 77% and a specificity of 79% for acromioclavicular joint pathology.Conclusion: Several physical examination maneuvers can isolate specific pathology of the shoulder, with widely ranging sensitivity and specificity.

The long head of the biceps tendon can be a source of pain in a variety of shoulder pathogies such as including biceps tenosynovitis, type II SLAP tears, partial long head of the biceps tears, and long head of the biceps subluxations or dislocations among others. When nonoperative management has failed and surgical management is indicated, the long head of the biceps can be treated with either tenotomy or tenodesis. Although tenotomy is reliably effective, tenodesis is often preferred as it helps prevent complications such as cramping, fatigue, and supination and elbow flexion weakness. Several biceps tenodesis techniques have been described including suprapectoral vs subpectoral, open vs arthroscopic and a variety of fixation methods have been used including a biotenodesis screw, cortical button, bone bridge, and suture anchor. This article describes the technique for a mini-open, subpectoral on-lay biceps tenodesis using an all-suture anchor double loaded with suture tape. We prefer this method as it provides effective fixation with minimal tendon slippage and minimizes the risk of complication. [ABSTRACT FROM AUTHOR]

This article offers a model for enhancing parent–adolescent relationships by using adventure-based counseling (ABC) activities through the conceptual lens of Adlerian theory. A case study is provided to demonstrate the application of an adventure-based activity to address the goal of misbehavior and enhance the characteristics necessary for a healthy parent–adolescent relationship with connectedness, communication, awareness, and support. Specific instructions are offered to enrich counselor development of ABC application in clinical practice.

The T-box transcription factor T-bet is regarded as a “master regulator” of CD4+ Th1 differentiation and IFN-γ production. However, in multiple models of infection, T-bet appears less critical for CD8+ T cell expansion and effector function. Here, we show that following vaccination with a replication-deficient strain of Toxoplasma gondii, CD8+ T cell expression of T-bet is required for optimal expansion of parasite-specific effector CD8+ T cells. Analysis of the early events associated with T cell activation reveals that the α chain of LFA1, CD11a, is a target of T-bet, and T-bet is necessary for CD8+ T cell upregulation of this integrin, which influences the initial priming of CD8+ effector T cells. We propose that the early expression of T-bet represents a T cell–intrinsic factor that optimizes T–DC interactions necessary to generate effector responses.

Alopecia areata (AA) is an autoimmune disease that generates non-scar loss of hair with varying degrees of involvement, including total loss of hair follicles. Despite being a benign entity, it has a great impact on the emotional and psychosocial life of patients. A wide variety of topical and oral treatments are currently available. We present the case of a 24-year-old patient with severe recurrent alopecia areata without response to multiple previous treatments, in which a secondary cause was ruled out and the histological diagnosis was confirmed with biopsy. Treatment with tofacitinib, a JAK inhibitor, was started, showing an excellent clinical response after one month of treatment.

Background: Life-threatening arterial bleeding from fragility fractures of the pelvis are very rare but associated with significant mortality, especially in anticoagulated patients.Case Description: We report the successful interdisciplinary management of a 78-year-old woman under anticoagulation and antiplatelet therapy who had life-threatening arterial hemorrhage from the pubic rami following a fragility fracture of the pelvis. Our management strategy included early hemorrhage control by means of selective arterial embolization followed by surgical fracture stabilization and surgical hematoma evacuation.Literature Review: We identified 6 cases within the English literature, all involving females older than 70 years. All patients under anticoagulation developed hemorrhagic shock, and in 2 cases selective embolization contributed to survival of the patient. However, a combined management including fracture stabilization and hematoma evacuation has not been reported, allowing an excellent clinical outcome and discharge to geriatric rehabilitation.Clinical Relevance: This case illustrates that elderly patients with apparently benign pelvic fragility fractures might develop severe hemorrhage due to arterial injury, especially when under dual anticoagulation, and stresses the importance of a high index of suspicion. If bleeding is suspected, detailed imaging studies are necessary to determine the source of bleeding and immediate angiographic or surgical interventions in combination with volume resuscitation and coagulation therapy should be readily available.

La terapia biológica basada en anticuerpos monoclonales, constituyen una nueva herramienta terapéutica, que de la mano del desarrollo de la biología molecular permiten intervenir puntos claves en la etiopatogenia de la enfermedad, permitiendo una terapia personalizada. Se han desarrollado nuevos anticuerpos monoclonales que intervienen en las enfermedades cardiovasculares, por lo que el entendimiento de los principios terapéuticos, los tipos y el mecanismo de acción de estos fármacos es esencial para un uso adecuado. En este artículo se discutirá el perfil de los anticuerpos monoclonales en la enfermedad cardiovascular, como los inhibidores de la PCSK-9 y el antídoto del Dabigatran, pasando por las moléculas ya conocidas como el abciximab, el antídoto de la digoxina y la terapia inmunomoduladora en el trasplante cardiaco. Del mismo modo, se evalúa una posible aplicación de los anticuerpos monoclonales usados en reumatología que podrían tener un papel importante en el manejo de las enfermedades cardiovasculares.

Epidermolysis bullosa acquisita (EBA) is a rare blistering skin disease induced by autoantibodies directed against type VII collagen. The transfer of antibodies against murine type VII collagen into mice mimics the effector phase of EBA and results in a subepidermal blistering phenotype. Activation of the complement system, and especially the C5a/C5aR1 axis driving neutrophil activation, is critical for EBA pathogenesis. However, the role of the alternative C5a receptor, C5aR2, which is commonly thought to be more immunosuppressive, in the pathogenesis of EBA is still elusive. Therefore, we sought to delineate the functional relevance of C5aR2 during the effector phase of EBA. Interestingly, C5ar2–/–mice showed an attenuated disease phenotype, suggesting a pathogenic contribution of C5aR2 in disease progression. In vitro, C5ar2–/–neutrophils exhibited significantly reduced intracellular calcium flux, ROS release, and migratory capacity when activated with immune complexes or exposed to C5a. These functions were completely absent when C5ar1–/–neutrophils were activated. Moreover, C5aR2 deficiency lowered the ratio of activating and inhibitory FcγRs, impeding the sustainment of inflammation. Collectively, we show here a proinflammatory contribution of C5aR2 in the pathogenesis of antibody-induced tissue damage in experimental EBA.

Objective.Treating patients with rheumatoid arthritis (RA) within 3 months of symptom onset leads to significantly improved clinical outcomes. However, many people with RA symptoms wait a long time before seeking medical attention. To develop effective health interventions to encourage people to seek help early, it is important to understand what the general public knows about RA, how they would react to the symptoms of RA, and what might delay help-seeking.Methods.Qualitative interviews were conducted with 38 members of the general public (32 women) without any form of inflammatory arthritis about their perceptions of RA symptoms and decisions to seek help were they to experience such symptoms. The interviews were audio-recorded, transcribed verbatim, and analyzed using thematic analysis.Results.A number of barriers and drivers to help-seeking were identified and grouped into 5 themes: perceived causes of symptoms; factors related to presentation, location, and experience of symptoms; perceived effect of symptoms on daily life; self-management of symptoms; and general practitioner-related drivers and barriers.Conclusion.To our knowledge, our study is the first to investigate barriers to and drivers of help-seeking in response to the onset of RA symptoms in individuals without a diagnosis of RA. It has revealed a number of additional factors (e.g., the importance of the location of the symptoms) besides those previously identified in retrospective studies of patients with RA. Together with the data from previous research, these findings will help inform future health interventions aimed at increasing knowledge of RA and encouraging help-seeking.

A few surviving documents tell of exchanges along the Silk Road that were not welcome. In the ancient world, upper-class marriages were often about alliances, not love. On the borders […]

ABSTRACTThe intracellular parasite Toxoplasma gondiihas multiple strategies to alter host cell function, including the injection of rhoptry proteins into the cytosol of host cells as well as bystander populations, but the consequence of these events is unclear. Here, a reporter system using fluorescent parasite strains that inject Cre recombinase with their rhoptry proteins (Toxoplasma-Cre) was combined with Ai6 Cre reporter mice to identify cells that have been productively infected, that have been rhoptry injected but lack the parasite, or that have phagocytosed T. gondii. The ability to distinguish these host-parasite interactions was then utilized to dissect the events that lead to the production of interleukin-12 p40 (IL-12p40), which is required for resistance to T. gondii. In vivo, the use of invasion-competent or invasion-inhibited (phagocytosed) parasites with IL-12p40 (YET40) reporter mice revealed that dendritic cell (DC) and macrophage populations that phagocytose the parasite or are infected can express IL-12p40 but are not the major source, as larger numbers of uninfected cells secrete this cytokine. Similarly, the use of Toxoplasma-Cre parasite strains indicated that dendritic cells and inflammatory monocytes untouched by the parasite and not cells injected by the parasite are the primary source of IL-12p40. These results imply that a soluble host or parasite factor is responsible for the bulk of IL-12p40 production in vivo, rather than cellular interactions with T. gondiithat result in infection, infection and clearance, injection of rhoptry proteins, or phagocytosis of the parasite.

Self-renewal and differentiation of stem cells depend on asymmetric division and polarized motility processes that in other cell types are modulated by nonmuscle myosin-II (MII) forces and matrix mechanics. Here, mass spectrometry-calibrated intracellular flow cytometry of human hematopoiesis reveals MIIB to be a major isoform that is strongly polarized in hematopoietic stem cells and progenitors (HSC/Ps) and thereby downregulated in differentiated cells via asymmetric division. MIIA is constitutive and activated by dephosphorylation during cytokine-triggered differentiation of cells grown on stiff, endosteum-like matrix, but not soft, marrow-like matrix. In vivo, MIIB is required for generation of blood, while MIIA is required for sustained HSC/P engraftment. Reversible inhibition of both isoforms in culture with blebbistatin enriches for long-term hematopoietic multilineage reconstituting cells by 5-fold or more as assessed in vivo. Megakaryocytes also become more polyploid, producing 4-fold more platelets. MII is thus a multifunctional node in polarized division and niche sensing.

An obituary for historian and editor Jerry H. Bentley is presented.

We evaluate real estate investment trust (REIT) responses to the release of REIT-specific and macroeconomic news over two periods with differing economic climates. More specifically, using high-frequency data, we track the response function over a period of 60 minutes following each announcement. Tests show REIT-specific information to have larger, and in many instances opposite, effects to that of macroeconomic news. REITs also tend to be more sensitive to public information when the economy experiences a downturn. REIT size, leverage, and focus also play an important mediating role between REIT trading activity and public information.

Polyphosphoinositides are among the most highly charged molecules in the cell membrane, and the most common polyphosphoinositide, phosphatidylinositol-4,5-bisphosphate (PIP2), is involved in many mechanical and biochemical processes in the cell membrane. Divalent cations such as calcium can cause clustering of the polyanionic PIP2, but the origin and strength of the effective attractions leading to clustering has been unclear. In addition, the question of whether the ion-mediated attractions could be strong enough to alter the mechanical properties of the membrane, to our knowledge, has not been addressed. We study phase separation in mixed monolayers of neutral and highly negatively charged lipids, induced by the addition of divalent positively charged counterions, both experimentally and numerically. We find good agreement between experiments on mixtures of PIP2and 1-stearoyl-2-oleoyl phosphatidylcholine and simulations of a simplified model in which only the essential electrostatic interactions are retained. In addition, we find numerically that under certain conditions the effective attractions can rigidify the resulting clusters. Our results support an interpretation of PIP2clustering as governed primarily by electrostatic interactions. At physiological pH, the simulations suggest that the effective attractions are strong enough to give nearly pure clusters of PIP2even at small overall concentrations of PIP2.