Miracle-dz/UniFAR-FTUs huggingface dataset:
Endothelial CD2AP Binds the Receptor ICAM-1 To Control Mechanosignaling, Leukocyte Adhesion, and the Route of Leukocyte Diapedesis In Vitro

Inflammation is driven by excessive transmigration (diapedesis) of leukocytes from the blood to the tissue across the endothelial cell monolayer that lines blood vessels. Leukocyte adhesion, crawling, and transmigration are regulated by clustering of the endothelial mechanosensitive receptor intercellular adhesion molecule-1 (ICAM-1). Whereas several proteins are known to promote ICAM-1 function, the molecular mechanisms that limit ICAM-1–mediated adhesion to prevent excessive leukocyte transmigration remain unknown. We identify the endothelial actin-binding protein CD2-associated protein (CD2AP) as a novel interaction partner of ICAM-1. Loss of CD2AP stimulates the dynamics of ICAM-1 clustering, which facilitates the formation of ICAM-1 complexes on the endothelial cell surface. Consequently, neutrophil adhesion is increased, but crawling is decreased. In turn, this promotes the neutrophil preference for the transcellular over the paracellular transmigration route. Mechanistically, CD2AP is required for mechanosensitive ICAM-1 downstream signaling toward activation of the PI3K, and recruitment of F-actin and of the actin-branching protein cortactin. Moreover, CD2AP is necessary for ICAM-1–induced Rac1 recruitment and activation. Mechanical force applied on ICAM-1 impairs CD2AP binding to ICAM-1, suggesting that a tension-induced negative feedback loop promotes ICAM-1–mediated neutrophil crawling and paracellular transmigration. To our knowledge, these data show for the first time that the mechanoreceptor ICAM-1 is negatively regulated by an actin-binding adaptor protein, i.e., CD2AP, to allow a balanced and spatiotemporal control of its adhesive function. CD2AP is important in kidney dysfunction that is accompanied by inflammation. Our findings provide a mechanistic basis for the role of CD2AP in inflamed vessels, identifying this adaptor protein as a potential therapeutic target.
Innate Control of Adaptive Immunity: Beyond the Three-Signal Paradigm

Activation of cells in the adaptive immune system is a highly orchestrated process dictated by multiples cues from the innate immune system. Although the fundamental principles of innate control of adaptive immunity are well established, it is not fully understood how innate cells integrate qualitative pathogenic information to generate tailored protective adaptive immune responses. In this review, we discuss complexities involved in the innate control of adaptive immunity that extend beyond TCR engagement, costimulation, and priming cytokine production but are critical for the generation of protective T cell immunity.
Compulsion in the community: Mental health professionals' views and experiences of CTOs

Aims and method We surveyed the views and experiences of all mental health professionals in adult community mental health teams and approved mental health professionals in 2Gether and Oxford Health NHS Foundation Trusts, regarding the use of community treatment orders (CTOs). Results A total of 288 surveys were completed (response rate 48%). Forty-eight (83%) psychiatrists and 142 (67%) non-psychiatrist mental health professionals were in favour of CTOs. The decision-making regarding CTOs was overwhelmingly clinically oriented for all professional groups. However, there were significant differences in views between groups regarding the effects of bureaucracy, the infringement of human rights and coercion. Clinical implications Multidisciplinary team involvement is crucial in decisions regarding CTOs and may protect against idiosyncratic or unhelpful practice. Further training for staff is urgently required and there may be a case for creating small local reference groups that can develop expertise and provide advice and support for clinical teams.
Antiparasitic Treatment Induces an Improved CD8+ T Cell Response in Chronic Chagasic Patients

Chagas disease is a chronic infection caused by Trypanosoma cruzi, an intracellular protozoan parasite. Chronic chagasic patients (CCPs) have dysfunctional CD8+ T cells that are characterized by impaired cytokine production, high coexpression of inhibitory receptors, and advanced cellular differentiation. Most patients diagnosed in the chronic phase of Chagas disease already exhibit heart involvement, and there is no vaccination that protects against the disease. Antiparasitic treatment is controversial as to its indication for this stage of the disease. There is a lack of biological markers to evaluate the effectiveness of antiparasitic treatment, and little is known about the effect of the treatment on CD8+ T cells. Thus, the aim of the current study was to analyze the early effects of antiparasitic treatment on CD8+ T cells from CCPs with asymptomatic clinical forms of disease. To evaluate the CD8+ T cell subsets, expression of inhibitory receptors, and functionality of T cells in CCPs, PBMCs were isolated. The results showed that treatment of CCPs with the asymptomatic form of the disease induces an increase in the frequency of CD8+ central memory T cells and terminal effector T cells, a decrease in the coexpression of inhibitory receptors, an improved Ag-specific CD8+ T cell response exhibited by the individual production of IFN-γ or IL-2, and a multifunctional CD8+ T cell profile of up to four functions (IFN-γ+IL-2+Perforin+Granzyme B+). These findings suggest that, in CCPs, antiparasitic treatment improved the quality of Ag-specific CD8+ T cell responses associated with a decrease in inhibitory receptor coexpression, which could serve as biomarkers for monitoring the effectiveness of antiparasitic treatment.
N-Arachidonoyl Dopamine Modulates Acute Systemic Inflammation via Nonhematopoietic TRPV1

N-Arachidonoyl dopamine (NADA) is an endogenous lipid that potently activates the transient receptor potential vanilloid 1 (TRPV1), which mediates pain and thermosensation. NADA is also an agonist of cannabinoid receptors 1 and 2. We have reported that NADA reduces the activation of cultured human endothelial cells by LPS and TNF-α. Thus far, in vivo studies using NADA have focused on its neurologic and behavioral roles. In this article, we show that NADA potently decreases in vivo systemic inflammatory responses and levels of the coagulation intermediary plasminogen activator inhibitor 1 in three mouse models of inflammation: LPS, bacterial lipopeptide, and polymicrobial intra-abdominal sepsis. We also found that the administration of NADA increases survival in endotoxemic mice. Additionally, NADA reduces blood levels of the neuropeptide calcitonin gene-related peptide but increases the neuropeptide substance P in LPS-treated mice. We demonstrate that the anti-inflammatory effects of NADA are mediated by TRPV1 expressed by nonhematopoietic cells and provide data suggesting that neuronal TRPV1 may mediate NADA’s anti-inflammatory effects. These results indicate that NADA has novel TRPV1-dependent anti-inflammatory properties and suggest that the endovanilloid system might be targeted therapeutically in acute inflammation.
Anti-Cancer Drug HMBA Acts as an Adjuvant during Intracellular Bacterial Infections by Inducing Type I IFN through STING

The anti-proliferative agent hexamethylene bisacetamide (HMBA) belongs to a class of hybrid bipolar compounds developed more than 30 y ago for their ability to induce terminal differentiation of transformed cells. Recently, HMBA has also been shown to trigger HIV transcription from latently infected cells, via a CDK9/HMBA inducible protein-1 dependent process. However, the effect of HMBA on the immune response has not been explored. We observed that pretreatment of human peripheral blood mononuclear cells with HMBA led to a markedly increased production of IL-12 and IFN-γ, but not of TNF-α, IL-6, and IL-8 upon subsequent infection with Burkholderia pseudomallei and Salmonella enterica. HMBA treatment was also associated with better intracellular bacterial control. HMBA significantly improved IL-12p70 production from CD14+ monocytes during infection partly via the induction of type I IFN in these cells, which primed an increased transcription of the p35 subunit of IL-12p70 during infection. HMBA also increased early type I IFN transcription in human monocytic and epithelial cell lines, but this was surprisingly independent of its previously reported effects on positive transcription elongation factor b and HMBA inducible protein-1. Instead, the effect of HMBA was downstream of a calcium influx, and required the pattern recognition receptor and adaptor STING but not cGAS. Our work therefore links the STING-IRF3 axis to enhanced IL-12 production and intracellular bacterial control in primary monocytes. This raises the possibility that HMBA or related small molecules may be explored as therapeutic adjuvants to improve disease outcomes during intracellular bacterial infections.
Functional Genomic Analysis in Arthritis-Affected Cartilage: Yin-Yang Regulation of Inflammatory Mediators by α5β1 and αVβ3 Integrins1

Osteoarthritis-affected cartilage exhibits enhanced expression of fibronectin (FN) and osteopontin (OPN) mRNA in differential display and bioinformatics screen. Functional genomic analysis shows that the engagement of the integrin receptors α5β1 and αvβ3 of FN and OPN, respectively, have profound effects on chondrocyte functions. Ligation of α5β1 using activating mAb JBS5 (which acts as agonist similar to FN N-terminal fragment) up-regulates the inflammatory mediators such as NO and PGE2 as well as the cytokines, IL-6 and IL-8. Furthermore, up-regulation of these proinflammatory mediators by α5β1 integrin ligation is mediated via induction and autocrine production of IL-1β, because type II soluble IL-1 decoy receptor inhibits their production. In contrast, αvβ3 complex-specific function-blocking mAb (LM609), which acts as an agonist similar to OPN, attenuates the production of IL-1β, NO, and PGE2 (triggered by α5β1, IL-1β, IL-18, or IL-1β, TNF-α, plus LPS) in a dominant negative fashion by osteoarthritis-affected cartilage and activated bovine chondrocytes. These data demonstrate a cross-talk in signaling mechanisms among integrins and show that integrin-mediated “outside in” and “inside out” signaling very likely influences cartilage homeostasis, and its deregulation may play a role in the pathogenesis of osteoarthritis.
Comparisons and Limitations of Current Definitions of Bronchopulmonary Dysplasia for the Prematurity and Respiratory Outcomes Program.

RATIONALE Bronchopulmonary dysplasia is the most common morbidity of prematurity, but the validity and utility of commonly used definitions have been questioned. OBJECTIVES To compare three commonly used definitions of bronchopulmonary dysplasia in a contemporary prospective, multicenter observational cohort of extremely preterm infants. METHODS At 36 weeks postmenstrual age, the following definitions of bronchopulmonary dysplasia were applied to surviving infants with and without imputation: need for supplemental oxygen (Shennan definition), National Institutes of Health Workshop definition, and "physiologic" definition after a room-air challenge. MEASUREMENTS AND MAIN RESULTS Of 765 survivors assessed at 36 weeks, bronchopulmonary dysplasia was diagnosed in 40.8, 58.6, and 32.0% of infants, respectively, with the Shennan, workshop and physiologic definitions. The number of unclassified infants was lowest with the workshop definition (2.1%) and highest with the physiologic definition (16.1%). After assigning infants discharged home in room air before 36 weeks as no bronchopulmonary dysplasia, the modified Shennan definition compared favorably to the workshop definition, with 2.9% unclassified infants. Newer management strategies with nasal cannula flows up to 4 L/min or more and 0.21 FiO2 at 36 weeks obscured classification of bronchopulmonary dysplasia status in 12.4% of infants. CONCLUSIONS Existing definitions of bronchopulmonary dysplasia differ with respect to ease of data collection and number of unclassifiable cases. Contemporary changes in management of infants, such as use of high-flow nasal cannula, limit application of existing definitions and may result in misclassification. A contemporary definition of bronchopulmonary dysplasia that correlates with respiratory morbidity in childhood is needed. Clinical trial registered with www.clinicaltrials. gov (NCT01435187).
Lis1 Regulates Germinal Center B Cell Antigen Acquisition and Affinity Maturation

The germinal center (GC) is the site where activated B cells undergo rapid expansions, somatic hypermutation, and affinity maturation. Affinity maturation is a process of Ag-driven selection. The amount of Ag acquired and displayed by GC B cells determines whether it can be positively selected, and therefore Ag acquisition has to be tightly regulated to ensure the efficient affinity maturation. Cell expansion provides sufficient quantity of GC B cells and Abs, whereas affinity maturation improves the quality of Abs. In this study, we found that Lis1 is a cell-intrinsic regulator of Ag acquisition capability of GC B cells. Lack of Lis1 resulted in redistribution of polymerized actin and accumulation of F-actin at uropod; larger amounts of Ags were acquired and displayed by GC B cells, which presumably reduced the selection stringency. Affinity maturation was thus compromised in Lis1-deficient mice. Consistently, overexpression of Lis1 in GC B cells led to less Ag acquisition and display. Additionally, Lis1 is required for GC B cell expansion, and Lis1 deficiency blocked the cell cycle at the mitotic phase and GC B cells were prone to apoptosis. Overall, we suggest that Lis1 is required for GC B cell expansion, affinity maturation, and maintaining functional intact GC response, thus ensuring both the quantity and quality of Ab response.
A prospective cohort study of pain with intrauterine device insertion among women with and without vaginal deliveries

Abstract The purpose of this prospective cohort study was to compare pain during IUD insertion between women with a history of vaginal delivery and women without a history of vaginal delivery. First-time IUD users chose either the CuT380A or the levonorgestrel IUS. We enrolled 49 women with previous vaginal delivery and 49 women with no history of vaginal delivery (either only caesarean deliveries or nulliparous). The mean pain score on a 0–100 mm visual analog scale during insertion in the vaginal delivery group was 34.7 (SD 31.6) compared with 51.2 (SD 29.2) in the group without previous vaginal delivery (p = 0.009). In multivariable analysis controlling for age, breast-feeding, expected pain, baseline anxiety, insertion timing (6–12 weeks postpartum, 2–4 weeks post-abortion or interval), and insertion difficulty, history of vaginal delivery was associated with a 15.5 point reduction in pain (95% CI, –27.4, –3.7). Other significant predictors of pain were ‘expected pain’ and ‘insertion difficulty’.
A Consensus Definitive Classification of Scavenger Receptors and Their Roles in Health and Disease

Scavenger receptors constitute a large family of proteins that are structurally diverse and participate in a wide range of biological functions. These receptors are expressed predominantly by myeloid cells and recognize a diverse variety of ligands including endogenous and modified host-derived molecules and microbial pathogens. There are currently eight classes of scavenger receptors, many of which have multiple names, leading to inconsistencies and confusion in the literature. To address this problem, a workshop was organized by the United States National Institute of Allergy and Infectious Diseases, National Institutes of Health, to help develop a clear definition of scavenger receptors and a standardized nomenclature based on that definition. Fifteen experts in the scavenger receptor field attended the workshop and, after extensive discussion, reached a consensus regarding the definition of scavenger receptors and a proposed scavenger receptor nomenclature. Scavenger receptors were defined as cell surface receptors that typically bind multiple ligands and promote the removal of nonself or altered-self targets. They often function by mechanisms that include endocytosis, phagocytosis, adhesion, and signaling that ultimately lead to the elimination of degraded or harmful substances. Based on this definition, nomenclature and classification of these receptors into 10 classes were proposed. This classification was discussed at three national meetings and input from participants at these meetings was requested. The following manuscript is a consensus statement that combines the recommendations of the initial workshop and incorporates the input received from the participants at the three national meetings.
Cutting Edge: 2B4-Mediated Coinhibition of CD4+ T Cells Underlies Mortality in Experimental Sepsis

Sepsis is a leading cause of death in the United States, but the mechanisms underlying sepsis-induced immune dysregulation remain poorly understood. 2B4 (CD244, SLAM4) is a cosignaling molecule expressed predominantly on NK cells and memory CD8+ T cells that has been shown to regulate T cell function in models of viral infection and autoimmunity. In this article, we show that 2B4 signaling mediates sepsis lymphocyte dysfunction and mortality. 2B4 expression is increased on CD4+ T cells in septic animals and human patients at early time points. Importantly, genetic loss or pharmacologic inhibition of 2B4 significantly increased survival in a murine cecal ligation and puncture model. Further, CD4-specific conditional knockouts showed that 2B4 functions on CD4+ T cell populations in a cell-intrinsic manner and modulates adaptive and innate immune responses during sepsis. Our results illuminate a novel role for 2B4 coinhibitory signaling on CD4+ T cells in mediating immune dysregulation.
Hydroxyethyl Starch Effects on Rat Warm Renal Ischemia

Fractions of hydroxyethyl starch (HES), 100,000-1,000,000 daltons, have been shown to reduce increased permeability changes in postcapillary venules associated with ischemia-reperfusion injury in canine myocardium and rat skel etal muscle. The authors studied the effect of intravenous administration of two fractions of the biodegradable HES, Fm (100,000-300,000 daltons) and FLm (300,000-1,000,000 daltons), in the prevention of acute renal failure in a rat warm renal ischemia model. A series of renal artery cross-clamp times was used to determine the threshold for irreversible damage (thirty minutes). After thirty minutes of warm renal ischemia, 2.5 cc of 6 % Fm or FLm solution, 5% human serum albumin, or 9% normal saline was administered. The effect of the solutions was evaluated by four criteria: (1) forty-eight hours' serum BUN/creatinine, (2) forty-eight hours' urine output, (3) percent of water content in the kidney, and (4) a histopathologic grading. There were no differences among the animals in any of the four groups in renal function at forty-eight hours, percent of water content of the kidneys, urine output, and extent of medullary and cortical injury. The authors attribute the lack of protective effect by the HES macromolecules to intrinsic properties of the kidney such as the extensive endothelial cell surface area of the well-vascularized kidney and the hypersensitivity of the kidney to hypoxic injury.
Etiology of Non-Cystic Fibrosis Bronchiectasis in Adults and Its Correlation to Disease Severity.

RATIONALE Testing for underlying etiology is a key part of bronchiectasis management, but it is unclear whether the same extent of testing is required across the spectrum of disease severity. OBJECTIVES The aim of the present study was to identify the etiology of bronchiectasis across European cohorts and according to different levels of disease severity. METHODS We conducted an analysis of seven databases of adult outpatients with bronchiectasis prospectively enrolled at the bronchiectasis clinics of university teaching hospitals in Monza, Italy; Dundee and Newcastle, United Kingdom; Leuven, Belgium; Barcelona, Spain; Athens, Greece; and Galway, Ireland. All the patients at every site underwent the same comprehensive diagnostic workup as suggested by the British Thoracic Society. MEASUREMENTS AND MAIN RESULTS Among the 1,258 patients enrolled, an etiology of bronchiectasis was determined in 60%, including postinfective (20%), chronic obstructive pulmonary disease related (15%), connective tissue disease related (10%), immunodeficiency related (5.8%), and asthma related (3.3%). An etiology leading to a change in patient's management was identified in 13% of the cases. No significant differences in the etiology of bronchiectasis were present across different levels of disease severity, with the exception of a higher prevalence of chronic obstructive pulmonary disease-related bronchiectasis (P < 0.001) and a lower prevalence of idiopathic bronchiectasis (P = 0.029) in patients with severe disease. CONCLUSIONS Physicians should not be guided by disease severity in suspecting specific etiologies in patients with bronchiectasis, although idiopathic bronchiectasis appears to be less common in patients with the most severe disease.
Klhl6 Deficiency Impairs Transitional B Cell Survival and Differentiation

Klhl6 belongs to the KLHL gene family, which is composed of an N-terminal BTB-POZ domain and four to six Kelch motifs in tandem. Several of these proteins function as adaptors of the Cullin3 E3 ubiquitin ligase complex. In this article, we report that Klhl6 deficiency induces, as previously described, a 2-fold reduction in mature B cells. However, we find that this deficit is centered on the inability of transitional type 1 B cells to survive and to progress toward the transitional type 2 B cell stage, whereas cells that have passed this step generate normal germinal centers (GCs) upon a T-dependent immune challenge. Klhl6-deficient type 1 B cells showed a 2-fold overexpression of genes linked with cell proliferation, including most targets of the anaphase-promoting complex/cyclosome complex, a set of genes whose expression is precisely downmodulated upon culture of splenic transitional B cells in the presence of BAFF. These results thus suggest a delay in the differentiation process of Klhl6-deficient B cells between the immature and transitional stage. We further show, in the BL2 Burkitt’s lymphoma cell line, that KLHL6 interacts with Cullin3, but also that it binds to HBXIP/Lamtor5, a protein involved in cell-cycle regulation and cytokinesis. Finally, we report that KLHL6, which is recurrently mutated in B cell lymphomas, is an off-target of the normal somatic hypermutation process taking place in GC B cells in both mice and humans, thus leaving open whether, despite the lack of impact of Klhl6 deficiency on GC B cell expansion, mutants could contribute to the oncogenic process.