Regulatory T cell (Treg) therapy using recipient‐derived Tregs expanded ex vivo is currently being investigated clinically by us and others as a means of reducing allograft rejection following organ ...transplantation. Data from animal models has demonstrated that adoptive transfer of allospecific Tregs offers greater protection from graft rejection compared to polyclonal Tregs. Chimeric antigen receptors (CAR) are clinically translatable synthetic fusion proteins that can redirect the specificity of T cells toward designated antigens. We used CAR technology to redirect human polyclonal Tregs toward donor‐MHC class I molecules, which are ubiquitously expressed in allografts. Two novel HLA‐A2‐specific CARs were engineered: one comprising a CD28‐CD3ζ signaling domain (CAR) and one lacking an intracellular signaling domain (ΔCAR). CAR Tregs were specifically activated and significantly more suppressive than polyclonal or ΔCAR Tregs in the presence of HLA‐A2, without eliciting cytotoxic activity. Furthermore, CAR and ΔCAR Tregs preferentially transmigrated across HLA‐A2‐expressing endothelial cell monolayers. In a human skin xenograft transplant model, adoptive transfer of CAR Tregs alleviated the alloimmune‐mediated skin injury caused by transferring allogeneic peripheral blood mononuclear cells more effectively than polyclonal Tregs. Our results demonstrated that the use of CAR technology is a clinically applicable refinement of Treg therapy for organ transplantation.
Human HLA class I–allospecific regulatory T cells generated using chimeric antigen receptor technology exhibit an enhanced suppressive capacity in the presence of their target antigen, and inhibit undesired alloimmune‐mediated damage of human skin grafts more effectively than polyclonal regulatory T cells. See page 854 for Brouard and Mooney's editorial.
Low-molecular-weight (LMW) emulsifiers are used to promote controlled destabilization in many dairy-type emulsions in order to obtain stable foams in whippable products. The relation between fat ...globule aggregation induced by three LMW emulsifiers, lactic acid ester of monoglyceride (LACTEM), saturated monoglyceride (GMS), and unsaturated monoglyceride (GMU) and their effect on interfacial protein displacement was investigated. It was found that protein displacement by LMW emulsifiers was not necessary for fat globule aggregation in emulsions, and conversely fat globule aggregation was not necessarily accompanied by protein displacement. The three LMW emulsifiers had very different effects on emulsions. LACTEM induced shear instability of emulsions, which was accompanied by protein displacement. High stability was characteristic for emulsions with GMS where protein was displaced from the interface. Emulsions containing GMU were semisolid, but only low concentrations of protein were detected in the separated serum phase. The effects of LACTEM, GMS, and GMU may be explained by three different mechanisms involving formation of interfacial α-gel, pickering stabilization and increased exposure of bound casein to the water phase. The latter may facilitate partial coalescence. Stabilizing hydrocolloids did not have any effect on the LMW emulsifiers’ ability to induce protein displacement.
T‐cell‐mediated immunity has been linked not only to a variety of heart diseases, including classic inflammatory diseases such as myocarditis and post‐myocardial infarction (Dressler's) syndrome, but ...also to conditions without an obvious inflammatory component such as idiopathic dilated cardiomyopathy and hypertensive cardiomyopathy. It has been recently proposed that in all these conditions, the heart becomes the focus of T‐cell‐mediated autoimmune inflammation following ischaemic or infectious injury. For example, in acute myocarditis, an inflammatory disease of heart muscle, T‐cell responses are thought to arise as a consequence of a viral infection. In a number of patients, persistent T‐cell‐mediated responses in acute viral myocarditis can lead to autoimmunity and chronic cardiac inflammation resulting in dilated cardiomyopathy. In spite of the major progress made in understanding the mechanisms of pathogenic T‐cell responses, effective and safe therapeutic targeting of the immune system in chronic inflammatory diseases of the heart has not yet been developed due to the lack of specific diagnostic and prognostic biomarkers at an early stage. This has also prevented the identification of targets for patient‐tailored immunomodulatory therapies that are both disease‐ and organ‐selective. In this review, we discuss current knowledge of the development and functional characteristics of pathogenic T‐cell‐mediated immune responses in the heart, and, in particular, in myocarditis, as well as recent advances in experimental models which have the potential to translate into heart‐selective immunomodulation.
Linked Articles
This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc
SARS-CoV-2 might directly activate NLRP3 inflammasome resulting in an endogenous adjuvant activity necessary to mount a proper adaptive immune response against the virus. Heterogeneous response of ...COVID-19 patients could be attributed to differences in not being able to properly downregulate NLRP3 inflammasome activation. This relates to the fitness of the immune system of the individual challenged by the virus. Patients with a reduced immune fitness can demonstrate a dysregulated NLRP3 inflammasome activity resulting in severe COVID-19 with tissue damage and a cytokine storm. We sketch the outlines of five possible scenarios for COVID-19 in medical practice and provide potential treatment options targeting dysregulated endogenous adjuvant activity in severe COVID-19 patients.
Individuals with an evening chronotype are at increased risk of experiencing emotional problems, including depressive symptoms. However, the mechanisms underlying these associations remain unclear. ...The present study aimed to determine whether poor sleep quality, substance use and cognitive emotion regulation difficulties - which have been implicated in the etiology of depression - mediate the relationship between chronotype and depressive symptoms in a student sample, which was assessed cross-sectionally and after 1 year. A total of 742 Dutch students (75% women, mean age 21.4 ± 2.9 years) completed the Quick Inventory of Depressive Symptomatology, the Morningness-Eveningness Questionnaire, the Pittsburgh Sleep Quality Index, a questionnaire assessing alcohol, caffeine, tobacco and cannabis use, the Cognitive Emotion Regulation Questionnaire and the Behavioral Inhibition/Activation Scale. A subsample (n = 115) was assessed 1 year later with the same questionnaires. Cross-sectional analyses showed that evening chronotype was associated with more depressive symptoms, adjusted for age and gender (β = -0.082, p = 0.028). The relationship between eveningness and depressive symptoms was mediated by sleep quality, alcohol consumption and the cognitive emotion regulation strategies of self-blame and positive reappraisal. In longitudinal analyses, eveningness at baseline predicted more depressive symptoms at follow-up, adjusted for age and gender (β = -0.29, p = 0.002); after additional adjustment for baseline depressive symptoms, chronotype remained a significant predictor of depressive symptoms at T2 (β = -0.16, t = -2.01, p = 0.047). Only poor sleep quality at follow-up was a significant mediator of this relationship. Even though the effect is small in terms of explained variance, eveningness is related to depressive symptoms and this relationship is mediated by poor sleep quality, also in a prospective design. Self-blame and reduced positive reappraisal are correlated with eveningness. Further research is needed to assess the efficacy of chronotherapeutic interventions for the prevention of depression, in addition to sleep education and cognitive approaches.
Background
Measurement of free metanephrines is recommended for screening of pheochromocytoma (PCC) but requires appropriate reference intervals (RIs).
Hypothesis/Objectives
To report RIs for plasma, ...urinary and salivary concentrations of free metanephrines and to determine the diagnostic performance of plasma free normetanephrine (pNMN) and metanephrine (pMN) concentrations in dogs with PCC, hypercortisolism (HC), and nonadrenal illness (NAI).
Animals
Eighty healthy dogs, 11 PCC dogs, 25 HC dogs, 6 NAI dogs.
Methods
Plasma, urine, and saliva were collected prospectively from healthy dogs, and free metanephrine concentrations were determined by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). In addition, medical records of dogs that had plasma free metanephrine concentrations measured by LC‐MS/MS between 2018‐2021 were studied retrospectively.
Results
The RIs for free metanephrines in plasma, urine and saliva are reported. Dogs with PCC had significantly higher pNMN than dogs with HC (P < .001) and NAI (P = .002). The PCC dogs had significantly higher pMN than HC dogs (P < .001), but not higher than NAI dogs (P = .29). Using the upper reference limit, pNMN (>3.56 nmol/L) showed high sensitivity (100%, 95% confidence interval CI: 72‐100) and specificity (94%, 95% CI: 79‐99) for diagnosis of PCC, whereas pMN (>2.49 nmol/L) showed moderate sensitivity (73%, 95% CI: 39‐94) and high specificity (94%, 95% CI: 79‐99).
Conclusions and Clinical Importance
With establishment of these RIs, biochemical testing for PCC in dogs can be substantially improved. Measurement of pNMN is superior to pMN in dogs with PCC.
We describe the model and construction of a two-flow (or
divided-flow) humidity generator, developed at LNE-Cnam, that uses mass flow
controllers to mix a stream of dry gas with a stream of humid gas ...saturated
at 28 ∘C. It can generate a wide range of humidity, with mole
fractions in the range of 0.7×10-6<x<9000×10-6, without using low temperature or high pressure.
This range is suitable for calibrating balloon-borne instruments that
measure humidity in the stratosphere, where x∼5×10-6. The generator's novel feature is a saturator that comprises 5 m
of silicone tubing immersed in water. Water enters the humid gas stream by
diffusing through the wall of the tubing until the gas stream flowing
through the tubing is saturated. This design provides a simple, low-cost
humidity generator with an accuracy that is acceptable for many
applications. The key requirement is that the tubing be long enough to
ensure saturation so that the saturator's output is independent of the
dimensions and permeability of the tube. A length of only a few meters was
sufficient because the tube was made of silicone; other common polymers have
permeabilities that are 1000 times smaller. We verified the model of the
transition from unsaturated flow to saturated flow by measuring the humidity
while using three tube lengths, two of which were too short for saturation.
As a more complete test, we used the generator as a primary device after
correcting the calibrations of the mass flow controllers that determined the
mixing ratio. At mole fractions of 50×10-6<x<5000×10-6, the generator's output mole fraction xgen
agreed to within 1 % with the value xcm measured by a calibrated
chilled-mirror hygrometer; in other words, their ratio fell in the range
xgen/xcm=1.00±0.01. At smaller mole fractions, their
differences fell in the range of xgen-xcm=±1×10-6.
Objective
The objective of this study was to predict rehospitalisation in a psychiatric clinic in older inpatients with a psychotic disorder.
Methods/Design
In this prospective, observational study, ...all eligible inpatients aged 55 years and over with a primary psychotic disorder, admitted to a specialised ward for older psychotic patients in a large psychiatric inpatient clinic in the Netherlands, were asked to participate. Whether or not patients were rehospitalised and time to rehospitalisation were assessed 1 year after discharge from the ward. We recorded age, gender, living arrangement, psychiatric diagnosis, severity of psychotic symptoms, duration of index episode, age of onset of psychotic disorder, number of previous admissions, involuntary admission and use of depot medication at discharge. All patients underwent a neuropsychological assessment.
Results
Of the 90 patients that were included, 32 (35.6%) had been readmitted within 1 year after discharge. None of the demographic or clinical variables predicted rehospitalisation or the time to rehospitalisation.
Conclusion
Factors that predict rehospitalisationin younger adult patients with schizophrenia may not predict rehospitalisationin older patients with a psychotic disorder, of which the majority suffered from schizophrenia. We expect that other factors than those investigated may be of greater importance to predict rehospitalisation, as for example social support and coping mechanisms.
Type III CRISPR-Cas immunity is widespread in prokaryotes and is generally mediated by multisubunit effector complexes. These complexes recognize complementary viral transcripts and can activate ...ancillary immune proteins. Here, we describe a type III-E effector from
“Scalindua brodae” (
-gRAMP), which is natively encoded by a single gene with several type III domains fused together. This effector uses CRISPR RNA to guide target RNA recognition and cleaves single-stranded RNA at two defined positions six nucleotides apart.
-gRAMP physically combines with the caspase-like TPR-CHAT peptidase to form the CRISPR-guided caspase (Craspase) complex, suggesting a potential mechanism of target RNA–induced protease activity to gain viral immunity.
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