Coronavirus disease 2019-related myocardial injury is associated with immune dysregulation in symptomatic patients with cardiac magnetic resonance imaging abnormalities.

Aims: While acute cardiovascular complications of coronavirus disease 2019 (COVID-19) are well described, less is known about longer-term cardiac sequelae. For many individuals with cardiac signs or symptoms arising after COVID-19 infection, the aetiology remains unclear. We examined immune profiles associated with magnetic resonance imaging (MRI) abnormalities in patients with unexplained cardiac injury after COVID-19.

Marginal zone B cells produce 'natural' atheroprotective IgM antibodies in a T cell-dependent manner.

Aims: The adaptive immune response plays an important role in atherosclerosis. In response to a high-fat/high-cholesterol (HF/HC) diet, marginal zone B (MZB) cells activate an atheroprotective programme by regulating the differentiation and accumulation of 'poorly differentiated' T follicular helper (Tfh) cells. On the other hand, Tfh cells activate the germinal centre response, which promotes atherosclerosis through the production of class-switched high-affinity antibodies.

Innate Lymphoid Cells Promote Recovery of Ventricular Function After Myocardial Infarction.

Background: Innate lymphoid cells type 2 (ILC2s) play critical homeostatic functions in peripheral tissues. ILC2s reside in perivascular niches and limit atherosclerosis development.

Objectives: ILC2s also reside in the pericardium but their role in postischemic injury is unknown.

Design and Synthesis of Pyrrolo[2,3-]pyrimidine-Derived Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Checkpoint Kinase 1 (CHK1)-Derived Crystallographic Surrogate.

Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and mutants, such as G2019S, have potential utility in Parkinson's disease treatment. Fragment hit-derived pyrrolo[2,3-]pyrimidines underwent optimization using X-ray structures of LRRK2 kinase domain surrogates, based on checkpoint kinase 1 (CHK1) and a CHK1 10-point mutant. (2)-2-Methylpyrrolidin-1-yl derivative (LRRK2 G2019S c 0.

Macrophage beta2-adrenergic receptor is dispensable for the adipose tissue inflammation and function.

Objective: Neuroimmune interactions between the sympathetic nervous system (SNS) and macrophages are required for the homeostasis of multiple tissues, including the adipose tissue. It has been proposed that the SNS maintains adipose tissue macrophages (ATMs) in an anti-inflammatory state via direct norepinephrine (NE) signaling to macrophages. This study aimed to investigate the physiological importance of this paradigm by utilizing a mouse model in which the adrenergic signaling from the SNS to macrophages, but not to other adipose tissue cells, was disrupted.

Multiple life-stage inbreeding depression impacts demography and extinction risk in an extinct-in-the-wild species.

Inbreeding can depress individuals' fitness traits and reduce population viability. However, studies that directly translate inbreeding depression on fitness traits into consequences for population viability, and further, into consequences for management choices, are lacking. Here, we estimated impacts of inbreeding depression (B, lethal equivalents) across life-history stages for an extinct-in-the-wild species, the sihek (Guam kingfisher, Todiramphus cinnamominus).

Interleukin-33 Signaling Controls the Development of Iron-Recycling Macrophages.

Splenic red pulp macrophages (RPMs) contribute to erythrocyte homeostasis and are required for iron recycling. Heme induces the expression of SPIC transcription factor in monocyte-derived macrophages and promotes their differentiation into RPM precursors, pre-RPMs. However, the requirements for differentiation into mature RPMs remain unknown.

2019 Plenary Lecture: Interleukin-2 Therapy in Cardiovascular Disease: The Potential to Regulate Innate and Adaptive Immunity.

Regulatory T cells and type-2 innate lymphoid cells represent 2 subsets of immune cells, which have been shown in preclinical models to be important in atherosclerosis and myocardial repair. Regulatory T cells play a crucial role in immune homeostasis and tolerance via their interactions with effector T cells, dendritic cells, and monocytes/macrophages. They also utilize and secrete inhibitory cytokines, including interleukin 10 and transforming growth factor β, to regulate or suppress pathogenic immune responses.

Impaired Autophagy in CD11b Dendritic Cells Expands CD4 Regulatory T Cells and Limits Atherosclerosis in Mice.

Rationale: Atherosclerosis is a chronic inflammatory disease. Recent studies have shown that dysfunctional autophagy in endothelial cells, smooth muscle cells, and macrophages, plays a detrimental role during atherogenesis, leading to the suggestion that autophagy-stimulating approaches may provide benefit.

Objective: Dendritic cells (DCs) are at the crossroad of innate and adaptive immune responses and profoundly modulate the development of atherosclerosis.

MARK4 (Microtubule Affinity-Regulating Kinase 4)-Dependent Inflammasome Activation Promotes Atherosclerosis-Brief Report.

Objective: MARK4 (microtubule affinity-regulating kinase 4) regulates NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3) inflammasome activation. The aim of the study is to examine the role of MARK4 in hematopoietic cells during atherosclerosis.

Methods And Results: We show increased MARK4 expression in human atherosclerotic lesions compared with adjacent areas.

Deletion of IRF8 (Interferon Regulatory Factor 8)-Dependent Dendritic Cells Abrogates Proatherogenic Adaptive Immunity.

Rationale: Despite an established role for adaptive immune responses in atherosclerosis, the contribution of dendritic cells (DCs) and their various subsets is still poorly understood.

Objective: Here, we address the role of IRF8 (interferon regulatory factor 8)-dependent DCs (lymphoid CD8α and their developmentally related nonlymphoid CD103 DCs) in the induction of proatherogenic immune responses during high fat feeding.

Methods And Results: Using a fate-mapping technique to track DCs originating from a DNGR1 (dendritic cell natural killer lectin group receptor 1) precursor ( mice), we first show that YFPCD11cMHCII (major histocompatibility complex class II) DCs are present in the atherosclerotic aorta of low-density lipoprotein receptor-deficient () mice and are CD11bCD103IRF8.

A Structure-Based Assembly Screen of Protein Cage Libraries in Living Cells: Experimentally Repacking a Protein-Protein Interface To Recover Cage Formation in an Assembly-Frustrated Mutant.

Cage proteins, which assemble into often highly symmetric hollow nanoscale capsules, have great potential in applications as far reaching as drug delivery, hybrid nanomaterial engineering, and catalysis. In addition, they are promising model systems for understanding how cellular nanostructures are constructed through protein-protein interactions, and they are beginning to be used as scaffolds for synthetic biology approaches. Recently, there has been renewed interest in the engineering of protein cages, and in support of these strategies, we have recently described a fluorescence-based assay for protein cage assembly that is specific for certain oligomerization states and symmetry-related protein-protein interfaces.

Design of Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Crystallographic Surrogate Derived from Checkpoint Kinase 1 (CHK1).

Mutations in leucine-rich repeat kinase 2 (LRRK2), such as G2019S, are associated with an increased risk of developing Parkinson's disease. Surrogates for the LRRK2 kinase domain based on checkpoint kinase 1 (CHK1) mutants were designed, expressed in insect cells infected with baculovirus, purified, and crystallized. X-ray structures of the surrogates complexed with known LRRK2 inhibitors rationalized compound potency and selectivity.

X-Box Binding Protein-1 Dependent Plasma Cell Responses Limit the Development of Atherosclerosis.

Rationale: Diverse B cell responses and functions may be involved in atherosclerosis. Protective antibody responses, such as those against oxidized lipid epitopes, are thought to mainly derive from T cell-independent innate B cell subsets. In contrast, both pathogenic and protective roles have been associated with T cell-dependent antibodies, and their importance in both humans and mouse models is still unclear.

Type-2 innate lymphoid cells control the development of atherosclerosis in mice.

Type-2 innate lymphoid cells (ILC2) are a prominent source of type II cytokines and are found constitutively at mucosal surfaces and in visceral adipose tissue. Despite their role in limiting obesity, how ILC2s respond to high fat feeding is poorly understood, and their direct influence on the development of atherosclerosis has not been explored. Here, we show that ILC2 are present in para-aortic adipose tissue and lymph nodes and display an inflammatory-like phenotype atypical of adipose resident ILC2.

Marginal zone B cells control the response of follicular helper T cells to a high-cholesterol diet.

Splenic marginal zone B (MZB) cells, positioned at the interface between circulating blood and lymphoid tissue, detect and respond to blood-borne antigens. Here we show that MZB cells in mice activate a homeostatic program in response to a high-cholesterol diet (HCD) and regulate both the differentiation and accumulation of T follicular helper (T) cells. Feeding mice an HCD resulted in upregulated MZB cell surface expression of the immunoregulatory ligand PDL1 in an ATF3-dependent manner and increased the interaction between MZB cells and pre-T cells, leading to PDL1-mediated suppression of T cell motility, alteration of T cell differentiation, reduced T abundance and suppression of the proatherogenic T response.

Influence of dopant substitution mechanism on catalytic properties within hierarchical architectures.

A range of hierarchically porous (HP) AlPO-5 catalysts, with isomorphously substituted transition metal ions, have been synthesized using an organosilane as a soft template. By employing a range of structural and spectroscopic characterization protocols, the properties of the dopant-substituted species within the HP architectures have been carefully evaluated. The resulting nature of the active site is shown to have a direct impact on the ensuing catalytic properties in the liquid-phase Beckmann rearrangement of cyclic ketones.

The Schistosoma mansoni T2 ribonuclease omega-1 modulates inflammasome-dependent IL-1β secretion in macrophages.

The T2 ribonuclease omega-1 is a powerful Th2-inducing factor secreted by the eggs of the blood fluke Schistosoma mansoni. Omega-1 can modulate pattern recognition receptor-induced inflammatory signatures and alter antigen presentation by dendritic cells. Recent findings have suggested that component(s) contained in or secreted by S.

Predictive design of engineered multifunctional solid catalysts.

The ability to devise and design multifunctional active sites at the nanoscale, by drawing on the intricate ability of enzymes to evolve single-sites with distinctive catalytic function, has prompted complimentary and concordant developments in the field of catalyst design and in situ operando spectroscopy. Innovations in design-application approach have led to a more fundamental understanding of the nature of the active site and its mechanistic influence at a molecular level, that have enabled robust structure-property correlations to be established, which has facilitated the dextrous manipulation and predictive design of redox and solid-acid sites for industrially-significant, sustainable catalytic transformations.

Detection of specific protein-protein interactions in nanocages by engineering bipartite FlAsH binding sites.

Proteins that form cage-like structures have been of much recent cross-disciplinary interest due to their application to bioconjugate and materials chemistry, their biological functions spanning multiple essential cellular processes, and their complex structure, often defined by highly symmetric protein–protein interactions. Thus, establishing the fundamentals of their formation, through detecting and quantifying important protein–protein interactions, could be crucial to understanding essential cellular machinery, and for further development of protein-based technologies. Herein we describe a method to monitor the assembly of protein cages by detecting specific, oligomerization state dependent, protein–protein interactions.

The nonconventional MHC class II molecule DM governs diabetes susceptibility in NOD mice.

The spontaneous destruction of insulin producing pancreatic beta cells in non-obese diabetic (NOD) mice provides a valuable model of type 1 diabetes. As in humans, disease susceptibility is controlled by the classical MHC class II genes that guide CD4(+) T cell responses to self and foreign antigens. It has long been suspected that the dedicated class II chaperone designated HLA-DM in humans or H-2M in mice also makes an important contribution, but due to tight linkage within the MHC, a possible role played by DM peptide editing has not been previously tested by conventional genetic approaches.

PD-L1 blockade overrides Salmonella typhimurium-mediated diabetes prevention in NOD mice: no role for Tregs.

Increasingly, evidence suggests that there is a strong environmental component to the development of the autoimmune disease type 1 diabetes. Our previous data showed that NOD mice are protected from developing diabetes after infection with Salmonella typhimurium and there is some evidence that changes within the DC compartment play a crucial role in this protective effect. This paper further characterises this Salmonella-modulated protective phenotype.

Epigenetic changes at Il12rb2 and Tbx21 in relation to plasticity behavior of Th17 cells.

Plasticity within Th cell populations may play a role in enabling site-specific immune responses to infections while limiting tissue destruction. Epigenetic processes are fundamental to such plasticity; however, to date, most investigations have focused on in vitro-generated T cells. In this study, we have examined the molecular mechanisms underpinning murine Th17 plasticity in vivo by assessing H3K4 and H3K27 trimethylation marks at Tbx21, Rorc, Il17a, Ifng, and Il12rb2 loci in purified ex vivo-isolated and in vitro-generated Th17 cells.