Protocol for analyzing transforming growth factor β signaling in dextran-sulfate-sodium-induced colitic mice using flow cytometry and western blotting.

Transforming growth factor β (TGF-β) is critical to the maintenance of intestinal immune homeostasis. Here, we present techniques for analyzing Smad molecules downstream of TGF-β receptor signaling in dextran-sulfate-sodium-induced colitic mice. We describe colitis induction, cell isolation, and flow cytometric cell sorting of dendritic cells and T cells.

microRNA-92a promotes CNS autoimmunity by modulating the regulatory and inflammatory T cell balance.

A disequilibrium between immunosuppressive Tregs and inflammatory IL-17-producing Th17 cells is a hallmark of autoimmune diseases, including multiple sclerosis (MS). However, the molecular mechanisms underlying the Treg and Th17 imbalance in CNS autoimmunity remain largely unclear. Identifying the factors that drive this imbalance is of high clinical interest.

Deletion of STAT3 from Foxd1 cell population protects mice from kidney fibrosis by inhibiting pericytes trans-differentiation and migration.

Signal transduction and activator of transcription 3 (STAT3) is a key transcription factor implicated in the pathogenesis of kidney fibrosis. Although Stat3 deletion in tubular epithelial cells is known to protect mice from fibrosis, vFoxd1 cells remains unclear. Using Foxd1-mediated Stat3 knockout mice, CRISPR, and inhibitors of STAT3, we investigate its function.

Treatment of Experimental Autoimmune Encephalomyelitis with an Inhibitor of Phosphodiesterase-8 (PDE8).

After decades of development, inhibitors targeting cyclic nucleotide phosphodiesterases (PDEs) expressed in leukocytes have entered clinical practice for the treatment of inflammatory disorders, with three PDE4 inhibitors being in clinical use as therapeutics for psoriasis, psoriatic arthritis, chronic obstructive pulmonary disease and atopic dermatitis. In contrast, the PDE8 family that is upregulated in pro-inflammatory T cells is a largely unexplored therapeutic target. We have previously demonstrated a role for the PDE8A-Raf-1 kinase complex in the regulation of myelin oligodendrocyte glycoprotein peptide 35-55 (MOG) activated CD4 effector T cell adhesion and locomotion by a mechanism that differs from PDE4 activity.

Myeloid cell subsets that express latency-associated peptide promote cancer growth by modulating T cells.

Myeloid suppressor cells promote tumor growth by a variety of mechanisms which are not fully characterized. We identified myeloid cells (MCs) expressing the latency-associated peptide (LAP) of TGF-β on their surface and LAP MCs that stimulate Foxp3 Tregs while inhibiting effector T cell proliferation and function. Blocking TGF-β inhibits the tolerogenic ability of LAP MCs.

Regulation of splenic monocyte homeostasis and function by gut microbial products.

Splenic Ly6C monocytes are innate immune cells involved in the regulation of central nervous system-related diseases. Recent studies have reported the shaping of peripheral immune responses by the gut microbiome via mostly unexplored pathways. In this study, we report that a 4-day antibiotic treatment eliminates certain families of the Bacteroidetes, Firmicutes, Tenericutes, and Actinobacteria phyla in the gut and reduces the levels of multiple pattern recognition receptor (PRR) ligands in the serum.

MicroRNA-146a limits tumorigenic inflammation in colorectal cancer.

Chronic inflammation can drive tumor development. Here, we have identified microRNA-146a (miR-146a) as a major negative regulator of colonic inflammation and associated tumorigenesis by modulating IL-17 responses. MiR-146a-deficient mice are susceptible to both colitis-associated and sporadic colorectal cancer (CRC), presenting with enhanced tumorigenic IL-17 signaling.

PD1 Blockade in Cancer: Impact on Myeloid Cells.

Programmed death 1 (PD1) has emerged as a major inhibitor of antitumor T cells, and anti-PD1 therapies have demonstrated clinical efficacy in multiple cancers. However, the impact of PD1 on other immune cells had remained unclear. A recent study by Strauss et al.

Remyelination-Promoting Inflammation: Novel Role for MyD88 Signaling in Microglia/Macrophages.

Inflammation in the central nervous system (CNS) has been linked to demyelination and remyelination. Using zebrafish and mouse models of demyelination and remyelination, Cunha et al. now describe a novel role for myeloid differentiation factor 88 (MyD88) signaling in supporting remyelination by promoting myeloid cell-mediated inflammatory responses via TNF-α, which are essential for phagocytic myelin debris clearance and for oligodendrogenesis.

Effects of mono- and dialkylglucosides on the characterisation and blood circulation of lipid nanoemulsions.

Effects of two cosurfactants, -alkylglycosides with mono- or disaccharide groups - -nonyl -D-glucopyranoside (N-Glu) and -decyl -D-maltoside (D-Mal) - were studied to the stability in saline solution, interaction with serum albumin, and blood circulation of the lipid nanoemulsion (LNE). The LNEs composed of soybean oil, phosphatidylcholine, and sodium palmitate were prepared without (Control-LNE) and with N-Glu or D-Mal (NG-LNE and DM-LNE, respectively). In saline solution, NG-LNE exhibited a smaller droplet size than Control-LNE, while the size of DM-LNE was significantly increased compared with the other LNEs.

Smad7 Controls Immunoregulatory PDL2/1-PD1 Signaling in Intestinal Inflammation and Autoimmunity.

Smad7, a negative regulator of TGF-β signaling, has been implicated in the pathogenesis and treatment of inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC). Here, we found that Smad7 mediates intestinal inflammation by limiting the PDL2/1-PD1 axis in dendritic cells (DCs) and CD4T cells. Smad7 deficiency in DCs promotes TGF-β responsiveness and the co-inhibitory molecules PDL2/1 on DCs, and it further imprints T cell-PD1 signaling to promote Treg differentiation.

Partial left superior pulmonary vein potential elimination by an inferior ganglionated plexus ablation.

Ganglionated plexus (GP) plays an important role in the initiation and maintenance of atrial fibrillation (AF). The GP ablation has been found to be effective for AF treatment. In this case, we reported an AF case in which the pulmonary vein (PV) potentials of the anterior region of the left superior PV were eliminated by an inferior right GP ablation.

Cbl-b Deficiency Mediates Resistance to Programmed Death-Ligand 1/Programmed Death-1 Regulation.

Casitas B-lineage lymphoma-b (Cbl-b) is an E3 ubiquitin ligase that negatively regulates T cell activation. Cbl-b T cells are hyper-reactive and co-stimulation independent, and Cbl-b mice demonstrate robust T cell and NK cell-mediated antitumor immunity. As a result of these murine studies, Cbl-b is considered a potential target for therapeutic manipulation in human cancer immunotherapy.

TLR Tolerance as a Treatment for Central Nervous System Autoimmunity.

The role of TLR signaling in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is unclear. This role is especially controversial in models of adoptive transfer EAE in which no adjuvant and no TLR ligands are administered. We recently reported that a microbiome-derived TLR2 ligand, Lipid 654 (L654), is present in healthy human serum but significantly decreased in the serum of MS patients.

Effects of Dabigatran on the Resolution of Left Ventricular Thrombus after Acute Myocardial Infarction.

Left ventricular thrombus (LVT) after acute myocardial infarction (AMI) is a risk factor for embolic complications. Although warfarin has traditionally been used to treat LVT, it has relevant disadvantages that limit its use. We herein describe the case of a 78-year-old man with AMI who had a history of paroxysmal atrial fibrillation.

Interaction between anti-Alzheimer and antipsychotic drugs in modulating extrapyramidal motor disorders in mice.

Antipsychotics are often used in conjunction with anti-Alzheimer drugs to treat the behavioral and psychological symptoms of dementia (BPSD). Here, we examined the effects of cholinesterase inhibitors (ChEIs), donepezil and galantamine, on antipsychotic-induced extrapyramidal side effects (EPS) in mice. The effects of serotonergic agents on the EPS drug interaction were also evaluated.

Cbl-b-deficient mice express alterations in trafficking-related molecules but retain sensitivity to the multiple sclerosis therapeutic agent, FTY720.

The variable response to therapy in multiple sclerosis (MS) suggests a need for personalized approaches based on individual genetic differences. GWAS have linked CBLB gene polymorphisms with MS and recent evidence demonstrated that these polymorphisms can be associated with abnormalities in T cell function and response to interferon-β therapy. Cbl-b is an E3 ubiquitin ligase that regulates T cell activation and Cbl-b-deficient (Cbl-b(-/-)) mice show T cell abnormalities described in MS patients.

Bacterial lipodipeptide, Lipid 654, is a microbiome-associated biomarker for multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of unknown etiology. Infectious agents have been suggested to have a role as environmental factors in MS, but this concept remains controversial. Recently, gastrointestinal commensal bacteria have been implicated in the pathogenesis of autoimmune diseases, but mechanisms underlying the relationship of human systemic autoimmunity with the commensal microbiome have yet to be identified.

Mechanical and substrate abnormalities of the left atrium assessed by 3-dimensional speckle-tracking echocardiography and electroanatomic mapping system in patients with paroxysmal atrial fibrillation.

Background: Left atrial (LA) remodeling progresses to electrical remodeling, contractile remodeling, and subsequently structural remodeling. Little is known about the relationship between LA electrical and anatomical remodeling and LA mechanical function.

Objectives: We aimed to clarify the relationship between LA mechanical function using 3-dimensional speckle-tracking echocardiography (3D-STE) and LA electrical remodeling using an electroanatomic mapping system (CARTO 3) and to estimate atrial fibrillation (AF) substrate in patients with paroxysmal AF (PAF).

Preoperative tissue Doppler imaging-derived atrial conduction time can predict postoperative atrial fibrillation in patients undergoing aortic valve replacement for aortic valve stenosis.

Background: Postoperative atrial fibrillation (POAF) is a common complication of cardiac surgery and may result in stroke or heart failure and poor prognosis. This study aimed to evaluate a novel index of total atrial conduction time derived from the P-wave onset (lead II) to the peak A' wave on tissue Doppler imaging (PA-TDI duration). The PA-TDI duration was compared with previously reported predictors of POAF, and the optimal cutoff value of PA-DTI was calculated in patients undergoing aortic valve replacement (AVR) for AV stenosis (AS).

Type III interferon attenuates a vesicular stomatitis virus-based vaccine vector.

Unlabelled: Vesicular stomatitis virus (VSV) has been extensively studied as a vaccine vector and oncolytic agent. Nevertheless, safety concerns have limited its widespread use in humans. The type III lambda interferon (IFN-λ) family of cytokines shares common signaling pathways with the IFN-α/β family and thus evokes similar antiviral activities.

Incomplete cure of tachycardia-induced cardiomyopathy secondary to rapid atrial fibrillation by heart rate control without sinus conversion.

Background: It is uncertain whether rate or rhythm control is more favorable for patients experiencing tachycardia-induced cardiomyopathy (TIC) secondary to rapid atrial fibrillation (AF).

Methods And Results: We compared the electrophysiological and hemodynamic properties and outcome after AF ablation in 20 patients with a history of decompensated TIC who maintained sinus rhythm or had paroxysmal AF (group 1), 32 with a history of decompensated TIC who had persistent or longstanding persistent AF (group 2), 377 without TIC who had paroxysmal AF (group 3), and 225 without TIC who had persistent or longstanding persistent AF (group 4). The corrected sinus node recovery time was more prolonged in group 2 than in groups 1, 3, or 4 (1,066 ± 946 vs.

Time-domain T-wave alternans is strongly associated with a history of ventricular fibrillation in patients with Brugada syndrome.

Aims: T-wave alternans (TWA) is an indicator of vulnerability to ventricular arrhythmias and is useful for predicting sudden cardiac death (SCD) in patients with various structural heart diseases. We evaluated whether high levels of time-domain TWA on ambulatory ECG (AECG) are associated with a history of ventricular fibrillation (VF) in Brugada syndrome (BrS) patients.

Methods And Results: We examined the associations among VF history, family history of SCD, spontaneous type 1 electrocardiogram (ECG), late potentials, VF induction by programmed electrical stimulation, and TWA in 45 BrS patients (44 males; mean age, 45 ± 15 years).

Prediction of atrial fibrillation after off-pump coronary artery bypass grafting using preoperative total atrial conduction time determined on tissue Doppler imaging.

Background: Postoperative atrial fibrillation (POAF) is a common complication of cardiac surgery and results in increased health-care utilization. This study identified new transthoracic echocardiographic predictors of POAF using an index of the total atrial conduction time derived on tissue Doppler imaging (PA-TDI duration) in patients undergoing off-pump coronary artery bypass grafting (OPCAB).

Methods And Results:  A total of 88 patients undergoing isolated OPCAB were enrolled.