A distal enhancer of GATA3 regulates Th2 differentiation and allergic inflammation.

Asthma is a widespread airway disorder where GATA3-dependent Type-2 helper T (Th2) cells and group 2 innate lymphoid cells (ILC2s) play vital roles. Asthma-associated single nucleotide polymorphisms (SNPs) are enriched in a region located 926-970 kb downstream from GATA3 in the 10p14 (hG900). However, it is unknown how hG900 affects the pathogenesis of allergic airway inflammation. To investigate the roles of the asthma-associated GATA3 enhancer region in experimental allergic airway inflammation, we first examined the correlation between GATA3 expression and the activation of the hG900 region was analyzed by flow cytometry and ChIP-qPCR. We found that The activation of enhancers in the hG900 region was strongly correlated to the levels of GATA3 in human peripheral T cell subsets. We next generated mice lacking the mG900 region (mG900KO mice) were generated by the CRISPR-Cas9 system, and the development and function of helper T cells and ILCs in mG900KO mice were analyzed in steady-state conditions and allergic airway inflammation induced by papain or house dust mite (HDM). The deletion of the mG900 did not affect the development of lymphocytes in steady-state conditions or allergic airway inflammation induced by papain. However, mG900KO mice exhibited reduced allergic inflammation and Th2 differentiation in the HDM-induced allergic airway inflammation. The analysis of the chromatin conformation around Gata3 by circular chromosome conformation capture coupled to high-throughput sequencing (4C-seq) revealed that the mG900 region interacted with the transcription start site of Gata3 with an influencing chromatin conformation in Th2 cells. These findings indicate that the mG900 region plays a pivotal role in Th2 differentiation and thus enhances allergic airway inflammation.

Association between preoperative neutrophil-lymphocyte ratio, uric acid, and postoperative delirium in elderly patients undergoing degenerative spine surgery.

PURPOSE: There are few reports regarding the association between the neutrophil-lymphocyte ratio (NLR), uric acid, and the development of postoperative delirium (POD) in patients who are undergoing spine surgeries. We investigated the associations between the NLR, uric acid as a natural antioxidant, and POD in elderly patients undergoing degenerative spine surgery. PATIENTS AND METHODS: This was a single-center, observational, and retrospective study conducted in Japan. We enrolled 410 patients who underwent degenerative spine surgery. POD was diagnosed after the surgeries by psychiatrists, based on the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V). We performed a multivariable logistic regression analysis to clarify whether the NLR and uric acid values were associated with the development of POD in the patients. RESULTS: 129 of the 410 patients were excluded from the analysis. Of the 281 patients (137 females, 144 males), 32 patients (11.4%) were diagnosed with POD. The multivariable logistic regression analysis revealed that the preoperative uric acid level (adjusted odds ratio [aOR]: 0.67, 95% confidence interval [CI]: 0.49-0.90, p = 0.008) and age (aOR: 1.09, 95% CI: 1.02-1.16, p = 0.008) were significantly associated with POD. The preoperative NLR (aOR: 0.82, 95% CI: 0.60-1.13, p = 0.227) and antihyperuricemic medication (aOR: 0.97, 95% CI: 0.24-3.82, p = 0.959) were not significantly associated with POD. CONCLUSION: Our results demonstrated that in elderly patients undergoing degenerative spine surgery, the preoperative NLR was not significantly associated with POD, but a lower preoperative uric acid value was an independent risk factor for developing POD. Uric acid could have a neuroprotective impact on POD in patients with degenerative spine diseases.

Copper-Catalyzed Regio- and Enantioselective Aminoboration of Unactivated Terminal Alkenes.

A CuCl/(R,R)-PTBP-BDPP-catalyzed regioselective and enantioselective aminoboration of simple and unactivated terminal alkenes with bis(pinacolato)diboron (pinB-Bpin) and hydroxylamines has been developed. The amino group and boryl group were incorporated at the internal position and terminal position, respectively, and the corresponding chiral ß-borylalkylamines were obtained with good to high enantiomeric ratios. The asymmetric copper catalysis allows rapid and concise transformation of readily available olefinic feedstock-like materials into functionalized chiral alkylamines of high potential in medicinal and pharmaceutical chemistry.

Copper/Bisphosphine Catalysts in the Internally Borylative Aminoboration of Unactivated Terminal Alkenes with Bis(pinacolato)diboron.

Cu(I)/modified dppbz catalyst systems for the regioselective aminoboration of unactivated terminal alkenes have been developed. The bisphosphine-based Cu catalysis enables the introduction of the readily transformable Bpin group at the more congested internal position and shows better regioselectivity for broader terminal alkenes involving sterically demanding allylbenzenes, which are relatively challenging substrates in the previous IPrCuBr catalysis. Additionally, the second-generation catalyst systems accommodate the exo-methylene-type disubstituted alkenes to deliver the corresponding aminoborated products in good yields with a high regioselectivity.

Synthesis of ß-Boryl-α-Aminosilanes by Copper-Catalyzed Aminoboration of Vinylsilanes.

A copper-catalyzed regioselective and stereospecific aminoboration of vinylsilanes with bis(pinacolato)diboron (pinB-Bpin) and hydroxylamines has been developed. In the presence of a CuCl/MeO-dppbz catalyst, the boryl group and amino group are incorporated at the ß position and α position, respectively, and the corresponding ß-boryl-α-aminosilanes are obtained with good diastereoselectivity. The boryl group is a good latent functional group, and subsequent manipulations provide a variety of ß-functionalized α-aminosilanes of great potential in medicinal chemistry. Additionally, preliminary application to asymmetric catalysis is also described.

Successful Fluid Management in Respiratory Failure due to Clazosentan Following a Cerebral Aneurysm Clipping: A Case Report.

Clazosentan, a potent selective endothelin receptor subtype A antagonist, has been demonstrated to be effective in preventing cerebral vasospasms after subarachnoid hemorrhage. We report the successful management of respiratory failure due to pulmonary edema associated with clazosentan, with a hemodynamic monitoring system. A 49-year-old Japanese man underwent emergency clipping for a right internal carotid-posterior communicating artery aneurysm. The surgery and general anesthesia for the rupture proceeded with no complications. Clazosentan was administered from postoperative day 1 to prevent cerebral vasospasm. He presented with respiratory failure six days post surgery and chest X-ray imaging showed pulmonary edema. In our intensive care unit, the patient's N-terminal pro-brain natriuretic peptide was 476 pg/mL although trans-thoracic echography indicated a normal left ventricular ejection fraction (>60%) and normal diastolic function. The hemodynamic monitoring system showed 11 L/minute cardiac output and a cardiac index of 5.6 L/minute/m2. We thus diagnosed the cause of the patient's respiratory failure as due to excessive volume, as an adverse event of clazosentan. We changed the cerebral vasospasm-preventive drug to fasudil hydrochloride hydrate and forced urination. His body weight dropped approximately 9 kg as of day 9 in the ICU and he was weaned off the ventilator 23 days post surgery. This case indicates the importance of optimal infusion in patients with clazosentan. Optimal fluid management using a hemodynamic monitoring system could be useful for clazosentan-induced respiratory failure.

Stage-specific GATA3 induction promotes ILC2 development after lineage commitment.

Group 2 innate lymphoid cells (ILC2s) are a subset of innate lymphocytes that produce type 2 cytokines, including IL-4, IL-5, and IL-13. GATA3 is a critical transcription factor for ILC2 development at multiple stages. However, when and how GATA3 is induced to the levels required for ILC2 development remains unclear. Herein, we identify ILC2-specific GATA3-related tandem super-enhancers (G3SE) that induce high GATA3 in ILC2-committed precursors. G3SE-deficient mice exhibit ILC2 deficiency in the bone marrow, lung, liver, and small intestine with minimal impact on other ILC lineages or Th2 cells. Single-cell RNA-sequencing and subsequent flow cytometry analysis show that GATA3 induction mechanism, which is required for entering the ILC2 stage, is lost in IL-17RB+PD-1- late ILC2-committed precursor stage in G3SE-deficient mice. Cnot6l, part of the CCR4-NOT deadenylase complex, is a possible GATA3 target during ILC2 development. Our findings implicate a stage-specific regulatory mechanism for GATA3 expression during ILC2 development.

Fulminant myocarditis with adult-onset Still's disease: case-based review.

Myocarditis has been reported as a life-threatening complication of adult-onset Still's disease (AOSD), but fulminant myocarditis with AOSD is very rare. We hereby report a case of a 43-year-old female with fulminant myocarditis with AOSD. She had a refractory AOSD and cardiogenic shock with markedly elevated ferritin level up to 67,370 ng/mL. She was successfully treated with canakinumab and mechanical circulatory support (MCS) such as venoarterial extracorporeal membrane oxygenation and Impella CP. We also reviewed the previous cases of fulminant myocarditis with AOSD published from 1976 to December 2022, and only 8 cases of fulminant myocarditis with AOSD have been reported. The characteristics of these cases showed that the average age at presentation was 37.6 years (range 24-47 years). The time to myocarditis from the onset of AOSD ranged from 2 weeks to 2 years; however, most cases developed myocarditis within 1 year. Initial presenting symptoms included fever, dyspnea, chest pain, myalgia, rash, and sore throat. The median peak ferritin was 13,000 ng/mL. Left ventricular ejection fractions were not greater than 35%. Our case was the first reported case successfully treated with canakinumab and MCS. This review suggests that myocarditis may be an early phase of the complication in patients with AOSD, and the severity of AOSD may correlate with the severity of myocarditis. Canakinumab for AOSD and MCS for fulminant myocarditis may be one of the choices for overcoming the comorbidities.