PLCG2-associated immune dysregulation (PLAID) comprises broad and distinct clinical presentations related to functional classes of genetic variants.

BACKGROUND: Pathogenic variants of phospholipase C gamma 2 (PLCG2) cause 2 related forms of autosomal-dominant immune dysregulation (ID), PLCγ2-associated antibody deficiency and immune dysregulation (PLAID) and autoinflammatory PLAID (APLAID). Since describing these conditions, many PLCG2 variants of uncertain significance have been identified by clinical sequencing of patients with diverse features of ID. OBJECTIVE: We sought to functionally classify PLCG2 variants and explore known and novel genotype-function-phenotype relationships. METHODS: Clinical data from patients with PLCG2 variants were obtained via standardized questionnaire. PLCG2 variants were generated by mutagenesis of enhanced green fluorescent protein (EGFP)-PLCG2 plasmid, which was overexpressed in Plcg2-deficient DT-40 B cells. B-cell receptor-induced calcium flux and extracellular signal-regulated kinase phosphorylation were assayed by flow cytometry. In some cases, stimulation-induced calcium flux was also measured in primary patient cells. RESULTS: Three-fourths of PLCG2 variants produced functional alteration of B-cell activation, in vitro. Thirteen variants led to gain of function (GOF); however, most functional variants defined a new class of PLCG2 mutation, monoallelic loss of function (LOF). Susceptibility to infection and autoinflammation were common with both GOF and LOF variants, whereas a new phenotypic cluster consisting of humoral immune deficiency, autoinflammation, susceptibility to herpesvirus infection, and natural killer cell dysfunction was observed in association with multiple heterozygous LOF variants detected in both familial and sporadic cases. In some cases, PLCG2 variants produced greater effects in natural killer cells than in B cells. CONCLUSIONS: This work expands the genotypic and phenotypic associations with functional variation in PLCG2, including a novel form of ID in carriers of heterozygous loss of PLCG2 function. It also demonstrates the need for more diverse assays for assessing the impact of PLCG2 variants on human disease.

Semi-wet methanogen cathode composed of oak white charcoal for developing sustainable microbial fuel cells.

The present study aimed to evaluate a semi-wet biocathode composed of oak white charcoal and agarose gel as an alternative to the standard carbon felt biocathodes used in microbial fuel cells (MFCs). The MFC containing the oak white charcoal cathode (Oak-MFC) recorded a higher current value than that of the MFC containing a carbon felt cathode (CF-MFC). The Oak-MFC produced approximately 4.0-fold more electrons in the external circuit and 1.7-fold more methane (CH4) than the CF-MFC. A real-time PCR targeting mcrA showed that the number of methanogens adhering to the oak white charcoal cathode was approximately 15-fold that adhering to the carbon felt cathode. These results suggest that the methanogens attached to the cathode of both MFCs received electrons and CH4 was produced from carbon dioxide (CO2). Furthermore, Oak-MFC performed better than CF-MFC, thereby suggesting that oak white charcoal bound by agarose gel can be used as an alternative methanogen cathode. The propionic acid degradation rate of Oak-MFC was faster than that of CF-MFC suggesting that the cathodic reaction may affect the anodic reaction. The use of oak-derived electrode as a methanogen cathode also could contribute to sustainable forest management and promote regular thinning of oak trees. Further, its use will enable carbon fixation and efficient energy conversion from CO2 to CH4, thus contributing to sustainable energy use.

Thiourea fused γ-amino alcohol organocatalysts for asymmetric Mannich reaction of ß-keto active methylene compounds with imines.

Catalytic functionality of new optically active thiourea fused γ-amino alcohols was examined in the asymmetric Mannich reaction of ß-keto active methylene compounds with imines to afford chiral Mannich products, ß-amino keto compounds, with continuous chiral centers, that are versatile synthetic intermediates for deriving various biologically active compounds. In particular, the thiourea fused γ-amino alcohols showed satisfactory catalytic activity in this reaction and afforded chiral Mannich products in excellent chemical yield (up to 88%) and stereoselectivities (up to syn : anti/93 : 7 dr, up to 99% ee).

New boro amino amide organocatalysts for asymmetric cross aldol reaction of ketones with carbonyl compounds.

Distinct types of new boron fused primary amino amide organocatalysts were designed and synthesized from commercially available amino acids. Their catalytic activities were investigated in asymmetric crossed aldol reaction of ketones with aromatic aldehydes to afford the corresponding chiral anti-aldol adducts with good chemical yields, moderate diastereoselectivity and good to excellent enantioselectivities (up to 94% yields, up to 90 : 10 dr, up to 94% ee).

Relapsing Anti-MOG Antibody-associated Disease following COVID-19 Vaccination: A Rare Case Report and Review of the Literature.

Anti-myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an autoimmune demyelinating disorder that mainly occurs post-infection or post-vaccination. MOGAD after inoculation with coronavirus disease 2019 (COVID-19) vaccines is rare, and we herein report a rare case of a patient with MOGAD after vaccination using the Pfizer-BioNTech COVID-19 vaccine (BNT162b2, Pfizer Japan, Tokyo). Our report highlights the fact that MOGAD following inoculation with COVID-19 vaccine may show clinical relapse during reduction of the oral steroid dose, and continuous treatments with immunological agents is needed to prevent disease recurrence.

Chemical analysis of amyloid ß aggregation inhibitors derived from Geranium thunbergii.

Amyloid ß (Aß) aggregates in the brains of patients with Alzheimer's disease (AD) and accumulates via oligomerization and subsequent fiber elongation processes. These toxicity-induced neuronal damage and shedding processes advance AD progression. Therefore, Aß aggregation-inhibiting substances may contribute to the prevention and treatment of AD. We screened for Aß42 aggregation inhibitory activity using various plant extracts and compounds, and found high activity for a Geranium thunbergii extract (EC50 = 18 µg/mL). Therefore, we screened for Aß42 aggregation inhibitors among components of a G. thunbergii extract and investigated their chemical properties in this study. An active substance was isolated from the ethanol extract of G. thunbergii based on the Aß42 aggregation inhibitory activity as an index, and the compound was identified as geraniin (1) based on spectral data. However, although geraniin showed in vitro aggregation-inhibition activity, no binding to Aß42 was observed via saturation transfer difference-nuclear magnetic resonance (STD-NMR). In contrast, the hydrolysates gallic acid (2) and corilagin (5) showed aggregation-inhibiting activity and binding was observed via STD-NMR. Therefore, the hydrolysates produced under the conditions of the activity test may contribute to the Aß42 aggregation-inhibition activity of G. thunbergii extracts. Geraniin derivatives may help prevent and treat AD.

Deterioration after Liver Transplantation and Transthyretin Stabilizer Administration in a Patient with ATTRv Amyloidosis with a Leu58Arg (p.Leu78Arg) TTR Variant.

We herein report a 44-year-old Japanese man with hereditary transthyretin amyloidosis (ATTRv amyloidosis) harboring the variant Leu58Arg (p.Leu78Arg) in TTR in whom we conducted an observational study with liver transplantation (LT) and transthyretin (TTR) stabilizers (tafamidis and diflunisal) for 9 years. This patient showed gradual deterioration of sensory, motor, and autonomic neuropathy symptoms after LT. Furthermore, cardiac amyloidosis gradually developed. Although the present case showed deterioration of the symptoms after disease-modifying treatments, LT might be suitable in patients with the same variant if they are young and in good condition due to a long survival after LT.

Behçet's disease and activities of daily living.

OBJECTIVES: No large-scale registration study has comprehensively evaluated the activities of daily living (ADL) in patients with Behçet's disease. METHODS: The Japanese government provided us with a dataset of confirmed or suspected Behçet's disease cases derived from ongoing national registration. ADL were categorized and analysed into four categories in patients who satisfied the International Criteria for Behçet's Disease. RESULTS: Data from 2960 patients (men 38.9%, women 61.1%; median age 39 years) were assessed. While 1767 patients (59.7%) had normal ADL, the others had impaired ADL comprising limited but not assisted [n = 1058 (35.7%)], partially assisted [n = 116 (3.9%)] and fully assisted [n = 19 (0.6%)]. Logistic regression analysis showed that chronic ocular lesions [odds ratio (OR) 1.85 (95% CI 1.46, 2.35), P < 0.001], paralysis [OR 2.51 (95% CI 1.58, 3.97), P < 0.001], psychosis [OR 3.16 (95% CI 2.02, 4.95), P < 0.001] and arthritis [OR 1.69 (95% CI 1.44, 1.99), P < 0.001] led to the risk of impaired ADL. Chronic ocular lesions [OR 3.61 (95% CI 2.27, 5.72), P < 0.001], paralysis [OR 3.43 (95% CI 1.87, 6.30), P < 0.001] and psychosis [OR 3.60 (95% CI 2.00, 6.50), P < 0.001] were related to the requirement of physical assistance (partially or fully assisted), although arthritis [OR 1.39 (95% CI 0.93, 2.06), P = 0.108] was not a significant factor in this model. CONCLUSION: Ocular lesions, neurological manifestations and arthritis affected ADL. Patients with ocular lesions or neurological manifestations more frequently required physical assistance.

Simple amino silyl ether organocatalyst for asymmetric hetero Diels-Alder reaction of isatins with enones.

New two catalysts component system comprising of a primary ß-amino silyl ethers as an organocatalyst and N-protected amino acids as a co-catalyst put together worked as an efficient organocatalyst system in the hetero Diels-Alder reaction of isatins with enones affording the chiral spirooxindole-tetrahydropyranones in good chemical yields and stereoselectivities (up to 94%, up to dr 78:22., up to 85% ee).

Elevated serum gasdermin D N-terminal implicates monocyte and macrophage pyroptosis in adult-onset Still's disease.

OBJECTIVES: Elevation of serum IL-18 in adult-onset Still's disease (AOSD) and systemic JIA (sJIA) suggests the role of the inflammasome in these diseases. Gasdermin D is a pore-forming protein playing central roles in inflammasome-mediated inflammation, but its role in rheumatic disease is unknown. We aimed to elucidate the auto-inflammatory mechanisms in AOSD and sJIA. METHODS: Patients with AOSD, sJIA, hemophagocytic lymphohistiocytosis (HLH) and Behçet's disease followed at Yokohama City University (YCU), or US National Institutes of Health (NIH) were included in the study. Disease activity was evaluated by the modified Pouchot score. Ferritin and N-terminal gasdermin D levels in serum and culture supernatant were measured by ELISA. Primary monocytes (Mo) were stimulated with GM-CSF or M-CSF and differentiated into M1 macrophages (Mφ) or M2Mφ, respectively. The number of Mo/Mφ and their viability were monitored over time. RESULTS: Patients with active AOSD and sJIA had increased levels of serum gasdermin D N-terminal, which correlated with serum ferritin and IL-18 levels. Mo-derived Mφ from active AOSD patients showed reduced cell viability and increased cell death. The number of cultured Mφ cells on day nine was negatively correlated with the serum ferritin and gasdermin D levels. Higher ferritin and gasdermin D levels were observed in the M1Mφ culture supernatant of active AOSD patients. Gasdermin D inhibitors reduced the pyroptosis-mediated ferritin release in Mo. CONCLUSION: Elevation of serum gasdermin D N-terminal provides evidence for inflammasome activation triggering gasdermin D-mediated Mo and Mφ pyroptosis in AOSD and possibly sJIA.

HLA-A26 is a risk factor for Behçet's disease ocular lesions.

BACKGROUND: How HLA-A26 modulates Behçet's disease (BD) ocular lesions such as iridocyclitis and retinochorioiditis has not been scrutinized. METHODS: Ministry of Health, Labour and Welfare of Japan provided us a database of BD patients who were registered from 2003 to 2014. We selected patients who satisfied International Criteria for BD and whose data for HLA-A26 was available. RESULTS: Eligible 557 patients consisting of 238 men (42.7%) and 319 women (57.3%), whose median age was 38 years old (interquartile range 29-47) were analyzed. Prevalence of general ocular lesions, iridocyclitis, retinochorioiditis, and chronic lesions were 43.1%, 30.7%, 34.1%, and 17.4%, respectively. The prevalence of ocular lesions was higher among HLA-A26 carriers compared to that among HLA-A26 non-carriers with odds ratio (OR) of 2.5 (95% confidence interval (95% CI) 1.8-3.5, p < .001) for general ocular lesions, OR of 2.5 (95% CI 1.7-3.6, p < .001) for iridocyclitis, OR of 2.8 (95% CI 1.9-4.0, p < .001) for retinochorioiditis, and OR of 2.7 (95% CI 1.7-4.3, p < .001) for 'chronic ocular lesion following iridocyclitis or retinochorioiditis'. The HLA-A26 had a similar impact on ocular lesions between HLA-B51 positive and negative cases (Breslow-Day test, p > .05). However, the HLA-A26 had a larger impact on iridocyclitis for men compared to women (Breslow-Day test, p = .040). The male HLA-A26 carriers had higher risk of iridocyclitis with OR of 3.4 (95% CI 2.0-5.9, p < .001), while the OR for women was 1.5 (95% CI 0.9-2.6, p = .146). CONCLUSION: HLA-A26 carriers had higher risk for iridocyclitis and retinochorioiditis. However, the impact was more prominent for men.

New small γ-turn type N-primary amino terminal tripeptide organocatalyst for solvent-free asymmetric aldol reaction of various ketones with aldehydes.

New small γ-turn type N-primary amino terminal tripeptides were synthesized and their functionality as an organocatalyst was examined in the asymmetric aldol reaction of various ketones with different aromatic aldehydes under solvent-free neat conditions to afford the desired chiral anti-aldol products in good to excellent chemical yields, diastereoselectivities and enantioselectivities (up to 99%, up to syn : anti/13 : 87 dr, up to 99% ee).

Advances in Oncology in US and Japan: Focusing on Cancer and Infectious Diseases.

This is a review article based on the international symposium report of the "US-Japan Conference on Advances in Oncology: Cancer and Infectious Diseases" held online on June 25, 2021, which provided an update on the association between oncology and infectious disease research from cutting-edge basic science to high-impact clinical trials.

Simple primary ß-amino alcohols as organocatalysts for the asymmetric Michael addition of ß-keto esters to nitroalkenes.

Simple primary ß-amino alcohols act as an efficient organocatalysts in the asymmetric Michael addition of ß-keto esters with nitroalkenes affording highly pure chiral Michael adducts. Also, both enantiomers of the adducts were obtained, depending on the specific catalyst used and reaction temperature.

Simple organocatalyst component system for asymmetric hetero Diels-Alder reaction of isatins with enones.

A simple two catalyst component system consisting of primary ß-amino alcohols as a catalyst and amino acids as a co-catalyst put together works as an efficient organocatalyst system in the hetero Diels-Alder reaction of isatins with enones to afford the chiral spirooxindole-tetrahydropyranones in good chemical yields and stereoselectivities (up to 86%, up to 85 : 15 dr., up to 95% ee).