The Loss of PGAM5 Suppresses the Mitochondrial Degeneration Caused by Inactivation of PINK1 in Drosophila

PTEN-induced kinase 1 (PINK1), which is required for mitochondrial homeostasis, is a gene product responsible for early-onset Parkinson's disease (PD). Another early onset PD gene product, Parkin, has been suggested to function downstream of the PINK1 signalling pathway based on genetic studies in Drosophila. PINK1 is a serine/threonine kinase with a predicted mitochondrial target sequence and a probable transmembrane domain at the N-terminus, while Parkin is a RING-finger protein with ubiquitin-ligase (E3) activity. However, how PINK1 and Parkin regulate mitochondrial activity is largely unknown. To explore the molecular mechanism underlying the interaction between PINK1 and Parkin, we biochemically purified PINK1-binding proteins from human cultured cells and screened the genes encoding these binding proteins using Drosophila PINK1 (dPINK1) models to isolate a molecule(s) involved in the PINK1 pathology. Here we report that a PINK1-binding mitochondrial protein, PGAM5, modulates the PINK1 pathway. Loss of Drosophila PGAM5 (dPGAM5) can suppress the muscle degeneration, motor defects, and shorter lifespan that result from dPINK1 inactivation and that can be attributed to mitochondrial degeneration. However, dPGAM5 inactivation fails to modulate the phenotypes of parkin mutant flies. Conversely, ectopic expression of dPGAM5 exacerbated the dPINK1 and Drosophila parkin (dParkin) phenotypes. These results suggest that PGAM5 negatively regulates the PINK1 pathway related to maintenance of the mitochondria and, furthermore, that PGAM5 acts between PINK1 and Parkin, or functions independently of Parkin downstream of PINK1

Autoantibodies against type I IFNs in patients with critical influenza pneumonia

In an international cohort of 279 patients with hypoxemic influenza pneumonia, we identified 13 patients (4.6%) with autoantibodies neutralizing IFN-alpha and/or -omega, which were previously reported to underlie 15% cases of life-threatening COVID-19 pneumonia and one third of severe adverse reactions to live-attenuated yellow fever vaccine. Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-alpha 2 alone (five patients) or with IFN-omega (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-alpha 2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-omega. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients 70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-alpha 2 and IFN-omega (OR = 11.7, P = 1.3 x 10(-5)), especially those <70 yr old (OR = 139.9, P = 3.1 x 10(-10)). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for similar to 5% of cases of life-threatening influenza pneumonia in patients <70 yr old

Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

Development and validation of a prediction model based on the organ-based metabolic tumor volume on FDG-PET in patients with differentiated thyroid carcinoma

Background Although patients with differentiated thyroid cancer (DTC) generally have a good prognosis, patients with a large metabolic tumor volume (MTV) on FDG-PET may experience poor clinical courses. We measured organ-based MTVs and tested its prognostic performance in comparison to conventional MTV (cMTV). Methods We retrospectively analyzed the cases of 280 patients who received their first I-131 therapy in 2003-2014 at our hospital and showed an FDG-avid metastatic lesion. We randomly divided the patients into training (n = 190) and validation (n = 90) datasets. We classified the MTVs as MTVneck-node, MTVdistant-node, MTVlung, MTVbone, and MTVother-organs and tested with/without dichotomization vis-a-vis overall survival (OS). Based on the estimated weighting coefficients of the organ-based MTVs, we propose a new index: the adjusted whole-body MTV (aMTV). Using the validation dataset, we compared the aMTV with cMTV for predicting OS. Results In a univariate analysis, MTVdistant-node and MTVother-organs were more strongly correlated with the OS than the dichotomized forms, whereas the dichotomized forms of MTVneck-node, MTVlung, and MTVbone were more strongly correlated with OS than the continuous variables. The aMTV was thus expressed as 0.69 x dic(MTVneck-node) + 0.02 x MTVdistant-node + 1.05 x dic(MTVlung) + 1.58 x dic(MTVbone) + 0.01 x MTVother-organs, where dic(x) represents 0 or 1 based on the optimized cut-off. In the model evaluation using the validation group, aMTV was a significant predictor of OS with a higher c-index (0.7676) than cMTV (0.7218). Conclusion In DTC patients with FDG-avid metastasis before I-131 therapy, all organ-based MTVs were significant predictors of prognosis. As the aMTV outperformed the cMTV for predicting prognoses, we recommend measuring the MTV on an organ basis

Copper(I)-Catalyzed Asymmetric Desymmetrization: Synthesis of Five-Membered-Ring Compounds Containing All-Carbon Quaternary Stereocenters

A highly stereoselective catalytic alkylation sequence for the synthesis of highly functionalized and versatile five-membered-ring compounds bearing all-carbon quaternary stereocenters was developed. Enantioselective desymmetrization of achiral cyclopentene-1,3-diones was thus executed by chiral Cu–phosphoramidite catalysts. A variety of complicated cyclopentane derivatives can be synthesized with excellent stereoselectivities using a low catalyst loading in a one-pot operation

Identification of patients with Graves' disease who benefit from high-dose radioactive iodine therapy

Objective Radioactive iodine (RAI) therapy is a useful treatment for Graves' disease (GD). Most RAI sessions administer 500 MBq (n = 35). The therapeutic effect was defined as achieving remission and reaching the point of participating in thyroid hormone replacement therapy within 1 year after RAI. We compared the LD and HD groups' remission rates and conducted a multivariate logistic regression analysis of predictive factors for remission. In a simulation, using the formula for predicting the probability of remission obtained from the analysis results, we estimated how much the remission rate would change if the I-131 dose is increased from 500 to 1110 MBq. Results The mean +/- standard deviation I-131 dose administered in the LD group was 480 +/- 6 MBq, and that of the HD group was 1054 +/- 265 MBq. Thirty-five patients (80%) in the LD group and 26 patients (74%) in the HD group achieved remission; this difference in the remission rate was not significant. The multivariate analysis results demonstrated that the absorbed dose and thyroid-stimulating antibody (TSAb) were independent predictors of remission. Seven patients (8.9%) showed an increased probability of remission from 50% when the higher RAI dose was applied (1110 MBq instead of 500 MBq). The thyroid volume and TSAb values in these patients were relatively large at 54.7 +/- 34.2 mL and 1378.4 +/- 586.3%, respectively. Conclusion Although the overall remission rate was not significantly different between the patients who received high- or low-dose I-131, treatment with high-dose RAI may improve the probability of remission in patients with a massive thyroid volume and/or high-TSAb Graves' disease