METHODS: Patients were randomly assigned to double-blind treatment for 6 weeks with lurasidone, 20-60 mg/day (n = 184) or 80-120 mg/day (n = 169), or placebo (n = 172). The primary end-point was change from baseline to Week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS).

RESULTS: Lurasidone treatment significantly reduced mean MADRS total scores from baseline to Week 6 for the 20-60-mg/day group (-13.6; adjusted P = 0.007; effect size = 0.33), but not for the 80-120-mg/day group (-12.6; adjusted P = 0.057; effect size = 0.22) compared with placebo (-10.6). Treatment with lurasidone 20-60 mg/day also improved MADRS response rates, functional impairment, and anxiety symptoms. The most common adverse events associated with lurasidone were akathisia and nausea. Lurasidone treatments were associated with minimal changes in weight, lipids, and measures of glycemic control.

METHODS AND RESULTS: The addition of MG-132 to the liquid medium reduced the specific riboflavin production by 79% in A. gossypii at 25 μM after 24 h. The addition of the inhibitor also caused the accumulation of reactive oxygen species and ubiquitinated proteins. These results indicated that MG-132 works in A. gossypii without any genetic engineering and reduces riboflavin production. In the presence of 25 μM MG-132, specific NADH dehydrogenase activity was increased by 1.4-fold compared to DMSO, but specific succinate dehydrogenase (SDH) activity was decreased to 52% compared to DMSO. Additionally, the amount of AgSdh1p (ACR052Wp) was also reduced. Specific riboflavin production was reduced to 22% when 20 mM malonate, a SDH inhibitor, was added to the culture medium. The riboflavin production in heterozygous AgSDH1 gene-disrupted mutant (AgSDH1-/+ ) was reduced to 63% compared to that in wild type.

CONCLUSIONS: MG-132 suppresses the riboflavin production and SDH activity in A. gossypii. SDH is one of the flavoproteins involved in the riboflavin production in A. gossypii.

RESULTS: In the genomic analysis, 33 homozygous and 1377 heterozygous mutations in the coding sequences of the genome of MT strain were detected. Among these heterozygous mutations, the proportion of mutated reads in each gene was different, ranging from 21 to 75%. These results suggest that the MT strain may contain multiple nuclei containing different mutations. We tried to isolate haploid spores from the MT strain to prove its ploidy, but this strain did not sporulate under the conditions tested. Heterozygous mutations detected in genes which are important for sporulation likely contribute to the sporulation deficiency of the MT strain. Homozygous and heterozygous mutations were found in genes encoding enzymes involved in amino acid metabolism, the TCA cycle, purine and pyrimidine nucleotide metabolism and the DNA mismatch repair system. One homozygous mutation in AgILV2 gene encoding acetohydroxyacid synthase, which is also a flavoprotein in mitochondria, was found. Gene ontology (GO) enrichment analysis showed heterozygous mutations in all 22 DNA helicase genes and genes involved in oxidation-reduction process.

RESULTS: In the MT strain, mitochondrial membrane potential was decreased compared with that in the wild type (WT) strain, resulting in increased reactive oxygen species. Additionally, diphenyleneiodonium (DPI), a universal flavoprotein inhibitor, inhibited riboflavin production in the WT and MT strains at 50 µM, indicating that some flavoproteins may be involved in riboflavin production. The specific activities of NADH and succinate dehydrogenases were significantly reduced in the MT strain, but those of glutathione reductase and acetohydroxyacid synthase were increased by 4.9- and 25-fold, respectively. By contrast, the expression of AgGLR1 gene encoding glutathione reductase was increased by 32-fold in the MT strain. However, that of AgILV2 gene encoding the catalytic subunit of acetohydroxyacid synthase was increased by only 2.1-fold. These results suggest that in the MT strain, acetohydroxyacid synthase, which catalyzes the first reaction of branched-chain amino acid biosynthesis, is vital for riboflavin production. The addition of valine, which is a feedback inhibitor of acetohydroxyacid synthase, to a minimal medium inhibited the growth of the MT strain and its riboflavin production. In addition, the addition of branched-chain amino acids enhanced the growth and riboflavin production in the MT strain.

METHOD: This study was approved by the institutional Ethics Committees. Postmortem nasal mucosa and brain tissues from patients with AD (n = 10) and normal subjects (n = 10) were collected with patient consent at the Fukushimura Brain Bank. Nasal and brain tissue homogenates were added to HEK293 cells expressing tau 3-repeat domain with the L266V and V337M mutations (3RD∗VM) or 4-repeat domain with the P301L and V337M mutations (4RD∗LM), which was fused with GFP at the C-terminus.

RESULT: GFP fluorescence was detected uniformly within the cell bodies of HEK293T cells expressing 3RD∗VM-EGFP and 4RD∗LM-EGFP. There were no changes in the fluorescence after the additions of the brain homogenates from normal subjects. In contrast, a large number of fluorescent puncta was detected both in HEK293T cells expressing 3RD∗VM-EGFP and 4RD∗LM-EGFP at 4 days after the additions of the brain homogenates from patients with AD. Furthermore, the nasal tissue homogenates from patients with AD also induce the formation of fluorescent aggregates in HEK293T cells expressing 3RD∗VM-EGFP and 4RD∗LM-EGFP. Quantitative analysis revealed that the nasal tissue homogenates from AD patients significantly induced the aggregate formation, compared with normal subjects.

METHODS: This cross-sectional web-based survey was conducted in April-May 2023 among physicians and individuals aged ≥18 years with self-reported physician diagnosis of MDD (9-item Patient Health Questionnaire [PHQ-9] score ≥ 10) further stratified by anhedonia as measured by the Snaith-Hamilton Pleasure Scale (SHAPS): MDD-ANH (SHAPS score > 2) and MDD non-ANH (SHAPS score ≤ 2). The study assessed the prevalence of anhedonia in MDD as well as the perspectives on the treatment of anhedonia in MDD in terms of expectations and satisfaction among patients and physicians.

RESULTS: The regional estimated prevalence of MDD was 16.1% where 52.5% of MDD respondents had ANH (SHAPS score ≥2). Depressed mood, mental changes, and changes in sleeping patterns prompted MDD-ANH (n = 1448) or MDD non-ANH (n = 836) respondents to seek medical consultation. Respondents with MDD-ANH (vs MDD non-ANH) reported significantly higher levels of depression and anhedonia, longer treatment duration, and preferred switching their existing medications over adding additional medications (all, p < 0.001). Over half of physicians (55.0%) were not treating anhedonia separately. Anhedonia-specific treatment goals seemed important to all respondents, while avoiding suicidal ideation was significantly important to physicians. MDD-ANH respondents reported in general the lowest level of satisfaction with treatment goals than MDD non-ANH and physician, with "improvements in sexual satisfaction" being the treatment goal with the lowest level of satisfaction.

METHODS: A cross-sectional web-based survey was conducted across six countries/territories. Adult participants were categorized as MDD-ANH, MDD non-ANH, and General Population based on self-reported MDD diagnosis, Patient Health Questionnaire (PHQ-9), and Snaith-Hamilton Pleasure Scale (SHAPS). Multivariate/generalized linear regression modeling (GLMs) and mediation analysis were used to assess anhedonia's impact on HRQoL/function, HRU, and work productivity.

METHODS: We enrolled 96 participants, including 48 nonfamilial ALS patients and 48 age- and sex-matched healthy controls (HCs), in this study and conducted whole-brain FBA and voxel-based morphometry analysis. We compared the fiber density (FD), fiber morphology (fiber cross-section [FC]), and a combined index of FD and FC (FDC) between the ALS and HC groups. We performed a tract-of-interest analysis to extract FD values across the significant regions in the whole-brain analysis. Then, we evaluated the associations between FD values and clinical variables.