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Prion disease is a neurodegenerative disorder with progressive neurologic symptoms and accelerated cognitive decline. The causative protein of prion disease is the prion protein (PrP), and structural transition of PrP from the normal helix rich form (PrP C ) to the abnormal β-sheet rich form (PrP Sc ) occurs in prion disease. While so far numerous therapeutic agents for prion diseases have been developed, none of them are still useful. A fluorinated alcohol, hexafluoro isopropanol (HFIP), is a precursor to the inhalational anesthetic sevoflurane and its metabolites. HFIP is also known as a robust α-helix inducer and is widely used as a solvent for highly aggregated peptides. Here we show that the α-helix-inducing activity of HFIP caused the conformational transformation of the fibrous structure of PrP into amorphous aggregates in vitro. HFIP added to the ScN2a cell medium, which continuously expresses PrP Sc , reduced PrP Sc protease resistance after 24-h incubation. It was also clarified that ScN2a cells are more susceptible to HFIP than any of the cells being compared. Based on these findings, HFIP is expected to develop as a therapeutic agent for prion disease.

Introduction The enduring COVID-19 pandemic has had persistent, intermittent socioeconomic impacts on migrants. This raises the concern that many Vietnamese migrants in Japan may have developed mental health issues due to the socioeconomic impact. The study aimed to examine changes in the socio-economic and mental health status of Vietnamese migrants in Japan and factors affecting mental health status during the early to mid-COVID-19 period. Methods We conducted a prospective cohort study among Vietnamese migrants in Japan from September to October 2021 (baseline) and from May to June 2022 (follow-up) using an online questionnaire. Multiple linear regression analyses were conducted to examine the association between changes in socioeconomic status and alterations in symptoms of depression and anxiety within this demographic. Results The mean age of the 159 participants was 26.1 ± 4.9 years, with a mean length of residency in Japan of 4.0 ± 4.1 years. The mean PHQ-9 score exhibited a significant decrease from 7.89 ( SD  = 6.34) to 6.62 ( SD  = 5.87) ( p  = 0.01). Variables associated with changes in depression and anxiety included subjective socioeconomic status (unstandardized partial regression coefficient (UPRC): 1.901, 95% confidence interval (CI) 0.30 to 3.50, p = 0.02) and (UPRC: 2.060, 95% CI 0.80 to 3.32, p = 0.002), as well as changes in having someone with whom to discuss one’s health (UPRC: 2.689, 95% CI 0.89 to 4.49, p = 0.004) and (UPRC: 1.955, 95% CI 0.54 to 3.38, p = 0.007). Conclusions In this prospective cohort study of depression and anxiety, depressive symptoms among Vietnamese migrants decreased from 2021 to 2022. Key findings underscore the importance of socioeconomic status improvement and having someone to discuss to about their health as protective factors against mental health challenges. Employment and social support have emerged as crucial determinants of mental health among Vietnamese migrants in Japan, emphasizing the necessity for comprehensive support strategies addressing both economic vulnerabilities and social connectedness.

This study aimed to examine the mental health status and related factors among Vietnamese migrants in Japan during the COVID-19 pandemic. We conducted an online cross-sectional survey between September 21 and October 21, 2021. Along with Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder 7-item (GAD-7) scores, we collected data on demographics, changes in socioeconomic status due to the pandemic, language proficiency, social support, and health conditions. Multivariate logistic regression was performed to identify factors related to symptoms of depression and anxiety. Among 621 participants who completed the questionnaire, moderate-to-severe symptoms of depression (PHQ-9 score ≥ 10 points) and mild-to-severe symptoms of anxiety (GAD-7 score ≥ 5 points) were observed in 203 (32.7%) and 285 (45.9%) individuals, respectively. Factors related to depressive symptoms were age (95% confidence interval [CI]=0.89-0.99), pre-existing health conditions (95% [CI]=1.61–3.76), and a low subjective socioeconomic status (95% [CI]=1.64–3.71). Factors related to anxiety symptoms were being single (95% [CI]=1.01–2.93), having pre-existing health conditions (95% [CI]=1.63–3.88), subjective socioeconomic status (95% [CI]=1.87–3.97), and absence of a partner to discuss one’s health with (95% [CI]=1.11–2.47). Vietnamese migrants in Japan experienced a decrease in income, worsening working conditions, and poor mental health status during the COVID-19 pandemic. Further investigations are necessary to find an effective way to increase their social support and mitigate socioeconomic adversities.

The sodium-independent cystine-glutamate antiporter plays an important role in extracellular cystine uptake. It comprises the transmembrane protein, xCT and its chaperone, CD98. Because glutathione is only weakly cell membrane permeable, cellular uptake of its precursor, cystine, is known to be a key step in glutathione synthesis. Moreover, it has been reported that xCT expression affects the progression of tumors and their resistance to therapy. Sulfasalazine is an inhibitor of xCT that is known to increase cellular oxidative stress, giving it anti-tumor potential. Here, we describe a radio-sensitizing effect of sulfasalazine using a B16F10 melanoma model. Sulfasalazine decreased glutathione concentrations and resistance to H2O2 in B16F10 melanoma cells, but not in mouse embryonic fibroblasts. It synergistically enhanced the cyto-killing effect of X-irradiation in B16F10 cells. It inhibited cellular DNA damage repair and prolonged cell cycle arrest after X-irradiation. Furthermore, in an in vivo transplanted melanoma model, sulfasalazine decreased intratumoral glutathione content, leading to enhanced susceptibility to radiation therapy. These results suggest the possibility of using SAS to augment the treatment of radio-resistant cancers.

A post-exposure cohort study in Hiroshima and Nagasaki reported that low-dose exposure to radiation heightened the risk of cardiovascular diseases (CVD), such as stroke and myocardial infarction, by 14–18% per Gy. Moreover, the risk of atherosclerosis in the coronary arteries reportedly increases with radiation therapy of the chest, including breast and lung cancer treatment. Cellular senescence of vascular endothelial cells (ECs) is believed to play an important role in radiation-induced CVDs. The molecular mechanism of age-related cellular senescence is believed to involve genomic instability and DNA damage response (DDR); the chronic inflammation associated with senescence causes cardiovascular damage. Therefore, vascular endothelial cell senescence is believed to induce the pathogenesis of CVDs after radiation exposure. The findings of several prior studies have revealed that ionizing radiation (IR) induces cellular senescence as well as cell death in ECs. We have previously reported that DDR activates endothelial nitric oxide (NO) synthase, and NO production promotes endothelial senescence. Endothelial NO synthase (eNOS) is a major isoform expressed in ECs that maintains cardiovascular homeostasis. Therefore, radiation-induced NO production, a component of the DDR in ECs, may be involved in CVDs after radiation exposure. In this article, we describe the pathology of radiation-induced CVD and the unique radio-response to radiation exposure in ECs.

The cytoplasmic peptide:N-glycanase (Ngly1 in mammals) is a de-N-glycosylating enzyme that is highly conserved among eukaryotes. It was recently reported that subjects harboring mutations in the NGLY1 gene exhibited severe systemic symptoms (NGLY1-deficiency). While the enzyme obviously has a critical role in mammals, its precise function remains unclear. In this study, we analyzed Ngly1-deficient mice and found that they are embryonic lethal in C57BL/6 background. Surprisingly, the additional deletion of the gene encoding endo-β-N-acetylglucosaminidase (Engase), which is another de-N-glycosylating enzyme but leaves a single GlcNAc at glycosylated Asn residues, resulted in the partial rescue of the lethality of the Ngly1-deficient mice. Additionally, we also found that a change in the genetic background of C57BL/6 mice, produced by crossing the mice with an outbred mouse strain (ICR) could partially rescue the embryonic lethality of Ngly1-deficient mice. Viable Ngly1-deficient mice in a C57BL/6 and ICR mixed background, however, showed a very severe phenotype reminiscent of the symptoms of NGLY1-deficiency subjects. Again, many of those defects were strongly suppressed by the additional deletion of Engase in the C57BL/6 and ICR mixed background. The defects observed in Ngly1/Engase-deficient mice (C57BL/6 background) and Ngly1-deficient mice (C57BL/6 and ICR mixed background) closely resembled some of the symptoms of patients with an NGLY1-deficiency. These observations strongly suggest that the Ngly1- or Ngly1/Engase-deficient mice could serve as a valuable animal model for studies related to the pathogenesis of the NGLY1-deficiency, and that cytoplasmic ENGase represents one of the potential therapeutic targets for this genetic disorder.

In humans, the adaptive immune system uses the exchange of information between cells to detect and eliminate foreign or damaged cells; however, the removal of unwanted cells does not always require an adaptive immune system 1 , 2 . For example, cell selection in Drosophila uses a cell selection mechanism based on ‘fitness fingerprints’, which allow it to delay ageing 3 , prevent developmental malformations 3 , 4 and replace old tissues during regeneration 5 . At the molecular level, these fitness fingerprints consist of combinations of Flower membrane proteins 3 , 4 , 6 . Proteins that indicate reduced fitness are called Flower-Lose, because they are expressed in cells marked to be eliminated 6 . However, the presence of Flower-Lose isoforms at a cell’s membrane does not always lead to elimination, because if neighbouring cells have similar levels of Lose proteins, the cell will not be killed 4 , 6 , 7 . Humans could benefit from the capability to recognize unfit cells, because accumulation of damaged but viable cells during development and ageing causes organ dysfunction and disease 8 – 17 . However, in Drosophila this mechanism is hijacked by premalignant cells to gain a competitive growth advantage 18 . This would be undesirable for humans because it might make tumours more aggressive 19 – 21 . It is unknown whether a similar mechanism of cell-fitness comparison is present in humans. Here we show that two human Flower isoforms (hFWE1 and hFWE3) behave as Flower-Lose proteins, whereas the other two isoforms (hFWE2 and hFWE4) behave as Flower-Win proteins. The latter give cells a competitive advantage over cells expressing Lose isoforms, but Lose-expressing cells are not eliminated if their neighbours express similar levels of Lose isoforms; these proteins therefore act as fitness fingerprints. Moreover, human cancer cells show increased Win isoform expression and proliferate in the presence of Lose-expressing stroma, which confers a competitive growth advantage on the cancer cells. Inhibition of the expression of Flower proteins reduces tumour growth and metastasis, and induces sensitivity to chemotherapy. Our results show that ancient mechanisms of cell recognition and selection are active in humans and affect oncogenic growth. A cell competition mechanism based on the differential expression of isoforms of Flower proteins is found in humans as well as Drosophila , and promotes tumorigenesis.

Focal segmental glomerulosclerosis, characterized by decreased numbers of podocytes in glomeruli, is a common cause of refractory nephrotic syndrome. Recently, we showed that enhanced glycosphingolipid GM3 expression after administration of valproic acid, an upregulator of ST3GAL5/St3gal5 , was effective in preventing albuminuria and podocyte injury. We also revealed the molecular mechanism for this preventive effect, which involves GM3 directly binding nephrin that then act together in glycolipid-enriched membrane (GEM) fractions under normal conditions and in non-GEM fractions under nephrin injury conditions. Kidney disease is frequently referred to as a “silent killer” because it is often difficult to detect subjective symptoms. Thus, primary treatment for these diseases is initiated after the onset of disease progression. Consequently, the efficacy of enhanced levels of GM3 induced by valproic acid needs to be evaluated after the onset of the disease with severe albuminuria such as focal segmental glomerulosclerosis. Here, we report the therapeutic effect of enhanced GM3 expression induced via administration of valproic acid on albuminuria and podocyte injury after the onset focal segmental glomerulosclerosis in anti-nephrin antibody treated mice. Our findings suggest elevated levels of GM3 following treatment with valproic acid has therapeutic utility for kidney disease associated with severe albuminuria and podocyte injury.

Background Stigma towards people with mental health problems (PMHP) is known to have substantial negative impacts on their lives. More in-depth exploration of the stigma and discrimination experienced by PMHP in low- and middle-income countries is needed. Previous research suggests that negative attitudes towards PMHP are widespread among the Filipino general public. However, no study has investigated PMHP’s own experiences of being stigmatised in the Philippines. Methods A qualitative study was conducted on the stigma experienced by PMHP (including people with epilepsy) and its related factors in the Philippines, employing the constructivist grounded theory approach. We analysed data on 39 PMHP collected through interviews with PMHP, their carers, and community health volunteers who know them well. Results The findings highlight the culturally and socio-economically specific contexts, consequences, and impact modifiers of experiences of stigma. Participants emphasised that PMHP face stigma because of the cultural traits such as the perception of mental health problem as a disease of the family and the tendency to be overly optimistic about the severity of the mental health problem and its impact on their life. Further, stigma was experienced under conditions where mental health care was not readily available and people in the local community could not resolve the PMHP’s mental health crisis. Stigma experiences reduced social networks and opportunities for PMHP, threatened the economic survival of their entire family, and exacerbated their mental health problems. An individual’s reaction to negative experiences can be fatalistic in nature (e.g. believing in it is God’s will). This fatalism can help PMHP to remain hopeful. In addition, traditional communal unity alleviated some of the social exclusion associated with stigma. Conclusions The study indicates that existing stigma-reduction strategies might have limitations in their effectiveness across cultural settings. Therefore, we propose context-specific practical implications (e.g. emphasis on environmental factors as a cause of mental health problems, messages to increase understanding not only of the possibility of recovery but also of challenges PMHP face) for the Philippines.

Initial events of T-cell activation involve movement of the T-cell receptor into lipid rafts. Gangliosides are major components of lipid rafts. While investigating T-cell activation in ganglioside-deficient mice, we observed that CD4+ and CD8+ T cells required different ganglioside subsets for activation. Activation of CD4+ T cells from GM3 synthase-null mice, deficient in GM3-derived gangliosides, is severely compromised, whereas CD8+ T-cell activation is normal. Conversely, in cells from GM2/GD2 synthase-null mice, expressing only GM3 and GD3, CD4+ T-cell activation is normal, whereas CD8+ T-cell activation is deficient. Supplementing the cells with the corresponding missing gangliosides restores normal activation. GM3 synthase-null mice do not develop experimental asthma. Distinct expression patterns of ganglioside species in CD4+ T and CD8+ T cells, perhaps in uniquely functional lipid rafts, define immune functions in each T-cell subset. Control of ganglioside expression would offer a strategy targeting for specific T-cell subpopulations to treat immune diseases.