ABSTRACT
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.
ABSTRACT
BACKGROUND: Over the past 5 years, the number of Vietnamese migrant workers in Japan has grown rapidly to become the largest group of migrant workers in the country. They hold various statuses of residence and are subjected to multifactorial stressors. AIMS: The current study's aim is to investigate the association between psychological distress experienced by Vietnamese workers and their work environment. Another aim is to discuss issues involving migrant workers by comparing the characteristics of workers in the major statuses of residence. METHODS: The study applied a cross-sectional design, and included a nationwide self-administered online questionnaire that was conducted in Vietnamese in 2022. The questionnaire included the Kessler Psychological Distress Scale (K10), workplace interpersonal factors as well as factors related to work and health. A multiple logistic regression analysis was conducted to investigate factors associated with psychological distress. RESULTS: Of 933 Vietnamese workers, 37% were grouped as distressed under the K10 cutoff. Fewer opportunities to speak with Japanese co-workers, lower welfare and workload ratings, and the visa statuses including 'Technical Intern Training' were significantly associated with psychological distress. Unexpectedly, those in 'Engineer/Specialist in Humanities/International Services (ESI)' category who are deemed to hold better conditions demonstrated the highest amounts of distress. CONCLUSION: Outside of unsatisfactory working environments, differing situations depending on status of residence could produce various sources of distress. The difficult aspects of Japan's distinct culture seem to contribute to their distress, especially for those who have more interactions with Japanese co-workers. A push for a multicultural society, where migrant workers can pursue proactive life designs of their own choosing, is warranted.
Subject(s)
Mental Health , Transients and Migrants , Humans , Japan , Cross-Sectional Studies , VietnamABSTRACT
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.
ABSTRACT
Background: The economic struggles faced by many technical intern trainees in Japan include the necessity to remit money to their home country, debts owed to intermediaries facilitating their arrival, and reduced working hours due to the COVID-19 pandemic. Furthermore, there is concern that the pandemic may contribute to mental instability resulting from the significant life changes experienced by the trainees. This study examined the experience of material deprivation among Vietnamese intern trainees in Japan and explored the correlation between material deprivation and suicidal ideation. Methods: A cross-sectional study was conducted between September and October 2021, involving 310 Vietnamese technical intern trainees. Data from 200 participants were analyzed. The questionnaire included gender, age, duration of residence in Japan, proficiency in the Japanese language, income changes due to the COVID-19 pandemic, material deprivation status, and suicidal ideation. Suicidal ideation was assessed using the ninth item of the Patient Health Questionnaire-9. Logistic regression analysis was performed to investigate the relationship between material deprivation items and suicidal ideation. Results: The mean age of the respondents was 26.0 ± 5.1 years, with 62.0% (n = 124) being male. Among the material deprivation items, 74.0% (n = 148) reported food deprivation, 59.0% (n = 118) reported cellphone bill deprivation, and 55.0% (n = 110) reported medical expense deprivation. Suicidal ideation was reported by 23.0% (n = 46) of the respondents. The prevalence of suicidal ideation was associated with age (p = 0.031, odds ratio [OR] = 0.889, 95% confidence interval [CI] = 0.799-0.990), deprivation of food expenses (p = 0.003, OR = 3.897, 95% CI = 1.597-9.511), and deprivation of cellphone usage (p = 0.021, OR = 3.671, 95% CI = 1.217-11.075). Conclusion: Vietnamese technical intern trainees in Japan faced various forms of material deprivation, which correlated with a high prevalence of significant psychological issues. Suicidal ideation was influenced by factors such as age, deprivation of food expenses, and inability to pay cellphone bills. The experience of material deprivation could have intensified the mental health challenges faced by Vietnamese trainees, particularly in the demanding circumstances of the COVID-19 pandemic.
ABSTRACT
BACKGROUND: Somatic and germline variants are not distinguishable by circulating tumor DNA (ctDNA) testing without analyzing non-tumor samples. Although confirmatory germline testing is clinically relevant, the criteria for selecting presumed germline variants have not been established in ctDNA testing. In the present study, we aimed to evaluate the prevalence of pathogenic germline variants in clinical ctDNA testing through their variant allele fractions (VAFs). METHODS: A total of consecutive 106 patients with advanced solid tumors who underwent ctDNA testing (Guardant360®) between January 2018 and March 2020 were eligible for this study. To verify the origin of pathogenic variants reported in ctDNA testing, germline sequencing was performed using peripheral blood DNA samples archived in the Clinical Bioresource Center in Kyoto University Hospital (Kyoto, Japan) under clinical research settings. RESULTS: Among 223 pathogenic variants reported in ctDNA testing, the median VAF was 0.9% (0.02-81.8%), and 88 variants with ≥ 1% VAFs were analyzed in germline sequencing. Among 25 variants with ≥ 30% VAFs, seven were found in peripheral blood DNA (BRCA2: n = 6, JAK2: n = 1). In contrast, among the 63 variants with VAFs ranging from 1 to < 30%, only one variant was found in peripheral blood DNA (TP53: n = 1). Eventually, this variant with 15.6% VAF was defined to be an acquired variant, because its allelic distribution did not completely link to those of neighboring germline polymorphisms. CONCLUSION: Our current study demonstrated that VAFs values are helpful for selecting presumed germline variants in clinical ctDNA testing.
Subject(s)
Circulating Tumor DNA , Neoplasms , Biomarkers, Tumor , Circulating Tumor DNA/genetics , Germ Cells , Humans , Mutation , Neoplasms/genetics , PrevalenceABSTRACT
BACKGROUND: The European Society for Medical Oncology Precision Medicine Working Group (ESMO-PMWG) published recommendations regarding confirmatory germline testing for presumed germline pathogenic variants (PGPVs) in tumor-only comprehensive genomic profiling (CGP). However, the clinical validity of these recommendations has not been investigated in a real-world practice. METHODS: Medical records of 180 consecutive patients who obtained the results of a tumor-only CGP (FoundationOne® CDx, Foundation Medicine, Inc, Cambridge, MA, USA) between October 2018 and March 2020, were retrospectively reviewed. After excluding patients with no reported variants in 45 actionable genes (n = 6), or no archived germline DNA samples (n = 31), 143 patients were investigated. The PGPVs were selected from the CGP report and germline sequencing were performed using DNA samples archived in Clinical Bioresource Center in Kyoto University Hospital (Kyoto, Japan). RESULTS: A total of 195 variants were classified as PGPV based on the conventional criteria. Germline sequencing disclosed that 12 variants (6.2%) were of germline origin. In contrast, after filtering these 195 variants through the ESMO-PMWG recommendation criteria for confirmatory germline testing, following seven PGPVs, BRCA2 (n = 2), BRIP1 (n = 1), BAP1 (n = 1), PMS2 (n = 1), MSH2 (n = 1), and SDHB (n = 1) remained and six variants (85.7%) were confirmed to be of germline origin. CONCLUSION: Our current data suggested that the application of ESMO-PMWG criteria is helpful in selecting PGPVs with a high likelihood of germline origin in a tumor-only CGP in daily clinical practice.
Subject(s)
Germ-Line Mutation , Neoplasms , Genomics/methods , Germ Cells/pathology , Germ-Line Mutation/genetics , Humans , Neoplasms/genetics , Neoplasms/pathology , Retrospective StudiesABSTRACT
We examined whether there were gains in lifespan among patients who died from hematological cancers in Japan between 1990 and 2015 using the novel average lifespan shortened (ALSS) measure. We obtained mortality data from the World Health Organization mortality database. Years of life lost (YLL) was calculated using Japanese life tables. ALSS measure was calculated as a ratio of YLL to the expected lifespan. The ALSS results showed that the lifespan of patients who died from hematological cancers has improved over time. For instance, women who died of leukemia in 1990 lost about 34% of their lifespan; conversely, those who died in 2015 lost about 20%. Likewise, men dying from non-Hodgkin lymphoma lost about 22% of their lifespan in 1990, whereas men lost about 14% in 2015. In summary, the new ALSS measure shows prolonged lifespans among patients who died from hematological cancers in Japan over the study period.
Subject(s)
Hematologic Neoplasms , Leukemia , Lymphoma, Non-Hodgkin , Lymphoma , Multiple Myeloma , Female , Humans , Japan/epidemiology , Life Expectancy , Longevity , Lymphoma, Non-Hodgkin/diagnosis , Lymphoma, Non-Hodgkin/epidemiology , Lymphoma, Non-Hodgkin/etiology , Male , Multiple Myeloma/diagnosis , Multiple Myeloma/epidemiologyABSTRACT
BACKGROUND: Tumor heterogeneity has been known to cause inter-assay discordance among next-generation sequencing (NGS) results. However, whether preclinical factors such as sample type, sample quality and analytical features of gene panel can affect the concordance between two different assays remains largely unexplored. METHODS: Replicate sets of DNA samples extracted from formalin-fixed paraffin-embedded tissues (FFPE) (n = 20) and fresh frozen (FF) tissues (n = 10) were herein analyzed using a tumor-only (TO) and paired tumor-normal (TN) gene panel in laboratories certified by the Clinical Laboratory Improvement Amendment. Reported variants from the TO and TN panels were then compared. Furthermore, additional FFPE samples were sequentially sliced from the same FFPE block and submitted to another TN panel assay. RESULTS: Substantial discordance (71.8%) was observed between the results of the two panels despite using identical DNA samples, with the discordance rate being significantly higher for FFPE samples (p < 0.05). Among the 99 variants reported only in the TO panel, 32.3% were consistent with germline variants, which were excluded in the TN panel, while 30.3% had an allele frequency of less than 5%, some of which were highly likely to be artificial calls. The comparison of two independent TN panel assay results from the same FFPE block also showed substantial discordance rate (55.3%). CONCLUSIONS: In the context of clinical settings, our comparative analysis revealed that inter-NGS assay discordance commonly occurred due to sample types and the different analytical features of each panel.
Subject(s)
Formaldehyde , Neoplasms , DNA , High-Throughput Nucleotide Sequencing/methods , Humans , Neoplasms/genetics , Neoplasms/pathology , Paraffin Embedding , Tissue FixationABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and pathogenic coronavirus responsible for the pandemic coronavirus disease 19 (COVID-19). It has significant impact on human health and public safety along with negative social and economic consequences. Vaccination against SARS-CoV-2 is likely the most effective approach to sustainably control the global COVID-19 pandemic. Vaccination is highly effective in reducing the risk of severe COVID-19 disease. Mass-scale vaccination will help us in attaining herd immunity and will lessen the negative impact of the disease on public health, social and economic conditions. The present pandemic stimulated the development of several effective vaccines based on different platforms. Although the vaccine is safe and efficacious, rare cases of thrombosis and thrombocytopenia following the use of vaccination with the ChAdOx1 CoV-19 vaccine (AstraZeneca, University of Oxford, and Serum Institute of India) or the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) have been reported globally. This review focussed on the definition, epidemiology, pathogenesis, clinical features, diagnosis, and management of vaccine associated thrombosis.
ABSTRACT
The SARS-CoV-2 is a new coronavirus responsible for the COVID-19 disease and has caused the pandemic worldwide. A large number of cases have overwhelmed the healthcare system worldwide. The COVID-19 infection has been associated with a heightened risk of thromboembolic complications. Various mechanisms are leading to the high thrombotic risk in COVID-19 patients such as inflammation, endotheliitis, hyperviscosity, and hypercoagulability. We searched PubMed, EMBASE, and CINAHL from January 2020 to December 2020. We used the following search terms: COVID-19, coagulopathy, and thrombosis. We reviewed the epidemiology, clinical features, mechanisms, and treatment of COVID-19-associated coagulopathy.
Subject(s)
COVID-19 , Thromboembolism , Thrombophilia , Humans , Pandemics , SARS-CoV-2 , Thrombophilia/complications , Thrombophilia/epidemiologyABSTRACT
Comprehensive genomic profiling (CGP) testing by next-generation sequencing has been introduced into clinical practice as part of precision cancer medicine to select effective targeted therapies. However, whether CGP testing at the time of first-line chemotherapy could be clinically useful is not clear. We conducted this single-center, prospective, observational study to investigate the feasibility of CGP testing for chemotherapy-naïve patients with stage III/IV gastrointestinal cancer, rare cancer, and cancer of unknown primary, using the FoundationOne® companion diagnostic (F1CDx) assay. The primary outcome was the detection rate of at least one actionable/druggable cancer genomic alteration. Actionable/druggable cancer genomic alterations were determined by the F1CDx report. An institutional molecular tumor board determined the molecular-based recommended therapies. A total of 197 patients were enrolled from October 2018 to June 2019. CGP success rate was 76.6% (151 of 197 patients), and median turnaround time was 19 days (range: 10-329 days). Actionable and druggable cancer genomic alterations were reported in 145 (73.6%) and 124 (62.9%) patients, respectively. The highest detection rate of druggable genomic alterations in gastrointestinal cancers was 80% in colorectal cancer (48 of 60 patients). Molecular-based recommended therapies were determined in 46 patients (23.4%). CGP testing would be a useful tool for the identification of a potentially effective first-line chemotherapy.
Subject(s)
High-Throughput Nucleotide Sequencing/methods , Molecular Targeted Therapy/methods , Neoplasms/genetics , Precision Medicine/methods , Sequence Analysis, DNA/methods , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Female , Gene Expression Profiling/methods , Humans , Male , Middle Aged , Prospective Studies , Young AdultABSTRACT
Sharing a common land border with China, Vietnam has faced a high risk of transmission of Coronavirus Disease 2019 (COVID-19). Rapid decision making and robust public health measures were established by the Vietnamese Government to control the situation. As of 17 May 2020, Vietnam reported 320 total confirmed cases of COVID-19, of whom 260 had fully recovered, while the remaining 60 cases were still under treatment. Noteworthy, the current data still confirms zero deaths and within the last 32 consecutive days prior to this submission, there have been no new infections in the country. Valuable lessons from Severe Acute Respiratory Syndrome in 2003 such as use of quarantine, early recognition and quick response to the infection, and increased awareness of its citizens have put Vietnam in a somewhat better position against COVID-19 compared to other places. Vietnam, at the current time, mulls declaring an end of the current COVID-19 outbreak.
Subject(s)
Coronavirus Infections/epidemiology , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/epidemiology , Pneumonia, Viral/prevention & control , Betacoronavirus , COVID-19 , Community-Acquired Infections/epidemiology , Community-Acquired Infections/virology , Humans , Quarantine , SARS-CoV-2 , Vietnam/epidemiologySubject(s)
Adenocarcinoma/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , BRCA2 Protein/genetics , Biomarkers, Tumor/genetics , DNA Mutational Analysis , Mutation , Pancreatic Neoplasms/genetics , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Adult , Drug Resistance, Neoplasm/genetics , Female , Fluorouracil/therapeutic use , Genetic Predisposition to Disease , Humans , Irinotecan/therapeutic use , Leucovorin/therapeutic use , Liquid Biopsy , Oxaliplatin/therapeutic use , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Phenotype , Predictive Value of Tests , Treatment OutcomeABSTRACT
PURPOSE: Premature mortality offers an alternative approach for monitoring the burden of mortality; however, little is known about its measures for stomach cancer. In the present study, we investigated temporal changes in premature mortality because of stomach cancer in the Japanese population from 1980 to 2015. METHODS: Mortality data for stomach cancer were obtained from the World Health Organization mortality database. Years of life lost (YLL) was calculated using Japanese life tables. The average lifespan shortened was calculated and defined as the ratio of YLL in relation to the expected lifespan. RESULTS: Over a 35-year time frame, the age-standardized rates adjusted to the World Standard Population for deaths from stomach cancer substantially decreased in both sexes. The results from the average YLL (AYLL) measure showed that lifespan of stomach cancer patients was prolonged by about 3 and 5 years in men and women, respectively. The average lifespan shortened measure showed that stomach cancer led to a loss of 18.5% of lifespan among men and of 21.9% among women in 1980, but these numbers were reduced to 13.6% and 14.5%, respectively, in 2015. CONCLUSIONS: Our study demonstrated decreasing trends in premature mortality for stomach cancer in Japan over a 35-year period.
Subject(s)
Life Expectancy , Mortality, Premature/trends , Stomach Neoplasms/mortality , Adult , Age Distribution , Aged , Female , Humans , Japan/epidemiology , Life Tables , Male , Middle Aged , Stomach Neoplasms/ethnologyABSTRACT
BACKGROUND: Tumor mutational burden (TMB) measured via next-generation sequencing (NGS)-based gene panel is a promising biomarker for response to immune checkpoint inhibitors (ICIs) in solid tumors. However, little is known about the preanalytical factors that can affect the TMB score. MATERIALS AND METHODS: Data of 199 patients with solid tumors who underwent multiplex NGS gene panel (OncoPrime), which was commercially provided by a Clinical Laboratory Improvement Amendments-licensed laboratory and covered 0.78 megabase (Mb) of capture size relevant to the TMB calculation, were reviewed. Associations between the TMB score and preanalytical factors, including sample DNA quality, sample type, sampling site, and storage period, were analyzed. Clinical outcomes of patients with a high TMB score (≥10 mutations per megabase) who received anti-programmed cell death protein 1 antibodies (n = 22) were also analyzed. RESULTS: Low DNA library concentration (<5 nM), formalin-fixed paraffin-embedded tissue (FFPE), and the prolonged sample storage period (range, 0.9-58.1 months) correlated with a higher TMB score. After excluding low DNA library samples from the analysis, FFPE samples, but not the sample storage period, exhibited a marked correlation with a high TMB score. Of 22 patients with a high TMB score, we observed the partial response in 2 patients (9.1%). CONCLUSION: Our results indicate that the TMB score estimated via NGS-based gene panel could be affected by the DNA library concentration and sample type. These factors could potentially increase the false-positive and/or artifactual variant calls. As each gene panel has its own pipeline for variant calling, it is unknown whether these factors have a significant effect in other platforms. IMPLICATIONS FOR PRACTICE: A high tumor mutational burden score, as estimated via next-generation sequencing-based gene panel testing, should be carefully interpreted as it could be affected by the DNA library concentration and sample type.
Subject(s)
Biomarkers, Tumor/metabolism , High-Throughput Nucleotide Sequencing/methods , Tumor Burden/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , Humans , Middle Aged , Young AdultABSTRACT
Splenic hemorrhage is a potentially life-threatening complication usually occurring after blunt trauma to the abdomen. Atraumatic splenic rupture (ASR) is an uncommon condition, and mostly results from pathology affecting the spleen, such as tumor infiltration or infection. Here, we report a case of atraumatic rupture of a normal spleen in a patient undergoing peritoneal dialysis, and review similar cases in the literature. The case involved a 58-year-old man with nephrotic syndrome who had been undergoing peritoneal dialysis for 1 year. He presented to the hospital with abdominal pain, nausea, and blood-stained dialysate. Laboratory data revealed severe anemia, with a hemoglobin of 4.3 g/dL. An abdominal computed tomography (CT) scan demonstrated a high-density area around the spleen and malposition of the catheter. Laparoscopy revealed large amounts of coagulated blood surrounding the spleen. The patient was diagnosed with atraumatic splenic bleeding. He improved with bed rest and blood transfusion, and could continue with peritoneal dialysis. It was considered that the etiology of bleeding was directly from the spleen. However, due to the temporary malposition of the peritoneal catheter, catheter-induced splenic trauma could not be ruled out. ASR is a rare entity that needs a high index of suspicion for diagnosis. Using CT scanning and peritoneal fluid analysis, these modalities may assist in the diagnosis. Emergency intervention is required upon definitive diagnosis. Increased awareness of ASR can enhance the early diagnosis and effective treatment.
Subject(s)
Peritoneal Dialysis/adverse effects , Rupture, Spontaneous/complications , Spleen/injuries , Splenic Rupture/diagnostic imaging , Catheters/adverse effects , Dialysis Solutions , Humans , Laparoscopy/methods , Male , Middle Aged , Nephrotic Syndrome/therapy , Spleen/diagnostic imaging , Spleen/pathology , Spleen/surgery , Splenic Rupture/pathology , Splenic Rupture/surgery , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
Autophagy, a major intracellular degradation system which is conserved from yeast to mammals, is essential for the cellular clearance and the maintenance of homeostasis inside the cell. The autophagic activity is reported to decrease in almost all cells and tissues following aging, and genetic inhibition of autophagy in mice leads to degenerative changes and diseases that are highly associated with aging. On the other hand, various intervention strategies that delay senescence or increase life span in model organisms often stimulate autophagy, and autophagy inhibition compromises these anti-aging effects. Here, we review recent evidences in support of tight connections between autophagy and aging.
Subject(s)
Aging/metabolism , Autophagy/physiology , Animals , Autophagy/genetics , Homeostasis/physiology , Humans , Phenotype , Signal Transduction/physiologyABSTRACT
Drastic protein degradation occurs during muscle atrophy induced by denervation, fasting, immobility, and various systemic diseases. Although the ubiquitin-proteasome system is highly up-regulated in denervated muscles, the involvement of autophagy and protein synthesis has been controversial. Here, we report that autophagy is rather suppressed in denervated muscles even under autophagy-inducible starvation conditions. This is due to a constitutive activation of mammalian target of rapamycin complex 1 (mTORC1). We further reveal that denervation-induced mTORC1 activation is dependent on the proteasome, which is likely mediated by amino acids generated from proteasomal degradation. Protein synthesis and ribosome biogenesis are paradoxically increased in denervated muscles in an mTORC1-dependent manner, and mTORC1 activation plays an anabolic role against denervation-induced muscle atrophy. These results suggest that denervation induces not only muscle degradation but also adaptive muscle response in a proteasome- and mTORC1-dependent manner.
Subject(s)
Autophagy , Muscle, Skeletal/physiology , Proteasome Endopeptidase Complex/metabolism , Proteins/metabolism , Animals , Cell Line , Denervation , Mechanistic Target of Rapamycin Complex 1 , Mice , Mice, Inbred C57BL , Multiprotein Complexes , Muscle, Skeletal/innervation , TOR Serine-Threonine KinasesABSTRACT
Although cerebellar mossy fibers are the most abundant cerebellar afferents and are deeply involved in cerebellar function, the organization of their projection has remained obscure, particularly in relation to cerebellar compartmentalization. The dorsal column nuclei (DCN) are a major source of cerebellar mossy fibers and possess distinct somatotopic representations of specific somatosensory submodalities. We reconstructed individual dextran-labeled DCN axons completely from serial sections and mapped their terminals on the longitudinal cerebellar compartments that were visualized by aldolase C immunostaining to clarify their projection pattern. Individual axons branched and formed about 100 rosette terminals in the cerebellar cortex, but infrequently projected to the cerebellar nuclei (1 out of 15 axons). Cortical terminals were clustered in multiple areas in the vermis and pars intermedia mostly, but not exclusively, ipsilateral to the origin of the axon. The gracile, cuneate, and external cuneate nuclei (ECuN) mainly projected to the copula pyramidis and lobule V, paramedian and simple lobules, and lobules I-V and VIII-IX, respectively, although there was some overlap. The majority of terminals were located within aldolase C negative or lightly positive compartments. However, terminals of a single axon can be located on aldolase C-negative as well as on aldolase C-positive compartments. In particular, the rostral ECuN, which is responsive to shoulder movements, projected consistently to lobule IX, which were mostly aldolase C-positive. In sum, DCN-cerebellar axons project to multiple compartments with terminals clustered mainly in the conventional spinocerebellar region with a coarse topography, which shows some relationship to the cortical compartments defined by aldolase C.
Subject(s)
Axons/enzymology , Axons/ultrastructure , Cerebellar Cortex/anatomy & histology , Cerebellar Nuclei/anatomy & histology , Fructose-Bisphosphate Aldolase/metabolism , Neural Pathways/anatomy & histology , Neural Pathways/enzymology , Animals , Brain Mapping/methods , Female , Male , Rats , Rats, Long-Evans , Staining and Labeling/methodsABSTRACT
Although the overall topography of the cerebellar corticonuclear projection formed by Purkinje cell (PC) axons has been described, only a few studies have dealt with the organization of this projection at the level of individual PC axons. Thus, we reconstructed 65 single PC axons that were labeled with biotinylated dextran amine in the rat. We then analyzed the relationship between the projections of these PCs and the compartmentalization of the cerebellar cortex and nuclei based on the topography of olivocerebellar projection and aldolase C expression in PCs. After giving rise to short local recurrent collaterals near the soma, a PC axon formed a terminal arbor in a specific small area in the cerebellar nuclei (CN). The terminal arbors of vermal PCs were spread more widely than those of hemispheric PCs and sometimes extended to extracerebellar targets. PCs located in any of the aldolase C-positive (Groups I and II) and -negative (Groups III and IV) stripes consistently projected to the caudoventral and rostrodorsal parts of the CN, respectively, precisely in accordance with the compartmentalization of the cortex and nuclei. Mediolateral segregation and rostrocaudal convergence were seen between projections of separate PCs in a single aldolase C compartment. The results revealed a tight link between the projection patterns of individual PC axons, the topography of the olivocerebellar pathway, and the aldolase C expression pattern. Their overall correspondence seems to reflect a basic aspect of cerebellar organization, although some area-dependent variation in the relationship of these three entities was also present.