Viral delivery of L1CAM promotes axonal extensions by embryonic cerebral grafts in mouse brain

遺伝子治療によるホスト脳の環境最適化が細胞移植効果を高める --ホスト脳へのL1CAMの強制発現によるマウス胎仔脳移植片の軸索伸長促進効果--. 京都大学プレスリリース. 2023-03-24.Combining cell transplantation and gene therapy to enhance axonal outgrowth in the central nervous system. 京都大学プレスリリース. 2023-04-06.Cell replacement therapy is expected as a new and more radical treatment against brain damage. We previously reported that transplanted human cerebral organoids extend their axons along the corticospinal tract in rodent brains. The axons reached the spinal cord but were still sparse. Therefore, this study optimized the host brain environment by the adeno-associated virus (AAV)-mediated expression of axon guidance proteins in mouse brain. Among netrin-1, SEMA3, and L1CAM, only L1CAM significantly promoted the axonal extension of mouse embryonic brain tissue-derived grafts. L1CAM was also expressed by donor neurons, and this promotion was exerted in a haptotactic manner by their homophilic binding. Primary cortical neurons cocultured on L1CAM-expressing HEK-293 cells supported this mechanism. These results suggest that optimizing the host environment by the AAV-mediated expression of axon guidance molecules enhances the effect of cell replacement therapy

Non-BAC Component but not Epidermal Growth Factor Receptor Gene Mutation is Associated with Poor Outcomes in Small Adenocarcinoma of the Lung

ObjectiveThe purpose of this study was to identify risk factors for poor clinical outcome after surgical resection of small lung adenocarcinoma.Materials and MethodsClinical records of 127 patients who had pathologic stage IA lung adenocarcinoma 20 mm or less and who had undergone a lobectomy with mediastinal lymph node dissection were reviewed. The percentage of non-bronchioloalveolar carcinoma (non-BAC) components quantified objectively, and epidermal growth factor receptor gene (EGFR) mutation determined by polymerase chain reaction-based assay were retrospectively linked with clinical data.ResultsBased on the percentage of non-BAC component, 127 patients were classified as follows: 26 in group I, BAC, 46 in group II mixed subtype with ≥ 50% BAC, 18 in group III, mixed subtype with under 50% BAC, and 37 in group IV, mixed subtype with all non-BAC components or a pure pattern of one of the non-BAC components. Groups I and II were considered to be a “low non-BAC component type” and groups III and IV were considered to be a “high non-BAC component type.” EGFR mutations in exon19 and exon21 were observed in 64 patients (50.4%). In terms of recurrence, the high non-BAC component type was the only independent factor for recurrence (p = 0.029). Regarding survival, the high age (p = 0.028) and high non-BAC component type (p = 0.046) were independent risk factors for poor overall survival. They were also independent risk factors for poor disease-free survival (p = 0.025 and p = 0.027, respectively).ConclusionThe high non-BAC component but not EGFR mutation status, is an independent risk factor for both recurrence and poor prognosis in patients with stage IA lung adenocarcinoma ≤20 mm

The Runx1 Transcription Factor Inhibits the Differentiation of Naive CD4+ T Cells into the Th2 Lineage by Repressing GATA3 Expression

Differentiation of naive CD4+ T cells into helper T (Th) cells is controlled by a combination of several transcriptional factors. In this study, we examined the functional role of the Runx1 transcription factor in Th cell differentiation. Naive T cells from transgenic mice expressing a dominant interfering form of Runx1 exhibited enhanced interleukin 4 production and efficient Th2 differentiation. In contrast, transduction of Runx1 into wild-type T cells caused a complete attenuation of Th2 differentiation and was accompanied by the cessation of GATA3 expression. Furthermore, endogenous expression of Runx1 in naive T cells declined after T cell receptor stimulation, at the same time that expression of GATA3 increased. We conclude that Runx1 plays a novel role as a negative regulator of GATA3 expression, thereby inhibiting the Th2 cell differentiation

Polymorphisms and Body Mass Index Across Life Course

Background: Obesity is a reported risk factor for various health problems. Genome-wide association studies (GWASs) have identified numerous independent loci associated with body mass index (BMI). However, most of these have been focused on Europeans, and little evidence is available on the genetic effects across the life course of other ethnicities. Methods: We conducted a cross-sectional study to examine the associations of 282 GWAS-identified single nucleotide polymorphisms with three BMI-related traits, current BMI, BMI at 20 years old (BMI at 20), and change in BMI (BMI change), among 11,586 Japanese individuals enrolled in the Japan Multi-Institutional Collaborative Cohort study. Associations were examined using multivariable linear regression models. Results: We found a significant association (P < 0.05/282 = 1.77 × 10−4) between BMI and 11 polymorphisms in or near FTO, BDNF, TMEM18, HS6ST3, and BORCS7. The trend was similar between current BMI and BMI change, but differed from that of the BMI at 20. Among the significant variants, those on FTO were associated with all BMI traits, whereas those on TMEM18 and HS6SR3 were only associated with BMI at 20. The association of FTO loci with BMI remained, even after additional adjustment for dietary energy intake. Conclusions: Previously reported BMI-associated loci discovered in Europeans were also identified in the Japanese population. Additionally, our results suggest that the effects of each loci on BMI may vary across the life course and that this variation may be caused by the differential effects of individual genes on BMI via different pathways

Accuracy management survey of nucleic acid amplification tests using inactivated SARS-CoV-2 in Hiroshima Prefecture

At the beginning of 2020, the number of laboratories performing SARS-CoV-2 testing increased with the rapid expansion of COVID-19 in Hiroshima Prefecture. Thus, it is necessary to compare and verify the validity of the test results among local laboratories. In this study, we distributed the same standard samples to laboratories that performed COVID-19 testing using the nucleic acid amplification method and confirmed the accuracy of the tests. The SARS-CoV-2 strain distributed by the National Institute of Infectious Diseases (NIID), Japan, was used for testing. As measured by RT-qPCR, a specific amount of the virus was inactivated by ethanol and dried as specimens for distribution. This study included 27 tests performed at 15 laboratories conducting or planning to conduct nucleic acid amplification tests (RT-qPCR and LAMP methods) for SARSCoV-2. The detection limit of each test method was set at the value provided by the NIID. The accuracy of the tests was examined to determine whether they met the required accuracy criteria. SARS-CoV-2 genomic RNA was reliably detected in all 27 tests. The inactivated specimens used in this study were safe to distribute and could be used as positive controls for all methods.This study was supported by a grant from the Government-Academia Collaboration of Hiroshima Prefecture and by a research grant for COVID-19 from AMED, Japan under Grant Number 20he0622011h0001(to J. T.)

Association of Dietary Acid Load with the Prevalence of Metabolic Syndrome among Participants in Baseline Survey of the Japan Multi-Institutional Collaborative Cohort Study

The association between dietary acid load and metabolic syndrome (MetS) has not been fully investigated. A cross-sectional study was performed on 14,042 men and 14,105 women (aged 35–69 years) who participated in a baseline survey of the Japan Multi-Institutional Collaborative Cohort study. Dietary acid load was assessed using the net-endogenous-acid-production (NEAP) score that is closely correlated with the rate of renal net acid excretion. MetS was diagnosed according to the Joint Interim Statement Criteria of 2009 using body-mass index instead of waist circumference. After adjusting for potential confounders, higher NEAP scores were associated with a significantly increased odds ratio (OR) of MetS, obesity, high blood pressure, and high fasting blood glucose. These associations remained significant after further adjustment for carbohydrate intake or two nutrient-pattern scores significantly associated with MetS. After adjustment for fiber, iron, potassium, and vitamin pattern scores, the OR of MetS for the highest quartile of NEAP scores, relative to the lowest quartile, was 1.25 (95% confidence interval 1.12–1.39). There was no significant interaction between sex, age, or body-mass index and NEAP. Higher dietary acid load was associated with a higher prevalence of MetS and several of its components, independently of carbohydrate intake or nutrient patterns

Associations between Dietary Patterns, ADRβ2 Gln27Glu and ADRβ3 Trp64Arg with Regard to Serum Triglyceride Levels : J-MICC Study

Interactions between dietary patterns and 2 β-adrenergic receptor (ADRβ) gene polymorphisms (ADRβ2 Gln27Glu and ADRβ3 Trp64Arg) were examined with regard to the effects on serum triglyceride levels. The cross-sectional study comprised 1720 men and women (aged 35–69 years) enrolled in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. Genotyping was conducted using a multiplex polymerase chain reaction-based invader assay. We used 46 items from a validated short food frequency questionnaire and examined major dietary patterns by factor analysis. We identified four dietary patterns: healthy, Western, seafood and bread patterns. There was no significant association between any dietary pattern and serum triglyceride levels. After a separate genotype-based analysis, significant interactions between ADRβ3 Trp64Arg genotype and the bread pattern (p for interaction = 0.01) were associated with serum triglyceride levels; specifically, after adjusting for confounding factors, Arg allele carriers with the bread pattern had lower serum triglycerides (p for trend = 0.01). However, the Trp/Trp homozygous subjects with the bread pattern showed no association with serum triglycerides (p for trend = 0.55). Interactions between other dietary patterns and ADRβ polymorphisms were not significant for serum triglyceride levels. Our findings suggest that ADRβ3 polymorphism modifies the effects of the bread pattern on triglyceride levels

Genetic variants of SLC17A1 are associated with cholesterol homeostasis and hyperhomocysteinaemia in Japanese men

Hyperuricaemia is an undisputed and highly predictive biomarker for cardiovascular risk. SLC17A1, expressed in the liver and kidneys, harbours potent candidate single nucleotide polymorphisms that decrease uric acid levels. Therefore, we examined SLC17A1 polymorphisms (rs1165196, rs1179086 and rs3757131), which might suppress cardiovascular risk factors and that are involved in liver functioning, via a large-scale pooled analysis of the Japanese general population in a cross-sectional study. Using data from the Japan Multi-Institutional Collaborative Cohort Study, we identified 1842 participants of both sexes, 35–69-years-old, having the requisite data and analysed their SLC17A1 genotypes. In men, logistic regression analyses revealed that minor alleles in SLC17A1 polymorphisms (rs1165196 and rs3757131) were associated with a low-/high-density lipoprotein cholesterol ratio >2.0 (rs1165196: odds ratio [OR], 0.703; 95% confidence interval [CI], 0.536–0.922; rs3757131: OR, 0.658; 95% CI, 0.500–0.866) and with homocysteine levels of >10.0 nmol/mL (rs1165196: OR, 0.544; 95% CI, 0.374–0.792; rs3757131: OR, 0.509; 95% CI, 0.347–0.746). Therefore, these polymorphisms had dominant negative effects on cholesterol homeostasis and hyperhomocysteinaemia, in men, independent of alcohol consumption, physical activity, or daily energy and nutrition intake. Thus, genetic variants of SLC17A1 are potential biomarkers for altered cholesterol homeostasis and hyperhomocysteinaemia in Japanese men

Association of perceived stress and coping strategies with the renal function in middle-aged and older Japanese men and women

Elucidating the risk factors for chronic kidney disease is important for preventing end-stage renal disease and reducing mortality. However, little is known about the roles of psychosocial stress and stress coping behaviors in deterioration of the renal function, as measured by the estimated glomerular filtration rate (eGFR). This cross-sectional study of middle-aged and older Japanese men (n = 31,703) and women (n = 38,939) investigated whether perceived stress and coping strategies (emotional expression, emotional support seeking, positive reappraisal, problem solving, and disengagement) were related to the eGFR, with mutual interactions. In multiple linear regression analyses adjusted for age, area, lifestyle factors, and psychosocial variables, we found a significant inverse association between perceived stress and the eGFR in men (Ptrend = 0.02), but not women. This male-specific inverse association was slightly attenuated after adjustment for the history of hypertension and diabetes and was more evident in lower levels of emotional expression (Pinteraction = 0.003). Unexpectedly, problem solving in men (Ptrend < 0.001) and positive reappraisal in women (Ptrend = 0.002) also showed an inverse association with the eGFR. Perceived stress may affect the eGFR, partly through the development of hypertension and diabetes. The unexpected findings regarding coping strategies require the clarification of the underlying mechanisms, including the hormonal and immunological aspects

Mendelian Randomization on hs-CRP and eGFR

Background: Inflammation is thought to be a risk factor for kidney disease. However, whether inflammatory status is either a cause or an outcome of chronic kidney disease remains controversial. We aimed to investigate the causal relationship between high-sensitivity C-reactive protein (hs-CRP) and estimated glomerular filtration rate (eGFR) using Mendelian randomization (MR) approaches. Methods: A total of 10,521 participants of the Japan Multi-institutional Collaborative Cohort Study was analyzed in this study. We used two-sample MR approaches (the inverse-variance weighted (IVW), the weighted median (WM), and the MR-Egger method) to estimate the effect of genetically determined hs-CRP on kidney function. We selected four and three hs-CRP associated single nucleotide polymorphisms (SNPs) as two instrumental variables (IV): IVCRP and IVAsian, based on SNPs previously identified in European and Asian populations. IVCRP and IVAsian explained 3.4% and 3.9% of the variation in hs-CRP, respectively. Results: Using the IVCRP, genetically determined hs-CRP was not significantly associated with eGFR in the IVW and the WM methods (estimate per 1 unit increase in ln(hs-CRP), 0.000; 95% confidence interval [CI], −0.019 to 0.020 and −0.003; 95% CI, −0.019 to 0.014, respectively). For IVAsian, we found similar results using the IVW and the WM methods (estimate, 0.005; 95% CI, −0.020 to 0.010 and −0.004; 95% CI, −0.020 to 0.012, respectively). The MR-Egger method also showed no causal relationships between hs-CRP and eGFR (IVCRP: −0.008; 95% CI, −0.058 to 0.042; IVAsian: 0.001; 95% CI, −0.036 to 0.036). Conclusion: Our two-sample MR analyses with different IVs did not support a causal effect of hs-CRP on eGFR