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Summary: Mitochondria play a vital role in non-shivering thermogenesis in both brown and subcutaneous white adipose tissues (BAT and scWAT, respectively). However, specific regulatory mechanisms driving mitochondrial function in these tissues have been unclear. Here we demonstrate that prolonged activation of β-adrenergic signaling induces epigenetic modifications in scWAT, specifically targeting the enhancers for the mitochondria master regulator genes Pgc1a/b. This is mediated at least partially through JMJD1A, a histone demethylase that in response to β-adrenergic signals, facilitates H3K9 demethylation of the Pgc1a/b enhancers, promoting mitochondrial biogenesis and the formation of beige adipocytes. Disruption of demethylation activity of JMJD1A in mice impairs activation of Pgc1a/b driven mitochondrial biogenesis and limits scWAT beiging, contributing to reduced energy expenditure, obesity, insulin resistance, and metabolic disorders. Notably, JMJD1A demethylase activity is not required for Pgc1a/b dependent thermogenic capacity of BAT especially during acute cold stress, emphasizing the importance of scWAT thermogenesis in overall energy metabolism.

How β-AR signaling coordinates epigenetic and transcriptional pathways is unknown. Here the authors show that cold-induced β-AR signaling negatively regulates MYPT1-PP1β phosphatase activity to orchestrate both pathways for beige adipogenesis.

Introduction: Immune checkpoint inhibitors (ICIs) induce long-term, durable responses in patients with advanced NSCLC. Nevertheless, these responses are limited to a few patients, and most responders have disease progression. The purpose of this study was to determine the differences in clinical factors and blood drug concentrations between long-term responders (LTRs) and non-LTRs. Methods: We retrospectively analyzed consecutive patients with advanced NSCLC who received antiprogrammed cell death protein 1 (PD-1) inhibitor monotherapy (nivolumab) from December 22, 2015, to May 31, 2017. Patients who obtained a clinical benefit for more than 6 months were referred to as “responders”; among these, individuals who had a durable response for more than 2 years were defined as “LTRs.” Those with a clinical benefit for less than 2 years were defined as “non-LTRs.” Results: A total of 212 patients received anti–PD-1 inhibitor monotherapy. The responders accounted for 35% (75 of 212) of the patients. Of these, 29 (39%) were LTRs and 46 (61%) were non-LTRs. The overall response rate and median tumor shrinkage in the LTR group were significantly higher than those in the non-LTR group (76% versus 35%, p < 0.0001, and 66% versus 16%, p < 0.001, respectively). The groups had no significant difference in PD-L1 expression and serum drug concentration at 3- and 6-month post-treatment initiation. Conclusions: Significant tumor shrinkage was associated with a long-term response to an anti–PD-1 inhibitor. Nevertheless, the PD-L1 expression level and pharmacokinetic profile of the inhibitor could not be used to predict the durable response among the responders.

While studying superfluid He of 2.4 MPa in 97.5 %-porosity aerogel with NMR/MRI techniques, we find that the T is reduced when more than adequate amount of He, which covers the surface of silica strands, is introduced. For a sample, whose T is reduced to as low as 0.9 mK, we find that the spin diffusion coefficient in the normal phase is increased by a factor of 1.56 both in high temperature region, where He-He scattering dominates, and in low temperature region, where He-aerogel scattering dominates. This enhancement is attributed to a modification of Landau parameter $F_{0}^{a}$ from −0.757 to −0.62, which is a change towards less ferromagnetic direction. The modification of microscopic quantity could be explained if small amount of He has homogeneously mixed into liquid He in the aerogel. [ABSTRACT FROM AUTHOR]

Background: While obesity in midlife is a risk factor for dementia, several studies suggested that obesity also protected against dementia, hence so-called obesity paradox. The current study aims to address the relationship between apolipoprotein E ( APOE ) genotype and obesity in dementia., Methods: Clinical and neuropathological records of the National Alzheimer's Coordinating Center (NACC) in the USA, which longitudinally followed approximately 20 000 subjects with different cognitive statues, APOE genotype and obesity states, were reviewed., Results: Obesity was associated with cognitive decline in early elderly cognitively normal individuals without APOE4 , especially those with APOE2 . Neuropathological analyses adjusted for dementia status showed that APOE2 carriers tended to have more microinfarcts and haemorrhages due to obesity. On the other hand, obesity was associated with a lower frequency of dementia and less cognitive impairment in individuals with mild cognitive impairment or dementia. Such trends were particularly strong in APOE4 carriers. Obesity was associated with fewer Alzheimer's pathologies in individuals with dementia., Conclusions: Obesity may accelerate cognitive decline in middle to early elderly cognitive normal individuals without APOE4 likely by provoking vascular impairments. On the other hand, obesity may ease cognitive impairment in both individuals with dementia and individuals at the predementia stage, especially those with APOE4 , through protecting against Alzheimer's pathologies. These results support that APOE genotype modifies the obesity paradox in dementia., Competing Interests: Competing interests: GB is currently an employee of SciNeuro Pharmaceuticals. All other authors declare that they have no conflicts of interest with the content of this article., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

People who experience natural disasters have a high risk of developing cardiovascular diseases. We investigated the association between the extent of house collapse and urine sodium-to-potassium (UNa/K) ratio of 2011 Great East Japan Earthquake victims. We used the baseline survey data of the Tohoku Medical Megabank Project Community-Based Cohort Study of 29 542 individuals (aged 20-74 years) residing in the affected areas. The UNa/K ratio was calculated using spot urinary electrolyte values. Analysis of covariance was used to calculate the multivariate-adjusted geometric means of the UNa/K ratio in the following groups stratified according to the self-reported extent of house collapse: total collapse (TC), half collapse (HC), partial collapse (PC), and no damage (ND). Multivariable-adjusted odds ratios (ORs) for a high UNa/K ratio were calculated using logistic regression. The TC, HC, PC, and ND groups comprised 5 359 (18.1%), 3 576 (12.1%), 7 331 (24.8%), and 13 276 (44.9%) participants, respectively. The TC (3.33; 95% confidence interval [CI], 3.28-3.38), HC (3.37; 3.30-3.43), and PC (3.32; 3.28-3.37) groups had significantly higher multivariate-adjusted geometric means of the UNa/K ratio than the ND (3.24; 3.21-3.27) group. The multivariable-adjusted ORs (95% CIs) for a high UNa/K ratio in the TC, HC, and PC groups vs. the ND group were 1.07 (0.99-1.15), 1.20 (1.11-1.31), and 1.20 (1.12-1.28), respectively. Similar associations between house collapse and UNa/K ratio were observed for both sexes. We report that victims of a natural disaster tend to have a diet with high sodium-to-potassium ratio., (© 2023. The Author(s).)

Pulmonary venous return development establishes the fetal circulation and is critical for the formation of pulmonary circulation independent of systemic circulation at birth. Anomalous returns lead to inappropriate drainage of blood flow, sometimes resulting in neonatal cyanosis and cardiac failure. While many classical studies have discussed the anatomical features of the pulmonary venous system development, the cellular dynamics of the endothelia based on the molecular marker expression remain unknown. In the present study, we examined the expression of several endothelial markers during early pulmonary vascular system development of murine embryos. We show that Endomucin and CD31 are expressed early in endothelial cells of the splanchnic plexus, which is the precursor of the pulmonary vascular system. Three-dimensional analyses of the expression patterns revealed the spatiotemporal modification of the venous returns to systemic venous systems or sinoatrial canal during the formation of the pulmonary plexus. We herein report the results of spatiotemporal analyses of the early pulmonary venous system development with histochemistry as well as a delineation of the anatomical features of the tentative drainage pathways., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Social isolation and mental health issues have become a severe problem in disaster areas in the Great East Japan Earthquake. This study examined whether the combination of the house damage and social isolation or the combination of the death of family members and social isolation is associated with depressive symptoms among survivors using the baseline study data of the Tohoku Medical Megabank Project Community-Based Cohort Study (TMM CommCohort Study)., Methods: We used cross-sectional data from a baseline survey of 48,958 participants (18,423 males, 30,535 females; aged 60.1 ± 11.2 years) to examine the association between social isolation measured by the Lubben social network scale 6 (LSNS-6) and depressive symptoms measured by the Center for Epidemiological Studies-Depressive Scale (CES-D). The presence of social isolation and depressive symptoms was defined by an LSNS-6 score of < 12 and a CES-D score of ≥16, respectively. We performed a logistic regression analysis to determine the multivariable-adjusted odds ratio (95% confidence interval) [AOR (95% CI)] for depressive symptoms according to sex in the social isolation in comparison to without social isolation, and the associations of the combination of the house damage or the death of family members and social isolation and depressive symptoms., Results: Social isolation was significantly associated with depressive symptoms (males: OR = 1.87; 95% CI = 1.72-2.04, females: OR = 2.13; 95% CI = 2.00-2.26). Both males and females respondents with severe house damage and social isolation had a greater risk of depressive symptoms in comparison to those with an undamaged house and without social isolation (males: OR = 3.40; 95% CI = 2.73-4.24, females: OR = 2.92; 95% CI = 2.46-3.46). The risk of depressive symptoms was also higher in both males and females respondents with the death of family members and social isolation in comparison to those without the death of family members and without social isolation (males: OR = 2.18; 95% CI = 1.90-2.50, females: OR = 2.60; 95% CI = 2.35-2.88)., Conclusion: The findings suggested that a combination of social isolation and severe house damage and the death of family members caused by a large-scale natural disaster was associated with a higher risk of depressive symptoms although the interaction was not statistically significant.

The purpose of this study was to investigate the association between xanthine oxidoreductase (XOR) activity and a high risk of cardiovascular disease (CVD) in a general Japanese population. The Iwate Tohoku Medical Megabank Organization pooled individual participant data from a general population-based cohort study in Iwate prefecture. The cardiovascular risk was calculated using the Framingham Risk Score (FRS). A total of 1605 of the 1631 participants (98.4%) had detectable XOR activity. Multiple regression analysis demonstrated that XOR activity was independently associated with body mass index (β = 0.26, p < 0.001), diabetes (β = 0.09, p < 0.001), dyslipidemia (β = 0.08, p = 0.001), and uric acid (β = 0.13, p < 0.001). Multivariate analysis showed that the highest quartile of XOR activity was associated with a high risk for CVD (FRS ≥ 15) after adjustment for baseline characteristics (OR 2.93, 95% CI 1.16-7.40). The area under the receiver operating characteristic curves of the FRS with XOR activity was 0.81 ( p = 0.008). XOR activity is associated with a high risk for CVD, suggesting that high XOR activity may indicate cardiovascular risk in a general Japanese population.

Stem cells are maintained in specific niches that strictly regulate their proliferation and differentiation for proper tissue regeneration and renewal. Molecular oxygen (O 2 ) is an important component of the niche microenvironment, but little is known about how O 2 governs epithelial stem cell (ESC) behavior. Here, we demonstrate that O 2 plays a crucial role in regulating the proliferation of ESCs using the continuously growing mouse incisors. We have revealed that slow-cycling cells in the niche are maintained under relatively hypoxic conditions compared with actively proliferating cells, based on the blood vessel distribution and metabolic status. Mechanistically, we have demonstrated that, during hypoxia, HIF1α upregulation activates the RhoA signal, thereby promoting cortical actomyosin and stabilizing the adherens junction complex, including merlin. This leads to the cytoplasmic retention of YAP/TAZ to attenuate cell proliferation. These results shed light on the biological significance of blood-vessel geometry and the signaling mechanism through microenvironmental O 2 to orchestrate ESC behavior, providing a novel molecular basis for the microenvironmental O 2 -mediated stem cell regulation during tissue development and renewal., (© 2021. Published by The Company of Biologists Ltd.)

Background: We established a community-based cohort study to assess the long-term impact of the Great East Japan Earthquake on disaster victims and gene-environment interactions on the incidence of major diseases, such as cancer and cardiovascular diseases., Methods: We asked participants to join our cohort in the health check-up settings and assessment center based settings. Inclusion criteria were aged 20 years or over and living in Miyagi or Iwate Prefecture. We obtained information on lifestyle, effect of disaster, blood, and urine information (Type 1 survey), and some detailed measurements (Type 2 survey), such as carotid echography and calcaneal ultrasound bone mineral density. All participants agreed to measure genome information and to distribute their information widely., Results: As a result, 87,865 gave their informed consent to join our study. Participation rate at health check-up site was about 70%. The participants in the Type 1 survey were more likely to have psychological distress than those in the Type 2 survey, and women were more likely to have psychological distress than men. Additionally, coastal residents were more likely to have higher degrees of psychological distress than inland residents, regardless of sex., Conclusion: This cohort comprised a large sample size and it contains information on the natural disaster, genome information, and metabolome information. This cohort also had several detailed measurements. Using this cohort enabled us to clarify the long-term effect of the disaster and also to establish personalized prevention based on genome, metabolome, and other omics information.

Anterior segmental medullary arteries cause spinal cord infarction due to circulatory disturbance, but are difficult to identify in diagnostic images. This study investigated the arterial distribution from the cervical to lumbar segments of the dissecting spinal cord in 100 cadavers. The 488 arteries were distributed from C2 to L2, of which 252 arteries from C2 to C8 were slightly dominant on the right side, but 236 arteries from Th1 to L2 were obviously dominant on the left side. This change occurred at the C8 and Th1 segments. Of the 252 arteries, 37.30% (94 arteries) were divided into ascending and descending branches. Both branches formed loops by anastomosis with the anterior spinal arteries. The loops, called "insel", have an unclear distribution and form. We focused on the features of inseln and found 63 of them in the cervical spinal cord of 45 cadavers. Their numbers and forms differed depending on whether the 94 arteries were bilateral (type A) or unilateral (type B), but the long axis of the insel was limited to one cervical segment. 90.63% of type A were bilateral at the same level, and 70% of type B were on the right side. The former always formed the insel. Further, 94 arteries were distributed from C2 to C7, 82.98% of which were concentrated at C3-C5. Therefore, the arterial blood supply of the spinal cord may differ between the cervical spinal cord and the thoracolumbar cord.

Excessive sodium intake is a global risk factor for hypertension. Sodium effects on blood pressure vary from person to person; hence, high-risk group targeting based on personal genetic information can play a complementary role to ongoing population preventive approaches to reduce sodium consumption. To identify genetic factors that modulate sodium effects on blood pressure, we conducted a population-based genome-wide interaction analysis in 8,768 Japanese subjects, which was >3 times larger than a similar previous study. We tested 7,135,436 polymorphisms in the discovery cohort, and loci that met suggestive significance were further examined in an independent replication cohort. We found that an interaction between a novel 3'-BCL11B gene desert locus and daily sodium consumption was significantly associated with systolic blood pressure in both discovery and replication cohorts under the recessive model. Further statistical analysis of rs8022678, the sentinel variant of the 3'-BCL11B gene desert locus, showed that differences in mean systolic blood pressure between high and low sodium consumption subgroups were 5.9 mm Hg (P = 8.8 × 10 -12 ) in rs8022678 A carriers and -0.3 mm Hg (P = 0.27) in rs8022678 A non-carriers, suggesting that the rs8022678 genotype can classify persons into sodium-sensitive (A carriers) and sodium-insensitive (A non-carriers) subgroups. Our results implied that rs8022678 A carriers may receive a greater benefit from sodium-lowering interventions than non-carriers.

Tyrosine sulfation is a crucial post-translational modification for certain antibodies that neutralize HIV. One of the most neutralizing sulfated anti-HIV antibodies, E51, contains a region in its V H CDR3 loop with five tyrosine (Tyr) residues, which are hypothesized to be partially or fully sulfated to bind to HIV's gp120 coat protein. However, the gp120-binding contribution of each sulfate or more complex sulfation patterns is unknown. In addition, natural sulfation of Tyr-rich loops usually yields a mixture of multiply sulfated products, complicating attempts to dissect the function of individual E51 sulfoforms with unique sulfation patterns. Here, we use an upgraded expanded genetic code for sulfotyrosine (sY) to express homogeneous E51 sulfoforms containing up to five sulfates. Through characterization of the 32 possible sulfoforms of E51, we show that only a subset of E51 sulfoforms with two, three, or four sYs bind to gp120 with potency similar to that of post-translationally sulfated E51, which we find is a mixture of sulfoforms. We show that sulfation of Tyr100i is necessary for gp120 binding whereas sulfation of Tyr100n is detrimental to binding. These results reveal that gp120 binding by E51 requires very specific sulfation patterns and should aid in the further design of sulfated E51-based peptides and immunoadhesins against HIV.

We launched an integrative multi-omics database, iMETHYL (http://imethyl.iwate-megabank.org). iMETHYL provides whole-DNA methylation (~24 million autosomal CpG sites), whole-genome (~9 million single-nucleotide variants), and whole-transcriptome (>14 000 genes) data for CD4 + T-lymphocytes, monocytes, and neutrophils collected from approximately 100 subjects. These data were obtained from whole-genome bisulfite sequencing, whole-genome sequencing, and whole-transcriptome sequencing, making iMETHYL a comprehensive database., Competing Interests: The authors declare no conflict of interest.

Glycated haemoglobin (HbA 1c ) is widely used as a biomarker for the diagnosis of diabetes, for population-level screening, and for monitoring the glycaemic status during medical treatment. Although the heritability of HbA 1c has been estimated at ~55-75%, a much smaller proportion of phenotypic variance is explained by the HbA 1c -associated variants identified so far. To search for novel loci influencing the HbA 1c levels, we conducted a genome-wide meta-analysis of 2 non-diabetic Japanese populations (n = 7,704 subjects in total). We identified 2 novel loci that achieved genome-wide significance: TMC6-TMC8 (P = 5.3 × 10 -20 ) and SIX3-SIX2 (P = 8.6 × 10 -9 ). Data from the largest-scale European GWAS conducted for HbA 1c supported an association between the novel TMC6-TMC8 locus and HbA 1c (P = 2.7 × 10 -3 ). The association analysis with glycated albumin and glycation gap conducted using our Japanese population indicated that the TMC6-TMC8 and SIX3-SIX2 loci may influence the HbA 1c level through non-glycaemic and glycaemic pathways, respectively. In addition, the pathway-based analysis suggested that the linoleic acid metabolic and 14-3-3-mediated signalling pathways were associated with HbA 1c . These findings provide novel insights into the molecular mechanisms that modulate the HbA 1c level in non-diabetic subjects.

Ocular vasculature consists of the central retinal and ciliary vascular systems, which are essential to maintaining visual function. Many researchers have attempted to determine their origins and development; however, the detailed, stepwise process of ocular vasculature formation has not been established. In zebrafish, two angioblast clusters, the rostral and midbrain organizing centers, form almost all of the cranial vasculature, including the ocular vasculature, and these are from where the cerebral arterial and venous angioblast clusters, respectively, differentiate. In this study, we first determined the anatomical architecture of the primary ocular vasculature and then followed its path from the two cerebral angioblast clusters using a time-lapse analysis of living Tg(flk1:EGFP)k7 zebrafish embryos, in which the endothelial cells specifically expressed enhanced green fluorescent protein. We succeeded in capturing images of the primary ocular vasculature formation and were able to determine the origin of each ocular vessel. In zebrafish, the hyaloid and ciliary arterial systems first organized independently, and then anastomosed via the inner optic circle on the surface of the lens by the lateral transfer of the optic vein. Finally, the choroidal vascular plexus formed around the eyeball to complete the primary ocular vasculature formation. To our knowledge, this study is the first to report successful capture of circular integration of the optic artery and vein, lateral transfer of the optic vein to integrate the hyaloidal and superficial ocular vasculatures, and formation of the choroidal vascular plexus. Furthermore, this new morphological information enables us to assess the entire process of the primary ocular vasculature formation, which will be useful for its precise understanding.

Epigenome-wide association studies, which searches for blood-based DNA methylation signatures associated with environmental exposures and/or disease susceptibilities, is a promising approach to a better understanding of the molecular aetiology of common diseases. To carry out large-scale epigenome-wide association studies while avoiding false negative detection, an efficient strategy to determine target CpG sites for microarray-based or sequencing-based DNA methylation profiling is essentially needed. Here, we propose and validate a hypothesis that a strategy focusing on CpG sites with high DNA methylation level variability may attain an improved efficacy. Through whole-genome bisulfite sequencing of purified blood cells collected from > 100 apparently healthy subjects, we identified ~2.0 million inter-individually variable CpG sites as potential targets. The efficacy of our strategy was estimated to be 3.7-fold higher than that of the most frequently used strategy. Our catalogue of inter-individually variable CpG sites will accelerate the discovery of clinically relevant DNA methylation biomarkers in future epigenome-wide association studies., Competing Interests: The authors declare no competing interests.