Adaptive thermogenesis is essential for survival, and therefore is tightly regulated by a central neural circuit. Here, we show that microRNA (miR)-33 in the brain is indispensable for adaptive ...thermogenesis. Cold stress increases miR-33 levels in the hypothalamus and miR-33
mice are unable to maintain body temperature in cold environments due to reduced sympathetic nerve activity and impaired brown adipose tissue (BAT) thermogenesis. Analysis of miR-33
dopamine-β-hydroxylase (DBH)-Cre mice indicates the importance of miR-33 in Dbh-positive cells. Mechanistically, miR-33 deficiency upregulates gamma-aminobutyric acid (GABA)
receptor subunit genes such as Gabrb2 and Gabra4. Knock-down of these genes in Dbh-positive neurons rescues the impaired cold-induced thermogenesis in miR-33
DBH-Cre mice. Conversely, increased gene dosage of miR-33 in mice enhances thermogenesis. Thus, miR-33 in the brain contributes to maintenance of BAT thermogenesis and whole-body metabolism via enhanced sympathetic nerve tone through suppressing GABAergic inhibitory neurotransmission. This miR-33-mediated neural mechanism may serve as a physiological adaptive defense mechanism for several stresses including cold stress.
Background Micro RNA (miR)-33 targets cholesterol transporter ATP -binding cassette protein A1 and other antiatherogenic targets and contributes to atherogenic progression. Its inhibition or deletion ...is known to result in the amelioration of atherosclerosis in mice. However, mice lack the other member of the miR-33 family, miR-33b, which exists in humans and other large mammals. Thus, precise evaluation and comparison of the responsibilities of these 2 miRs during the progression of atherosclerosis has not been reported, although they are essential. Methods and Results In this study, we performed a comprehensive analysis of the difference between the function of miR-33a and miR-33b using genetically modified mice. We generated 4 strains with or without miR-33a and miR-33b. Comparison between mice with only miR-33a (wild-type mice) and mice with only miR-33b (miR-33a
/miR-33b
) revealed the dominant expression of miR-33b in the liver. To evaluate the whole body atherogenic potency of miR-33a and miR-33b, we developed apolipoprotein E-deficient/miR-33a
/miR-33b
mice and apolipoprotein E-deficient/miR-33a
/miR-33b
mice. With a high-fat and high-cholesterol diet, the apolipoprotein E-deficient/miR-33a
/miR-33b
mice developed increased atherosclerotic plaque versus apolipoprotein E-deficient/miR-33a
/miR-33b
mice, in line with the predominant expression of miR-33b in the liver and worsened serum cholesterol profile. By contrast, a bone marrow transplantation study showed no significant difference, which was consistent with the relevant expression levels of miR-33a and miR-33b in bone marrow cells. Conclusions The miR-33 family exhibits differences in distribution and regulation and particularly in the progression of atherosclerosis; miR-33b would be more potent than miR-33a.
Recent high-throughput approaches have revealed a vast number of transcripts with unknown functions. Many of these transcripts are long noncoding RNAs (lncRNAs), and intergenic region-derived lncRNAs ...are classified as long intergenic noncoding RNAs (lincRNAs). Although Myosin heavy chain 6 (Myh6) encoding primary contractile protein is down-regulated in stressed hearts, the underlying mechanisms are not fully clarified especially in terms of lincRNAs. Here, we screen upregulated lincRNAs in pressure overloaded hearts and identify a muscle-abundant lincRNA termed Lionheart. Compared with controls, deletion of the Lionheart in mice leads to decreased systolic function and a reduction in MYH6 protein levels following pressure overload. We reveal decreased MYH6 results from an interaction between Lionheart and Purine-rich element-binding protein A after pressure overload. Furthermore, human LIONHEART levels in left ventricular biopsy specimens positively correlate with cardiac systolic function. Our results demonstrate Lionheart plays a pivotal role in cardiac remodeling via regulation of MYH6.
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•KUS121 was developed to selectively inhibit the adenosine triphosphatase activity of valosin-containing protein without affecting other cellular functions of valosin-containing ...protein.•KUS121 preserved adenosine triphosphate levels, reduced endoplasmic reticulum stress, and suppressed cell death in H9C2 rat cardiomyoblast cells, treated with tunicamycin or hydrogen peroxide, or cultured in glucose-free medium.•In murine ischemia and reperfusion injury models, KUS121 treatment after reperfusion attenuated the infarcted size and preserves cardiac function by maintaining adenosine triphosphate levels and reducing ER stress.•In porcine ischemia and reperfusion injury models, intracoronary administration of KUS121 also attenuated the infarcted area in a dose-dependent manner.•These results indicated that KUS121 is a promising novel therapeutic agent for myocardial infarction.
No effective treatment is yet available to reduce infarct size and improve clinical outcomes after acute myocardial infarction by enhancing early reperfusion therapy using primary percutaneous coronary intervention. The study showed that Kyoto University Substance 121 (KUS121) reduced endoplasmic reticulum stress, maintained adenosine triphosphate levels, and ameliorated the infarct size in a murine cardiac ischemia and reperfusion injury model. The study confirmed the cardioprotective effect of KUS121 in a porcine ischemia and reperfusion injury model. These findings confirmed that KUS121 is a promising novel therapeutic agent for myocardial infarction in conjunction with primary percutaneous coronary intervention.
The Hippo signaling pathway is involved in the pathophysiology of various cardiovascular diseases. Yes‐associated protein (YAP) and transcriptional enhancer activator domain (TEAD) transcriptional ...factors, the main transcriptional complex of the Hippo pathway, were recently identified as modulators of phenotypic switching of vascular smooth muscle cells (VSMCs). However, the intrinsic regulator of YAP/TEAD‐mediated gene expressions involved in vascular pathophysiology remains to be elucidated. Here, we identified Homeobox A4 (HOXA4) as a potent repressor of YAP/TEAD transcriptional activity using lentiviral shRNA screen. Mechanistically, HOXA4 interacts with TEADs and attenuates YAP/TEAD‐mediated transcription by competing with YAP for TEAD binding. We also clarified that the expression of HOXA4 is relatively abundant in the vasculature, especially in VSMCs. In vitro experiments in human VSMCs showed HOXA4 maintains the differentiation state of VSMCs via inhibition of YAP/TEAD‐induced phenotypic switching. We generated Hoxa4‐deficient mice and confirmed the downregulation of smooth muscle‐specific contractile genes and the exacerbation of vascular remodeling after carotid artery ligation in vivo. Our results demonstrate that HOXA4 is a repressor of VSMC phenotypic switching by inhibiting YAP/TEAD‐mediated transcription.
Synopsis
HOXA4 suppresses vascular smooth muscle cell phenotypic switching and vascular remodeling by inhibiting YAP/TEAD‐mediated transcription.
Unbiased shRNA screen identified HOXA4 as a repressor of YAP/TEAD transcriptional activity.
HOXA4 competes with YAP for binding to TEADs to preserve VSMC differentiation.
Hoxa4‐deficient mice showed exacerbated neointima formation after carotid artery ligation.
HOXA4 suppresses vascular smooth muscle cell phenotypic switching and vascular remodeling by inhibiting YAP/TEAD‐mediated transcription.
Backgrounds
This study aimed to examine the incidence of abusive head trauma (AHT) admissions by calculating admission rates of AHT cases among infants <12 months old in a population‐based sample in ...Chiba city, Chiba prefecture, Japan.
Methods
We retrospectively examined medical records of infants admitted to all pediatric secondary and tertiary hospitals in Chiba city between 2011 and 2015. We collected 13 AHT cases, as assessed by hospital‐based multidisciplinary child protection teams. One experienced pediatric radiologist and two pediatricians evaluated the case histories and computed tomography images of cases to evaluate them clinically as “strongly” or “moderately” suspected AHT.
Results
The overall incidence per 100 000 person‐years was 34.5 cases (95% confidence interval (CI): 18.4–59.1), of which 13.3 (95% CI: 4.3–31.0), were strongly suspected to be AHT and 21.3 (95% CI: 9.2–41.9) were moderately suspected. There were no statistical differences in computed tomography findings between severe and moderately suspected AHT.
Conclusions
The incidence of hospitalization of infants with AHT was similar to that reported in population‐based studies in other countries.
Signet‐ring cell/histiocytoid carcinoma (SRCHC) is a very rare skin appendage cancer, with an extremely rare occurrence in the axilla. This study describes the 11th case of SRCHC occurring in the ...axilla and reports the first gene alteration analysis performed for SRCHC. An 85‐year‐old Japanese male presented with a tumor in the left axilla. Biopsy of the axilla nodule demonstrated diffuse proliferation of histiocytoid neoplastic cells and signet‐ring cells in the dermis and subcutis. Immunohistochemistry revealed loss of E‐cadherin expression in these neoplastic cells. Accordingly, SRCHC of the axilla was diagnosed. Genetic analysis using next‐generation sequencing demonstrated missense mutation of PIK3CA (c1633G>A, pGlu545Lys) and no CDH1 gene mutation.SRCHC of the axilla is considered equivalent to a histiocytoid variant of invasive lobular breast carcinoma. The present SRCHC case demonstrated a pathogenic PIK3CA mutation, which is observed in invasive lobular carcinoma. Additional large case studies are required to clarify the clinicopathological features and gene alterations in SRCHC of the axilla.
The functionalization of single‐walled carbon nanotubes (SWNTs) is an effective method for controlling a local band gap, resulting in photoluminescence (PL) in the near‐infrared region. Herein, SWNTs ...were functionalized using a series of bromoalkanes and dibromoalkanes to evaluate the effects of their length on the nanotube PL properties. When bromoalkanes (CnH2n+1Br) or dibromoalkanes (CnH2nBr2) with tether lengths of six or more were utilized for six different semiconducting SWNTs, the obtained SWNT adducts exhibited two new PL peaks, whereas dibromoalkanes with tether lengths of 3–5 (CnH2nBr2: n=3–5) produced single peaks. Combined with theoretical calculations, the results suggested that the tether length of reagents changes the formation mechanism of functionalized adducts, that is, CnH2nBr2 (n=3–5) tends to result in kinetic products.
Near‐infrared (NIR) light controlled by tether length: New insights into controlling the photoluminescence (PL) properties of nanotubes were obtained. The tether length of alkylation reagents showed significant selectivity toward controlling the NIR PL wavelength of single‐walled carbon nanotubes.
Inflammatory endobronchial polyps (IEPs) are rare, benign bronchial tumors posing diagnostic and therapeutic challenges owing to limited data. A 55-year-old man, receiving treatment for allergic ...bronchopulmonary aspergillosis, presented with a one-week history of fever and purulent sputum. Diagnosed with pneumonia, he received antimicrobial treatment. However, because of persistent symptoms, an endobronchial tumor was suspected on computed tomography. IEP was confirmed through flexible bronchoscopy with forceps biopsy, and polyp removal improved symptoms, lung function, and imaging.
•IEPs are rare benign bronchial tumors caused by chronic respiratory diseases.•The appropriate treatment of IEPs should be selected considering comorbidities.•Monitoring lung function is crucial in IEPs patients with chronic lung diseases.•Data on the recurrence of IEPs are scarce owning to the rarity of this disease.
In patients with active ulcerative colitis (UC), adsorptive granulocyte/monocyte apheresis (GMA) is expected to promote remission. We conducted a retrospective cohort study to evaluate the efficacy ...and safety of GMA in patients with active UC. Twenty‐one UC patients including five pregnant or lactating mothers and four elderly patients (aged >60 years) received up to 10 GMA sessions. UC severity was evaluated at baseline and after GMA therapy according to Lichtiger's Clinical Activity Index (CAI). We defined clinical remission as CAI ≤4. Overall, the median CAI score after GMA therapy had decreased from 9 to 4 (P < 0.001). The clinical remission rate was 62%, but in the elderly and pregnant or lactating mothers, the remission rates were 100% and 60%, respectively. No severe adverse effects were seen in this study. Our results may support GMA as an effective and safe treatment for active UC patients, including elderly patients and pregnant cases.
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