In an aging society, it is important to visualize the conditions of people living with diseases or disabilities, such as frailty and sarcopenia, and determine the environmental and genetic factors ...underlying such conditions. Atherosclerosis and arterial stiffness are key conditions between these factors and noncommunicable diseases. In 2014, we launched a population-based prospective open-cohort study, the Nagasaki Islands Study (NaIS), which was conducted in Goto City, located in the remote islands of Nagasaki Prefecture, Japan, mostly involving middle-aged and older residents. We conducted our own health checkups along with the annual standardized checkups organized by the municipality; recruited study participants; and started to follow them for vital status (death), migration, and occurrence of diseases, such as myocardial infarction, stroke, fracture, and human T-cell leukemia virus type 1 (HTLV-1)-associated uveitis. Our checkups were conducted as baseline surveys in different areas of Goto City during the fiscal years 2014–2016, secondary surveys during 2017–2019, and tertiary surveys since 2021, consisting of medical interviews, physical examinations, blood and urine tests, body composition measurements, osteoporosis screening, arterial stiffness measurements, carotid ultrasonography, and dental examination. A total of 4,957 residents participated in either the baseline or secondary surveys and were followed; 3,594 and 3,364 residents (aged 27–96 and 28–98 years) participated in the baseline and secondary surveys, respectively. In conclusion, the NaIS has been undertaken to reveal the influence of aging and risk factors of noncommunicable diseases and disabilities, with an aim to contribute towards better healthcare in the future.
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FFLJ, NUK, ODKLJ, UL, UM, UPUK
Liver fibrosis is a major consequence of chronic liver disease, where excess extracellular matrix is deposited, due caused by the activation of hepatic stellate cells (HSCs). The suppression of ...collagen production in HSCs is therefore regarded as a therapeutic target of liver fibrosis. The present study investigated effects of harmine, which is a β-carboline alkaloid and known as an inhibitor of dual-specificity tyrosine-regulated kinases (DYRKs), on the production of collagen in HSCs. LX-2 cells, a human HSC cell line, were treated with harmine (0–10 μM) for 48 h in the presence or absence of TGF-β1 (5 ng/ml). The expression of collagen type I α1 (COL1A1) and DYRK isoforms was investigated by Western blotting, quantitative RT-PCR, or immunofluorescence. The influence of knockdown of each DYRK isoform on the COL1A1 expression was further investigated. The expression of COL1A1 was markedly increased by treating with TGF-β1 for 48 h in LX-2 cells. Harmine (10 μM) significantly inhibited the increased expression of COL1A1. LX-2 cells expressed mRNAs of DYRK1A, DYRK1B, DYRK2, and DYRK4, although the expression of DYRK4 was much lower than the others. Knockdown of DYRK1B, but not DYRK1A or DYRK2, with siRNA significantly suppressed TGF-β1-induced increase in COL1A1 expression. These results suggest that harmine suppresses COL1A1 expression via inhibiting DYRK1B in HSCs and therefore might be effective for the treatment of liver fibrosis.
•Harmine suppressed the production of collagen induced by TGF-β1 in LX-2 cells.•LX-2 cells expressed mRNAs of DYRK1A, DYRK1B, and DYRK2.•DYRK1B knockdown suppressed the production of collagen 1A1 induced by TGF-β1 in LX-2 cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
DIAPH1 encodes human DIA1, a formin protein that elongates unbranched actin. The c.3634+1G>T DIAPH1 mutation causes autosomal dominant nonsyndromic sensorineural hearing loss, DFNA1, characterized by ...progressive deafness starting in childhood. The mutation occurs near the C‐terminus of the diaphanous autoregulatory domain (DAD) of DIA1, which interacts with its N‐terminal diaphanous inhibitory domain (DID), and may engender constitutive activation of DIA1. However, the underlying pathogenesis that causes DFNA1 is unclear. We describe a novel patient‐derived DIAPH1 mutation (c.3610C>T) in two unrelated families, which results in early termination prior to a basic amino acid motif (RRKR1204–1207) at the DAD C‐terminus. The mutant DIA1(R1204X) disrupted the autoinhibitory DID‐DAD interaction and was constitutively active. This unscheduled activity caused increased rates of directional actin polymerization movement and induced formation of elongated microvilli. Mice expressing FLAG‐tagged DIA1(R1204X) experienced progressive deafness and hair cell loss at the basal turn and had various morphological abnormalities in stereocilia (short, fused, elongated, sparse). Thus, the basic region of the DAD mediates DIA1 autoinhibition; disruption of the DID‐DAD interaction and consequent activation of DIA1(R1204X) causes DFNA1.
Synopsis
A novel clinical DIAPH1 mutation (c.3610C>T) is found in two unrelated families, resulting in a constitutively active DIA1. Patients and mice expressing the DIA1(R1204X) protein show progressive hearing loss beginning in the high‐frequency range and mimicking a novel DFNA1 subtype.
A novel DIAPH1 mutation results in early termination of DIA1 at the diaphanous autoregulatory domain (DAD), R1204X.
DIA1(R1204X) disrupts the diaphanous inhibitory domain (DID)–DAD interaction and is constitutively active.
Mice expressing DIA1(R1204X) show progressive deafness and OHC loss at the basal turn.
DIA1(R1204X) causes a novel DFNA1 subtype showing progressive hearing loss beginning in the high‐frequency range and in childhood.
A novel clinical DIAPH1 mutation (c.3610C>T) is found in two unrelated families, resulting in a constitutively active DIA1. Patients and mice expressing the DIA1(R1204X) protein show progressive hearing loss beginning in the high‐frequency range and mimicking a novel DFNA1 subtype.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
An enhanced vasoconstrictor activity of cutaneous arteries participates in the reduction of skin blood flow induced by cooling stimulation. Raynaud's phenomenon, which is characterized by intense ...cooling-induced constriction of cutaneous arteries, is more common in women during the period from menarche to menopause. We thus investigated the effect of 17β-estradiol (E2) on cooling-induced reduction of plantar skin blood flow (PSBF) in mouse in vivo. Ovariectomized female ddY mice, anaesthetized with pentobarbital, were treated with tetrodotoxin for eliminating the sympathetic nerve tone and artificially ventilated. The PSBF was measured by laser Doppler flowmetry. Cooling air temperature around the foot from 25 to 20, 15, or 10°C decreased the PSBF in a temperature-dependent manner, which was suppressed by the specific α2C-adrenoceptor antagonist MK-912. When E2 was intravenously administered as a bolus followed by a constant infusion for 10min just before the cooling stimulation, the cooling-induced reduction of PSBF was facilitated by E2 in a dose-dependent manner. The facilitatory effect of E2 was not induced after the treatment with MK-912. Similar facilitatory effect was induced by an intravenous application of G-1, an agonist of G protein-coupled estrogen receptor (GPER, also termed GPR30). Moreover, the facilitatory effect of E2 was abolished by the GPER antagonist G15. These results suggest that acute administration of E2 leads to the facilitation of cooling-induced, α2C-adrenoceptor-mediated reduction of skin blood flow via the activation of the non-genomic estrogen receptor GPER.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Pendred syndrome (PDS)/DFNB 4 is a disorder with fluctuating and progressive hearing loss, vertigo, and thyroid goiter. We identified pathophysiology of a neurodegenerative disorder in PDS patient ...derived cochlear cells that were induced via induced pluripotent stem cells and found sirolimus, an mTOR inhibitor, as an inhibitor of cell death with the minimum effective concentration less than 1/10 of the approved dose for other diseases. Given that there is no rational standard therapy for PDS, we planned a study to examine effects of low dose oral administration of sirolimus for the fluctuating and progressive hearing loss, and the balance disorder of PDS by daily monitor of their audio-vestibular symptoms.
This is a phase I/IIa double blind parallel-group single institute trial in patient with PDS/DFNB4. Sixteen of outpatients with fluctuating hearing diagnosed as PDS in SLC26A4 genetic testing aged in between 7 and 50 years old at the time of consent are given either placebo or sirolimus tablet (NPC-12T). In NPC-12T placebo arm, placebo will be given for 36 weeks; in active substance arm, placebo will be given for 12 weeks and the NPC-12T for 24 weeks. Primary endpoints are safety and tolerability. The number of occurrences and types of adverse events and of side effects will be sorted by clinical symptoms and by abnormal change of clinical test results. A 2-sided 95% confidence interval of the incidence rate by respective dosing arms will be calculated using the Clopper-Pearson method. Clinical effects on audio-vestibular tests performed daily and precise physiological test at each visit will also be examined as secondary and expiratory endpoints.
JMA-IIA00361; Pre-results.
Our previous studies have shown that α1-adrenoceptors, in addition to α2-adrenoceptors, are involved in enhanced contraction of cutaneous blood vessels during cooling. The present study aimed to ...elucidate the mechanism underlying it. In tail and iliac arteries isolated from rats, isometric contraction was measured using a myograph and the phosphorylation level of myosin phosphatase target subunit 1 (MYPT1) was quantified by western blotting. The phenylephrine-induced contraction was enhanced by cooling to 24 °C in tail arteries, but was suppressed in iliac arteries. Endothelium denudation or treatment with iberiotoxin enhanced the phenylephrine-induced contraction in tail arteries at 37 °C; however, neither affected the contraction at 24 °C. The phenylephrine-induced contraction at 37 °C was largely suppressed by nifedipine in iliac arteries, but only slightly in tail arteries. The Rho kinase inhibitor H-1152 largely suppressed the phenylephrine-induced contraction at 24 °C, but only slightly at 37 °C, in both arteries. The phosphorylation level of MYPT1 at Thr855 in tail arteries was increased by the cooling. Taken together, these results suggest the following mechanism in regard to cooling-induced enhancement of α1-adrenoceptor-mediated contraction in tail arteries: Cooling enhances the contraction of tail arteries via α1-adrenoceptor stimulation by reducing endothelium-dependent, large-conductance Ca2+-activated K+ channel-mediated relaxation and by inducing Rho kinase-mediated Ca2+ sensitization, although the latter occurs even in iliac arteries. A smaller contribution of voltage-dependent Ca2+ channels, which are largely suppressed by cooling, to α1-adrenoceptor-mediated contraction in tail arteries seems to be more crucially involved in the appearance of the enhanced contractile response to cooling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
This exploratory study compared the inhibition of bone erosion progression in rheumatoid arthritis (RA) patients treated with a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) ...plus denosumab versus csDMARD therapy alone and investigated the effects of denosumab on bone micro-architecture and other bone-related parameters using high-resolution peripheral quantitative computed tomography (HR-pQCT).
In this open-label, randomized, parallel-group study, patients with RA undergoing treatment with a csDMARD were randomly assigned (1:1) to continue csDMARD therapy alone or to continue csDMARDs with denosumab (60-mg subcutaneous injection once every 6 months) for 12 months. The primary endpoint was the change from baseline in the depth of bone erosion, measured by HR-pQCT, in the second and third metacarpal heads at 6 months after starting treatment. Exploratory endpoints were also evaluated, and adverse events (AEs) were monitored for safety.
In total, 46 patients were enrolled, and 43 were included in the full analysis set (csDMARDs plus denosumab, N = 21; csDMARD therapy alone, N = 22). Most patients were female (88.4%), and the mean age was 65.3 years. The adjusted mean (95% confidence interval) change from baseline in the depth of bone erosion, measured by HR-pQCT, in the 2-3 metacarpal heads at 6 months was - 0.57 mm (- 1.52, 0.39 mm) in the csDMARDs plus denosumab group vs - 0.22 mm (- 0.97, 0.53 mm) in the csDMARD therapy alone group (between-group difference: - 0.35 mm - 1.00, 0.31; P = 0.2716). Similar results were shown for the adjusted mean between-group difference in the width and volume of bone erosion of the 2-3 metacarpal heads. Significant improvements in bone micro-architecture parameters were shown. The incidence of AEs and serious AEs was similar between the csDMARDs plus denosumab and the csDMARD therapy alone groups (AEs: 52.2% vs 56.5%; serious AEs: 4.3% vs 8.7%).
Although the addition of denosumab to csDMARDs did not find statistically significant improvements in bone erosion after 6 months of treatment, numerical improvements in these parameters suggest that the addition of denosumab to csDMARDs may be effective in inhibiting the progression of bone erosion and improving bone micro-architecture.
University Hospital Medical Information Network Clinical Trials Registry, UMIN000030575. Japan Registry for Clinical Trials, jRCTs071180018.
Ultrafast processes can now be studied with the combined atomic spatial resolution of diffraction methods and the temporal resolution of femtosecond optical spectroscopy by using femtosecond pulses ...of electrons or hard X-rays as structural probes. However, it is challenging to apply these methods to organic materials, which have weak scattering centres, thermal lability, and poor heat conduction. These characteristics mean that the source needs to be extremely bright to enable us to obtain high-quality diffraction data before cumulative heating effects from the laser excitation either degrade the sample or mask the structural dynamics. Here we show that a recently developed, ultrabright femtosecond electron source makes it possible to monitor the molecular motions in the organic salt (EDO-TTF)2PF6 as it undergoes its photo-induced insulator-to-metal phase transition. After the ultrafast laser excitation, we record time-delayed diffraction patterns that allow us to identify hundreds of Bragg reflections with which to map the structural evolution of the system. The data and supporting model calculations indicate the formation of a transient intermediate structure in the early stage of charge delocalization (less than five picoseconds), and reveal that the molecular motions driving its formation are distinct from those that, assisted by thermal relaxation, convert the system into a metallic state on the hundred-picosecond timescale. These findings establish the potential of ultrabright femtosecond electron sources for probing the primary processes governing structural dynamics with atomic resolution in labile systems relevant to chemistry and biology.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Reduced skin blood flow has been reported in neuropathic pain patients as well as various peripheral neuropathic pain model animals. We have previously shown that vasodilators, which improves reduced ...skin blood flow, correlatively alleviate neuropathic pain in chronic constriction injury (CCI) mice, a model of neuropathic pain from peripheral nerve injury. Here, we sought to elucidate the mechanism underlying the reduced skin blood flow in CCI rats. The skin blood flow of the ipsilateral plantar arteries was significantly reduced compared to that of the contralateral ones 4 weeks after loose ligation of the sciatic nerve. The contraction induced by noradrenaline, serotonin, and U46619, a thromboxane receptor agonist, in the isolated ipsilateral plantar arteries was significantly enhanced compared to that in the contralateral ones. KB-R7943, a Na+/Ca2+ exchanger (NCX) inhibitor, shifted the concentration-response curves of noradrenaline to the left in the contralateral arteries but had no effect on the ipsilateral side. There was no significant difference in concentration-response curves of noradrenaline between the ipsilateral and contralateral arteries in the presence of KB-R7943. Amiloride, a non-specific inhibitor of Na+ channels and transporters, comparably shifted concentration-response curves of noradrenaline to the left in both the contralateral and ipsilateral arteries. One hundred nM of noradrenaline induced intracellular Ca2+ elevation in the ipsilateral arteries, which was significantly larger than that induced by 300-nM noradrenaline in the contralateral arteries. These results suggest that reduced peripheral blood flow after nerve injury is due to Na+-dependent inactivation of NCX in the ipsilateral plantar arteries.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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