Introduction
Untreated nonalcoholic fatty liver may progress to nonalcoholic steatohepatitis (NASH) and cirrhosis and induce hepatocellular carcinoma and liver failure. Type 2 diabetes mellitus ...(T2DM), often complicated with nonalcoholic fatty liver disease (NAFLD), is a driver of NAFLD progression. Thus, efficacious treatment strategies for patients with coexisting NAFLD and T2DM are important for preventing NAFLD progression. Although previous studies have demonstrated that either sodium-glucose transporter 2 inhibitors (SGLT2is) or glucagon-like peptide 1 receptor agonists (GLP-1 RAs) benefit NASH patients with T2DM, the rate of NASH resolution has not sufficiently improved. Therefore, we developed a protocol for a randomized controlled trial to examine whether the addition of an SGLT2i to the treatment regimen of patients receving a GLP-1 RA (combination therapy), within the therapeutic dose range for T2DM, increases the rate of NASH resolution in patients with coexisting NASH and T2DM.
Methods
This open-label, randomized, parallel-group study commenced in June 2021, will conclude recruitment in May 2023, and will end by March 2025. Sixty patients with NASH complicated by T2DM are enrolled at the Ehime University Hospital in Toon, Japan. Participants will be randomized into: (1) an intervention group receiving combination therapy with the SGLT2i luseogliflozin 2.5 mg, once daily (Taisho Pharmaceutical, Tokyo, Japan) and the GLP-1 RA semaglutide 0.5 mg, once per week (Novonordisk, Copenhagen, Denmark); and (2) a control group receiving monotherapy with the GLP-1 analog semaglutide. The primary endpoints, which will be ascertained by liver biopsy, are: (1) NASH resolution rate from baseline without worsening of liver fibrosis after 52 weeks of intervention; (2) rate of improvement from baseline of at least 1 point in the NAFLD activity score without worsening of liver fibrosis after 52 weeks of intervention; and (3) rate of improvement from baseline of at least one fibrosis stage without worsening of NASH after 52 weeks of intervention.
Trial Registration
University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR) number: UMIN000045003. Japan Registry of Clinical Trials registration number: jRCTs061210009.
•Proteomics reveals genetic background as the highest source of variability in iPSC(-derivatives).•Proteins responsible for variability in iPSC derivatives vary across culturing period and ...donors.•Increased statistical power results from including more independent donors.
The use of induced pluripotent stem cells (iPSC) to model human complex diseases is gaining popularity as it allows investigation of human cells that are otherwise sparsely available. However, due to its laborious and cost intensive nature, iPSC research is often plagued by limited sample size and putative large variability between clones, decreasing statistical power for detecting experimental effects. Here, we investigate the source and magnitude of variability in the proteome of parallel differentiated astrocytes using mass spectrometry. We compare three possible sources of variability: inter-donor variability, inter- and intra-clonal variability, at different stages of maturation. We show that the interclonal variability is significantly smaller than the inter-donor variability, and that including more donors has a much larger influence on statistical power than adding more clones per donor. Our results provide insight into the sources of variability at protein level between iPSC samples derived in parallel and will aid in optimizing iPSC studies.
Abstract Objective Monosomy 1p36 syndrome is the most commonly observed subtelomeric deletion syndrome. Patients with this syndrome typically have common clinical features, such as intellectual ...disability, epilepsy, and characteristic craniofacial features. Method In cooperation with academic societies, we analyzed the genomic copy number aberrations using chromosomal microarray testing. Finally, the genotype–phenotype correlation among them was examined. Results We obtained clinical information of 86 patients who had been diagnosed with chromosomal deletions in the 1p36 region. Among them, blood samples were obtained from 50 patients (15 males and 35 females). The precise deletion regions were successfully genotyped. There were variable deletion patterns: pure terminal deletions in 38 patients (76%), including three cases of mosaicism; unbalanced translocations in seven (14%); and interstitial deletions in five (10%). Craniofacial/skeletal features, neurodevelopmental impairments, and cardiac anomalies were commonly observed in patients, with correlation to deletion sizes. Conclusion The genotype–phenotype correlation analysis narrowed the region responsible for distinctive craniofacial features and intellectual disability into 1.8–2.1 and 1.8–2.2 Mb region, respectively. Patients with deletions larger than 6.2 Mb showed no ambulation, indicating that severe neurodevelopmental prognosis may be modified by haploinsufficiencies of KCNAB2 and CHD5 , located at 6.2 Mb away from the telomere. Although the genotype–phenotype correlation for the cardiac abnormalities is unclear, PRDM16 , PRKCZ , and RERE may be related to this complication. Our study also revealed that female patients who acquired ambulatory ability were likely to be at risk for obesity.
We herein present the case of a 56-year-old woman who presented with symptoms of psoriatic arthritis (PsA) with erythema that progressed to annular pustular psoriasis. The patient had a 15-year ...history of polyarthritis. Annular pustular psoriasis is not typically observed in cases of arthritis. This is the first reported case of PsA with annular pustular psoriasis.
Similar to cacao pod rot, cherelle wilt decreases production from cacao fields. Among all known fungal pathogens of the cacao,
spp. are common infectious agents that affect the cherelles and pods of ...cacao; thus, cacao diseases are often classified by stage. Therefore, knowing whether these pathogens are common in both fruit stages is necessary for implementing disease control measures. Symptoms of cherelle wilt were found in cacao plants in Pangasinan, Philippines, in 2022. The fungal strain obtained from the lesion was found to be pathogenic towards cherelles, but not towards pods. The strain was classified as an unknown species belonging to the gigasporum species complex, based on the morphological and molecular phylogenetic analyses of ITS,
,
,
, and
. We propose
sp. nov. as a causal agent of cacao cherelle wilt, but not pod rot.
Abstract
On 2011 March 7, the Solar Neutron Telescope located at Mt. Sierra Negra, Mexico (4600 m) observed enhancements of the counting rate from 19:57 to 20:04 UT with statistical significance 6.8σ ...and from 20:36 to 21:03 UT with 5.8σ. One plausible physical explanation for the observation enhancements is that they were produced by solar gamma-rays. The intensities were estimated to be (0.16 ± 0.03) photons cm−2 s−1 for the first flare and (0.22 ± 0.04) photons cm−2 s−1 for the second one at the top of the atmosphere. As far as we know, this is the first report on the detection of solar gamma-rays with a ground-based detector. In association with these events, the solar neutron detector Space Environment Data Acquisition Equipment on board the International Space Station registered two solar neutrons with statistical significances of 7.3σ and 6.6σ. The Large Area Telescope on board the Fermi observatory also observed high-energy gamma-rays from this flare with a statistical significance of 6.7σ. In this paper we propose a unified model to explain the production mechanism of high-energy gamma-rays and neutrons in association with this flare.
Background
In patients with IgA nephropathy (IgAN), recurrence after steroid pulse therapy is associated with reduced renal survival. However, the predictors of recurrence have not yet been ...clarified.
Methods
All patients who received 6-month steroid pulse therapy from 2004 to 2010 in our four affiliated hospitals and achieved a reduction of proteinuria to <0.4 g/day 1 year after treatment were retrospectively evaluated. The primary outcome was proteinuria ≥1.0 g/day during follow-up or additional antiproteinuric therapy. Two histological classifications were evaluated, the Oxford Classification with a split system and Japanese histological grades (HGs) with a lumped system.
Results
During a median follow-up of 3.4 years, 27 (26.7 %) of the 101 patients showed recurrence. Multivariate analysis showed that HG was the only significant predictor of recurrence, with HG 2+3+4 vs HG 1 having a hazard ratio of 7.38 (95 % confidence interval 1.52–133). Furthermore, in patients with mesangial hypercellularity according to the Oxford Classification, cumulative rate of recurrence-free survival was greater in patients with steroid therapy plus tonsillectomy compared with those who received steroid therapy alone (Log-rank test,
P
= 0.022). However, this association was not observed in patients without mesangial hypercellularity.
Conclusions
HG is a novel predictor of recurrence after steroid pulse therapy in patients with IgAN. Moreover, the combination of steroid pulse therapy plus tonsillectomy may indicate a lower risk of recurrence in patients with mesangial hypercellularity, as defined by the Oxford Classification.
Solar flares are broadly classified as impulsive or gradual. Ions accelerated in a gradual flare are thought to be accelerated through a shock acceleration mechanism, but the particle acceleration ...process in an impulsive flare is still largely unexplored. To understand the acceleration process, it is necessary to measure the high-energy gamma rays and neutrons produced by the impulsive flare. Under such circumstances, on 7 November 2004, a huge X2.0 flare occurred on the solar surface, where ions were accelerated to energies greater than 10 GeV. The accelerated primary protons collided with the solar atmosphere and produced line gamma rays and neutrons. These particles were received as neutrons and line gamma rays, respectively. Neutrons of a few GeV, on the other hand, decay to produce secondary protons while traveling 0.06 au in the solar–terrestrial space. These secondary protons arrive at the magnetopause. Although the flux of secondary protons is very low, the effect of collecting secondary protons arriving in a wide region of the magnetosphere (the Funnel or Horn effect) has resulted in significant signals being received by the solar neutron telescope at Mt. Sierra Negra (4600 m). This information suggests that ions on the solar surface are accelerated to over 10 GeV with an impulsive flare.
► The remodeling of white and brown adipose tissues of CR rats was examined. ► CR affected mitochondrial function of both adipose tissues differentially. ► We suggest that both adipose tissues ...cooperate to use energy effectively in CR animals.
Caloric restriction (CR) slows the aging process and extends longevity, but the exact underlying mechanisms remain debatable. It has recently been suggested that the beneficial action of CR may be mediated in part by adipose tissue remodeling. Mammals have two types of adipose tissue: white adipose tissue (WAT) and brown adipose tissue (BAT). In this study, proteome analysis using two-dimensional gel electrophoresis combined with MALDI-TOF MS, and subsequent analyses were performed on both WAT and BAT from 9-month-old male rats fed ad libitum or subjected to CR for 6 months. Our findings suggest that CR activates mitochondrial energy metabolism and fatty acid biosynthesis in WAT. It is likely that in CR animals WAT functions as an energy transducer from glucose to energy-dense lipid. In contrast, in BAT CR either had no effect on, or down-regulated, the mitochondrial electron transport chain, but enhanced fatty acid biosynthesis. This suggests that in CR animals BAT may change its function from an energy consuming system to an energy reservoir system. Based on our findings, we conclude that WAT and BAT cooperate to use energy effectively via a differential response of mitochondrial function to CR.
The massive flare of 27 December 2004 from the soft γ-ray repeater SGR 1806-20, a possible magnetar, saturated almost all γ-ray detectors, meaning that the profile of the pulse was poorly ...characterized. An accurate profile is essential to determine physically what was happening at the source. Here we report the unsaturated γ-ray profile for the first 600 ms of the flare, with a time resolution of 5.48 ms. The peak of the profile (of the order of 107 photons cm-2 s-1) was reached ∼50 ms after the onset of the flare, and was then followed by a gradual decrease with superposed oscillatory modulations possibly representing repeated energy injections with ∼60-ms intervals. The implied total energy is comparable to the stored magnetic energy in a magnetar (∼ 1047 erg) based on the dipole magnetic field intensity (∼ 1015 G), suggesting either that the energy release mechanism was extremely efficient or that the interior magnetic field is much stronger than the external dipole field.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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