In flowering plants, the tapetum, the innermost layer of the anther, provides both nutrient and lipid components to developing microspores, pollen grains, and the pollen coat. Though the programmed ...cell death of the tapetum is one of the most critical and sensitive steps for fertility and is affected by various environmental stresses, its regulatory mechanisms remain mostly unknown. Here we show that autophagy is required for the metabolic regulation and nutrient supply in anthers and that autophagic degradation within tapetum cells is essential for postmeiotic anther development in rice. Autophagosome-like structures and several vacuole-enclosed lipid bodies were observed in postmeiotic tapetum cells specifically at the uninucleate stage during pollen development, which were completely abolished in a retrotransposon-insertional OsATG7 (autophagy-related 7)-knockout mutant defective in autophagy, suggesting that autophagy is induced in tapetum cells. Surprisingly, the mutant showed complete sporophytic male sterility, failed to accumulate lipidic and starch components in pollen grains at the flowering stage, showed reduced pollen germination activity, and had limited anther dehiscence. Lipidomic analyses suggested impairment of editing of phosphatidylcholines and lipid desaturation in the mutant during pollen maturation. These results indicate a critical involvement of autophagy in a reproductive developmental process of rice, and shed light on the novel autophagy-mediated regulation of lipid metabolism in eukaryotic cells.
ObjectivesThis study documents the time elapsed from the diagnosis of osteonecrosis of the femoral head (ONFH) to surgery, exploring the factors that influence ONFH severity.DesignRetrospective ...observational study of a nationwide database.SettingThe Kaplan-Meier method with log-rank tests was applied to examine the period from definitive diagnosis of ONFH to surgery using any surgery as the end point. For bilateral cases, the date of the first surgery was the endpoint.ParticipantsThis study included 2074 ONFH cases registered in 34 university hospitals and highly specialised hospitals of the multicentre sentinel monitoring system of the Japanese Investigation Committee between 1997 and 2018.Main outcome measureThe primary outcome was the time from diagnosis to surgery. The secondary outcome was the proportion of subjects remaining without surgery at 3, 6 and 9 months, and at 1, 2 and 5 years after diagnosis.ResultsThe median time to surgery was 9 months (IQR 4–22 months) after diagnosis of ONFH. The time to surgery was significantly shorter in the alcohol alone group and the combined corticosteroid and alcohol group than in the corticosteroid alone group (p=0.018 and p<0.001, respectively), in early stage ONFH with no or mild joint destruction (stages II and III, p<0.001), and with joint preserving surgery (p<0.001). The proportion without surgery was 75.8% at 3 months, 59.6% at 6 months, 48.2% at 9 months, 40.5% at 1 year, 22.2% at 2 years and 8.3% at 5 years.ConclusionONFH has been considered to be an intractable disease that often requires surgical treatment, but the fact that surgery was performed in more than half of the patients within 9 months from diagnosis suggests severe disease with a significant clinical impact.Trial registration numberChiba University ID1049.
Purpose
This study was designed to assess the tolerability, efficacy, and safety of tri-weekly irinotecan plus S-1 (IRIS) and weekly cetuximab in patients with metastatic colorectal cancer (mCRC).
...Methods
The main eligibility criteria were
RAS
wild-type mCRC with no prior chemotherapy. S-1 was given orally at a dose of 40 mg/m
2
(40–60 mg) twice for 2 weeks, followed by a 1-week rest. Irinotecan was given on day 1 of each cycle at a dose of 150 mg/m
2
. Cetuximab was administered on days 1 (400 mg/m
2
), 8 (250 mg/m
2
), and 15 (250 mg/m
2
), and then once weekly (250 mg/m
2
) thereafter. A standard 3 + 3 phase I dose de-escalation design was used to determine the maximum tolerated dose and the recommended dose (RD) of irinotecan. The primary end point of the Phase II study was overall response rate (ORR).
Results
Between December 2014 and September 2017, 4 and 54 patients were enrolled in phase I and phase II studies, respectively. No dose-limiting toxicity was observed in the phase I study, and the RD of irinotecan was 150 mg/m
2
. In the phase II study, the ORR was 56.9% (90% confidence interval 44.4%–68.7%). The safety profile revealed that the most common grade 3/4 adverse events were neutropenia (31.4%), appetite loss (27.5%), hypokalemia (11.8%), and diarrhea (11.8%). Grade 3/4 hand–foot skin syndrome occurred in nine patients (9.8%).
Conclusion
This study showed that the efficacy and safety of IRIS combined with cetuximab were comparable to those for other first-line treatments. This regimen is a good candidate for first-line treatment of
RAS
wild-type mCRC.
Proteinuria is a powerful prognostic factor for end-stage renal disease in IgA nephropathy (IgAN) patients. However, it is not known whether proteinuria exacerbations are related to seasonal changes.
...We retrospectively enrolled consecutive patients diagnosed with IgAN by kidney biopsy at our hospital between 2002 and 2014. Proteinuria remission was defined as urinary protein <0.3 g/gCr in two consecutive outpatient urinalyses and exacerbation as urinary protein ≥0.75 g/gCr. Four seasons were defined: spring (March-May), summer (June-August), autumn (September-November), and winter (December-February). We performed a multivariate analysis to identify factors associated with the second remission following a proteinuria exacerbation.
We analyzed 116 patients. Proteinuria remission and exacerbation occurred in 77, and 43 patients, respectively. The incidence of proteinuria exacerbation was significantly higher in autumn and winter than in spring and summer (p = 0.040). The cumulative second remission rate was significantly higher in patients with autumn and winter proteinuria exacerbation than in patients with spring and summer exacerbations (p = 0.0091). In multivariate analyses, exacerbation onset in autumn and winter (hazard ratio HR, 3.51; 95% confidence interval CI, 1.41-8.74) and intensive therapy (HR, 2.26; 95% CI, 1.05-4.88) were significantly associated with a second proteinuria remission.
In IgAN patients in proteinuria remission, proteinuria exacerbation frequently occurred in autumn and winter. Exacerbations occurring in autumn and winter tended to remit early.
We examined whether glucagon-like peptide-1 (GLP-1) affects β-cell mass and proliferation through neural pathways, from hepatic afferent nerves to pancreatic efferent nerves via the central nervous ...system, in high-fat diet (HFD)-induced obese rats. The effects of chronic administration of GLP-1 (7-36) and liraglutide, a GLP-1 receptor agonist, on pancreatic morphological alterations, c-fos expression and brain-derived neurotrophic factor (BDNF) content in the hypothalamus, and glucose metabolism were investigated in HFD-induced obese rats that underwent hepatic afferent vagotomy (VgX) and/or pancreatic efferent sympathectomy (SpX). Chronic GLP-1 (7-36) administration to HFD-induced obese rats elevated c-fos expression and BDNF content in the hypothalamus, followed by a reduction in pancreatic β-cell hyperplasia and insulin content, thus resulting in improved glucose tolerance. These responses were abolished by VgX and SpX. Moreover, administration of liraglutide similarly activated the hypothalamic neural pathways, thus resulting in a more profound amelioration of glucose tolerance than native GLP-1 (7-36). These data suggest that GLP-1 normalizes the obesity-induced compensatory increase in β-cell mass and glucose intolerance through a neuronal relay system consisting of hepatic afferent nerves, the hypothalamus, and pancreatic efferent nerves.
In the present study, the characteristics of supersonic rectangular microjets are investigated experimentally using molecular tagging velocimetry. The jets are discharged from a convergent–divergent ...rectangular nozzle whose exit height is 500 μm. The jet Mach number is set to 2.0 for all tested jets, and the Reynolds number
Re
is altered from 154 to 5,560 by changing the stagnation pressure. The experimental results reveal that jet velocity decays principally due to abrupt jet spreading caused by jet instability for relatively high Reynolds numbers (
Re
> ~450). The results also reveal that the jet rapidly decelerates to a subsonic speed near the nozzle exit for a low Reynolds number (
Re
= 154), although the jet does not spread abruptly; i.e., a transition in velocity decay processes occurs as the Reynolds number decreases. A supersonic core length is estimated from the streamwise distribution of the centerline velocity, and the length is then normalized by the nozzle exit height and plotted against the Reynolds number. As a result, it is found that the normalized supersonic core length attains a maximum value at a certain Reynolds number near which the transition in the velocity decay process occurs.
Laparoscopic deroofing of liver cysts is widely accepted as the treatment of symptomatic huge liver cysts. As bile leakage is a common complication of this procedure, indocyanine green (ICG) imaging ...has played an active role in detecting intrahepatic biliary tract. However, infusion ICG imaging needs time rag after injection due to moving from bloodstream to bile, and also, additional injection is needed when the fluorescent imaging is not clear. To cover this weakness of ICG imaging, we first applied ICG imaging via 5-Fr endoscopic nasal biliary drainage (ENBD) during laparoscopic deroofing of liver cysts. This technique promptly gives us ICG imaging after ICG injection from ENBD; in addition, direct ICG imaging sometimes reveals minor leakage from sealing line and staple lines; therefore, we believe that direct ICG imaging via ENBD helps us to prevent post-operative bile leakage.
To prove the hypothesis that paddy rice utilizes soil nonexchangeable potassium (neK) and causes associated structural changes in clay minerals, K status and clay mineralogy of 22 surface soils from ...three paddy fields under long‐term fertilizer management for 51–93 years were investigated. Soil neK content was determined as the difference between 1 mol L−1 hot HNO3 extractable K and 1 mol L−1 ammonium acetate exchangeable K. Clay mineralogy was identified by X‐ray diffraction (XRD). The radiocesium interception potential (RIP), an index of frayed edge sites in the interlayer sites of 2:1 type clay minerals, was also determined. The neK contents under the ‐K and NPK treatments were considerably lower than those under the unfertilized treatment in all the fields, indicating the exploitation of soil neK by rice. XRD analysis of the clay samples revealed 7% shift from the 1.0 peak to 1.4 nm one under the ‐K treatment compared with the unfertilized one, and the amounts of neK were negatively correlated with those of RIP (p < .01), suggesting the expansion of interlayer spaces of the 2:1 type phyllosilicates such as mica due to the release of neK. In addition, the neK content positively correlated with K balance of the long‐term experiments (p < .05). The differences of neK between unfertilized K and ‐K treatments corresponded to 22–157 kg K ha−1, or 0.42–1.68 kg K ha−1 year−1. In conclusion, utilization of considerable amount of soil neK under K depleted conditions should be considered to establish sustainable K management for paddy rice.
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