Summary
Nitrogen (N) is one of the key essential macronutrients that affects rice growth and yield. Inorganic N fertilizers are excessively used to boost yield and generate serious collateral ...environmental pollution. Therefore, improving crop N use efficiency (NUE) is highly desirable and has been a major endeavour in crop improvement. However, only a few regulators have been identified that can be used to improve NUE in rice to date. Here we show that the rice NIN‐like protein 4 (OsNLP4) significantly improves the rice NUE and yield. Field trials consistently showed that loss‐of‐OsNLP4 dramatically reduced yield and NUE compared with wild type under different N regimes. In contrast, the OsNLP4 overexpression lines remarkably increased yield by 30% and NUE by 47% under moderate N level compared with wild type. Transcriptomic analyses revealed that OsNLP4 orchestrates the expression of a majority of known N uptake, assimilation and signalling genes by directly binding to the nitrate‐responsive cis‐element in their promoters to regulate their expression. Moreover, overexpression of OsNLP4 can recover the phenotype of Arabidopsis nlp7 mutant and enhance its biomass. Our results demonstrate that OsNLP4 plays a pivotal role in rice NUE and sheds light on crop NUE improvement.
Nitrogen (N) is an essential macronutrient for crop growth and yield. Improving the N use efficiency (NUE) of crops is important to agriculture. However, the molecular mechanisms underlying NUE ...regulation remain largely elusive. Here we report that the OsNLP3 (NIN‐like protein 3) regulates NUE and grain yield in rice under N sufficient conditions. OsNLP3 transcript level is significantly induced by N starvation and its protein nucleocytosolic shuttling is specifically regulated by nitrate. Loss‐of‐function of OsNLP3 reduces plant growth, grain yield, and NUE under sufficient nitrate conditions, whereas under low nitrate or different ammonium conditions, osnlp3 mutants show no clear difference from the wild type. Importantly, under sufficient N conditions in the field, OsNLP3 overexpression lines display improved grain yield and NUE compared with the wild type. OsNLP3 orchestrates the expression of multiple N uptake and assimilation genes by directly binding to the nitrate‐responsive cis‐elements in their promoters. Overall, our study demonstrates that OsNLP3, together with OsNLP1 and OsNLP4, plays overlapping and differential roles in N acquisition and NUE, and modulates NUE and the grain yield increase promoted by N fertilizer. Therefore, OsNLP3 is a promising candidate gene for the genetic improvement of grain yield and NUE in rice.
Summary Statement
Crop nitrogen use efficiency (NUE) is an important agronomic trait. But the molecular mechanisms underlying NUE regulation are not well understood. This study reveals that rice NIN‐like protein 3 (OsNLP3) regulates NUE and grain yield especially under N sufficient conditions and is a promising candidate gene for improving grain yield and NUE in rice.
Data regarding the real-world effectiveness and safety of sofosbuvir/velpatasvir (SOF/VEL) with or without low-dose ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) infection and ...severe renal impairment (RI) are limited. We evaluated the performance of SOF/VEL with or without low-dose RBV in HCV-infected patients with chronic kidney disease stage 4 or 5.
191 patients with compensated (n=181) and decompensated (n=10) liver diseases receiving SOF/VEL (400/100 mg/day) alone and SOF/VEL with low-dose RBV (200 mg/day) for 12 weeks were retrospectively recruited at 15 academic centres in Taiwan. The effectiveness was determined by sustained virological response at off-treatment week 12 (SVR
) in evaluable (EP) and per-protocol populations (PP). The safety profiles were assessed.
The SVR
rates by EP and PP analyses were 94.8% (95% CI 90.6% to 97.1%) and 100% (95% CI 97.9% to 100%). In patients with compensated liver disease, the SVR
rates were 95.0% and 100% by EP and PP analyses. In patients with decompensated liver disease, the SVR
rates were 90.0% and 100% by EP and PP analyses. Ten patients who failed to achieve SVR
were attributed to non-virological failures. Among the 20 serious adverse events (AEs), none were judged related to SOF/VEL or RBV. The AEs occurring in ≥10% included fatigue (14.7%), headache (14.1%), nausea (12.6%), insomnia (12.0%) and pruritus (10.5%). None had ≥grade 3 total bilirubin or alanine aminotransferase elevations.
SOF/VEL with or without low-dose RBV is effective and well-tolerated in HCV-infected patients with severe RI.
MicroRNAs (miRNAs) take part in a variety of biological processes by regulating target genes. Transforming growth factor β receptor 1 (TGFBR1) and TGFBR2 are crucial members of the TGF‐β family and ...are serine/threonine kinase receptors. The aim of this study was to explore the functions of ssc‐miR‐204 in porcine preadipocyte differentiation and apoptosis with regard to the TGFβ/Smad pathway. We identified miRNAs predicted to target TGFBR1 and TGFBR2 using a database and selected ssc‐miR‐204 as a candidate miRNA. ssc‐miR‐204 overexpression dramatically reduced the levels of TGFBR1 and TGFBR2. However, after transfection with ssc‐miR‐204 inhibitor, TGFBR1 and TGFBR2 levels were dramatically increased. ssc‐miR‐204 overexpression dramatically promoted porcine preadipocyte differentiation and apoptosis. After transfection with ssc‐miR‐204 inhibitor, porcine preadipocyte differentiation and apoptosis were dramatically inhibited. After transfection with ssc‐miR‐204 mimics, Smad2, Smad3, Smad4, p‐Smad2, and p‐Smad3 protein levels significantly decreased, and adipogenesis was regulated by inhibiting the TGF‐β/Smad3 signaling pathway. Taken together, these results verified that ssc‐miR‐204 regulates porcine preadipocyte differentiation and apoptosis by targeting TGFBR1 and TGFBR2.
Collectively, our results indicate that ssc‐miR‐204 is a negative regulator that targets transforming growth factor β receptor 1 (TGFBR1) and TGFBR2 in the TGF‐β signaling pathway to promote preadipocyte differentiation and apoptosis. A better understanding of ssc‐miR‐204 in the context of preadipocytes will be beneficial for human medical research.
Rhythmic auditory stimulation (RAS) belongs to neurologic music therapy, which has attracted clinical attention because of its efficacy in motor function after stroke. This study aimed to summarize ...the effectiveness of rhythmic auditory stimulation (RAS) for the treatment of motor function and balance ability in stroke through a systematic review and meta-analysis.
All studies were retrieved from six databases. The effects of RAS on stroke were determined using the following indicators: motor function including step length, step cadence, velocity, Fugl-Meyer assessment (FMA); and balance ability including overall balance index (OBI) and Berg Balance Scale (BBS). The risk map of bias of the quality of the studies and the meta-analysis results of the indicators was prepared using RevMan 5.2 software.
A total of 1,363 abstracts were retrieved. Among them, 325 duplicate studies were eliminated, and 971 studies were excluded after reading the titles and abstracts. In addition, by downloading the full text for further reading and screening, 47 studies were excluded. A total of 22 studies were included in the systematic review, and 18 studies were included in the meta-analysis. Assessment of quality, based on the PEDro scale, two studies had low quality, three studies had excellent quality, and the other studies had good quality; based on the Cochrane Collaborative Network Bias Risk Assessment Scale. A total of 15 studies specifically explained the random methods used. Meanwhile, seven studies did not report random sequence generation. A total of 10 studies reported that the evaluation of experimental results was blinded. In the meta-analysis, the results of motor function namely, velocity (SMD = 0.99, 95% CI (0.43, 1.55)), step length (SMD = 0.97, 95% CI (0.74, 1.20)), and step cadence (MD = 5.16, 95% CI (4.17, 6.14)), FMA (MD = 2.93, 95% CI (2.04, 3.83)), were statistically significant (
< 0.01). The results of balance ability OBI (MD = -0.51, 95% CI (-0.86, -0.16)) and BBS (MD = 2.93, 95% CI (1.67, 4.20)), were also statistically significant (
< 0.01). Among all the outcome indicators, three indicators were included in more than 10 studies: these are step length, step cadence, and velocity. The results showed that the two sides of the funnel chart were asymmetrical, thus these results all showed heterogeneity. The GRADEpro GDT online tool was used to evaluate the quality of evidence for the outcome indicators in the included studies. Five outcome indicators were included, of which three were low-quality indicators and two were moderate-quality indicators.
RAS could improve gait parameters, walking function, and balance ability of individuals with stroke. However, studies or samples of outcome indicators for balance ability of stroke patients is relatively insufficient, which also requires further research in the future.
PROSPERO, identifier: CRD42021225102.
To evaluate virological breakthrough (VBT) and the risk of hepatocellular carcinoma (HCC) in HBeAg-positive chronic hepatitis B (CHB) patients receiving entecavir (ETV) treatment.
A retrospective ...cohort study was conducted in a tertiary referral hospital and a total of 228 HBeAg-positive CHB patients treated with ETV for more than 48 weeks were enrolled. Clinical outcome measures included HBeAg seroclearance, maintained virological response and the development of HCC.
During a median follow-up period of 197 weeks, VBT developed in 26 (11.4%) patients (VBT group), and the other 202 patients without VBT (non-VBT group). The overall cumulative rate of HBeAg seroclearance in the VBT group and non-VBT group were 23.1% and 23.8%, 27.1% and 37.9%, 27.1% and 55.1%, 27.1% and 74.1%, 27.1% and 76.7% from week 48 to 240, respectively(p = 0.013). The cumulative probability of maintained virological responses from week 48 to 240 were 7.69% and 21.78%, 7.69% in the VBT groups and 36.85%, 7.69% and 51.68%, 7.69% and 64.97%, 7.69% and 72.1% in the non-VBT groups, respectively (p<0.001). In the multivariate analysis, age (p<0.001) and virological response at week 24 (p = 0.005) were independently associated with VBT. Cox regression analysis showed that cirrhosis had carried the highest risk for HCC (HR = 4.99, CI = 1.14-21.81, p = 0.033). Subgroup survival analysis by Kaplan-Meier method showed that patients with VBT had higher incidence of developing HCC than without VBT in cirrhotic patients (50% (95%CI = 1-99%) vs 9% (95% CI = 1-9%); p = 0.048).
VBT was associated with adverse clinical outcomes, including a low probability of HBeAg seroclearance, failure to achieve maintained virological responses, and a risk of developing HCC. Patients, particularly with cirrhosis, who had experienced VBT during ETV treatment, more likely developed HCC.
Electrostatic discharge (ESD) robustness of lowvoltage (LV) field-oxide devices in stacked configuration for highvoltage (HV) applications was investigated in a 0.5-μm HV silicon on insulator (SOI) ...process. Stacked LV field-oxide devices with different stacking numbers have been verified in a silicon chip to exhibit both a high ESD robustness and latch-up immunity for HV applications. The effect of turn-on resistance in the stacked ESD protection device on ESD current waveform under human body model (HBM) and machine model (MM) ESD tests was studied. The resistance of stacked device has a significant impact on the ESD peak current and damping waveform, especially in MM ESD test. The MM ESD level can be increased by the numbers of LV field-oxide devices in stacked configuration, but the HBM ESD level is still kept the same. The mechanism to cause such a result has been theoretically analyzed in detail in this paper.
Long noncoding RNAs (lncRNAs) are important regulators that have multiple functions in a variety of biological processes. However, the contributions of lncRNAs to follicle-stimulating hormone (FSH) ...secretion remain largely unknown. In this study, we first identified a novel lncRNA, lncRNAm433s1, as an intergenic lncRNA located in the cytoplasm. We next used MS2-RIP assays to demonstrate that lncRNA-m433s1 interacted with miR-433. Furthermore, we detected the levels of lncRNA-m433s1, miR-433, and Fshβ expression, FSH concentrations, and apoptosis upon overexpression and knockdown of lncRNA-m433s1, revealing that lncRNA-m433s1 upregulated Fshβ expression. Globally, lncRNA-m433s1 reduced the inhibitory effect of miR-433 on Fshβ and further regulated FSH secretion as a competing endogenous RNA (ceRNA) by sponging miR-433. This ceRNA model will provide novel insight into the regulatory mechanisms of lncRNAs associated with rat reproduction. Summary Sentence A regulatory mechanism of lncRNA in rat anterior pituitary cell which was that lncRNA-m433s1 reduced the inhibitory effect of miR-433 on Fshβ and further regulated FSH secretion by acting as a ceRNA to sponge miR-433.
The use of oncoplastic reconstruction for breast-conserving surgery (BCS) extends benefits beyond merely minimizing poor cosmetic results. However, the feasibility and oncological safety of ...oncoplastic surgery (OPS) are controversial.
This meta-analysis aimed to compare the short-term and long-term oncological outcomes of BCS alone and BCS plus OPS. Relevant studies published before July 2017 in the Embase, the Cochrane Library, PubMed, and Web of Science databases were screened and collected. The meta-analysis was performed using STATA software (Stata Corp.).
A total of 3,789 patients from 11 studies were included, with 2,691 patients in the BCS-alone group and 1,098 patients in the BCS plus OPS group. The demographics were similar between both groups, and no significant difference was observed in pathological T and N stages between the two groups. Re-excision was less common (relative risk RR, 0.66;
=0.009) and the positive-margin rate was lower, but not significantly (RR, 0.83;
=0.191), in the BCS plus OPS group than in the BCS-alone group. The local and distal recurrence rates were similar in both groups. Both disease-free survival (hazard ratio HR, 1.19; 95% confidence interval CI, 0.96-1.49;
=0.112) and overall survival (HR, 1.14; 95% CI, 0.76-1.69;
=0.527) did not differ between the two groups.
A combination of BCS and OPS is preferred over BCS alone for decreasing re-excisions and provides similar long-term survival as BCS alone in patients with breast cancer.
The therapeutic options for hepatocellular carcinoma (HCC) have greatly expanded recently, and current first-line therapies include sorafenib, lenvatinib, and atezolizumab-bevacizumab. The aim of ...this study was to investigate the therapeutic efficacy of sequential systemic treatments after progressing to the first-line agent in patients with unresectable HCC.
Data were collected from subjects with HCC, BCLC stage B or C, who received first-line sorafenib, lenvatinib, or atezolizumab-bevacizumab from September 2020 to December 2022. The patients who progressed after first-line therapy were evaluated according to individual clinical status in order to decide whether or not to accept sequential therapy. The clinical baseline characteristics and overall survival (OS) of enrolled patients were collected and further analyzed.
Among the 127 enrolled patients, percentage of sequential therapy was 67.9%, 21.6%, and 37.5% in those with tumor progression after first-line sorafenib, lenvatinib, or atezolizumab-bevacizumab, respectively. Acceptance of sequential therapy (HR 0.46,
= 0.041) and presentation of ALBI grade I (HR 0.36,
= 0.002) had a significantly positive impact on OS. Pre-treatment ALBI grade had a significant impact on the decision to accept sequential therapy in patients with progressed HCC.
The patients who were able to undergo sequential therapy had a better survival outcome compared to those who received only one agent, and the pre-treatment ALBI level might be regarded as a cornerstone tool to assess survival outcomes in patients undergoing treatment for HCC.
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