OsNLP3 enhances grain weight and reduces grain chalkiness in rice.

Grain weight, a key determinant of yield in rice (Oryza sativa L.), is governed primarily by genetic factors, whereas grain chalkiness, a detriment to grain quality, is intertwined with environmental factors such as mineral nutrients. Nitrogen (N) is recognized for its effect on grain chalkiness, but the underlying molecular mechanisms remain to be clarified. This study revealed the pivotal role of rice NODULE INCEPTION-LIKE PROTEIN 3 (OsNLP3) in simultaneously regulating grain weight and grain chalkiness. Our investigation showed that loss of OsNLP3 leads to a reduction in both grain weight and dimension, in contrast to the enhancement observed with OsNLP3 overexpression. OsNLP3 directly suppresses the expression of OsCEP6.1 and OsNF-YA8, which were identified as negative regulators associated with grain weight. Consequently, two novel regulatory modules, OsNLP3-OsCEP6.1 and OsNLP3-OsNF-YA8, were identified as key players in grain weight regulation. Notably, the OsNLP3-OsNF-YA8 module not only increases grain weight but also mitigates grain chalkiness in response to N. This research clarifies the molecular mechanisms that orchestrate grain weight through the OsNLP3-OsCEP6.1 and OsNLP3-OsNF-YA8 modules, highlighting the pivotal role of the OsNLP3-OsNF-YA8 module in alleviating grain chalkiness. These findings reveal potential targets for simultaneous enhancement of rice yield and quality.

Arabidopsis MADS-box factor AGL16 is a negative regulator of plant response to salt stress by downregulating salt-responsive genes.

Sessile plants constantly experience environmental stresses in nature. They must have evolved effective mechanisms to balance growth with stress response. Here we report the MADS-box transcription factor AGL16 acting as a negative regulator in stress response in Arabidopsis. Loss-of-AGL16 confers resistance to salt stress in seed germination, root elongation and soil-grown plants, while elevated AGL16 expression confers the opposite phenotypes compared with wild-type. However, the sensitivity to abscisic acid (ABA) in seed germination is inversely correlated with AGL16 expression levels. Transcriptomic comparison revealed that the improved salt resistance of agl16 mutants was largely attributed to enhanced expression of stress-responsive transcriptional factors and the genes involved in ABA signalling and ion homeostasis. We further demonstrated that AGL16 directly binds to the CArG motifs in the promoter of HKT1;1, HsfA6a and MYB102 and represses their expression. Genetic analyses with double mutants also support that HsfA6a and MYB102 are target genes of AGL16. Taken together, our results show that AGL16 acts as a negative regulator transcriptionally suppressing key components in the stress response and may play a role in balancing stress response with growth.

Delineating the Role of Mitophagy Inducers for Alzheimer Disease Patients.

Alzheimer's disease (AD) is the most common cause of dementia in elderly that serves to be a formidable socio-economic and healthcare challenge in the 21st century. Mitochondrial dysfunction and impairment of mitochondrial-specific autophagy, namely mitophagy, have emerged as important components of the cellular processes contributing to the development of AD pathologies, namely amyloid-ß plaques (Aß) and neurofibrillary tangles (NFT). Here, we highlight the recent advances in the association between impaired mitophagy and AD, as well as delineate the potential underlying mechanisms. Furthermore, we conduct a systematic review the current status of mitophagy modulators and analyzed their relevant mechanisms, evaluating on their advantages, limitations and current applications in clinical trials for AD patients. Finally, we describe how deep learning may be a promising method to rapid and efficient discovery of mitophagy inducers as well as general guidance for the workflow of the process.

Administration of quercetin improves mitochondria quality control and protects the neurons in 6-OHDA-lesioned Parkinson's disease models.

Mounting evidence suggests that mitochondrial dysfunction and impaired mitophagy lead to Parkinson's disease (PD). Quercetin, one of the most abundant polyphenolic flavonoids, displays many health-promoting biological effects in many diseases. We explored the neuroprotective effect of quercetin in vivo in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD and in vitro in 6-OHDA-treated PC12 cells. In vitro, we found that quercetin (20 µM) treatment improved mitochondrial quality control, reduced oxidative stress, increased the levels of the mitophagy markers PINK1 and Parkin and decreased α-synuclein protein expression in 6-OHDA-treated PC12 cells. Moreover, our in vivo findings demonstrated that administration of quercetin also relieved 6-OHDA-induced progressive PD-like motor behaviors, mitigated neuronal death and reduced mitochondrial damage and α-synuclein accumulation in PD rats. Furthermore, the neuroprotective effect of quercetin was suppressed by knockdown of either Pink1 or Parkin.

Arabidopsis MADS-box factor AGL16 negatively regulates drought resistance via stomatal density and stomatal movement.

Drought is one of the most important environmental factors limiting plant growth and productivity. The molecular mechanisms underlying plant drought resistance are complex and not yet fully understood. Here, we show that the Arabidopsis MADS-box transcription factor AGL16 acts as a negative regulator in drought resistance by regulating stomatal density and movement. Loss-of-AGL16 mutants were more resistant to drought stress and had higher relative water content, which was attributed to lower leaf stomatal density and more sensitive stomatal closure due to higher leaf ABA levels compared with the wild type. AGL16-overexpressing lines displayed the opposite phenotypes. AGL16 is preferentially expressed in guard cells and down-regulated in response to drought stress. The expression of CYP707A3 and AAO3 in ABA metabolism and SDD1 in stomatal development was altered in agl16 and overexpression lines, making them potential targets of AGL16. Using chromatin immunoprecipitation, transient transactivation, yeast one-hybrid, and electrophoretic mobility shift assays, we demonstrated that AGL16 was able to bind the CArG motifs in the promoters of the CYP707A3, AAO3, and SDD1 and regulate their transcription, leading to altered leaf stomatal density and ABA levels. Taking our findings together, AGL16 acts as a negative regulator of drought resistance by modulating leaf stomatal density and ABA accumulation.

Levodopa/Benserazide PLGA Microsphere Prevents L-Dopa-Induced Dyskinesia via Lower ß-Arrestin2 in 6-Hydroxydopamine Parkinson's Rats.

Prolonged pulsatile administration of Levodopa (L-dopa) can generate L-dopa-induced dyskinesia (LID). Numerous research has reported that continuous dopamine delivery (CDD) was useful in reducing the severity of LID. 6-OHDA lesioned rats were divided into two groups to receive intermittent L-dopa stimulation (L-dopa/benserazide) or Levodopa/benserazide PLGA microsphere (LBPM) for 3 weeks. rAAV (recombinant adeno-associated virus) vector was used to overexpress and ablation of ß-arrestin2. We found that LBPM developed less AIM severity compared with standard L-dopa administration, whereas selective deletion of ß-arrestin2 in striatum neurons dramatically enhanced the severity of dyskinesia by LBPM. On the contrary, the effects of LBPM in terms of ALO AIM were further relieved by ß-arrestin2 overexpression. Furthermore, no significant change in motor behavior was seen either in inhibition or overexpression of ß-arrestin2. In short, our experiments provided evidence that LBPM's prevention of LID behavior was likely due to ß-arrestin2, suggesting that a therapy modulating ß-arrestin2 may offer a more efficient anti-dyskinetic method with a low risk of untoward effects.

Poor-Grade Aneurysmal Subarachnoid Hemorrhage: Risk Factors Affecting Clinical Outcomes in Intracranial Aneurysm Patients in a Multi-Center Study.

Objective: Patients with poor-grade aneurysm subarachnoid hemorrhage (SAH) have commonly been considered to have a poor prognosis. The objective of this study was to investigate the independent risk factors affecting clinical outcomes in intracranial aneurysm patients with poor-grade aneurysm subarachnoid hemorrhage (aSAH) underwent different intervention therapies. Methods: A multicenter observational registry of 324 poor-grade aSAH patients treated at tertiary referral centers from October 2010 to March 2012 were enrolled in this study. The clinical data including patient characteristics on admission and during treatment course, treatment modality, aneurysm size and location, radiologic features, signs of cerebral herniation (dilated pupils), and functional neurologic outcome were collected. Clinical outcomes were assessed via a modified Rankin Scale at 12 months. Multivariate logistic regression models were used to develop prognostic models. The area under the receiver operator characteristic curves (AUC) and Hosmer-Lemeshow tests were used to assess discrimination and calibration. WAP score was developed to predict risk of poor outcome. Results: Older age, female gender, ventilated breathing status, non-reactive pupil response, pupil dilation, lower GCS score, a WFNS grade of V, intraventricular hemorrhage, a higher Fisher grade, a higher modified Fisher grade, and conservative treatment were calculated to be associated with a relatively poor outcome. Multivariate analyses revealed that older age, lower Glasgow coma scale score (GCS), the absence of pupillary reactivity, higher modified Fisher grade, and conservative treatment were independent predictors of poor outcome, showed good discrimination and calibration. Patients with WFNS grade V, older age and non-reactive pupillary reactivity were predicted to have a poor outcome by WAP risk score. Conclusions: A simple WAP risk score had good discrimination and calibration in the prediction of outcome. The risk score can be easily measured and may complement treatment decision-making.

Mean Platelet Volume-To-Lymphocyte Ratio Predicts Poor Functional Outcomes Among Ischemic Stroke Patients Treated With Intravenous Thrombolysis.

Background and Purpose: According to previous studies, the mean platelet volume-to-lymphocyte ratio (MPVLR) represents a novel marker of a poor short-term prognosis in patients with a myocardial infarction who underwent primary percutaneous coronary intervention. We aimed to evaluate the association between MPVLR and clinical outcomes of patients with acute ischemic stroke who were treated with intravenous thrombolysis. Methods: Two hundred forty-one patients with ischemic stroke receiving intravenous thrombolysis were prospectively enrolled in this study. Blood samples for MPVLR were obtained at admission and at 18-24 h after treatment with intravenous thrombolysis. A poor functional outcome was defined as a modified Rankin scale score of 3-6 at 3 months after stroke. Results: At admission, the area under the curve of MPVLR to predict poor functional outcomes at 3 months was 0.613 [95% confidence interval (CI), 0.541-0.686; P = 0.003), and the best predictive MPVLR value was 5.8. Patients with an MPVLR ≥5.8 had a 3.141-fold increased risk of a poor outcome at 3 months (95% CI, 1.491-6.615; P = 0.003) compared to patients with an MPVLR <5.8. At 18-24 h after treatment with intravenous thrombolysis, the area under the curve of MPVLR to predict a poor outcome at 3 months was 0.697 (95% CI, 0.630-0.765, P < 0.001), and the best predictive MPVLR value was 6.9. The inclusion of MPVLR as a continuous (odds ratio, 1.145; 95% CI, 1.044-1.256, P = 0.004) and categorical variable (odds ratio, 6.555; 95% CI, 2.986-14.393, P < 0.001) was independently associated with poor outcomes at 3 months. Conclusions: Both the values of MPVLR at admission and 18-24 h after intravenous thrombolysis were independently associated with poor functional outcomes. MPVLR may serve as an activity marker for a poor prognosis in patients with acute ischemic stroke receiving intravenous thrombolysis.

ß-arrestin2 alleviates L-dopa-induced dyskinesia via lower D1R activity in Parkinson's rats.

The cause of the L-dopa-induced dyskinesia (LID) has been ascribed to G-protein coupled receptor (GPCR) supersensitivity and uncontrolled downstream signaling. It is now supposed that ß-arrestin2 affects GPCR signaling through its ability to scaffold various intracellular molecules. We used the rAAV (recombinant adeno-associated virus) vectors to overexpress and ablation of ß-arrestin2. L-dopa-induced changes in expression of signaling molecules and other proteins in the striatum were examined by western blot and immunohistochemically. Our data demonstrated that via AAV-mediated overexpression of ß-arrestin2 attenuated LID performance in 6-OHDA-lesioned rodent models. ß-arrestin2 suppressed LID behavior without compromising the antiparkinsonian effects of L-dopa. Moreover, we also found that the anti-dyskinetic effect of ß-arrestin2 was reversed by SKF38393, a D1R agonist. On the contrary, the rat knockdown study demonstrated that reduced availability of ß-arrestin2 deteriorated LID performance, which was counteracted by SCH23390, a D1R antagonist. These data not only demonstrate a central role for ß-arrestin2/GPCR signaling in LID, but also show the D1R signal pathway changes occurring in response to dopaminergic denervation and pulsatile administration of L-dopa.

Effects of mGluR5 Antagonists on Parkinson's Patients With L-Dopa-Induced Dyskinesia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Modulation of Metabotropic glutamate receptor 5 (mGluR5) may be a novel therapeutic approach to manage Parkinson's disease (PD) Patients with L-dopa-induced dyskinesia (LID). Objectives: The objective of this meta-analysis was to evaluate the effects of mGluR5 antagonists for the treatment of LID patients. Methods: Several electronic databases were consulted up to July 30, 2017. Randomized clinical trials (RCTs) that compared mGluR5 antagonists vs. placebo in LID patients were included. Pooled weighted mean difference (WMD) with 95% confidence intervals (CIs) were calculated using random-effects models. Results: Nine trials including 776 patients met all inclusion criteria. We pooled the whole data and found apparent difference between mGluR5 antagonists and placebo in terms of mAIMS (p = 0.010). However, there was no significant improvements on antidyskinetic in terms of LFADLDS (p = 0.42) and UPDRS Part IV (p = 0.20). Meanwhile, the effect size of UPDRS part III was similar in mGluR5 antagonist groups with in placebo groups (p = 0.25). Adverse events incidence was higher with mGluR5 antagonists than with placebo, especially at the expense of increased dizziness (16.3 vs. 4.3%), visual hallucination (10.1 vs. 1.1%), or fatigue (10.1 vs. 4.8%). Conclusions: mGluR5 antagonists had a greater treatment effect on the mAIMS in LID patients, however, there was no improvements on antidyskinetic in terms of LFADLDS and UPDRS Part IV compared with placebo. According to these results, we unable to recommend mGluR5 antagonists for the routine treatment of LID patients right now.

Modulation of CaMKIIa-GluN2B interaction in levodopa-induced dyskinesia in 6-OHDA-lesioned Parkinson's rats.

Long-term treatment with L-dopa leads to involuntary aimless movements called L-dopa-induced dyskinesia (LID) has hindered its use in Parkinson's disease (PD) patients. Emerging evidence suggests a possible role of CaMKIIa and its interacting partners in the development of LID. In this study, we found that CaMKIIa was found to form complexes with GluN2B after chronic administration of L-dopa in adult rat striatal neurons. Intrastriatal injection of KN-93 significantly reduced the level of GluN2B in CaMKIIa precipitates with a dose dependent response, as well as reduced the Global ALO AIM score without ablation of the therapeutic response to L-dopa. In parallel, intrastriatal injection of MK-801 significantly alleviated the level of CaMKIIa in GluN2B precipitates compared to LID group (p < 0.01), and this is accompanied by realizing improvement of the Global ALO AIM score also without affect the efficacy of L-dopa. In summary, the present study indicated that CaMKIIa-GluN2B interaction had an important role in the development of LID. Disrupt of this link by intrastriatal infusion of KN-93 or MK-801 ameliorated dyskinesia in 6-OHDA-lesioned PD rats.

Comparison of Aggressive Surgical Treatment and Palliative Treatment in Elderly Patients with Poor-Grade Intracranial Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: To compare the current treatment approach in elderly patients with poor-grade aneurysmal subarachnoid hemorrhage (SAH) and identify the independent predictors of the outcome after aggressive surgical treatment. METHOD: This prospective, multicenter cohort study included 104 poor-grade aneurysmal SAH elderly patients, 60 years or older, treated in our institution from October 2010 to March 2013. Patients were grouped according to three treatment arms. Neurological outcome was assessed using the Glasgow Outcome Scale (GOS) at baseline and at a 12-month follow-up. Univariate and multivariate analysis were performed using the following factors: sex, age, smoking history, breathing ability, alcohol consumption, cerebral hernia, aneurysm location, aneurysm diameter, WFNS grade, CT Fisher grade, treatment approach, and the timing of the aneurysm surgery. RESULTS: At the 12-month follow-up, patients in the coiling group and clipping group had better prognosis than patients in the palliative treatment group. Univariate analysis confirmed that the treatment approach, WFNS grade, CT Fisher grade, and age are critical factors for neurological outcomes in poor-grade SAH. Multivariate analysis indicated that WFNS grade V, CT Fisher grades 3-5, and palliative treatment were independent predictors of poor prognoses. CONCLUSION: Aggressive surgical treatment improves the prognoses in poor-grade aneurysm elderly patients with SAH. Elderly Patients of WFNS grade IV and CT Fisher grades 1-2 are more likely to have a better outcome.

An Overview of Meta-Analyses of Endovascular Bridging Therapies for Acute Ischemic Stroke.

BACKGROUND: Acute Ischemic Stroke (AIS) is a common cause of death worldwide and the leading cause of long-term severe disability. Endovascular bridging therapies (EBT), including endovascular thrombectomy (ET) and intra-arterial thrombolytic (IAT), have been recommended to realize a favorable functional outcome for AIS patients. METHODS: An overview of meta-analyses of primary randomized controlled trial (RCT) studies was performed evaluating EBT for AIS patients compared with usual care. RESULTS: Ten meta-analyses were included in this overview. ET was associated with a higher incidence of achieving functional outcome improvement, defined as a modified Rankin scale of 0 to 1 (mRS, p = 0.003), 0 to 2 (p < 0.00001), and 0 to 3 (p = 0.005). The risk of symptomatic intracranial hemorrhage (sICH) rate and all-cause mortality were similar between the two groups. Moreover, IAT treatment was also related to significantly improved outcomes in terms of the mRS score (p < 0.05), but no significant difference in rates of sICH and mortality within 90 days. CONCLUSIONS: In conclusion, our analysis supports that EBT, regardless of format (e.g., ET or IAT), is superior to the best medical therapy alone (e.g., IVT) in terms of mRS score in patients with AIS. In addition, the safety of EBT is similar to IVT.

Plasma long non-coding RNA BACE1 as a novel biomarker for diagnosis of Alzheimer disease.

BACKGROUNDS: Long non-coding RNA (LncRNA) have been reported to be involved in the pathogenesis of neurodegenerative diseases, but whether it can serve as a biomarker for Alzheimer disease (AD) is not yet known. METHODS: The present study selected four specific LncRNA (17A, 51A, BACE1 and BC200) as possible AD biomarker. RT-qPCR was performed to validate the LncRNA. Receiver operating characteristic curve (ROC) and area under the ROC curve (AUC) were applied to study the potential of LncRNA as a biomarker in a population of 88 AD patients and 72 control individuals. RESULTS: We found that the plasma LncRNA BACE1 level of AD patients was significantly higher than that of healthy controls (p = 0.006). Plasma level of LncRNA 17A, 51A and BC200 did not show a significant difference between two groups (p = 0.098, p = 0.204 and p = 0.232, respectively). ROC curve analysis showed that LncRNA BACE1 was the best candidate of these LncRNA (95% CI: 0.553-0.781, p = 0.003). In addition, no correlation was found for expression of these LncRNA in both control and AD groups with age or MMSE scale (p > 0.05). CONCLUSIONS: Our present study compared the plasma level of four LncRNA between AD and non-AD patients, and found that the level of the BACE1 is increased in the plasma of AD patients and have a high specificity (88%) for AD, indicating BACE1 may be a potential candidate biomarker to predict AD.

Eight-and-a-half syndrome caused by a pontine haemorrhage: a case report and review of the literature.

BACKGROUND: Eight-and-a-half syndrome is caused by a lesion in the dorsal tegmentum of the caudal pons involving parapontine reticular formation and median longitudinal fasciculus, as well as the nucleus and/or the fasciculus of the facial nerve. It is characterized by one-and-a-half syndrome and an ipsilateral cranial nerve VII palsy. Also, many variants of eight-and-a-half syndrome have been described, including nine syndrome, thirteen-and-a-half syndrome and fifteen-and-a-half syndrome. METHODS: We describe a case of a 49-year-old man who presented with eight-and-a-half syndrome combined with contralateral hemiparesis. We reviewed the literature describing the related spectrum of eight-and-a-half syndrome associated with various etiologies. RESULTS: Brain computed tomography scan revealed a hyperdensity located in the left paramedian aspect of the dorsal pons. T2-weighted magnetic resonance imaging at the 11-month follow-up showed hyperintensity and enlargement of the inferior olivary nuclei, which were compatible with a diagnosis of hypertrophic olivary degeneration. In light of our observations and cases reported in the literature, we categorize the spectrum of eight-and-a-half syndrome into three types, namely classic eight-and-a-half syndrome, eight-and-a-half syndrome variants and eight-and-a-half plus syndrome. Besides, the clinical feature and outcome of the three types are discussed in this article. CONCLUSIONS: Recognition of the spectrum of eight-and-a-half syndrome allows precise anatomic localization of the lesion to pontine tegmentum region.

Derivation and Validation of a Clinical Prediction Scale for Isolated Distal Deep Venous Thrombosis in Patients after Acute Ischemic Stroke.

BACKGROUND: Isolated distal deep venous thrombosis (IDDVT) is a common complication after ischemic stroke. However, there is a paucity of evidence regarding the clinical features and risk factors of IDDVT in patients with acute ischemic stroke. This study aimed to establish and validate a clinical prediction scale of IDDVT at an early stage of ischemic stroke development. METHODS: We retrospectively studied consecutive patients with stroke admitted to our neurology department between January and December 2016. Selected clinical variables were assessed by multivariable logistic regression to determine the independent risk factors for IDDVT. A prediction scale was developed and verified by the receiver operating characteristic curve. RESULTS: A total of 671 patients with ischemic stroke were included in the study, with 450 patients allocated into the derivation group and 221 patients into the validation group. A substantial proportion (22.1%) of patients developed IDDVT. A 16-point prediction scale (female gender = 2, older age [≥60 years] = 3, atrial fibrillation = 2, acute infection = 2, active cancer = 5, and higher [≥2.6 mmol/L] level of low-density lipoprotein = 2) derived from a multivariable logistic regression model was highly predictive of 10-day risk of IDDVT in both the validation group (c statistic = .70, 95% confidence interval [CI], .63-0.78, P < .0001) and the derivation group (c statistic = .68, 95% CI, .63-0.74, P < .0001). CONCLUSIONS: This prediction scale may help to identify patients with ischemic stroke who are at a higher risk of developing IDDVT.