OsLCD3 interacts with OsSAMS1 to regulate grain size via ethylene/polyamine homeostasis control.

A fundamental question in developmental biology is how to regulate grain size to improve crop yields. Despite this, little is still known about the genetics and molecular mechanisms regulating grain size in crops. Here, we provide evidence that a putative protein kinase-like (OsLCD3) interacts with the S-adenosyl-L-methionine synthetase 1 (OsSAMS1) and determines the size and weight of grains. OsLCD3 mutation (lcd3) significantly increased grain size and weight by promoting cell expansion in spikelet hull, whereas its overexpression caused negative effects, suggesting that grain size was negatively regulated by OsLCD3. Importantly, lcd3 and OsSAMS1 overexpression (SAM1OE) led to large and heavy grains, with increased ethylene and decreased polyamines production. Based on genetic analyses, it appears that OsLCD3 and OsSAMS1 control rice grain size in part by ethylene/polyamine homeostasis. The results of this study provide a genetic and molecular understanding of how the OsLCD3-OsSAMS1 regulatory module regulates grain size, suggesting that ethylene/polyamine homeostasis is an appropriate target for improving grain size and weight.

Remote ischemic conditioning improves cerebral hemodynamics in symptomatic intracranial atherosclerosis: A PET/CT-guided randomized controlled study.

Patients with symptomatic intracranial arterial stenosis (sICAS) suffer embarrassed hemodynamic status and acute ischemic stroke (AIS) recurrence. We aimed to assess the efficacy of remote ischemic conditioning (RIC) on improving this status by evaluating cerebral blood flow (CBF) and cerebral glucose metabolism (CGM) via PET/CT. Adult patients with unilateral sICAS in middle cerebral artery and/or intracranial segment of internal carotid artery-related AIS or transient ischemic attack within 6 months prior to randomization were enrolled. Individuals who received intravenous thrombolysis or endovascular treatment, or sICAS caused by cardiac embolism, small vessel occlusion, or other determined causes were excluded. Twenty-three eligible patients were randomly assigned to standard medical treatment (SMT) (n = 10) or RIC group (n = 13). The RIC protocol consisted of 5 cycles, each for 5-min bilateral upper limb ischemia and 5-min reperfusion period, twice a day, with a total duration of 3 months. Ten healthy volunteers were enrolled as healthy control group. We tested CBF and CGM at the rest stage and the methazolamide-induced stress stage. All patients received PET/CT at baseline and three-month followup. Both CBF and CGM in ipsilateral hemisphere of sICAS patients were significantly decreased at the rest stage and the stress stage (p < .05), which were improved by three-month RIC (p < .05). The lesions decreased notably in RIC group compared to SMT group (p < .05). RIC ameliorated the hemodynamic status and glucose metabolism in regions at high risk of infarction, which might improve the resistance capacity towards ischemic load in sICAS patients.

White matter hyperintensity burden and collateral circulation in acute ischemic stroke with large artery occlusion.

OBJECTIVE: This study aimed to investigate the association between white matter hyperintensity (WMH) burden and pial collaterals in acute strokes caused by intracranial large artery occlusion treated with mechanical thrombectomy in the anterior circulation, focusing on stroke subtypes. METHODS: Consecutive patients undergoing mechanical thrombectomy between December 2019 and June 2022 were retrospectively screened. The Fazekas scale assessed WMH burden. Pial collaterals were categorized as either poor (0-2) or good (3-4) based on the Higashida score. A multivariable analysis was used to determine the relationship between WMH burden and pial collaterals. Subgroup analyses delved into associations stratified by stroke subtypes, namely cardioembolism (CE), tandem lesions (TLs), and intracranial atherosclerosis (ICAS). RESULTS: Of the 573 patients included, 274 (47.8%) demonstrated poor pial collaterals. Multivariable regression indicated a strong association between extensive WMH burden (Fazekas score of 3-6) and poor collaterals [adjusted OR 3.04, 95% CI 1.70-5.46, P < 0.001]. Additional independent predictors of poor collaterals encompassed ICAS-related occlusion (aOR 0.26, 95% CI 0.09-0.76, P = 0.014), female sex (aOR 0.63, 95% CI 0.41-0.96, P = 0.031), and baseline Alberta Stroke Program Early Computed Tomography scores (aOR 0.80, 95% CI 0.74-0.88, P < 0.001). Notably, an interaction between extensive WMH burden and stroke subtypes was observed in predicting poor collaterals (P = 0.001), being pronounced for CE (adjusted OR 2.30, 95% CI 1.21-4.37) and TLs (adjusted OR 5.09, 95% CI 2.32-11.16), but was absent in ICAS (adjusted OR 1.24, 95% CI 0.65-2.36). CONCLUSIONS: Among patients treated with mechanical thrombectomy for anterior circulation large artery occlusion, extensive WMH burden correlates with poor pial collaterals in embolic occlusion cases (CE and TLs), but not in ICAS-related occlusion.

Association Between Hypoperfusion Intensity Ratio and Postthrombectomy Malignant Brain Edema for Acute Ischemic Stroke.

BACKGROUND: Malignant brain edema (MBE) is a life-threatening complication that can occur after mechanical thrombectomy (MT) for acute ischemic stroke. The hypoperfusion intensity ratio (HIR) reflects the tissue-level perfusion status within the ischemic territory. This study investigated the association between HIR and MBE occurrence after MT in patients with anterior circulation large artery occlusion. METHODS: We conducted a retrospective cohort study of patients who received MT at a comprehensive stroke center from February 2020 to June 2022. Using computed tomography perfusion, the HIR was derived from the ratio of tissue volume with a time to maximum (Tmax) > 10 s to that with a Tmax > 6 s. We dichotomized patients based on the occurrence of MBE following MT. The primary outcome, assessed using a multivariable logistic regression model, was the MBE occurrence post MT. The secondary outcome focused on favorable outcomes, defined as achieving a modified Rankin Scale score of 0-2 at 90 days. RESULTS: Of the 603 included patients, 90 (14.9%) developed MBE after MT. The median HIR exhibited a significantly higher value in the MBE group compared with the non-MBE group (0.5 vs. 0.3; P < 0.001). Multivariable logistic regression analysis indicated that a higher HIR (adjusted odds ratio [aOR] 8.98; 95% confidence interval [CI] 2.85-28.25; P < 0.001), baseline large infarction (Alberta Stroke Program Early Computed Tomography Score < 6; aOR 1.77; 95% CI 1.04-3.01; P = 0.035), internal carotid artery occlusion (aOR 1.80; 95% CI 1.07-3.01; P = 0.028), and unsuccessful recanalization (aOR 8.45; 95% CI 4.75-15.03; P < 0.001) were independently associated with MBE post MT. Among those with successful recanalization, a higher HIR (P = 0.017) and baseline large infarction (P = 0.032) remained as predictors of MBE occurrence. Furthermore, a higher HIR (P = 0.001) and the occurrence of MBE (P < 0.001) both correlated with reduced odds of achieving favorable outcomes. CONCLUSIONS: The presence of a higher HIR on pretreatment perfusion imaging serves as a robust predictor for MBE occurrence after MT, irrespective of successful recanalization.

Perfusion deficits in thrombolysis-treated acute ischemic stroke patients with negative or positive diffusion-weighted imaging.

OBJECTIVE: Magnetic resonance imaging (MRI) and CT perfusion may provide diagnostic information for intravenous tissue-type plasminogen activator (IV t-PA) administration in acute ischemic stroke (AIS) patients. We aimed to compare the clinical features and perfusion deficits of diffusion weighted imaging (DWI)-negative and DWI-positive AIS patients. METHODS: This retrospective and observational study included thrombolysis-treated AIS patients undergoing multimodel CT imaging before treatment and DWI after treatment between 2021 and 2022. Two experienced neuroradiologists blindly and independently examined the images to identify perfusion deficits in AIS patients. The patients were divided into DWI-positive and DWI-negative groups based on visible hyperintense lesions on DWI. A modified Rankin scale (mRS) score of ≤ 2 indicated good functional outcomes at discharge. Sensitivity analysis was conducted to determine whether CT perfusion was an independent predictor of positive DWI imaging on follow-up. RESULTS: This study included 151 patients, of whom 35 (23.2%) patients were DWI-negative on follow-up. These DWI-negative patients were less likely to have a medical history of atrial fibrillation; they had lower triglyceride levels, a shorter admission time, lower National Institutes of Health Stroke Scale (NIHSS) scores after IV t-PA and lower mRS scores at discharge, and had better functional outcomes. A total of 37.1% of DWI-positive and 25.7% of DWI-negative patients had vascular stenosis (P = 0.215). A total of 47.4% of DWI-positive and 37.1% of DWI-negative patients had CT perfusion deficits (P = 0.284). A total of 73.5% of patients with normal CT perfusion had positive DWI, while 19.1% of patients with perfusion deficits had negative DWI. The sensitivity and specificity of NCCT were 14.8% and 97.1% (Kappa = 0.061, P = 0.074), CTP was 47.4% and 62.9% for predicting DWI lesion (Kappa = 0.069, P = 0.284). CONCLUSIONS: About 23.2% of AIS patients who received intravenous thrombolysis treatment did not have a relevant DWI-MRI lesion on follow-up. Over one-third of patients in the DWI-MRI negative group showed CT perfusion deficits, with a sensitivity of 47.4% for predicting DWI lesions in non-mechanical thrombectomy patients.

Peripheral neuropathy associated with chronic lymphoproliferative disorders of natural killer cells (CLPD-NK): a case report and literature review.

BACKGROUND: Chronic lymphoproliferative disorders of natural killer cells (CLPD-NK) is a rare lymphoproliferative disease. Peripheral neuropathy is an unusual symptom of CLPD-NK. We report a case of peripheral neuropathy associated with CLPD-NK and perform a review of literatures. CASE PRESENTATION: a 62-year-old woman presented with progressive numbness and weakness in both extremities. Electrophysiological examinations indicated a sensorimotor polyneuropathy. Peripheral blood examination revealed that the number of white blood cells (WBC) and lymphocytes were significantly increased. Flow cytometry analysis identified that 84% of the lymphocytes are NK cells that mainly expressed CD56, combined with variable expression of CD16, CD2, CD7, CD94, granzyme B, perforin, and CD158 but negative for CD3. Sural nerve biopsy revealed that a plethora of NK cells infiltrated into nerve fascicles. On treatment with combined cyclophosphamide and corticosteroids, her symptoms rapidly improved. Moreover, the absolute lymphocyte count and its proportion recovered to normal range after 3 months' treatment. CONCLUSION: To the best of our knowledge, this is the first case report of peripheral neuropathy associated with CLPD-NK from Chinese. This rare lymphoproliferative disease should be considered if peripheral neuropathy combines with increased WBC or lymphocytes. Immunosuppressive drugs are the major treatment and most patients can achieve a good prognosis.

Effect of leukoaraiosis on collateral circulation in acute ischemic stroke treated with endovascular therapy: a meta-analysis.

BACKGROUND AND OBJECTIVE: The recruitment of collateral circulation correlates with a balance of the microvasculature. Uncertainty remains to be made about the association of leukoaraiosis with leptomeningeal collaterals. To explore the effect of leukoaraiosis on leptomeningeal collaterals in patients treated with endovascular therapy. METHODS: Observational studies exploring the correlation between leukoaraiosis and leptomeningeal collaterals in large vessel occlusion treated with endovascular therapy were searched from PubMed, EMBASE, and Cochrane Libraries databases. Two independent reviewers retrieved eligible literature, extracted purpose-related data, and utilized the Newcastle-Ottawa Scale to evaluate the risk of bias. A Mantel-Haenszel method was used to calculate the odds ratio (OR). Meta-regression and subgroup analyses were conducted to clarify heterogeneity. RESULTS: Data from 10 studies with 1606 patients were extracted for pooled analysis. Compared to non-severe leukoaraiosis, patients with severe leukoaraiosis showed significant relevance to poor leptomeningeal collaterals (OR, 2.13; 95% confidence interval [1.27-3.57]; P = 0.004). Meta-regression indicated that sample size (coefficient = -0.007299, P = 0.035) and the number of female patients (coefficient = -0.0174709, P = 0.020) were sources of heterogeneity. Furthermore, all of the countries (USA versus France versus China, Q = 3.67, P = 0.159), various assessment scales of leukoaraiosis (the Fazekas scale versus Non-Fazekas scales, Q = 0.77, P = 0.379), and different imaging methods of leukoaraiosis (computed tomography versus magnetic resonance imaging, Q = 2.12, P = 0.146) and leptomeningeal collaterals (computed tomography angiography versus digital subtraction angiography, Q = 1.21, P = 0.271) showed no contribution to the effect size. CONCLUSION: Severe leukoaraiosis is associated with poor leptomeningeal collaterals in patients treated with endovascular therapy. Further studies may focus on whether the finding applies to different stroke subtypes.

Genetic variation in glia-neuron signalling modulates ageing rate.

The rate of behavioural decline in the ageing population is remarkably variable among individuals. Despite the considerable interest in studying natural variation in ageing rate to identify factors that control healthy ageing, no such factor has yet been found. Here we report a genetic basis for variation in ageing rates in Caenorhabditis elegans. We find that C. elegans isolates show diverse lifespan and age-related declines in virility, pharyngeal pumping, and locomotion. DNA polymorphisms in a novel peptide-coding gene, named regulatory-gene-for-behavioural-ageing-1 (rgba-1), and the neuropeptide receptor gene npr-28 influence the rate of age-related decline of worm mating behaviour; these two genes might have been subjected to recent selective sweeps. Glia-derived RGBA-1 activates NPR-28 signalling, which acts in serotonergic and dopaminergic neurons to accelerate behavioural deterioration. This signalling involves the SIR-2.1-dependent activation of the mitochondrial unfolded protein response, a pathway that modulates ageing. Thus, natural variation in neuropeptide-mediated glia-neuron signalling modulates the rate of ageing in C. elegans.

Cerebral Microbleeds Are Associated with Widespread Blood-Brain Barrier Leakage.

INTRODUCTION: The pathogenesis of cerebral microbleeds (CMBs) is incompletely understood, but blood-brain barrier (BBB) leakage may play a key role. This study aimed to investigate the relationship between compromised BBB integrity and CMBs as well as cognitive function. METHODS: Ninety-seven participants were enrolled in this cross-sectional study, involving 24 CMB patients. Dynamic contrast-enhanced-magnetic resonance imaging was used to measure BBB permeability, and cognitive function was assessed by Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). RESULTS: Compared with participants without CMBs, CMB patients had higher volume transfer constant (Ktrans, all p < 0.01) and area under the concentration curve (AUC, all p < 0.05) in normal-appearing white matter (NAWM), white matter hyperintensities (WMH), cortical gray matter (CGM), and deep gray matter (DGM). Multivariable linear regression analyses revealed that CMB patients had significantly higher Ktrans in NAWM and AUC in NAWM, WMH, and CGM after adjustment for age, sex, vascular risk factors, and cognitive scores. MMSE and MoCA scores decreased with increasing Ktrans in WMH and DGM as well as AUC in WMH after adjustment for age, sex, CMB group, and education length. CONCLUSION: This study demonstrated that widespread BBB leakage was prevalent in CMB patients, suggesting that compromised BBB integrity may play a key role in the pathogenesis of CMBs and could lead to cognitive impairment.

Impact of Cerebral Microbleeds on Gait, Balance, and Upper Extremities Function in Cerebral Small Vessel Disease.

BACKGROUND AND PURPOSE: White matter hyperintensites (WMHs) , lacunes and brain atrophy have been demonstrated to be positively related to gait disorder. However, cerebral microbleeds (CMBs) as a manifestation of cerebral small vessel disease (CSVD) is still under-investigated. Therefore, correlations between CMBs and upper extremity, gait and balance performance were investigated in this study. METHODS: A cross-sectional study of middle-aged to older adults was conducted. CSVD burden was measured with magnetic resonance imaging (MRI) and the location and number of CMBs were analysed. Gait and balance functions were evaluated using a four meter walkway, Tinetti, Timed-Up-and-Go (TUG) and Short Physical Performance Battery (SPPB) tests. Upper extremity function was measured by 10 repeated pronation-supination time, 10 repeated finger tapping time, and 10 repeated opening and closings of the hands. RESULTS: A total of 224 participants were included in this study, with a mean age of 60.6 ± 10.5 years. The prevalence of CMB was 34.8% and most was lobar. Multiple linear regression analysis showed that CMB was associated with lower gait velocity, wider stride width, longer TUG test time, and poor performance on Tinetti and SPPB tests independently of other coexisting CSVD markers and risk factors. These relationships appeared to be explained by CMBs in the frontal, temporal, basal ganglia and infratentorial regions. The motor function of upper extremity also had independent correlations with CMBs especially in frontal, parietal, and temporal areas, and in the basal ganglia. CONCLUSIONS: CMBs were found to be associated with both gait, balance and upper extremity disturbances. The presence of CMB seems to be another major driving force for CSVD on lower and upper extremity impairment in healthy elderly subjects.

OsGA3ox genes regulate rice fertility and plant height by synthesizing diverse active GA.

Gibberellin (GA) is an important hormone, which is involved in regulating various growth and development. GA biosynthesis pathway and synthetase have been basically clarified. Gibberellin 3ß hydroxylase (GA3ox) is the key enzyme for the synthesis of various active GA. There are two GA3ox genes (OsGA3ox1 and OsGA3ox2) in rice, and their physiological functions have been preliminarily studied. However, it is not clear how they work together to synthesize active GA to regulate rice development. In this study, the knockout mutants ga3ox1 and ga3ox2 were obtained by CRISPR/Cas9 technology. The pollen fertility of ga3ox1 decreased significantly, while the plant height of ga3ox2 decreased significantly. It shows that OsGA3ox1 is necessary for normal pollen development, while OsGA3ox2 is necessary for stem and leaf elongation. Tissue expression analysis showed that OsGA3ox1 was mainly expressed in unopened flowers, while OsGA3ox2 was mainly expressed in unexpanded leaves. The GA in different tissues of wild type (WT), and two ga3ox mutants were detected. It was found that pollen fertility is most closely related to the content of GA7, and plant height is most closely related to the content of GA1. It was found that OsGA3ox1 catalyzes GA9 to GA7 in flowers, which is closely related to pollen fertility; OsGA3ox2 catalyzes the GA20 to GA1 in unexpanded leaves, thereby regulating plant height; OsGA3ox1 catalyzes the GA19 to GA20 in roots, regulating the generation of GA3. OsGA3ox1 and OsGA3ox2 respond to developmental and environmental signals, and cooperate to synthesize endogenous GA in different tissues to regulate rice development. This study provides a reference for clarifying its role in GA biosynthesis pathway and further understanding the function of OsGA3ox.

Fine mapping of powdery mildew resistance gene MlWE74 derived from wild emmer wheat (Triticum turgidum ssp. dicoccoides) in an NBS-LRR gene cluster.

KEY MESSAGE: Powdery mildew resistance gene MlWE74, originated from wild emmer wheat accession G-748-M, was mapped in an NBS-LRR gene cluster of chromosome 2BS. Wheat powdery mildew, caused by Blumeria graminis f. sp. tritici (Bgt), is a globally devastating disease. Wild emmer wheat (Triticum turgidum var. dicoccoides) is a valuable genetic resource for improving disease resistance in common wheat. A powdery mildew resistance gene was transferred to hexaploid wheat line WE74 from wild emmer accession G-748-M. Genetic analysis revealed that the powdery mildew resistance in WE74 is controlled by a single dominant gene, herein temporarily designated MlWE74. Bulked segregant analysis (BSA) and molecular mapping delimited MlWE74 to the terminal region of chromosome 2BS flanking by markers WGGBD412 and WGGBH346 within a genetic interval of 0.25 cM and corresponding to 799.9 kb genomic region in the Zavitan reference sequence. Sequence annotation revealed two phosphoglycerate mutase-like genes, an alpha/beta-hydrolases gene, and five NBS-LRR disease resistance genes that could serve as candidates for map-based cloning of MlWE74. The geographical location analysis indicated that MlWE74 is mainly distributed in Rosh Pinna and Amirim regions, in the northern part of Israel, where environmental conditions are favorable to the occurrence of powdery mildew. Moreover, the co-segregated marker WGGBD425 is helpful in marker-assisted transfer of MlWE74 into elite cultivars.

Regio- and Diastereoselective Construction of Functionalized Benzo[b]oxepines and Benzo[b]azepines via Recyclable Gold(I)-Catalyzed Cyclizations.

The heterogeneous gold-catalyzed cyclization of (o-alkynyl)phenoxy- or N-(o-alkynylphenyl)tolylsulfonamidoacrylates with alcohols has been developed by using an MCM-41-anchored diphenylphosphine-Au(I) complex [MCM-41-Ph2P-AuNTf2] as the catalyst under mild reaction conditions, yielding diverse functionalized benzo[b]oxepines or benzo[b]azepines with good to high yields and excellent diastereoselectivity. This heterogenized gold(I) catalyst exhibits a comparable activity to homogeneous Ph3PAuNTf2 and can be facilely recovered by a simple filtration of the reaction solution and reused more than seven times with almost a consistent catalytic efficiency.

Pyrroloquinoline quinone ameliorates diabetic cardiomyopathy by inhibiting the pyroptosis signaling pathway in C57BL/6 mice and AC16 cells.

PURPOSE: Diabetic cardiomyopathy (DCM), a common complication of diabetes mellitus and is characterized by myocardial hypertrophy and myocardial fibrosis. Pyrroloquinoline quinone (PQQ), a natural nutrient, exerts strong protection against various myocardial diseases. Pyroptosis, a type of inflammation-related programmed cell death, is vital to the development of DCM. However, the protective effects of PQQ against DCM and the associated mechanisms are not clear. This study aimed to investigate whether PQQ protected against DCM and to determine the underlying molecular mechanism. METHODS: Diabetes was induced in mice by intraperitoneal injection of streptozotocin, after which the mice were administered PQQ orally (10, 20, or 40 mg/kg body weight/day) for 12 weeks. AC16 human myocardial cells were divided into the following groups and treated accordingly: control (5.5 mmol/L glucose), high glucose (35 mmol/L glucose), and HG + PQQ groups (1 and 10 nmol/L PQQ). Cells were treated for 24 h. RESULTS: PQQ reduced myocardial hypertrophy and the area of myocardial fibrosis, which was accompanied by an increase in antioxidant function and a decrease in inflammatory cytokine levels. Moreover, myocardial hypertrophy-(ANP and BNP), myocardial fibrosis-(collagen I and TGF-ß1), and pyroptosis-related protein levels decreased in the PQQ treatment groups. Furthermore, PQQ abolished mitochondrial dysfunction and the activation of NF-κB/IκB, and decreased NLRP3 inflammation-mediated pyroptosis in AC16 cells under high-glucose conditions. CONCLUSION: PQQ improved DCM in diabetic mice by inhibiting NF-κB/NLRP3 inflammasome-mediated cell pyroptosis. Long-term dietary supplementation with PQQ may be greatly beneficial for the treatment of DCM. Diagram of the underlying mechanism of the effects of PQQ on DCM. PQQ inhibits ROS generation and NF-κB activation, which stimulates activation of the NLRP3 inflammasome and regulates the expression of caspase-1, IL-1ß, and IL-18. The up-regulated inflammatory cytokines trigger myocardial hypertrophy and cardiac fibrosis and promote the pathological process of DCM.

A Retrospective Study of the Clinical Characteristics of Japanese Encephalitis in Adults.

OBJECTIVE: This study aimed to explore the diagnostic points and treatment modes of the clinical characteristics of Japanese encephalitis (JE) in the middle-aged and elderly population. METHODS: Six patients aged 47-72 who were diagnosed with JE at the Beijing Chaoyang Hospital Affiliated with the Capital Medical University between August 2018 and September 2019 were enrolled in the study. Their clinical manifestations, biochemical indicators, imaging data, diagnostic methods, and the evolution and outcomes of the treatments they underwent were retrospectively analyzed. RESULTS: (1) All six patients had severe clinical symptoms and poor prognoses that were more likely to be associated with other systemic diseases. (2) Lesions were most commonly distributed in the thalamus, basal ganglia, and midbrain. The appearance of hyperintensity in the corpus callosum, hippocampus, and subcortical white matter was more specific. The hyperperfusion metabolism in the lesion area in head computed tomography perfusion imaging indicated the state of inflammatory activity in the lesion. In cranial magnetic resonance imaging (MRI), T2 and fluid-attenuated inversion recovery (FLAIR) were more sensitive. (3) After a patient has been systematically treated in the intensive care unit (ICU), the patient gradually recovered and the level of consciousness improved (p < 0.05). CONCLUSIONS: In brain MRI-especially T2 and FLAIR-intracranial infection is often accompanied by abnormal signals in the thalamus, midbrain, hippocampus, and white matter hyperintensity (WMH), which is highly suggestive of JE. The positive detection of anti-JE virus immunoglobulin M antibodies in a patient's serum and/or cerebrospinal fluid can confirm the diagnosis of JE, and comprehensive ICU treatment (hormones combined with anti-inflammatory, antiviral, and mild hypothermic cerebral protection therapies) can improve the survival rate.

Incidence and clinical features of acute multiple small cerebellar infarction.

OBJECTIVE: To investigate the clinical and imaging features and to identify possible etiology of acute multiple small cerebellar infarction (MSCI). METHODS: We retrospectively enrolled 220 patients with acute cerebellar infarction, divided them into MSCI and large cerebellar infarction (LCI) groups, according to the quantity and size of lesions confirmed by MRI analysis. Clinical and imaging features were compared between the two groups to explore the possible etiology and pathogenesis. RESULTS: Among 220 patients, 90 patients presented MSCI symptoms. The proportions of extracerebellar lesions (P = 0.001) and bilateral infarction (P = 0.001) in the MSCI group were higher than those in the LCI group. No significant differences were found in terms of age, gender, and common vascular risk factors between the two groups. The proportions of vertigo and headache in the MSCI group were significantly lower than those in the LCI group (P < 0.000 and 0.034, respectively), and limb weakness was significantly higher (P = 0.039) in the MSCI patients. Moreover, the proportions of nystagmus and ataxia in the MSCI group were significantly lower than those in the LCI group (P < 0.043 and 0.003, respectively). The MSCI group had higher proportions of ACA and MCA stenosis, while the proportion of posterior circulation stenosis was similar between the two groups. Infarctions involving the posterior inferior cerebellar (PICA) region and mixed territories were far more frequent than those involving the anterior inferior cerebellar artery (AICA) region and superior cerebellar artery (SCA) territory (P < 0.05). Large-artery atherosclerosis and multiple plus undetermined etiology were the main etiological factors of MSCI. CONCLUSION: In patients with acute cerebellar infarction, 30% of patients presented with MSCI. MSCI and LCI showed similar vascular risk factors and vascular stenosis in the posterior circulation system. Patients with MSCI should pay more attention to evaluating anterior circulation vessels' anatomy. Large-artery atherosclerosis was the main pathogenesis of acute MSCI. Assessment of cerebral vessels might be critically required in patients with MSCI complicated atrial fibrillation.

PD-L1 positively regulates MET phosphorylation through inhibiting PTP1B.

Increasing bodies of evidence support the involvement of tumor-intrinsic action in PD-L1-mediated cancer progression. However, the mechanisms underlying the tumor-intrinsic function of PD-L1 are less well understood. In the present study, we found a positive correlation between PD-L1 expression and MET phosphorylation in lung cancer and melanoma cell lines. PD-L1 inhibition led to a decrease in MET phosphorylation, while PD-L1 induction by IFN-γ resulted in a PD-L1-dependent increase of MET phosphorylation both in vitro and in vivo. The results indicated that MET phosphorylation can be positively regulated by PD-L1. Furthermore, we identified PTP1B as a mediator contributing to the regulation of MET phosphorylation by PD-L1. In agreement with the induction of MET phosphorylation by PD-L1, inhibition of PD-L1 caused reduced phosphorylation of ERKs, a known downstream kinase of MET, and inhibited cell proliferation. Collectively, the present study demonstrated for the first time that the MET pathway, as a downstream of PD-L1, contributed to its tumor-intrinsic effect, and provided a novel mechanistic explanation for the tumor-intrinsic function of PD-L1 and a rationale for the combination of immunotherapy and MET-targeted therapy in cancer treatment.

Methylseleninic acid overcomes programmed death-ligand 1-mediated resistance of prostate cancer and lung cancer.

Programmed death-ligand 1 (PD-L1)-mediated resistance has become a great challenge for tumor treatment. Cisplatin increased tumor PD-L1 expression, promoted chemotherapy resistance. Interferon-γ (IFN-γ)-induced PD-L1 expression might facilitate immunotherapy resistance. Methylseleninic acid (MSeA), a selenium (Se) compound, offered superior cancer chemo-preventive activities and enhanced tumor sensitivity to diverse chemotherapeutic drugs. This study explored the effects of MSeA on the PD-L1-mediated resistance using both in vitro and in vivo models. Results showed that MSeA substantially attenuated cisplatin-induced PD-L1 expression via inhibiting protein kinase B phosphorylation, thereby potentiated cisplatin cytotoxicity in prostate and lung cancer cell models. In lung cancer xenograft model, MSeA significantly suppressed cisplatin-induced PD-L1 expression, consequently enhanced T-cell immunity, ultimately improved the therapeutic efficacy of cisplatin. Moreover, IFN-γ-induced tumor PD-L1 expression was remarkably reduced by MSeA, with correlated reductions in janus kinase 2 and signal transducer and activator of transcription 3 (STAT3) phosphorylation in prostate and lung cancer cell models. Our findings, for the first time, demonstrated that MSeA is a potential agent to overcome PD-L1-mediated chemotherapy and immunotherapy resistance. Such information might have potential clinical implications for prostate and lung cancer treatment.

Circ-RNF121 regulates tumor progression and glucose metabolism by miR-1224-5p/FOXM1 axis in colorectal cancer.

AIM: Previous studies have reported that circular RNA (circRNA) is associated with the pathogenesis of CRC. This study was designed to reveal the mechanism of circ-ring finger protein 121 (circ-RNF121) in colorectal cancer (CRC). MATERIALS AND METHODS: The levels of circ-RNF121, microRNA-1224-5p (miR-1224-5p) and forkhead box M1 (FOXM1) were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Protein level was detected by western blot. Cell proliferation was analyzed by 3-(4,5-Dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and cell colony formation assays. Flow cytometry analysis was performed to investigate cell apoptosis. Cell migration and invasion were investigated by transwell and wound-healing assays. Cell glycolysis was detected using glucose, lactate and ADP/ATP ratio assay kits. The binding relationship between miR-1224-5p and circ-RNF121 or FOXM1 was predicted by starBase online database, and identified by dual-luciferase reporter assay. The impacts of circ-RNF121 silencing on tumor formation in vivo were disclosed by in vivo tumor formation assay. KEY FINDINGS: Circ-RNF121 and FOXM1 expression were dramatically upregulated, while miR-1224-5p expression was downregulated in CRC tissues or cells compared with control groups. Circ-RNF121 silencing repressed cell proliferation, migration, invasion and glycolysis but induced cell apoptosis in CRC, which were attenuated by miR-1224-5p inhibitor. Additionally, circ-RNF121 acted as a sponge of miR-1224-5p and miR-1224-5p bound to FOXM1. Circ-RNF121 silencing inhibited tumor growth in vivo. Furthermore, circ-RNF121 was secreted through being packaged into exosomes. SIGNIFICANCE: The finding provided a novel insight into studying circRNA-mediated CRC therapy.

Benzene-Bridged Organosilica Modified Mesoporous Silica Nanoparticles via an Acid-Catalysis Approach.

Surface functionalization of mesoporous silica nanoparticles is important for their applications but fairly challenging using benzene-bridged organosilane as the precursor through the postsynthesis approach. Herein, we report an acid-catalysis approach for the postmodification of benzene-bridged organosilica onto the surface of large-pore mesoporous silica nanoparticles. By using HCl (∼1 M) as the acid catalyst in a tetrahydrofuran solvent, the self-assembly of the bridged organosilica precursor is avoided, while surface modification of mesoporous silica nanoparticles is promoted with controllable organic contents and retained large pore sizes. This strategy can also be applied to the postmodification of organosilica with end benzene groups. The strategy developed in this study is expected to be applied for the postmodification of other organosilica precursors with various functions.