The ZAR1 resistosome is a calcium-permeable channel triggering plant immune signaling.

Nucleotide-binding, leucine-rich repeat receptors (NLRs) are major immune receptors in plants and animals. Upon activation, the Arabidopsis NLR protein ZAR1 forms a pentameric resistosome in vitro and triggers immune responses and cell death in plants. In this study, we employed single-molecule imaging to show that the activated ZAR1 protein can form pentameric complexes in the plasma membrane. The ZAR1 resistosome displayed ion channel activity in Xenopus oocytes in a manner dependent on a conserved acidic residue Glu11 situated in the channel pore. Pre-assembled ZAR1 resistosome was readily incorporated into planar lipid-bilayers and displayed calcium-permeable cation-selective channel activity. Furthermore, we show that activation of ZAR1 in the plant cell led to Glu11-dependent Ca2+ influx, perturbation of subcellular structures, production of reactive oxygen species, and cell death. The results thus support that the ZAR1 resistosome acts as a calcium-permeable cation channel to trigger immunity and cell death.

Cooperative actin filament nucleation by the Arp2/3 complex and formins maintains the homeostatic cortical array in Arabidopsis epidermal cells.

Precise control over how and where actin filaments are created leads to the construction of unique cytoskeletal arrays within a common cytoplasm. Actin filament nucleators are key players in this activity and include the conserved actin-related protein 2/3 (Arp2/3) complex as well as a large family of formins. In some eukaryotic cells, these nucleators compete for a common pool of actin monomers and loss of one favors the activity of the other. To test whether this mechanism is conserved, we combined the ability to image single filament dynamics in the homeostatic cortical actin array of living Arabidopsis (Arabidopsis thaliana) epidermal cells with genetic and/or small molecule inhibitor approaches to stably or acutely disrupt nucleator activity. We found that Arp2/3 mutants or acute CK-666 treatment markedly reduced the frequency of side-branched nucleation events as well as overall actin filament abundance. We also confirmed that plant formins contribute to side-branched filament nucleation in vivo. Surprisingly, simultaneous inhibition of both classes of nucleator increased overall actin filament abundance and enhanced the frequency of de novo nucleation events by an unknown mechanism. Collectively, our findings suggest that multiple actin nucleation mechanisms cooperate to generate and maintain the homeostatic cortical array of plant epidermal cells.

Evolution of the thermostability of actin-depolymerizing factors enhances the adaptation of pollen germination to high temperature.

Double fertilization in many flowering plants (angiosperms) often occurs during the hot summer season, but the mechanisms that enable angiosperms to adapt specifically to high temperatures are largely unknown. The actin cytoskeleton is essential for pollen germination and the polarized growth of pollen tubes, yet how this process responds to high temperatures remains unclear. Here, we reveal that the high thermal stability of 11 Arabidopsis (Arabidopsis thaliana) actin-depolymerizing factors (ADFs) is significantly different: ADFs that specifically accumulate in tip-growing cells (pollen and root hairs) exhibit high thermal stability. Through ancestral protein reconstruction, we found that subclass II ADFs (expressed specifically in pollen) have undergone a dynamic wave-like evolution of the retention, loss, and regeneration of thermostable sites. Additionally, the sites of AtADF7 with high thermal stability are conserved in ADFs specific to angiosperm pollen. Moreover, the high thermal stability of ADFs is required to regulate actin dynamics and turnover at high temperatures to promote pollen germination. Collectively, these findings suggest strategies for the adaptation of sexual reproduction to high temperature in angiosperms at the cell biology level.

Myosin XI-mediated BIK1 recruitment to nanodomains facilitates FLS2-BIK1 complex formation during innate immunity in Arabidopsis.

Plants rely on immune receptor complexes at the cell surface to perceive microbial molecules and transduce these signals into the cell to regulate immunity. Various immune receptors and associated proteins are often dynamically distributed in specific nanodomains on the plasma membrane (PM). However, the exact molecular mechanism and functional relevance of this nanodomain targeting in plant immunity regulation remain largely unknown. By utilizing high spatiotemporal resolution imaging and single-particle tracking analysis, we show that myosin XIK interacts with remorin to recruit and stabilize PM-associated kinase BOTRYTIS-INDUCED KINASE 1 (BIK1) within immune receptor FLAGELLIN SENSING 2 (FLS2)-containing nanodomains. This recruitment facilitates FLS2/BIK1 complex formation, leading to the full activation of BIK1-dependent defense responses upon ligand perception. Collectively, our findings provide compelling evidence that myosin XI functions as a molecular scaffold to enable a spatially confined complex assembly within nanodomains. This ensures the presence of a sufficient quantity of preformed immune receptor complex for efficient signaling transduction from the cell surface.

Engineering of NEMO as calcium indicators with large dynamics and high sensitivity.

Genetically encoded calcium indicators (GECIs) are indispensable tools for real-time monitoring of intracellular calcium signals and cellular activities in living organisms. Current GECIs face the challenge of suboptimal peak signal-to-baseline ratio (SBR) with limited resolution for reporting subtle calcium transients. We report herein the development of a suite of calcium sensors, designated NEMO, with fast kinetics and wide dynamic ranges (>100-fold). NEMO indicators report Ca2+ transients with peak SBRs around 20-fold larger than the top-of-the-range GCaMP6 series. NEMO sensors further enable the quantification of absolution calcium concentration with ratiometric or photochromic imaging. Compared with GCaMP6s, NEMOs could detect single action potentials in neurons with a peak SBR two times higher and a median peak SBR four times larger in vivo, thereby outperforming most existing state-of-the-art GECIs. Given their high sensitivity and resolution to report intracellular Ca2+ signals, NEMO sensors may find broad applications in monitoring neuronal activities and other Ca2+-modulated physiological processes in both mammals and plants.

Astaxanthin activates the Nrf2/Keap1/HO-1 pathway to inhibit oxidative stress and ferroptosis, reducing triphenyl phosphate (TPhP)-induced neurodevelopmental toxicity.

Triphenyl phosphate (TPhP) serves as a major organophosphorus flame retardant, and its induced neurodevelopmental toxicity has attracted widespread attention, but the mechanism remains unclear. In this study, we involved zebrafish to explore the new mechanism of TPhP inducing oxidative stress and ferroptosis to promote neurodevelopmental toxicity. The results suggested that TPhP affected the embryonic development, reduced the number of new neurons, and led to abnormal neural behavior in zebrafish larvae. TPhP also induced ROS accumulation, activated the antioxidant defense signal Nrf2 and Keap1, and significantly changed the activities of Acetylcholinesterase (AChE), Adenosine triphosphatase (ATPase) and glutathione S-transferase (GST). In addition, TPhP induced ferroptosis in zebrafish, which was reflected in the increase of Fe2+ content, the abnormal expression of GPX4 protein and genes related to iron metabolism (gpx4a, slc7a11, acsl4b, tfa, slc40a1, fth1b, tfr2, tfr1a, tfr1b and ncoa4). Astaxanthin intervention specifically inhibited ROS levels, and reversed SLC7A11 and GPX4 expression levels and Fe2+ metabolism thus alleviating ferroptosis induced by TPhP. Astaxanthin also partially reversed the activity of AChE, GST and the expression of neurodevelopmental-related genes (gap43, gfap, neurog1 and syn2a), so as to partially rescue the embryonic developmental abnormalities and motor behavior disorders induced by TPhP. More interestingly, the expression of mitochondrial apoptosis-related protein BAX, anti-apoptotic protein BCL-2, Caspase3 and Caspase9 was significantly altered in the TPhP exposed group, which could be also reversed by Astaxanthin intervention. In summary, our results suggested that TPhP exposure can induce oxidative stress and ferroptosis, thereby causing neurodevelopment toxicity to zebrafish, while Astaxanthin can partially reverse oxidative stress and reduce the neurodevelopmental toxicity of zebrafish larvae by activating Nrf2/Keap1/HO-1 signaling pathway.

Mediation of Systemic Inflammation on Insulin Resistance and Prognosis of Nondiabetic Patients With Ischemic Stroke.

BACKGROUND: Insulin resistance is associated with stroke recurrence and poor functional outcomes of nondiabetic patients with ischemic stroke. The study aimed to investigate whether the association between insulin resistance and the prognosis of nondiabetic patients with ischemic stroke was mediated by systematic inflammation. METHODS: Patients with ischemic stroke but without a history of diabetes who were enrolled in CNSR-III (Third China National Stroke Registry) were included in the study and followed up for 1 year after stroke onset. Insulin resistance was determined by using the homeostasis model assessment for insulin resistance (HOMA-IR) method. hs-CRP (high-sensitivity C-reactive protein) and Lp-PLA2 (lipoprotein-associated phospholipase A2) activity were measured at baseline. The primary outcome was stroke recurrence, and other outcomes included composite vascular events, mortality, and poor functional outcome (modified Rankin Scale score, 3-6). Multivariable Cox or logistic regression analyses were performed to estimate the association between HOMA-IR and the study outcomes. A mediation analysis was performed to examine the relationship between insulin resistance and the study outcomes mediated by systemic inflammation. RESULTS: Among a total of 3808 nondiabetic patients with ischemic stroke who were included in the study, the median HOMA-IR was 1.79 (interquartile range, 1.05-2.97). After adjustments for potential confounders, higher HOMA-IR quartiles were associated with higher risks of stroke recurrence, ischemic stroke, and composite vascular events, especially in the large artery atherosclerosis subtype. hs-CRP partially mediated the association between the HOMA-IR index and the prognosis of ischemic stroke (mediation proportion, 5.9% for stroke recurrence and 7.5% for composite vascular events). No evidence of Lp-PLA2 activity mediating the association of insulin resistance with stroke outcomes was observed. CONCLUSIONS: Our study found that insulin resistance was associated with poor clinical outcomes in nondiabetic patients with ischemic stroke, which was partially mediated by hs-CRP with a modest amount.

Basally distributed actin array drives embryonic hypocotyl elongation during the seed-to-seedling transition in Arabidopsis.

Seed germination is a vital developmental transition for the production of progeny by sexual reproduction in spermatophytes. The seed-to-seedling transition is predominately driven by hypocotyl cell elongation. However, the mechanism that underlies hypocotyl growth remains largely unknown. In this study, we characterized the actin array reorganization in embryonic hypocotyl epidermal cells. Live-cell imaging revealed a basally organized actin array formed during hypocotyl cell elongation. This polarized actin assembly is a barrel-shaped network, which comprises a backbone of longitudinally aligned actin cables and a fine actin cap linking these cables. We provide genetic evidence that the basal actin array formation requires formin-mediated actin polymerization and directional movement of actin filaments powered by myosin XIs. In fh1-1 and xi3ko mutants, actin filaments failed to reorganize into the basal actin array, and the hypocotyl cell elongation was inhibited compared with wild-type plants. Collectively, our work uncovers the molecular mechanisms for basal actin array assembly and demonstrates the connection between actin polarization and hypocotyl elongation during seed-to-seedling transition.

Cuproptosis-Associated lncRNA Gene Signature Establishes New Prognostic Profile and Predicts Immunotherapy Response in Endometrial Carcinoma.

Uterine corpus endometrial carcinoma (UCEC), a prevalent kind of cancerous tumor in female reproductive system that has a dismal prognosis in women worldwide. Given the very limited studies of cuproptosis-related lncRNAs (CRLs) in UCEC. Our purpose was to construct a prognostic profile based on CRLs and explore its assess prognostic value in UCEC victims and its correlation with the immunological microenvironment. METHODS: 554 UCEC tumor samples and 23 normal samples' RNA-seq statistics and clinical details were compiled from data in the TCGA database. CRLs were obtained using Pearson correlation analysis. Using LASSO Cox regression, multivariate Cox regression, and univariate Cox regression analysis, six CRLs are confirmed to develop a risk prediction model at last.We identified two main molecular subtypes and observed that multilayer CRLs modifications were related to patient clinicopathological features, prognosis, and tumor microenvironment (TME) cell infiltration characteristics, and then we verified the prognostic hallmark of UCEC and examined its immunological landscape.Finally, using qRT-PCR, model hub genes' expression patterns were confirmed. RESULTS: A unique CRL signature was established by the combination of six differently expressed CRLs that were highly linked with the prognosis of UCEC patients. According to their CRLs signatures, the patients were divided into two groups: the low-risk and the high-risk groups. Compared to individuals at high risk, patients at low risk had higher survival rates (p < 0.001). Additionally, Cox regression reveals that the profiles of lncRNAs linked to cuproptosis may independently predict prognosis in UCEC patients. The 1-, 3-, and 5-year risks' respective receiver operating characteristics (ROC) exhibited AUC values of 0.778, 0.810, and 0.854. Likewise, the signature could predict survival in different groups based on factors like stage, age, and grade, among others. Further investigation revealed differences between the different risk score groups in terms of drug sensitivity,immune cell infiltration,tumor mutation burden (TMB) score and microsatellite instability (MSI) score. Compared to the group of high risk, the low-risk group had greater rates of TMB and MSI. Results from qRT-PCR revealed that in UCEC vs normal tissues, AC026202.2, NRAV, AC079466.2, and AC090617.5 were upregulated,while LINC01545 and AL450384.1 were downregulated. CONCLUSIONS: Our research clarified the relationship between CRLs signature and the immunological profile and prognosis of UCEC.This signature will establish the framework for future investigations into the endometrial cancer CRLs mechanism as well as the exploitation of new diagnostic tools and new therapeutic.

Interleukin-6 and YKL-40 predicted recurrent stroke after ischemic stroke or TIA: analysis of 6 inflammation biomarkers in a prospective cohort study.

OBJECTIVE: Contribution of individual and combined inflammatory markers in prognosis after stroke was still undefined. We aimed to investigate the association of systemic and local vascular inflammatory markers and recurrent stroke as well as impact on poor functional outcome. METHODS: In this pre-specified substudy of the Third China National Stroke Registry (CNSR-III), 10,472 consecutive acute ischemic stroke or TIA patients with available centralized-measured levels of Interleukin-6 (IL-6), high sensitive C-reactive protein (hsCRP), IL-1 receptor antagonist (IL-1Ra), lipoprotein-associated phospholipase A2 mass (Lp-PLA2) and activity (Lp-PLA2-A), and YKL-40 from 171 sites were enrolled. The primary outcomes consisted of stroke recurrence and poor functional outcome defined as modified Rankin Scale (mRS) score of 2-6 within 1 year. RESULTS: There were 1026 (9.8%) and 2395 (23.4%) patients with recurrent stroke and poor functional outcome within 1 year. The highest quartiles of IL-6 (adjusted HR, 1.36; 95% CI 1.13-1.64; P = 0.001), hsCRP (adjusted HR, 1.41; 95% CI 1.17-1.69; P = 0.0003) and YKL-40 (adjusted HR, 1.28; 95% CI 1.06-1.56; P = 0.01) were associated with increased risk of recurrent stroke; and the highest quartiles of IL-6 (adjusted OR 1.93; 95% CI 1.64-2.27; P < 0.0001), IL-1Ra (adjusted OR 1.60; 95% CI 1.37-1.87; P < 0.0001), hsCRP (adjusted OR 1.60; 95% CI 1.37-1.86; P < 0.0001) and YKL-40 (adjusted OR 1.21; 95% CI 1.03-1.42; P = 0.02) were correlated with increased risk of poor functional outcome. In the multivariate stepwise regression analysis including all markers with backward selection, elevated levels of IL-6 or YKL-40 were associated with recurrent stroke (IL6: OR, 1.34; 95% CI 1.19-1.52; P < 0.0001; YKL-40: OR, 1.01; 95% CI 1.01-1.03; P = 0.004) and poor functional outcome (IL6: OR, 1.68; 95% CI 1.46-1.93; P < 0.0001; YKL-40: OR, 1.02; 95% CI 1.01-1.03; P = 0.0001). Adding IL-6 and YKL-40 significantly increased the area under the receiver operating characteristic curves for the prediction models of Essen Stroke Risk Score (0.03, P < 0.0001) and Totaled Health Risks in Vascular Events Score (0.07, P < 0.0001), and yielded continuous net reclassification improvement (19.0%, P < 0.0001; 33.0, P < 0.0001). CONCLUSIONS: In the patients with ischemic stroke or TIA, IL-6 and YKL-40 were independently associated with recurrent stroke and poor functional outcome, and improved risk classification of clinical risk algorithms.

Association of residual inflammatory risk with stroke recurrence in patients with acute ischaemic stroke or transient ischaemic attack.

BACKGROUND AND PURPOSE: The aim was to explore the association of residual inflammatory risk (RIR) with stroke recurrence after an index acute ischaemic stroke or transient ischaemic attack. METHODS: This study was based on the Third China National Stroke Registry. A total of 5840 patients with two high sensitivity C-reactive protein (hsCRP) measurements at baseline and at 3 months were included in the analysis. High RIR was defined as an hsCRP ≥3 mg/l. Patients were divided into four groups: persistent high RIR (first high then high hsCRP), attenuated RIR (first high then low hsCRP), increased RIR (first low then high hsCRP) and persistent low RIR (first low then low hsCRP). The primary outcome was new stroke onset during the 1-year follow-up. Secondary outcomes included composite vascular events, all-cause mortality and poor functional outcome (modified Rankin Scale score 3-6). RESULTS: During the 1-year follow-up, 523 (9.0%) patients had stroke recurrence. Patients with persistent high RIR had an increased risk of stroke recurrence (hazard ratio with 95% confidence interval 1.39, 1.08-1.78), compared with those with persistent low RIR. Similar results were found for the outcome of composite vascular events, mortality and poor functional outcome. An increased risk of stroke recurrence was further found in patients with persistent high RIR and intracranial artery stenosis or large-artery atherosclerosis stroke subtype. CONCLUSIONS: In patients with acute ischaemic stroke or transient ischaemic attack, persistent high RIR increased the risks of 1-year stroke recurrence, especially in those with intracranial artery stenosis or large-artery atherosclerosis subtype, composite vascular events, mortality and poor functional outcome.

Predictive values of baseline matrix metalloproteinase 9 levels in peripheral blood on 3-month outcomes of high-risk patients with minor stroke or transient ischemic attack.

BACKGROUND AND PURPOSE: To explore the relationship between baseline levels of matrix metalloproteinase 9 (MMP9) in peripheral blood and the outcomes in patients with acute minor stroke and transient ischemic attack (TIA). METHODS: We assessed data from patients with acute minor ischemic stroke or TIA who were included in the CHANCE (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events) trial. Baseline level of MMP9 in peripheral blood is classified into five quintiles. We assessed the relationship between the baseline MMP9 and outcomes of stroke recurrence, composite vascular events, and poor functional outcomes within 90 days after stroke onset. RESULTS: Of the 3014 patients included, 295 (9.79%) had recurrent stroke, 289 (9.59%) had recurrent ischemic stroke, 297 (9.85%) had combined vascular events, and 199 (6.64%) had poor functional outcomes within 90 days. We used MMP9 concentrations near hazard ratio (HR) = 1 (Q3) in restricted cubic splines as the reference. The result showed that, compared to patients in the Q3 group, patients in the highest quintile (Q5 group) had an increased risk of poor functional outcomes at 90 days after adjusting the risk factors and confounders (p = 0.030), which may be associated with an increased risk of combined vascular events (p = 0.052). Using Cox regression models or logistic regression models with restricted cubic spline, we also observed that higher MMP9 ratios were associated with an increased risk of stroke recurrence, combined events, and poor functional outcomes at a range of concentrations. CONCLUSIONS: For patients with acute minor stroke or TIA, higher baseline MMP9 level was associated with an increased risk of poor functional outcomes, which might be related to stroke recurrence and combined vascular events.

Characterization of the deformation behaviors under uniaxial stress for bicontinuous nanoporous amorphous alloys.

In this paper, the deformation behaviors of Cu50Zr50 bicontinuous nanoporous amorphous alloys (BNAMs) under uniaxial tension/compression are explored by molecular dynamics simulations. Scaling laws between mechanical properties and relative density are investigated. The results demonstrate that the bending deformation of the ligament is the main elastic deformation mechanism under tension. Necking and subsequent fracture of ligaments are the primary failure mechanism under tension. Under tensile loading, shear bands emerge near the plastic hinges for the BNAMs with large porosities. The typical compressive behaviors of porous structure are observed in the BNAMs with large porosities. However, for small porosity, no distinguished plateau and densification are captured under compression. The tension-compression asymmetry of modulus increases with increasing porosity, whereas the BNAMs can be seen as tension-compression symmetry of yield strength. The modulus and yield strength are negatively correlated with temperature, but a positive relationship between the tensile ductility and temperature is shown. This work will help to provide a useful understanding of the mechanical behaviors of the BNAMs.

Molecular dynamics simulations of cold welding of nanoporous amorphous alloys: effects of welding conditions and microstructures.

Nanoscale cold welding is a promising method in the bottom-up fabrication of nanodevices. Herein, cold welding mechanisms of Cu50Zr50 nanoporous amorphous alloys (NPAAs) are investigated by molecular dynamics simulations, along with the mechanical properties of the welded products. Effects of welding conditions and microstructural parameters are considered. Our results demonstrate that the welded joint has superior mechanical properties. The ultimate strength of the welded NPAAs can be as high as 94-99% that of the original NPAAs but 62-75% for the yield strength and elastic modulus. Voronoi analysis declares that the changes in atomic clusters of NPAAs caused by cold welding are mild. The welding conditions do not have remarkable influences on the mechanical responses of the welded structure. The NPAAs with smaller ligament sizes are more suitable for cold welding, benefiting from the size effect of amorphous alloys. We also successfully use cold welding to fabricate gradient NPAAs and repair fractured NPAAs. It is found that the ultimate tensile strength of the NPAAs changes very little with each successful cold welding. After ten fracture-welding cycles, the ultimate strength of the as-welded specimen is slightly lower than that of the raw materials.

Residual Inflammatory Risk Predicts Poor Prognosis in Acute Ischemic Stroke or Transient Ischemic Attack Patients.

Background and Purpose: It is still unclear whether the residual cholesterol and inflammatory risk in the acute phase is associated with prognosis of stroke. We aimed to investigate the proportion and relative contribution of residual cholesterol and inflammatory risk, determined by baseline low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hsCRP) levels, to the risk of recurrent stroke and poor functional outcome at 1 year. Methods: In this prospective multicenter cohort study, 10 499 consecutive acute ischemic stroke and transient ischemic attack patients with levels of LDL-C and hsCRP were enrolled. Patients were divided into 4 groups: residual cholesterol risk only (LDL-C ≥2.6 mmol/L and hsCRP <3 mg/L), residual inflammatory risk (RIR) only (LDL-C <2.6 mmol/L and hsCRP ≥3 mg/L), both risk (LDL-C ≥2.6 mmol/L and hsCRP ≥3 mg/L), and neither risk (LDL-C <2.6 mmol/L and hsCRP <3 mg/L). The primary outcomes consisted of stroke recurrence and a modified Rankin Scale score of 2 to 6 within 1 year. Results: The relative proportions of patients with RIR only, residual cholesterol risk only, both risk, and neither were 21.3%, 23.7%, 14.4%, and 40.6%, respectively. RIR only was independently associated with recurrent stroke (adjusted hazard ratio, 1.18 [95% CI, 1.00­1.40]; P=0.05). The association was slightly attenuated after further adjusting for usage of antiplatelet agent and statin during 1-year follow-up in addition to the traditional risk factors (hazard ratio, 1.31 [95% CI, 0.99­1.76]; P=0.07). When applying the LDL-C cutoff value of 1.8 mmol/L in the sensitivity analyses, such association in large-artery atherosclerosis subtype was more significant (adjusted hazard ratio, 1.69 [95% CI, 1.06­2.67]; P=0.03). Patients with RIR only also had increased risk of poor functional outcome (adjusted odds ratio, 1.43 [95% CI, 1.24­1.64]; P<0.0001). Conclusions: In the patients with acute ischemic stroke or transient ischemic attack, RIR only could be predictive for recurrent stroke, especially for those with large-artery atherosclerosis, and poor functional outcome.

Intraluminal Thrombus and Outcomes of Patients With Acute Large Vessel Occlusive Stroke Undergoing Endovascular Treatment.

BACKGROUND AND PURPOSE: Intraluminal thrombus (ILT) is an emerging imaging marker in acute ischemic stroke. We aimed to investigate the association of ILT with outcomes of acute large vessel occlusion (LVO) patients receiving endovascular treatment. METHODS: Acute LVO stroke patients who underwent endovascular treatment within 24 hours, in a prospective, nationwide registry were enrolled. Pretreatment digital subtraction angiography was reviewed for the presence of ILT. The primary outcome was 90-day functional dependence (modified Rankin Scale scores, 3-6). Secondary outcomes included 24-hour LVO, 90-day death, and symptomatic intracranial hemorrhage. RESULTS: Among 711 patients enrolled, 75 (10.5%) with ILT were less likely to have 90-day functional dependence compared with those without ILT (adjusted odds ratio, 0.53 [95% CI, 0.31-0.90]; P=0.021). The same trend was found among those with successful reperfusion (modified Thrombolysis in Cerebral Infarction 2b-3; P=0.008) but not in those without successful reperfusion (P=0.107). Presence of ILT was also independently associated with a lower rate of 24-hour LVO (adjusted odds ratio 0.34 [95% CI, 0.13-0.89]; P=0.028). However, those with or without ILT had similar risks of symptomatic intracranial hemorrhage and 90-day death. CONCLUSIONS: Among acute LVO patients receiving endovascular treatment, pretreatment ILT-positive patients may have a better 90-day functional outcome (versus ILT-negative) but similar risk of death and symptomatic intracranial hemorrhage. The possibly favorable effect of ILT patients remained in those with successful reperfusion. Registration: URL: http://www.chictr.org.cn; Unique identifier: ChiCTR1900022154.

Homocysteine Level Predicts Response to Dual Antiplatelet in Women With Minor Stroke or Transient Ischemic Attack: Subanalysis of the CHANCE Trial.

OBJECTIVES: To investigate the relationship of homocysteine levels with the efficacy and safety of dual antiplatelet therapy in female and male patients. Approach and Results: The CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) randomized patients with acute minor ischemic stroke or high-risk transient ischemic attack to clopidogrel plus aspirin or aspirin alone from October 1, 2009, to July 30, 2012, in China. A subgroup of 3044 consecutive patients with baseline homocysteine levels from 73 (64%) prespecified clinical sites was analyzed. Participants were grouped by sex. Primary outcome was stroke recurrence within 90 days. Secondary outcomes consisted of composite vascular events and independent living or death. Safety outcome was any bleeding. Cox proportional-hazards models were used to assess the interaction of homocysteine levels with randomized antiplatelet therapy on efficacy and safety outcomes. A significant interaction between homocysteine levels and the randomized antiplatelet therapies was found on recurrent stroke after adjustment for confounding factors in women (P=0.010) but not in men (P=0.595). Compared with aspirin alone, clopidogrel plus aspirin significantly reduced the risk of recurrent stroke in women without elevated homocysteine levels (adjusted hazard ratio, 0.459 [95% CI, 0.271-0.776]; P=0.004). Such benefit disappeared in female patients with increased homocysteine level. No significant interaction on functional outcome or bleeding rate was observed. CONCLUSIONS: Homocysteine could be a potential biomarker to discriminate the effects of dual and single antiplatelet therapy in female patients with minor ischemic stroke or high-risk transient ischemic attack. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00979589.

An Auxin Transport Inhibitor Targets Villin-Mediated Actin Dynamics to Regulate Polar Auxin Transport.

Auxin transport inhibitors are essential tools for understanding auxin-dependent plant development. One mode of inhibition affects actin dynamics; however, the underlying mechanisms remain unclear. In this study, we characterized the action of 2,3,5-triiodobenzoic acid (TIBA) on actin dynamics in greater mechanistic detail. By surveying mutants for candidate actin-binding proteins with reduced TIBA sensitivity, we determined that Arabidopsis (Arabidopsis thaliana) villins contribute to TIBA action. By directly interacting with the C-terminal headpiece domain of villins, TIBA causes villin to oligomerize, driving excessive bundling of actin filaments. The resulting changes in actin dynamics impair auxin transport by disrupting the trafficking of PIN-FORMED auxin efflux carriers and reducing their levels at the plasma membrane. Collectively, our study provides mechanistic insight into the link between the actin cytoskeleton, vesicle trafficking, and auxin transport.

Capping Protein Modulates Actin Remodeling in Response to Reactive Oxygen Species during Plant Innate Immunity.

Plants perceive microbe-associated molecular patterns and damage-associated molecular patterns to activate innate immune signaling events, such as bursts of reactive oxygen species (ROS). The actin cytoskeleton remodels during the first 5 min of innate immune signaling in Arabidopsis (Arabidopsis thaliana) epidermal cells; however, the immune signals that impinge on actin cytoskeleton and its response regulators remain largely unknown. Here, we demonstrate that rapid actin remodeling upon elicitation with diverse microbe-associated molecular patterns and damage-associated molecular patterns represent a conserved plant immune response. Actin remodeling requires ROS generated by the defense-associated NADPH oxidase, RBOHD. Moreover, perception of flg22 by its cognate receptor complex triggers actin remodeling through the activation of RBOHD-dependent ROS production. Our genetic studies reveal that the ubiquitous heterodimeric capping protein transduces ROS signaling to the actin cytoskeleton during innate immunity. Additionally, we uncover a negative feedback loop between actin remodeling and flg22-induced ROS production.

Molecular dynamics study on cold-welding of 3D nanoporous composite structures.

Nanoporous metals are a class of novel nanomaterials with potential applications in many fields. Herein, we demonstrate the cold-welding mechanism of nanoporous metals with various combinations using molecular dynamics simulations. This study shows that it is possible to cold-weld two nanoporous metals to form a novel composite material. The influence of temperature, in the range of 300-900 K, on the mechanical properties of the resultant composite material was investigated. With an increase in temperature, the weld stress and the mechanical strength of the nanoporous structures significantly decreased as an increase in disorder magnitude was observed. These results could lead to bottom-up nanofabrication and nanoassembly of combined nanoporous metals for high mechanical performance.