Exploring developmental toxicity of microplastics and nanoplastics (MNPS): Insights from investigations using zebrafish embryos.

Microplastics and nanoplastics (MNPs) have received increasing attention due to their high detection rates in human matrices and adverse health implications. However, the toxicity of MNPs on embryo/fetal development following maternal exposure remains largely unexplored. Zebrafish, sharing genetic similarities with human, boast a shorter life cycle, rapid embryonic development, and the availability of many transgenic strains, is a suitable model for environmental toxicology studies. This review comprehensively explores the existing research on the impacts of MNPs on zebrafish embryo development. MNPs exposure induces a wide array of toxic effects, encompassing neurodevelopmental toxicity, immunotoxicity, gastrointestinal effects, microbiota dysbiosis, cardiac dysfunctions, vascular toxicity, and metabolic imbalances. Moreover, MNPs disrupt the balance between reactive oxygen species (ROS) production and antioxidant capacity, culminating in oxidative damage and apoptosis. This study also offers insight into the current omics- and multi-omics based approaches in MNPs research, which greatly expedite the discovery of biochemical or metabolic pathways, and molecular mechanisms underlying MNPs exposure. Additionally, this review proposes a preliminary adverse outcome pathway framework to predict developmental toxicity caused by MNPs. It provides a comprehensive overview of pathways, facilitating a clearer understanding of the exposure and toxicity of MNPs, from molecular effects to adverse outcomes. The compiled data in this review provide a better understanding for MNPs effects on early life development, with the goal of increasing awareness about the risks posed to pregnant women by MNPs exposure and its potential impact on the health of their future generations.

Two successful pregnancies in a membranous nephropathy patient: Case report and literature review.

BACKGROUND: Pregnancy in patients with nephrotic syndrome presents enormous challenges to both the mother and fetus, and there are no treatment guidelines for these patients. METHODS: We show a case of a woman with anti-PLA2R antibody-positive membranous nephropathy who did not have a kidney biopsy. Her clinical course during both pregnancies was closely followed and her medications were guided. RESULTS: She gave birth to 2 healthy babies and her condition was very well controlled with the help of medication. CONCLUSION: Patients with nephrotic syndrome can have successful pregnancies after drug treatment. In addition, similar to the non-pregnant population, percutaneous kidney biopsy is not required for the diagnosis of idiopathic membranous nephropathy (IMN) in pregnant nephrotic syndrome patients with anti-PLA2R antibody positive, but the etiology of secondary MN should be excluded.

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.

High-Sensitivity C-reactive Protein and Intracranial Arterial Stenosis Predicted Recurrent Stroke and Dependence or Death in Minor Stroke or Transient Ischemic Attack.

AIMS: Inflammation is associated with vascular events. We aimed to investigate the relationship between high-sensitivity C-reactive protein (hsCRP) levels with and without intracranial arterial stenosis (ICAS) and the prognosis of patients with minor stroke or transient ischemic attack. METHODS: We used data from the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events trial (derivation cohort) and the Third China National Stroke Registry (validation cohort). Patients were divided into four groups according to the dichotomy of hsCRP level and ICAS status. The primary outcome was new ischemic stroke within 90 days, and the secondary outcome was dependence or death (Modified Rankin Scale score of 3-6) at 90 days. The associations between hsCRP level with and without ICAS and risk of outcomes were analyzed using multivariate Cox regression and logistic regression models. RESULTS: In the derivation cohort, compared with patients with nonelevated hsCRP levels and no ICAS, those with both elevated hsCRP levels and ICAS had increased risk of recurrent stroke (adjusted hazard ratio [HR], 2.62; 95% confidence interval [CI], 1.28-5.34; p=0.008) and dependence or death (adjusted odds ratio [OR], 7.58; 95% CI, 1.30-44.13; p=0.02). Consistent relationships of elevated hsCRP levels and presence of ICAS with recurrent stroke (adjusted HR, 1.67; 95% CI, 1.13-2.45; p=0.009) and dependence or death (adjusted OR, 1.87; 95% CI, 1.23-2.84; p=0.003) were observed in the validation cohort. CONCLUSION: Concomitant presence of increased hsCRP levels and ICAS was associated with increased risk of stroke recurrence and dependence or death in patients with minor ischemic stroke or transient ischemic attack.

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.

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.

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.

Mediation effect of stroke recurrence in the association between post-stroke interleukin-6 and functional disability.

AIM: Post-stroke inflammation increases the risk of functional disability through enlarged cerebral infarct size directly and follow-up stroke event indirectly. We aimed to use post-stroke proinflammatory cytokine interleukin-6 (IL-6) as a marker of inflammatory burden and quantify post-stroke inflammation's direct and indirect effect on functional disability. METHODS: We analyzed patients with acute ischemic stroke admitted to 169 hospitals in the Third China National Stroke Registry. Blood samples were collected within 24 h of admission. Stroke recurrence and functional outcome measured by the modified Rankin scale (mRS) were assessed via face-to-face interviews at 3 months. Functional disability was defined as an mRS score ≥2. Mediation analyses under the counterfactual framework were performed to examine the potential causal chain in which stroke recurrence may mediate the relationship between IL-6 and functional outcome. RESULTS: Among the 7053 analyzed patients, the median (interquartile range [IQR]) NIHSS score was 3 (1-5), and the median (IQR) level of IL-6 was 2.61 (1.60-4.73) pg/mL. Stroke recurrence was observed in 458 (6.5%) patients, and functional disability was seen in 1708 (24.2%) patients at the 90-day follow-up. Per stand deviation (4.26 pg/mL) increase in the concentration of IL-6 was associated with an increased risk of stroke recurrence (adjusted odds ratio [aOR], 1.19; 95% CI, 1.09-1.29) and disability (aOR, 1.22; 95% CI, 1.15-1.30) within 90 days. Mediation analyses revealed that 18.72% (95% CI, 9.26%-28.18%) of the relationship between IL-6 and functional disability was mediated by stroke recurrence. CONCLUSIONS: Stroke recurrence mediates less than 20% of the association between IL-6 and functional outcome at 90 days among patients with acute ischemic stroke. In addition to typical secondary prevention strategies for preventing stroke recurrence, more attention should be paid to novel anti-inflammatory therapy to improve functional outcomes directly.

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.

Colchicine in High-risk Patients with Acute Minor-to-moderate Ischemic Stroke or Transient Ischemic Attack (CHANCE-3): Rationale and design of a multicenter randomized placebo-controlled trial.

BACKGROUND: Anti-inflammatory therapy using colchicine has reduced recurrent vascular events in patients with coronary heart disease. DESIGN: Colchicine in High-risk Patients with Acute Minor-to-moderate Ischemic Stroke or Transient Ischemic Attack (CHANCE-3) is a randomized, double-blind, placebo-controlled multicenter trial, in which 8,238 patients with acute minor-to-moderate ischemic stroke (NIHSS ⩽ 5) or high-risk transient ischemic attack (TIA) (ABCD2 score ⩾4) and a high-sensitivity CRP (hsCRP) level of ⩾2 mg/L will be randomly assigned within 24 h of symptom onset to colchicine (1 mg daily on days 1-3, followed by 0.5 mg daily for a total of 90 days) or matching placebo, on a background of optimal medical therapy. The study will have 90% power to detect a 25% reduction in the primary efficacy outcome of any stroke within 3 months of randomization. Adverse events potentially related to the use of colchicine will also be analyzed. The primary analysis will be by intention to treat. TRIAL REGISTRY NAME: Colchicine in High-risk Patients with Acute Minor-to-moderate Ischemic Stroke or Transient Ischemic Attack (CHANCE-3); URL: https://clinicaltrials.gov/ct2/show/NCT05439356?cond=CHANCE-3&draw=2&rank=1; Registration number: NCT05439356.

High-Sensitivity C-Reactive Protein Modifies P-Wave Terminal Force in Lead V1-Associated Prognosis in Acute Ischemic Stroke or TIA Patients.

Little is known about the role of high-sensitivity C-reactive protein (hsCRP) in the relationship between P-wave terminal force in lead V1 (PTFV1) and stroke prognosis. We aimed to investigate how hsCRP influences the effect of PTFV1 on ischemic stroke recurrence and mortality. In this study, patients enrolled in the Third China National Stroke Registry, which enrolled consecutive patients who had suffered an ischemic stroke or transient ischemic attack in China, were analyzed. After excluding patients with atrial fibrillation, 8271 patients with PTFV1 and hsCRP measurements were included in this analysis. Cox regression analyses were used to assess the association between PTFV1 and stroke prognosis according to different inflammation statuses stratified by an hsCRP level of 3 mg/L. A total of 216 (2.6%) patients died, and 715 (8.6%) patients experienced ischemic stroke recurrence within 1 year. In patients with hsCRP levels ≥ 3 mg/L, elevated PTFV1 was significantly associated with mortality (HR, 1.75; 95% CI, 1.05-2.92; p = 0.03), while in those with hsCRP levels < 3 mg/L, such an association did not exist. In contrast, in patients with hsCRP levels < 3 mg/L and those with hsCRP levels ≥ 3 mg/L, elevated PTFV1 remained significantly associated with ischemic stroke recurrence. The predictive role of PTFV1 towards mortality but not ischemic stroke recurrence differed in terms of hsCRP levels.

Analysis of Actin Array Rearrangement During the Plant Response to Bacterial Stimuli.

Plants are constantly exposed to various environmental stresses, among which, microbial pathogens are one of the major threats. Studies have shown that the host actin cytoskeleton undergoes active rearrangement during the plant-microbe interaction. This actin remodeling is required for plant resistance to bacterial infection. In this chapter, we introduce a protocol routinely used in our laboratory to investigate actin dynamics in response to bacterial cues. We describe the bacterial inoculation methods, plant sample preparation, and imaging techniques used to monitor actin responses in different Arabidopsis cell types including epidermal cells from light-grown leaves and dark-grown hypocotyls, as well as guard cells. We further introduce a high-throughput image analysis method for quantifying cytoskeletal changes. This protocol has allowed us to dissect the host cell contribution to actin remodeling and identify actin-binding proteins as stimulus-response regulators of the cytoskeleton.

Predictive Role of hsCRP in Recurrent Stroke Differed According to Severity of Cerebrovascular Disease: Analysis from a Prospective Cohort Study.

Elevated levels of high-sensitivity C-reactive protein (hsCRP) were associated with an increased risk of recurrent stroke. However, it is still unknown whether the predictive value of hsCRP differed according to the severity of cerebrovascular disease. We used the cohort of the prospective multicenter cohort study of the Third China National Stroke Registry (CNSR-III), in which 10,765 consecutive patients with acute ischemic stroke or transient ischemic attack (TIA) had hsCRP levels measured. Patients were classified into minor stroke, or TIA, and non-minor stroke. The primary outcome was a new stroke within 1 year. Cox proportional hazards models were used to assess the association of hsCRP and its outcome. Elevated levels of hsCRP were associated with an increased risk of recurrent stroke in minor stroke or TIA patients, irrespective of using a National Institutes of Health Stroke Scale (NIHSS) score of ≤3 (the highest quartile vs. the lowest quartile: adjusted hazard ratio, 1.48; 95% CI, 1.12-1.97; p = 0.007) or ≤5 (the highest quartile vs. the lowest quartile: adjusted hazard ratio, 1.45; 95% CI, 1.15-1.84; p = 0.002) to define minor stroke. Such association was more apparent in the large-artery atherosclerosis subtype. However, for the patients with non-minor stroke, the association of hsCRP with recurrent stroke disappeared.

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.

Elevated hs-CRP and Symptomatic Intracranial/Extracranial Artery Stenosis Predict Stroke Recurrence after Acute Ischemic Stroke or TIA.

AIM: This study aimed to investigate the relationship between symptomatic or asymptomatic intracranial/extracranial artery stenosis and high-sensitivity C-reactive protein (hs-CRP) levels in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA). METHODS: This study included 10404 patients from the Third China National Stroke Registry. Patients were divided into four or six groups according to patterns of intracranial or extracranial artery stenosis and hs-CRP levels. The outcomes were recurrence of ischemic stroke, stroke, and combined vascular events (CVE) at 1 year. The associations between different combinations of hs-CRP levels and patterns of artery stenosis and recurrent events were analyzed by multivariable Cox regression models. RESULTS: Patients in Group III (hs-CRP ＜3＋symptomatic intracranial or extracranial artery stenosis) had higher risk of recurrent ischemic stroke (adjusted hazard ratio (HR) 1.73, 95% confidence interval (CI) 1.20-2.48, p=0.003). Those in Group VI (hs-CRP ≥ 3＋symptomatic intracranial or extracranial artery stenosis) had the highest risk of recurrent ischemic stroke (HR 2.04, 95% CI 1.42-2.92, p=0.0001) within 1 year compared with Group I (hs-CRP ＜3＋no artery stenosis). Asymptomatic intracranial or extracranial artery stenosis did not increase the risk of ischemic events compared with no artery stenosis regardless of hs-CRP levels. CONCLUSION: Symptomatic intracranial or extracranial artery stenosis was associated with increased risk of recurrent ischemic stroke, stroke, and CVE at 1 year in patients with AIS or TIA, especially in patients with elevated hs-CRP levels. Asymptomatic intracranial or extracranial artery stenosis did not increase the risk of ischemic events compared with no artery stenosis regardless of hs-CRP levels.

Polo-like kinase 1 as a biomarker predicts the prognosis and immunotherapy of breast invasive carcinoma patients.

Background: Invasive breast carcinoma (BRCA) is associated with poor prognosis and high risk of mortality. Therefore, it is critical to identify novel biomarkers for the prognostic assessment of BRCA. Methods: The expression data of polo-like kinase 1 (PLK1) in BRCA and the corresponding clinical information were extracted from TCGA and GEO databases. PLK1 expression was validated in diverse breast cancer cell lines by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Single sample gene set enrichment analysis (ssGSEA) was performed to evaluate immune infiltration in the BRCA microenvironment, and the random forest (RF) and support vector machine (SVM) algorithms were used to screen for the hub infiltrating cells and calculate the immunophenoscore (IPS). The RF algorithm and COX regression model were applied to calculate survival risk scores based on the PLK1 expression and immune cell infiltration. Finally, a prognostic nomogram was constructed with the risk score and pathological stage, and its clinical potential was evaluated by plotting calibration charts and DCA curves. The application of the nomogram was further validated in an immunotherapy cohort. Results: PLK1 expression was significantly higher in the tumor samples in TCGA-BRCA cohort. Furthermore, PLK1 expression level, age and stage were identified as independent prognostic factors of BRCA. While the IPS was unaffected by PLK1 expression, the TMB and MATH scores were higher in the PLK1-high group, and the TIDE scores were higher for the PLK1-low patients. We also identified 6 immune cell types with high infiltration, along with 11 immune cell types with low infiltration in the PLK1-high tumors. A risk score was devised using PLK1 expression and hub immune cells, which predicted the prognosis of BRCA patients. In addition, a nomogram was constructed based on the risk score and pathological staging, and showed good predictive performance. Conclusions: PLK1 expression and immune cell infiltration can predict post-immunotherapy prognosis of BRCA patients.

Strengthening Modulus and Softening Strength of Nanoporous Gold in Multiaxial Tension: Insights from Molecular Dynamics.

The functionalized applications of nanoporous metals place clear requirements on their basic mechanical properties, yet there is a lack of research on the mechanical response under multiaxial loading conditions. In this work, the mechanical behaviors of nanoporous gold under multiaxial tension are investigated via molecular dynamics simulations. The mechanical properties under different loading conditions are compared and the microstructure evolution is analyzed to clarify the deformation mechanisms of nanoporous gold in biaxial and triaxial tension. It is found that the modulus of nanoporous gold in multiaxial tension is strengthened and the strength is softened compared to uniaxial tension. The failure of nanoporous gold in multiaxial tension is dominated by the progressive yielding, necking, and rupture of ligaments along the multiple uniaxial loading directions. The dislocation activity under multiaxial loads is more intense and more prone to plastic deformation, ultimately resulting in lower strength and smaller failure strain. The findings provide more insight into the understanding of the deformation mechanisms of nanoporous metals under complex stress states.

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.

Nanoindentation characteristics of nanocrystalline B2 CuZr shape memory alloy via large-scale atomistic simulation.

Nanoindentation tests are performed by molecular dynamics simulation to explore the mechanical properties of nanocrystalline B2 CuZr shape memory alloys with average grain sizes ranging from 6 to 18 nm. Some paramount aspects are monitored, including indentation force-depth curve, hardness, yield strength, and elastic recovery. The results demonstrate an inverse Hall-Petch effect, i.e., the hardness decreases with the decrease in grain size. For the single crystalline B2 CuZr, dislocation nucleation and propagation are the major plastic mechanisms. However, grain cleavage, grain boundary compression, and grain rotation prevail over the plastic behaviors of nanocrystalline B2 CuZr alloys. The elastic recovery becomes stronger with the increase in grain size. Besides, the effects of temperature, indenter size, and indenter speed on the nanoindentation responses are evaluated quantitively.