Until recently, Na2-salt of 4-acetamido-4'-isothiocyano-stilbene-2,2'-disulfonic acid (SITS or stilbene reagent) was applied to study transport of anions into bacterial cells by conventional methods; SITS has not yet been used for biosensor investigations of transport. In this study, SITS was first employed in a biosensor method to examine the stilbene reagent effect on process of substrate transport into intact and immobilized cells of cultures-receptors of microbial sensor devices. The biosensor-based technique (biosensor method for assessment of features of metabolism, BMAFM) for studying transport of substrate into microbial cells is currently under further development. To explore substrate transport, laboratory models of reactor and membrane microbial electrochemical sensor devices with the Clark-type oxygen electrode as a transducer and Pseudomonas sp. or Rhodococcus opacus 1CP as a culture-receptor were used in this study. For R. opacus cells stored for 7 months in non-growth conditions, an activating effect on benzoate 1,2-dioxygenase was observed for cells washed after treating with SITS. Using the electrochemical biosensor method, it has been shown that SITS inhibited transport of maltose/benzoate into both intact and immobilized cells of P. sp. and R. opacus leading to a decrease in the cells' response to substrate. Thus, SITS can be used as an inhibitor of anion transport while studying substrate transport into microbial cells by means of the biosensor method. Furthermore, the stilbene reagent-assisted biosensor technique may significantly facilitate and provide rapid measurements during research process.
Breast cancer remains a global challenge, with rising incidence rates. While treatment advancements have improved outcomes, systemic administration of cytostatic agents continues to cause severe adverse effects, including myelosuppression, heart failure, and infertility, due to non-specific biodistribution. Nanoparticle-based drug delivery systems have been explored as an alternative approach to improve therapeutics delivery and reduce non-specific effects. Zinc-based nanoparticles demonstrate ability to induce cytotoxic responses in cancer cells in vitro, making them suitable systems for probing cell-type-specific effects. In this study, we evaluated the in vitro cytotoxic effects of spherical zinc peroxide (ZnO₂) nanoparticles (20-80 nm and 50-300 nm), commercial ZnO nanoparticles, and tetrapodal ZnO (T-ZnO) microparticles in MCF-7 breast cancer cells and RMF-EG fibroblasts. ZnO₂ nanoparticles demonstrated dose-dependent cytotoxicity (1 µg/mL-10 mg/mL), inducing a significantly higher death rate of cancer cells than normal fibroblasts, which retained >75% viability at comparable doses. Flow cytometry investigations revealed that ZnO₂ nanoparticles exhibited preferential cellular uptake in MCF-7 cells as compared to fibroblasts. Overall, these findings indicate different cytotoxic responses of ZnO-based micro and nanoparticles between MCF-7 cells and RMF-EG fibroblasts under in vitro conditions. Further studies are required to validate these observations in more complex biological systems and to clarify the underlying mechanisms.
Erysiphe corylacearum is the main causal agent of hazelnut powdery mildew, causing substantial damage in the Black Sea region of Türkiye. Despite its economic importance, molecular resources for this obligate biotrophic pathogen remain severely limited. This study presents the first comprehensive transcriptomic dataset for E. corylacearum obtained through Illumina sequencing of mRNA from naturally infected hazelnut leaves. Using targeted epidermal peeling to enrich fungal material while minimizing host contamination, over 66 million high-quality paired-end reads were generated. De novo Trinity-based assembly yielded an initial set of 135,404 unigenes for annotation, and the final NCBI-cleaned TSA submission contains 100,824 transcript sequences. Functional annotation assigned database matches to 71% of the initial unigene set, including sequences related to pathogenicity, sexual compatibility, and reproduction. The dataset also includes over 29,000 high-confidence intra-sample sequence variants from this single metatranscriptomic sample providing a candidate resource for future marker development, diagnostic assays, and comparative analyses pending validation across additional isolates. This transcriptomic resource will facilitate investigations into pathogen biology, host-pathogen interactions, and improved disease management strategies.
Jumping spiders, a diverse and charismatic group of invertebrates, are renowned for their highly specialized visual systems, complex courtship behaviours, and broad ecological adaptability. However, the persistent lack of high-quality genomic resources has hindered investigations into the genetic basis and phenotypic evolution of these key traits. To address this gap, we performed a de novo assembly of a chromosome-level genome for Spartaeus platnicki, a species representing the basal lineages of jumping spiders. This assembly, achieved by integrating PacBio HiFi long reads, Illumina short reads, RNA-seq, and Hi-C data, comprises 15 pseudo-chromosomes including the X1 and X2 sex chromosomes, spanning a total length of 3.71 Gb with a scaffold N50 of 262 Mb and a BUSCO completeness of 98.60%. Repetitive elements account for approximately 65.57% of the genome. We annotated 15,660 protein-coding genes, achieving a BUSCO completeness of 97.60%. This high-quality genome establishes a foundational resource for investigating the genetic architecture underlying key traits and their phenotypic evolution in jumping spiders.
The production of precision workpieces from long products by shearing remains a challenging problem due to bending deformation, end-face cracking, and insufficient dimensional accuracy. Dies with differentiated clamping represent a promising solution; however, the influence of their design parameters on force transmission, energy efficiency, and deformation localization remains insufficiently understood. The aim of this study is to investigate the technological and design features of dies with differentiated clamping of long products and to establish quantitative relationships between wedge mechanism parameters, friction conditions, and process performance. A systematic classification of die designs was developed based on clamping method, force-transmission mechanism, blade kinematics, and structural configuration. Analytical models were derived to describe force transmission in wedge mechanisms and to determine the relationship between clamping force, shearing force, friction conditions, and mechanism efficiency. Finite-element simulations of the shearing process were performed using DEFORM 3D to analyze stress-strain state evolution, deformation localization, and damage development. Experimental investigations were carried out on a 2.5 MN crank press using strain-gauge measurements to validate the theoretical predictions and evaluate workpiece quality. The results demonstrate that force transmission efficiency and the clamping-to-shearing force ratio are strongly governed by wedge geometry and friction conditions. Rational ranges of force-transmission angles were identified, providing an optimal balance between force amplification and energy efficiency. Numerical simulations revealed that differentiated clamping localizes plastic deformation and damage accumulation within a narrow region adjacent to the blade clearance, suppresses workpiece bending, and promotes stable crack propagation along the intended separation plane. Experimental validation confirmed the adequacy of the developed analytical model, with the discrepancy between calculated and measured peak shearing forces not exceeding 8%. Magnetic particle and dye penetrant inspections verified the absence of end-face cracks in workpieces produced from Steel 0 and Steel 40H. The developed die design improved geometric accuracy while reducing overall dimensions and weight compared with conventional solutions. The scientific novelty of the work lies in establishing quantitative relationships between wedge geometry, friction conditions, force transmission efficiency, and deformation localization during shearing with differentiated clamping. The obtained results provide a scientific basis for controlling the stress-strain state and fracture behavior during precision separation of long products and may be used for the design and optimization of energy-efficient shearing technologies.
Plant "intelligence" and "sensation" are controversial notions in contemporary botany. While some scientists argue that sensory awareness, learning, memory, communication, and possibly a kind of consciousness should be ascribed to plants, a substantial part of the scientific community dismisses such claims because of insufficient evidence and the lack of neural systems in plants. In this paper, I will examine this issue from a historical and epistemological perspective. First, I will go back to a crucial precedent that is often evoked in these debates, i.e., Darwin's remarks on plant "sensation" and "behavior" and his analogy between roots and brains in the 1880 book The Power of Movement in Plants. I will point out that the issue was already well known and controversial in the nineteenth century. I will then examine contemporary debates starting from new experiments and evidence on plant cognitive powers. I will argue that current debates are partly based on elements that have been available since Darwin, such as postulates of biological continuity among living beings and the use of analogy, leading to an epistemological contrast between the need to avoid ungrounded anthropomorphic projections and the argument that kinds of cognitive states could be realized in plants. I also finally point out that investigations on animal ethics and the revaluation of non-Western views on animism and ecology have recently been introduced into this debate to break the epistemological balance between opposing views.
G protein-coupled receptor 124 (GPR124) has been implicated in endothelial dysfunction, but its role in ox-LDL-induced endothelial inflammatory injury remains incompletely understood. This study investigated whether GPR124 contributes to endothelial cell injury through disruption of mitochondrial autophagy homeostasis and subsequent activation of the NLRP3 inflammasome. Using an ox-LDL-treated EA.hy926 endothelial cell model, we found that GPR124 expression was significantly upregulated under injurious conditions. GPR124 overexpression aggravated ox-LDL-induced cellular dysfunction, as reflected by reduced proliferative activity, increased reactive oxygen species (ROS) production, and enhanced lipid accumulation. Mechanistically, GPR124 dysregulation was associated with impaired mitochondrial homeostasis, including loss of mitochondrial membrane potential, excessive ROS generation, and altered mitochondrial autophagy flux, accompanied by increased NLRP3 inflammasome activation and IL-1β release. In contrast, GPR124 knockdown partially attenuated these abnormalities and alleviated endothelial cell injury. In addition, pharmacological intervention with Mdivi-1 supported the involvement of mitochondrial autophagy-related processes in the inflammatory phenotype observed under ox-LDL stimulation. Bioinformatics analyses further suggested that GPR124-associated differentially expressed genes were enriched in pathways related to mitochondrial homeostasis, metabolic regulation, and inflammatory signaling. Taken together, these findings suggest that GPR124 may contribute to ox-LDL-induced endothelial inflammatory injury through dysregulation of the mitochondrial autophagy-NLRP3 axis and identify GPR124 as a potential target for further mechanistic investigation in endothelial dysfunction.
Numerous mood and behavior disorders have developmental origins resulting from genetic and environmental interactions. Maternal tryptophan hydroxylase 1 (TPH-1)-dependent serotonin (5-HT) depletion alters embryonic brain development, but its long-term impact on adult progeny has never been investigated. Here we demonstrate that adult WT male offspring born to hyposerotonergic Tph1+/- dams ( ~ 60% deficit) display hyperlocomotion, impaired self-care and an increased anxiety relative to those from WT dams. Concomitantly, norepinephrine (NE) levels and dopamine (DA) turnover are significantly reduced in the mesencephalon and brainstem, whereas monoaminergic cell density is not affected. In the frontal cortex of the offspring, maternal hyposerotonergic status results in significant reduction in DA, NE and 5-HT levels, accompanied by transcriptomic changes, notably in monoaminergic system signaling, synaptic function and plasticity, methylation processes and myelination. Myelination is also impaired as revealed by a reduced thickness of the corpus callosum. Maternal hyposerotonemia thus appears sufficient to affect the phenotype of the adult WT progeny. TPH-1-dependent 5-HT deficit during pregnancy could be considered as a risk factor for neurodevelopmental disorders in the offspring.
Nanoconfinement is known to alter polymer mechanics, yet how it couples with interfacial interactions to govern stiffness and fracture in polymer-graphene layered nanocomposites remains fundamentally elusive. This work provides a mechanistic decoupling of these effects by investigating well-defined polycarbonate-graphene heterostructures across a range of polymer thicknesses (hp). Using in situ MEMS tensile testing integrated with Raman spectroscopy, we demonstrate that geometric confinement significantly strengthens the interfacial anchoring. As the polymer thickness approaches molecular length scales (hp < 2Rg), the PC chains undergo a critical conformational transition from random coils to flattened, interface-parallel configurations. This molecular ordering drives a shift in the deformation mechanism from bulk-like chain slippage to interface-governed bond stretching. Consequently, we observe an anomalous modulus stiffening that significantly exceeds the theoretical upper bounds of classical mixture rules, accompanied by a concurrent ductile-to-brittle fracture transition. Enhanced Raman strain sensitivity and spatially distributed graphene lattice degradation provide direct evidence of highly efficient stress transfer under strong confinement. Our findings reveal that the synergistic coupling of geometric and interfacial constraints dictates the mechanical landscape of polymer-graphene heterostructures, offering essential guidelines for engineering high-performance layered nanocomposites.
Groundwater constitutes a critical supply for domestic, agricultural, and industrial needs. Understanding the dynamic interplay between rainfall, river discharge, and groundwater levels remains challenging due to the complexity of hydrogeological structures and variable recharge conditions. This study investigates the temporal relationships among rainfall, river stage-discharge, and groundwater levels in the Erbil Basin, North Iraq. A multivariate time series framework was employed for the data series spanning 2004-2022, combining wavelet coherence analysis to identify dominant periodicities and temporal correlations, with a vector autoregression (VAR) model to forecast future groundwater fluctuations. The wavelet analysis revealed strong monthly-scale variability during the wet season and a pronounced rainfall-groundwater coherence with a dominant 1-month periodicity, particularly after 2008. Spatial differences in coherence strength across monitoring wells indicate regionally consistent hydrogeological conditions, with stronger coupling observed in wells situated closer to the Lesser Zab River. The impulse response function (IRF) analysis additionally demonstrated positive groundwater responses within 2-6 months following rainfall events, consistent with regional recharge patterns. However, persistent groundwater declines identified in the VAR forecasting model reflect the combined effects of reduced recharge and continuous abstraction pressures. The integrated approach provides a comprehensive assessment of hydroclimatic interactions and groundwater dynamics in the Erbil regional aquifer. The findings emphasize the need for adaptive groundwater management strategies and demonstrate the potential of combining wavelet and VAR models for sustainable water resource planning in data-limited, semi-arid environments.
Colitis-associated colorectal cancer (CAC) is driven by chronic inflammation and immune dysregulation. However, how macrophage state heterogeneity is organized across different stages of CAC progression remains unclear. Here, using genetic depletion, single-cell transcriptomics, and pharmacological intervention, and analysis of human colitis-associated colorectal cancer specimens, we identify stage-associated remodeling of CD169-associated macrophage states during CAC progression. We demonstrate that CD169 marks functionally distinct macrophage states with opposing roles: CD169-low macrophages predominate during colitis and exhibit pro-inflammatory features, whereas CD169-mid/high macrophages emerge at tumor stages, localize preferentially to para-tumor regions, and display immunosuppressive and immune-inert interaction profiles. These observations support stage-associated remodeling of CD169-associated macrophage states during CAC progression. Importantly, CD169 depletion restrains tumor growth and enhances intratumoral T cell infiltration, highlighting CD169-associated macrophages as potential therapeutic targets in inflammation-driven colorectal tumorigenesis. Together, our findings reveal stage-associated remodeling of CD169-associated macrophage states during CAC progression, with distinct CD169 states exhibiting divergent immune regulatory features at different disease stages. These findings highlight the importance of considering macrophage state heterogeneity when targeting CD169-associated pathways and support further investigation of state-informed therapeutic strategies in inflammation-driven colorectal tumorigenesis.
In conventional Cuk power factor correction (PFC) circuits, the switching devices experience high voltage and current ripples, leading to switching losses and poor power transfer capability. To address these challenges associated with conventional boost circuits, we proposed a zero-voltage transition (ZVT) soft-switching step-up Cuk PFC converter. This circuit reduces input and output ripples while minimizing switching losses, enabling the switching devices to achieve a unity PFC with zero-voltage switching operation. The proposed ZVT network facilitates zero-voltage turn-on and turn-off for the primary switching device, while allowing the auxiliary switch to achieve zero-current turn-on. Additionally, it ensure that the diodes naturally turn off under zero-current conditions, thereby reducing reverse recovery losses and enhancing converter efficiency. Once the auxiliary switching device is turned off, the resonant inductor within the proposed topology resets, irrespective of the state of the main switching device, enabling operation across a broad range of duty cycles. Furthermore, we established an equivalent circuit model to elucidate the soft-switching operation, providing a comprehensive analysis of the operating principles and processes. We derived the device stresses and conditions required for soft switching and investigated key design parameters. To validate the effectiveness and feasibility of the proposed circuit, we developed an experimental prototype operating at a switching frequency of 100 kHz, delivering an output of 400 V / 0.75 A. The ZVT soft-switching scheme enhanced the efficiency of the step-up Cuk PFC converter, with a peak efficiency of 98.35%. The proposed converter achieved high-efficiency power conversion.
This commentary discusses the potential role of Bifidobacterium longum subsp. infantis M-63 supplementation during the weaning period, a critical phase of gut microbiota maturation and immune development in early life. The authors review and contextualize a recent randomized controlled trial investigating whether targeted probiotic supplementation could support gut health and resilience during complementary feeding. The study evaluated healthy infants and toddlers receiving an 8-week supplementation with B. infantis M-63 during weaning. Clinical outcomes, gut microbiota composition, and microbial metabolites were assessed to explore both physiological and functional effects of the intervention. Supplementation resulted in successful intestinal engraftment of the probiotic strain and was associated with modest improvements in stool consistency, alongside increased fecal short-chain fatty acid production, particularly acetate. However, broader clinical benefits remained limited and variable, with responses strongly influenced by dietary factors such as breastfeeding status. The findings also suggested ecological competition within the bifidobacterial community, potentially limiting sustained microbial expansion. Overall, the commentary highlights that probiotic supplementation during weaning can modulate the developing gut ecosystem, but consistent clinically meaningful benefits remain uncertain. Future studies integrating dietary, microbial, and host-related factors are needed to better define effective microbiome-targeted strategies in early life.
Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening condition with high morbidity and mortality, particularly in poor-grade patients (World Federation of Neurosurgical Societies grades IV-V). Intraventricular hemorrhage (IVH) is associated with worse outcomes, but its predictive value and interaction with demographic and clinical factors remain unclear. To evaluate the prognostic value of IVH volume (IVHV) quantified on admission computed tomography (CT) in association with mortality and long-term disability, as well as its interaction with demographic and clinical variables in patients with poor-grade aSAH. We retrospectively analyzed all consecutive patients with poor-grade aSAH and IVH that were admitted to nine Italian tertiary centers between 1 January 2015 and 31 May 2023. Bivariate and multivariable analyses were performed to identify factors associated with mortality and disability (modified Rankin Scale [mRS]). Global intracranial hemorrhage volume (GHV) as well as the volumes of ICH (ICHV), IVH (IVHV), and SAH (SAHV) were calculated by means of analytical software in a semiautomated setting. We employed an explainable machine learning approach to examine the interplay between hemorrhage volume distribution, demographic and clinical variables to define prognostic thresholds, and to develop a decision tree model. Among 326 patients with IVH (median age 61 years [IQR: 53-70], 65.6% male), IVHV was the strongest factor independently associated with mortality and disability. An IVHV threshold of 8 mL optimized sensitivity and specificity for the outcome. Combining IVHV with age and ICHV further improved prognostic thresholds in the studied population; specificity was 92% for mortality and 71% sensitivity for disability. Adding IVHV to the SAFIRE scale significantly improved its predictive power (De Long p .008). IVHV is a key factor associated with mortality and disability in poor-grade aSAH with intraventricular involvement. Quantifying hemorrhage volume on admission CT is a valuable tool for improving outcome stratification and guiding clinical decision-making.
This study investigated preoperative biometric measurements and perioperative complications of cataract surgery in eyes with shallow and non-shallow anterior chambers. This multicenter retrospective study included 1423 eyes of 1053 patients who underwent cataract surgery at five Japanese institutions between April 2016 and July 2023. Eyes with an anterior chamber depth (ACD) of ≤ 2.5 mm were classified as the shallow group; those with an ACD > 2.5 mm were categorized as the non-shallow group. The shallow group included older patients, more women, and better best-corrected visual acuity. Preoperative comorbidities, including retinitis pigmentosa, pseudoexfoliation syndrome, and a history of laser iridotomy or peripheral iridectomy, were more frequent in the shallow group. Intraoperatively, the eyes in the shallow group had higher rates of zonular dehiscence (ZD) (odds ratio [OR] 3.04; 95% confidence interval [CI] 1.32-6.94), use of a capsular tension ring (OR 3.52; 95% CI 1.54-8.07) or pupil expansion device (OR 2.17; 95% CI 1.20-3.85), and a higher incidence of postoperative corneal edema. In the shallow group, eyes with ZD had a smaller anterior lens radius of curvature and larger posterior lens radii of curvature. Lens curvature measurements may predict zonular instability in eyes with shallow anterior chambers.
Due to limited heat dissipation, wearing high-protection medical gowns against COVID-19 may lead to cognitive challenges and impaired performance in healthcare workers (HCWs). This study aimed to evaluate the cognitive performance of female HCWs wearing two commonly used types of medical gowns under varying temperature conditions during the COVID-19 pandemic. This study included 20 female HCWs. The experiment was conducted in six sessions under three temperature conditions (24, 28, and 32 °C) with a relative humidity of 40%, using both a Spunbond gown (SG) and a Laminated gown (LG). Participants walked on a treadmill for 30 min at a speed of 3 km/h with a 0% incline within a climate-controlled chamber. Cognitive and psychomotor performance was assessed using the psychomotor vigilance test (PVT), the continuous performance test (CPT), and the mirror test, conducted before and after walking on a treadmill. Additionally, a thermal sensation scale was used to evaluate participants' perceived heat. The number of errors in the mirror test for participants wearing LG was significantly higher than that for those wearing SG at 32 °C. In the PVT, participants wearing LG had 1.39% and 0.12% fewer correct responses than those wearing SG at 24 °C and 28 °C, respectively. In the CPT, the number of correct responses for LG at 28 °C was 0.8% lower than at the comfortable temperature (P < 0.05). Moreover, participants reported significantly higher thermal sensations while wearing LG compared with SG at both comfortable and elevated temperatures. Thermal sensation increased for both SG and LG as the environmental temperature rose. Compared to HCWs wearing SG, HCWs wearing LG exhibited 0.12-1.39% more errors, which may pose a potential safety risk. To mitigate this risk, it is recommended to maintain comfortable temperature conditions in hospitals, particularly for HCWs wearing high-protection gowns against COVID-19.
Land-use changes in tropical dry forests (TDF) have rapidly reduced native vegetation, disrupting gene flow dynamics of tree species. Bursera cuneata is a co-dominant TDF tree in central Mexico, which is threatened by habitat loss and overexploitation. We investigated landscape drivers of functional connectivity of B. cuneata across scales to inform species conservation efforts. We genotyped 227 B. cuneata individuals from 33 populations across five hydrological basins: covering western, central, and southern Mexico, at 10,499 single-nucleotide polymorphism (SNP) loci. We examined spatial patterns of genetic structure among hydrological basins and the landscape correlates of gene flow. We applied gravity models that incorporated within-site (i.e., local conditions within populations; slope and east aspect) and between-site (terrain roughness, habitat suitability, and habitat cover) factors associated with B. cuneata gene flow. Clustering analyses showed genetic structure among basins, with higher differentiation in more isolated regions. Gravity models revealed that functional connectivity is a scale-dependent process. Specifically, terrain roughness was the primary factor of connectivity at finer scales (1000-3000 m), while TDF cover became the main driver at regional scales (>4000 m). We recommend protecting and prioritizing crucial TDF remnants to maintain large-scale gene flow by integrating urban natural parks as important links to prevent genetic isolation between urban and rural populations.
Two-drug antiretroviral regimens are being investigated as alternatives to standard three-drug therapy for HIV-1. Doravirine/islatravir is a once-daily oral combination with promising efficacy and safety, but its overall clinical performance has not been systematically quantified. This study evaluated the efficacy and safety of doravirine/islatravir compared with standard triple option therapy in adults living with HIV-1. PubMed, Scopus, Web of Science, and the Cochrane Library were systematically searched for phase III randomized controlled trials comparing doravirine/islatravir with standard triple option therapy. Eligible studies were independently screened, and data were extracted and pooled using R software. Six phase III trials involving 3,518 adults were included. At 48 weeks, doravirine/islatravir was associated with a significantly lower risk of virological failure (HIV-1 RNA ≥ 50 copies/mL) compared with standard triple option therapy (RR: 0.51, 95% CI [0.30-0.88]; P = 0.015). Rates of virological suppression (< 50 and < 200 copies/mL) were comparable between groups. No significant differences were observed in overall, serious, or grade 3-4 adverse events, or treatment discontinuation due to adverse events. Dose-stratified analyses showed that the 100/0.75 mg formulation was associated with significant declines in CD4 cell count and total lymphocyte count at 48 weeks, whereas the optimized 100/0.25 mg dose showed no significant immunological differences compared with standard triple option therapy. Doravirine/islatravir is an effective and generally well-tolerated two-drug regimen for HIV-1. The optimized 100/0.25 mg formulation maintained virological efficacy without significant short-term immunological differences versus standard triple option therapy; however, longer follow-up is needed to confirm its long-term immunological safety.
The impact of crystallographic orientation, select grain boundaries, and vacancies on the shock response of aluminum was investigated using molecular dynamics simulations. Shock loading in the [001], [011], and [111] directions was explored, revealing anisotropic behavior in shock speed, generated dislocation density, and melting. The Hugoniot elastic limit (HEL) in the [100], [110], and [111] directions were calculated as 18.7 GPa, 17.8 GPa, and 22.5 GPa, respectively. These results were found to be an order of magnitude larger than the uniaxial compressive yield strengths computed at high strain rate using an affine loading scheme. Metastable melting in the [011] and [111] directions occurred around a pressure of 100 GPa and roughly 1000 K below the observed metastable melting [001] direction and the equilibrium melt curve. The role of select twist and tilt grain boundaries was assessed. Differences in the wave speed profile were observed for most grain boundaries, but only for piston velocities [Formula: see text]1.5 km/s. Additionally, the presence of vacancies, both randomly distributed and clustered, led to a decrease in shock speed with a larger decrease in shock speed recorded at higher vacancy concentrations. The change in shock speed, relative to a defect free cell, exhibited a dependence on the configuration of the defects. Melting was also found to occur at lower pressures for increasing vacancy concentrations. These results highlight key trends in the role of defects and crystallographic orientation in the behavior of FCC metals, such as aluminum, under extreme loading conditions.
Pathologic complete response after neoadjuvant treatment is considered a surrogate of cure in triple-negative breast cancer, yet around 10% of patients still relapse. Whether baseline stromal tumor-infiltrating lymphocytes can stratify this residual risk is unknown. Here, we report on GAMBIT, a multicentric real-world retrospective study of 2457 patients with triple-negative breast cancer or estrogen receptor-low disease, HER2-negative, of whom 1192 obtained a pathological complete response and 690 have evaluable tumor infiltrating lymphocytes. Among patients with pathological complete response, clinical nodal status and tumor infiltrating lymphocytes are independently prognostic and patients with clinical node-positive/low-tumor infiltrating lymphocytes tumors experience substantially worse outcomes, with five-year distant relapse-free survival of 83.4% and overall survival of 85.8%. In this high-risk subgroup, five-year cumulative incidence of central nervous system reaches 7.5%, including 6.9% presenting as isolated central nervous system relapse. In this work, we identify a high-risk subgroup despite pathologic complete response and provide a framework supporting risk-adapted trial design incorporating central nervous system-directed strategies.