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Tumor-resident microbiota in breast cancer promotes cancer initiation and malignant progression. However, targeting microbiota to improve the effects of breast cancer therapy has not been investigated in detail. Here, we evaluated the microbiota composition of breast tumors and found that enterotoxigenic Bacteroides fragilis(ETBF) was highly enriched in the tumors of patients who did not respond to taxane-based neoadjuvant chemotherapy. ETBF, albeit at low biomass, secreted the toxic protein BFT-1 to promote breast cancer cell stemness and chemoresistance. Mechanistic studies showed that BFT-1 directly bound to NOD1 and stabilized NOD1 protein. NOD1 was highly expressed on ALDH+breast cancer stem cells (BCSCs) and cooperated with GAK to phosphorylate NUMB and promote its lysosomal degradation, thereby activating the NOTCH1-HEY1 signaling pathway to increase BCSCs. NOD1 inhibition and ETBF clearance increase the chemosensitivity of breast cancer by impairing BCSCs.

Diabetic cardiomyopathy (DCM), one of the most serious long-term consequences of diabetes, is closely associated with oxidative stress, inflammation and apoptosis in the heart. MACRO domain containing 1 (Macrod1) is an ADP-ribosylhydrolase 1 that is highly enriched in mitochondria, participating in the pathogenesis of cardiovascular diseases. In this study, we investigated the role of Macrod1 in DCM. A mice model was established by feeding a high-fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ). We showed that Macrod1 expression levels were significantly downregulated in cardiac tissue of DCM mice. Reduced expression of Macrod1 was also observed in neonatal rat cardiomyocytes (NRCMs) treated with palmitic acid (PA, 400 μM) in vitro. Knockout of Macrod1 in DCM mice not only worsened glycemic control, but also aggravated cardiac remodeling, mitochondrial dysfunction, NAD+consumption and oxidative stress, whereas cardiac-specific overexpression of Macrod1 partially reversed these pathological processes. In PA-treated NRCMs, overexpression of Macrod1 significantly inhibited PARP1 expression and restored NAD+levels, activating SIRT3 to resist oxidative stress. Supplementation with the NAD+precursor Niacin (50 μM) alleviated oxidative stress in PA-stimulated cardiomyocytes. We revealed that Macrod1 reduced NAD+consumption by inhibiting PARP1 expression, thereby activating SIRT3 and anti-oxidative stress signaling. This study identifies Macrod1 as a novel target for DCM treatment. Targeting the PARP1-NAD+-SIRT3 axis may open a novel avenue to development of new intervention strategies in DCM.

•A deep learning-based framework is devised for the comprehensive molecular and prognostic stratifications of triple-negative breast cancer.•A tissue type classifier is developed and incorporated in the framework to decompose the tissue on whole slide images and replace manual annotation.•A novel online platform is built which can be clinically implemented and realize real-time one-stop prediction for new cases.

The hot compression behavior and tensile strength after compression of a new Ni–Co-based superalloy produced using electron beam smelting layered (EBSL) solidification technology were investigated. Isothermal compression tests were performed at temperatures of 1120 ℃ and 1150 ℃, with strain rates of 1 s−1and 0.01 s−1, reaching a true strain of 0.51. Tensile strength was evaluated at room temperature. The results revealed that this EBSL technology accelerates dynamic recrystallization (DRX), without compromising the strength of alloy. A significant correlation between the volume fraction of DRX and the strain rate was observed, with higher fractions at lower strain rates, leading to higher tensile strength. Additionally, at the same strain rate, the specimens compressed at 1120 ℃ exhibited higher tensile strength due to undissolved γ′ precipitates. After solution and aging heat treatment, the alloy maintained high tensile strength. The results suggested that the EBSL Ni–Co-based superalloy offers excellent prospects for practical applications.

Coarsening of cuboidal γ′ precipitates and relevant diffusion process in Ni-based single-crystal superalloy CMSX-4 were investigated at 1000, 1020 and 1040 °C for specific times. The γ′ coarsening kinetics followed a cubic rate law with time and was presumably controlled by bulk diffusion of elements in γmatrix. The associated diffusion activation energy was experimentally determined to be about 300 kJ/mol when it is considered the temperature-dependent thermo-physical parameters in modified Lifshitz–Slyozov–Wagner theory. The influence of temperature on γ/γ′ microstructure is briefly discussed based on pseudo-binary [Ni]–[Al] phase diagram. Interactions among elements can effectively raise the local vacancy formation and vacancy–atom exchange barriers close to γ- and γ′-partitioning elements, respectively. Thus, it can significantly reduce the inter-coupling migrations of atoms during the macroscopic cross-diffusion process associated with γ′ coarsening of Ni-based superalloys.

Cracks have consistently been a significant challenge limiting the development of additive manufactured nickel-based superalloys. It is essential to investigate the location of cracks and their forming mechanism. This study extensively examines the impact of solidification process, microstructural evolution, and stress concentration on crack initiation during direct energy deposition (DED). The results emphasize that the crack formation is significantly related to large-angle grain boundaries, rapid cooling rates. Cracks caused by large-angle grain boundaries and a fast-cooling rate predominantly appear near the edge of the deposited samples. Liquation cracks are more likely to form near the top of the deposited sample, due to the presence of γ/γ′ eutectics. The secondary dendritic arm and the carbides in the interdendritic regions can obstruct liquid flow during the final stage of solidification, which results in the formation of solidification cracks and voids. This work paves the way to avoid cracks in nickel-based superalloys fabricated by DED, thereby enhancing the performance of superalloys.

In this study, direct numerical simulations were conducted to investigate the compressible flow around a circular cylinder near a heated wall at a Reynolds number (Re) of 500 and a Mach number (Ma) of 0.4. The heating ratio T* ranging from 1.0 to 1.6 represents the different situations of a heated wall, whereas the gap ratio ranges from 0.3 to 1.0. This study analyzed the impact of heating effect and wall proximity on flow characteristics and aerodynamic forces. The results indicated that the stability of the flow was enhanced as the gap ratio decreased or the heating ratio increased. Through the calculation of enstrophy, it was found that the strength of shedding vortices weakens with a decrease in gap ratio or an increase in heating ratio. Furthermore, the mean drag coefficient decreases as the heating ratio increases or the gap ratio decreases. In contrast, the mean lift coefficient initially decreases and then increases as the gap ratio decreases. Finally, the drag reduction mechanism was analyzed by examining the pressure distribution on the surface of the cylinder.

Recent years have witnessed the transformative impact from the integration of artificial intelligence with organic and polymer synthesis. This synergy offers innovative and intelligent solutions to a range of classic problems in synthetic chemistry. These exciting advancements include the prediction of molecular property, multi-step retrosynthetic pathway planning, elucidation of the structure-performance relationship of single-step transformation, establishment of the quantitative linkage between polymer structures and their functions, design and optimization of polymerization process, prediction of the structure and sequence of biological macromolecules, as well as automated and intelligent synthesis platforms. Chemists can now explore synthetic chemistry with unprecedented precision and efficiency, creating novel reactions, catalysts, and polymer materials under the data-driven paradigm. Despite these thrilling developments, the field of artificial intelligence (AI) synthetic chemistry is still in its infancy, facing challenges and limitations in terms of data openness, model interpretability, as well as software and hardware support. This review aims to provide an overview of the current progress, key challenges, and future development suggestions in the interdisciplinary field between AI and synthetic chemistry. It is hoped that this overview will offer readers a comprehensive understanding of this emerging field, inspiring and promoting further scientific research and development.

Polyploidy (genome duplication) is a pivotal force in evolution. However, the interactions between parental genomes in a polyploid nucleus, frequently involving subgenome dominance, are poorly understood. Here we showcase analyses of a bamboo system (Poaceae: Bambusoideae) comprising a series of lineages from diploid (herbaceous) to tetraploid and hexaploid (woody), with 11 chromosome-level de novo genome assemblies and 476 transcriptome samples. We find that woody bamboo subgenomes exhibit stunning karyotype stability, with parallel subgenome dominance in the two tetraploid clades and a gradual shift of dominance in the hexaploid clade. Allopolyploidization and subgenome dominance have shaped the evolution of tree-like lignified culms, rapid growth and synchronous flowering characteristic of woody bamboos as large grasses. Our work provides insights into genome dominance in a remarkable polyploid system, including its dependence on genomic context and its ability to switch which subgenomes are dominant over evolutionary time.

As post-transcriptional regulators of gene expression, micro-ribonucleic acids (miRNAs) are regarded as potential biomarkers for a variety of diseases. Hence, the prediction of miRNA-disease associations (MDAs) is of great significance for an in-depth understanding of disease pathogenesis and progression. Existing prediction models are mainly concentrated on incorporating different sources of biological information to perform the MDA prediction task while failing to consider the fully potential utility of MDA network information at the motif-level. To overcome this problem, we propose a novel motif-aware MDA prediction model, namely MotifMDA, by fusing a variety of high- and low-order structural information. In particular, we first design several motifs of interest considering their ability to characterize how miRNAs are associated with diseases through different network structural patterns. Then, MotifMDA adopts a two-layer hierarchical attention to identify novel MDAs. Specifically, the first attention layer learns high-order motif preferences based on their occurrences in the given MDA network, while the second one learns the final embeddings of miRNAs and diseases through coupling high- and low-order preferences. Experimental results on two benchmark datasets have demonstrated the superior performance of MotifMDA over several state-of-the-art prediction models. This strongly indicates that accurate MDA prediction can be achieved by relying solely on MDA network information. Furthermore, our case studies indicate that the incorporation of motif-level structure information allows MotifMDA to discover novel MDAs from different perspectives.

Biomarker discovery is essential for the understanding, diagnosis, targeted therapy and prognosis assessment of malignant diseases. However, it remains a huge challenge due to the lack of sensitive methods to identify disease-specific rare molecules. Here we present MORAC, molecular recognition based on affinity and catalysis, which enables the effective identification of candidate biomarkers with low abundance. MORAC relies on a class of DNAzymes, each cleaving a sole RNA linkage embedded in their DNA chain upon specifically sensing a complex system with no prior knowledge of the system’s molecular content. We show that signal amplification from catalysis ensures the DNAzymes high sensitivity (for target probing); meanwhile, a simple RNA-to-DNA mutation can shut down their RNA cleavage ability and turn them into a pure affinity tool (for target pulldown). Using MORAC, we identify previously unknown, low-abundance candidate biomarkers with clear clinical value, including apolipoprotein L6 in breast cancer and seryl-tRNA synthetase 1 in polyps preceding colon cancer.

ObjectiveCurrently, there is no cure for chronic pancreatitis (CP). Germline loss-of-function variants in SPINK1(encoding trypsin inhibitor) are common in patients with CP and are associated with acute attacks and progression of the disease. This preclinical study was conducted to explore the potential of adeno-associated virus type 8 (AAV8)-mediated overexpression of human SPINK1(hSPINK1) for pancreatitis therapy in mice.DesignA capsid-optimised AAV8-mediated hSPINK1expression vector (AAV8-hSPINK1) to target the pancreas was constructed. Mice were treated with AAV8-hSPINK1by intraperitoneal injection. Pancreatic transduction efficiency and safety of AAV8-hSPINK1were dynamically evaluated in infected mice. The effectiveness of AAV8-hSPINK1on pancreatitis prevention and treatment was studied in three mouse models (caerulein-induced pancreatitis, pancreatic duct ligation and Spink1c.194+2T>C mouse models).ResultsThe constructed AAV8-hSPINK1vector specifically and safely targeted the pancreas, had low organ tropism for the heart, lungs, spleen, liver and kidneys and had a high transduction efficiency (the optimal expression dose was 2×1011vg/animal). The expression and efficacy of hSPINK1peaked at 4 weeks after injection and remained at significant level for up to at least 8 weeks. In all three mouse models, a single dose of AAV8-hSPINK1before disease onset significantly alleviated the severity of pancreatitis, reduced the progression of fibrosis, decreased the levels of apoptosis and autophagy in the pancreas and accelerated the pancreatitis recovery process.ConclusionOne-time injection of AAV8-hSPINK1safely targets the pancreas with high transduction efficiency and effectively ameliorates pancreatitis phenotypes in mice. This approach is promising for the prevention and treatment of CP.

Triple-negative breast cancer (TNBC) is an aggressive disease characterized by remarkable intratumor heterogeneity (ITH), which poses therapeutic challenges. However, the clinical relevance and key determinant of ITH in TNBC are poorly understood. Here, we comprehensively characterized ITH levels using multi-omics data across our center’s cohort (n= 260), The Cancer Genome Atlas cohort (n= 134), and four immunotherapy-treated cohorts (n= 109). Our results revealed that high ITH was associated with poor patient survival and immunotherapy resistance. Importantly, we identified zinc finger protein 689 (ZNF689) deficiency as a crucial determinant of ITH formation. Mechanistically, the ZNF689–TRIM28 complex was found to directly bind to the promoter of long interspersed element-1 (LINE-1), inducing H3K9me3-mediated transcriptional silencing. ZNF689 deficiency reactivated LINE-1 retrotransposition to exacerbate genomic instability, which fostered ITH. Single-cell RNA sequencing, spatially resolved transcriptomics and flow cytometry analysis confirmed that ZNF689 deficiency-induced ITH inhibited antigen presentation and T-cell activation, conferring immunotherapy resistance. Pharmacological inhibition of LINE-1 significantly reduced ITH, enhanced antitumor immunity, and eventually sensitized ZNF689-deficient tumors to immunotherapy in vivo. Consistently, ZNF689 expression positively correlated with favorable prognosis and immunotherapy response in clinical samples. Altogether, our study uncovers a previously unrecognized mechanism underlying ZNF689 deficiency-induced ITH and suggests LINE-1 inhibition combined with immunotherapy as a novel treatment strategy for TNBC.

Immunotherapy has enhanced breast cancer outcomes, but optimizing combination therapies is crucial. Integrating additional treatment modalities, like physical therapies, holds promise for optimizing efficacy. Pan et al. recently reported that combining preoperative immunotherapy with microwave ablation is safe and feasible in early-stage breast cancer, effectively sensitizing peripheral CD8+T cells.1

Immunotherapy has rejuvenated cancer therapy, especially after anti-PD-(L)1 came onto the scene. Among the many therapeutic options, therapeutic cancer vaccines are one of the most essential players. Although great progress has been made in research on tumor antigen vaccines, few phase III trials have shown clinical benefits. One of the reasons lies in obstruction from the tumor microenvironment (TME). Meanwhile, the therapeutic cancer vaccine reshapes the TME in an ambivalent way, leading to immune stimulation or immune escape. In this review, we summarize recent progress on the interaction between therapeutic cancer vaccines and the TME. With respect to vaccine resistance, innate immunosuppressive TME components and acquired resistance caused by vaccination are both involved. Understanding the underlying mechanism of this crosstalk provides insight into the treatment of cancer by directly targeting the TME or synergizing with other therapeutics.

Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer is the most prevalent type of breast cancer, in which endocrine therapy resistance and distant relapse remain unmet challenges. Accurate molecular classification is urgently required for guiding precision treatment. We established a large-scale multi-omics cohort of 579 patients with HR+/HER2−breast cancer and identified the following four molecular subtypes: canonical luminal, immunogenic, proliferative and receptor tyrosine kinase (RTK)-driven. Tumors of these four subtypes showed distinct biological and clinical features, suggesting subtype-specific therapeutic strategies. The RTK-driven subtype was characterized by the activation of the RTK pathways and associated with poor outcomes. The immunogenic subtype had enriched immune cells and could benefit from immune checkpoint therapy. In addition, we developed convolutional neural network models to discriminate these subtypes based on digital pathology for potential clinical translation. The molecular classification provides insights into molecular heterogeneity and highlights the potential for precision treatment of HR+/HER2−breast cancer.

The phosphorus-containing organic molecule as a novel fluorine-free multifunctional additive not only endows the commercial electrolytes with a good flame retardancy, but also is greatly helpful in stabilizing electrodes by regulating solid electrolyte interphase and solvation structure.

In this paper, the large eddy simulation (LES) method is used to calculate Reynolds numbers the range in the range of 3 000–30 000 (based on the diameter of the hemisphere D), and then the statistical analysis method is used to study the influence of Re on the characteristics of the flow field around the rough hemisphere and the evolution law of the tail vortex. The effect of the Reynolds number on the structure of the rough hemisphere flow field and the evolution of vortex structure is studied by vorticity distribution, POD method, and correlation analysis. It can be observed that with the increase of Reynolds number, the shear in the recirculating region of the rough hemisphere is enhanced, the large-scale structure is reduced, the small-scale structure is increased, and the angle between the hairpin vortex and the wall is reduced. λcivortex identification and the Q-criterion are used to capture the evolution of a periodic vortex structure. Q-criterion gives the three-dimensional vortex structure behind the hemispherical flow. It is found that the horseshoe vortex and arch vortex generated by the incoming flow after passing through the hemisphere will interact with the wall surface to form a hairpin vortex, and the hairpin vortex structure will continue to evolve downstream to form a new vortex structure.

Estrogen receptor (ER)-positive luminal breast cancer is a subtype with generally lower risk of metastasis to most distant organs. However, bone recurrence occurs preferentially in luminal breast cancer. The mechanisms of this subtype-specific organotropism remain elusive. Here we show that an ER-regulated secretory protein SCUBE2 contributes to bone tropism of luminal breast cancer. Single-cell RNA sequencing analysis reveals osteoblastic enrichment by SCUBE2 in early bone-metastatic niches. SCUBE2 facilitates release of tumor membrane-anchored SHH to activate Hedgehog signaling in mesenchymal stem cells, thus promoting osteoblast differentiation. Osteoblasts deposit collagens to suppress NK cells via the inhibitory LAIR1 signaling and promote tumor colonization. SCUBE2 expression and secretion are associated with osteoblast differentiation and bone metastasis in human tumors. Targeting Hedgehog signaling with Sonidegib and targeting SCUBE2 with a neutralizing antibody both effectively suppress bone metastasis in multiple metastasis models. Overall, our findings provide a mechanistic explanation for bone preference in luminal breast cancer metastasis and new approaches for metastasis treatment.

Acupuncture has been recommended as a nonpharmacological intervention for managing cancer-related symptoms. However, there are few bibliometric analysis-based studies concerning the overall trends and characteristics in acupuncture therapy for cancer management. This study aims to summarize the status and bibliometric characteristics of acupuncture as an intervention for cancer-related symptoms.

The microstructure and tensile properties of a new Ni-based superalloy specially designed for additive manufacture (AM) were investigated under different laser power (LP) conditions. The results measured by X-ray diffraction analysis and scanning electron microscopy show that no cracks are observed in as-deposited alloy, which has typical crystallography orientation and non-equilibrium solidification dendrite/cellular morphology. The elements such as Nb, Si and Ti are enriched in the interdendritic regions, while Al, Cr and Co segregate in the dendritic cores. When the LP is low, the cellular crystals of the alloy are arranged orderly, the primary dendrite arm space (PDAS) is small, the porosity is large, the strength is high and the elongation is low. With the increase of LP, the PDAS increases, the porosity decreases, the strength decreases and the elongation increases. When the LP is elevated further, Marangoni convection effect is enhanced and shows unique impacts, that is, the disordered arrangement of cellular crystals occurs. Then, the PDAS decreases, the porosity increases, the strength increases and the elongation decreases. The smaller PDAS favors the reduction for elements segregation, as well as microstructure refinement and strength improvement. The fitting formula between PDAS and yield strength (YS) was proposed, and the concentric ring patterns inside microstructure were rationalized.

ABSTRACT The effect of lightweight aggregate (LWA) type on the early-age autogenous shrinkage of lightweight aggregate concrete (LWAC) was investigated based on a corrugated tube testing method. The study reveals [...]

Only a small proportion of patients with triple-negative breast cancer benefit from immune checkpoint inhibitor (ICI) targeting PD-1/PD-L1 signaling in combination with chemotherapy. Here, we discovered that therapeutic response to ICI plus paclitaxel was associated with subcellular redistribution of PD-L1. In our immunotherapy cohort of ICI in combination with nab-paclitaxel, tumor samples from responders showed significant distribution of PD-L1 at mitochondria, while non-responders showed increased accumulation of PD-L1 on tumor cell membrane instead of mitochondria. Our results also revealed that the distribution pattern of PD-L1 was regulated by an ATAD3A-PINK1 axis. Mechanistically, PINK1 recruited PD-L1 to mitochondria for degradation via a mitophagy pathway. Importantly, paclitaxel increased ATAD3A expression to disrupt proteostasis of PD-L1 by restraining PINK1-dependent mitophagy. Clinically, patients with tumors exhibiting high expression of ATAD3A detected before the treatment with ICI in combination with paclitaxel had markedly shorter progression-free survival compared with those with ATAD3A-low tumors. Preclinical results further demonstrated that targeting ATAD3A reset a favorable antitumor immune microenvironment and increased the efficacy of combination therapy of ICI plus paclitaxel. In summary, our results indicate that ATAD3A serves not only as a resistant factor for the combination therapy of ICI plus paclitaxel through preventing PD-L1 mitochondrial distribution, but also as a promising target for increasing the therapeutic responses to chemoimmunotherapy.

Triple-negative breast cancer (TNBC) is a heterogeneous disease and lacks effective treatment. Our previous study classified TNBCs into four subtypes with putative therapeutic targets. Here, we report the final results of FUTURE, a phase II umbrella trial designed to explore whether the subtyping-based strategy may improve the outcomes in metastatic TNBC patients. A total of 141 patients with a median of three previous lines of therapies in the metastatic setting were enrolled in seven parallel arms. Confirmed objective responses were achieved in 42 patients (29.8%; 95% confidence interval [CI], 22.4–38.1). The median values of progression-free survival and overall survival were 3.4 (95% CI: 2.7–4.2) and 10.7 (95% CI: 9.1–12.3) months, respectively. Given Bayesian predictive probability, efficacy boundaries were achieved in four arms. Furthermore, integrated genomic and clinicopathological profiling illustrated associations of clinical and genomic parameters with treatment efficacy, and the efficacy of novel antibody–drug conjugates was explored in preclinical TNBC models of subtypes for which treatment was futile. In general, the FUTURE strategy recruits patients efficiently and provides promising efficacy with manageable toxicities, outlining a direction for further clinical exploration.

Human–machine interfaces (HMIs) enable users to interact with machines, thus playing a significant role in artificial intelligence, virtual reality, and the metaverse. Conventional HMIs are based on bulky and rigid electronic devices, seriously limiting their ductility, damage reconfiguration, and multifunctionality. In terms of replacing conventional HMIs, artificial bionic skins with good ductility, self-reparation, and multisensory ability are promising candidates. Still, they in their present form require innovations in mechanical and sensory properties, especially damage recovery and environmental stability, which seriously affect the service life and result in tons of electric waste. Herein, we present a new type of artificial bionic skin with excellent mechanical performance (>13,000% strain), high environmental stability (−80 to 80 °C), and multiple sensory properties toward strain, stress, temperature, solvent, and bioelectricity. Besides, this new type of artificial bionic skin also exhibits effective reconfiguration ability after damage and recyclability. The as-prepared artificial bionic skin was used as an interactive HMI to collect and distinguish the different sensory stimuli. The electronics assembled by HMI with artificial bionic skin can adhere compliantly on the human body for wireless motion capturing and sensing via Bluetooth, Wi-Fi, and the Internet. With simple programming, complex human motions can be mimicked in real-time by robots.

ABSTRACT High water absorption ceramsite (YAS), low water absorption ceramsite (YCS), and normal-weight coarse aggregate (NCA) were used as coarse aggregates in concrete. YCS, YAS and NCA were respectively presoaked [...]

ABSTRACT Concrete mixes were prepared with 50% recycled fine aggregate (RFA) and 50% natural fine aggregates. The moisture states of the RFA were controlled at oven-dried, air-dried and saturated surface-dried. [...]

ABSTRACT The mix proportion of manufactured sand concrete (MSC) was designed based on a minimum paste theory, where microfines was added to replace part of cement. The effect of microfines [...]

ABSTRACT Using a shrinkage-restrained ring device with a clapboard, the effect of steel fiber content, sand-binder ratio and water-binder ratio on the cracking resistant behavior of reactive powder concrete (RPC) [...]

Metabolic reprogramming is a hallmark of cancer. However, systematic characterizations of metabolites in triple-negative breast cancer (TNBC) are still lacking. Our study profiled the polar metabolome and lipidome in 330 TNBC samples and 149 paired normal breast tissues to construct a large metabolomic atlas of TNBC. Combining with previously established transcriptomic and genomic data of the same cohort, we conducted a comprehensive analysis linking TNBC metabolome to genomics. Our study classified TNBCs into three distinct metabolomic subgroups: C1, characterized by the enrichment of ceramides and fatty acids; C2, featured with the upregulation of metabolites related to oxidation reaction and glycosyl transfer; and C3, having the lowest level of metabolic dysregulation. Based on this newly developed metabolomic dataset, we refined previous TNBC transcriptomic subtypes and identified some crucial subtype-specific metabolites as potential therapeutic targets. The transcriptomic luminal androgen receptor (LAR) subtype overlapped with metabolomic C1 subtype. Experiments on patient-derived organoid and xenograft models indicate that targeting sphingosine-1-phosphate (S1P), an intermediate of the ceramide pathway, is a promising therapy for LAR tumors. Moreover, the transcriptomic basal-like immune-suppressed (BLIS) subtype contained two prognostic metabolomic subgroups (C2 and C3), which could be distinguished through machine-learning methods. We show that N-acetyl-aspartyl-glutamate is a crucial tumor-promoting metabolite and potential therapeutic target for high-risk BLIS tumors. Together, our study reveals the clinical significance of TNBC metabolomics, which can not only optimize the transcriptomic subtyping system, but also suggest novel therapeutic targets. This metabolomic dataset can serve as a useful public resource to promote precision treatment of TNBC.

In this study, high density electric current pulse (ECP) treatment was introduced instead of the conventional solution treatment, and the γ′ phase was completely dissolved under the ECP treatment within only several milliseconds at 1148 °C. Due to the extremely short treatment time and high cooling rate, the growth of γ-phase matrix grain and γ′ phase precipitate was effectively retarded. By comparing with the conventional heat process, the grain size of ECP treated sample was controlled to about 15 μm, the size of the re-precipitated γ′ phase reduced from 65 to 35 nm, and the number density of γ′ precipitate increased from 1.46 × 108to 3.03 × 108/mm2. The Vickers hardness, ultimate tensile strength and yield strength of the ECP treated sample were significantly improved. According to the theoretical derivation of kinetics, the ECP treatment introduces an extra electrical free energy which promoted the dissolution of γ′ phase. The ECP treatment may provide a new method for solution treatment of the Ni-based superalloy.

Supplemental Digital Content is available in the text.

The anomalous flow behavior of γ′-Ni3Al phases at high temperature is closely related to the cross-slip of 1/2〈110〉{111} super-partial dislocations. Generalized stacking fault energy curves (i.e., Γ-surfaces) along the lowest energy path can provide a great deal of information on the nucleation and movement of dislocations. With the first-principles calculation, the interplay between Re and W, Mo, Ta, Ti doped at preferential sites and their synergetic influence on Γ-surfaces and ideal shear strength (τmax) in γ′-Ni3Al phases are investigated. Similar to single Re-addition, the Suzuki segregation of W at stacking faults is demonstrated to enable to impede the movement of 1/6〈112〉{111} Shockley partial dislocations and promote the cross-slip of 1/2〈110〉{111} super-partial dislocations. With the replacement of a part of Re by W, a decreased indicates that the anomalous flow behavior of γ′phases at high temperature is not as excellent as the double Re-addition, but an increased τmaxmeans that the creep rupture strength of Ni-based single crystal superalloys can be benefited from this replacement to some extent, especially in the co-segregation of Re and W at Al−Al sites. As the interaction between X1Aland X2Alpoint defects is characterized by an correlation energy function , it is found that both strong attraction and strong repulsion are unfavarable for the improvement of yield strengths of γ′phase.

In this study, a kind of Ni-based superalloy specially designed for additive manufacturing (AM) was investigated. Thermo-Calc simulation and differential scanning calorimetry (DSC) analysis were used to determine phases and their transformation temperature. Experimental specimens were prepared by laser metal deposition (LMD) and traditional casting method. Microstructure, phase constitution and mechanical properties of the alloy were characterized by scanning electron microscopy (SEM), transmission scanning electron microscopy (TEM), X-ray diffraction (XRD) and tensile tests. The results show that this alloy contains two basic phases, γ/γ’, in addition to these phases, at least two secondary phases may be present, such as MC carbides and Laves phases. Furthermore, the as-deposited alloy has finer dendrite, its mean primary dendrite arm space (PDAS) is about 30–45 μm, and the average size of γ’ particles is 100–150 nm. However, the dendrite size of the as-cast alloy is much larger and its PDAS is 300–500 μm with secondary and even third dendrite arms. Correspondingly, the alloy displays different tensile behavior with different processing methods, and the as-deposited specimen shows better ultimate tensile stress (1,085.7±51.7 MPa), yield stress (697±19.5 MPa) and elongation (25.8%±2.2%) than that of the as-cast specimen. The differences in mechanical properties of the alloy are due to the different morphology and size of dendrites, γ’, and Laves phase, and the segregation of elements, etc. Such important information would be helpful for alloy application as well as new alloy development.

Access to 1,3-conjugated enynes with defined stereoselectivity is highly desirable and challenging. Herein, we report a facile synthesis of stereodefined 1,3-conjugated enynes via Ni-catalyzed intermolecular cross-alkylalkynylation of alkynes with unsaturated carbonyl compounds and alkynes or alkynyl silicates. The operational simple protocol proceeds at room temperature and tolerates a wide range of functional groups, providing an attractive alternative to carbonyl-tethered trisubstituted conjugated 1,3-enynes from easily accessible starting materials.

China will seek to improve its telecommunications and information systems in order to develop several key industries that rely on such technology. Airlines will grow remarkably in the 1990's, with the number of passengers increasing from 14.4 million in 1988 to 60 million in 2000. In related developments, China will see its tourism industry prosper, which brought 31.6 million people to China in 1988, although 30 million of them were overseas Chinese. Banking will also need a strong telecommunications infrastructure. The government must standardize China's information hardware and software.

K416B Ni-based superalloy with high W content has good high temperature properties and low cost, which has a great development potential. To investigate the room temperature tensile property and the deformation feature of K416B superalloy, tensile testing at room temperature was carried out, and optical microscopy (OM), scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to analyze the deformation and damage mechanisms. Results show that the main room temperature tensile deformation features of the K416B nickel-based superalloy are dislocations slipping in the matrix and shearing into γ′ phase. The <110> super-dislocations shearing into γ′ phase can form the anti-phase boundary two coupled (a/2)<110> partial-dislocations or decompose into the configuration of two (a/3)<112> partial dislocations plus stacking fault. In the later stage of tensile testing, the slip-lines with different orientations are activated in the grain, causing the stress concentration in the regions of block carbide or the porosity, and cracks initiate and propagate along these regions.

Metal-hydride-catalyzed alkene hydroalkylation has been developed as an efficient method for C(sp3)–C(sp3) coupling with broad substrate availability and high functional group compatibility. However, auxiliary groups, a conjugated group or a chelation-directing group, are commonly required to attain high regio- and enantioselectivities. Herein, we reported a ligand-controlled cobalt-hydride-catalyzed regio-, enantio-, and diastereoselective oxyheterocyclic alkene hydroalkylation without chelation-directing groups. This reaction enables the hydroalkylation of conjugated and unconjugated oxyheterocyclic alkenes to deliver C2- or C3-alkylated tetrahydrofuran or tetrahydropyran in uniformly good yields and with high regio- and enantioselectivities. In addition, hydroalkylation of C2-substituted 2,5-dihydrofuran resulted in the simultaneous construction of 1,3-distereocenters, providing convenient access to polysubstituted tetrahydrofuran with multiple enantioenriched C(sp3) centers.

Safety and energy density are significant for lithium-ion batteries (LIBs), and the flammable organic electrolyte is one of the most critical causes of the safety problem of LIBs. Although LiNi0.8Co0.1Mn0.1O2(NCM811) cathode with high capacity can improve the energy density, the interface stability between NCM811 cathode and electrolytes needs to be improved. Herein, we report a multifunctional additive, diethyl (2-(triethoxysilyl) ethyl) phosphonate (DETSP), which can suppress the flammability of the electrolyte and enhance the cycling stability of NCM811 cathode with a capacity retention of 89.9% after 400 cycles at 1 C, while that of the blank electrolyte is merely 61.3%. In addition, DETSP is compatible well with the graphite anode without impairing the electrochemical performances. Significantly, the performance and safety of NCM811/graphite full cells are also improved. Experimental and theoretical results demonstrate that DETSP can scavenge acidic byproducts and is beneficial to form a stable cathode-electrolyte interface (CEI). Accordingly, DETSP can potentially be an effective solution to ameliorating the safety of the commercial electrolyte and improving the stability of high-voltage cathodes.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis. TNBCs with high homologous recombination deficiency (HRD) scores benefit from DNA-damaging agents, including platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, whereas those with low HRD scores still lack therapeutic options. Therefore, we sought to exploit metabolic alterations to induce HRD and sensitize DNA-damaging agents in TNBCs with low HRD scores. We systematically analyzed TNBC metabolomics and identified a metabolite, guanosine diphosphate (GDP)–mannose (GDP-M), that impeded homologous recombination repair (HRR). Mechanistically, the low expression of the upstream enzyme GDP-mannose-pyrophosphorylase-A (GMPPA) led to the endogenous up-regulation of GDP-M in TNBC. The accumulation of GDP-M in tumor cells further reduced the interaction between breast cancer susceptibility gene 2 (BRCA2) and ubiquitin-specific peptidase 21 (USP21), which promoted the ubiquitin-mediated degradation of BRCA2 to inhibit HRR. Therapeutically, we illustrated that the supplementation of GDP-M sensitized DNA-damaging agents to impair tumor growth in both in vitro (cancer cell line and patient-derived organoid) and in vivo (xenograft in immunodeficient mouse) models. Moreover, the combination of GDP-M with DNA-damaging agents activated STING-dependent antitumor immunity in immunocompetent syngeneic mouse models. Therefore, GDP-M supplementation combined with PARP inhibition augmented the efficacy of anti–PD-1 antibodies. Together, these findings suggest that GDP-M is a crucial HRD-related metabolite and propose a promising therapeutic strategy for TNBCs with low HRD scores using the combination of GDP-M, PARP inhibitors, and anti–PD-1 immunotherapy.

Progression of triple-negative breast cancer (TNBC) constitutes a major unresolved clinical challenge, and effective targeted therapies are lacking. Because microtubule dynamics play pivotal roles in breast cancer metastasis, we performed RNA sequencing on 245 samples from TNBC patients to characterize the landscape of microtubule-associated proteins (MAPs). Here, our transcriptome analyses revealed that low expression of one MAP, tektin4, indicated poor patient outcomes. Tektin4 loss led to a marked increase in TNBC migration, invasion, and metastasis and a decrease in microtubule stability. Mechanistically, we identified a novel microtubule-associated complex containing tektin4 and histone deacetylase 6 (HDAC6). Tektin4 loss increased the interaction between HDAC6 and α-tubulin, thus decreasing microtubule stability through HDAC6-mediated tubulin deacetylation. Significantly, we found that tektin4 loss sensitized TNBC cells, xenograft models, and patient-derived organoid models to the HDAC6-selective inhibitor ACY1215. Furthermore, tektin4 expression levels were positively correlated with microtubule stability levels in clinical samples. Together, our findings uncover a metastasis suppressor function of tektin4 and support clinical development of HDAC6 inhibition as a new therapeutic strategy for tektin4-deficient TNBC patients.

MXene-based hydrogels, a flourishing family of soft materials, have recently emerged as promising candidates for stretchable electronics. Despite recent progress, most works use MXenes as conductive nanofillers. Herein, by tuning the molecular interactions between MXene nanosheets and other constituents within the hydrogels, we demonstrate Ti3C3TxMXene can act as a versatile cross-linker to activate the fast gelation of a wide range of hydrogels, starting from various monomer- and polymer-based precursors. The gelation behavior varies significantly across hydrogels. In general, the fast gelation mechanism is attributed to the easier generation of free radicals with the help of Ti3C2TxMXene and the presence of multiscale molecular interactions between MXene and polymers. The use of MXene as a dynamic cross-linker leads to superior mechanical properties, adhesion, and self-healing ability. Owing to the inherent photothermal behavior of Ti3C3Txand the heterogeneous phase-transforming features of polymers, a polymer-MXene hydrogel is demonstrated to exhibit distinctive thermosensation-based actuation upon near-infrared illumination, accompanied by rapid shape transformation.

The candidate anticancer drug curaxins can insert into DNA base pairs and efficiently inhibit the growth of various cancers. However, how curaxins alter the genomic DNA structure and affect the DNA binding property of key proteins remains to be clarified. Here, we first showed that curaxin CBL0137 strongly stabilizes the interaction between the double strands of DNA and reduces DNA bending and twist rigidity simultaneously, by single-molecule magnetic tweezers. More importantly, we found that CBL0137 greatly impairs the binding of CTCF but facilitates trapping FACT on DNA. We revealed that CBL0137 clamps the DNA double helix that may induce a huge barrier for DNA unzipping during replication and transcription and causes the distinct binding response of CTCF and FACT on DNA. Our work provides a novel mechanical insight into CBL0137’s anticancer mechanisms at the nucleic acid level.

The mineralocorticoid receptor (MR) plays a central role in sodium homoeostasis by transducing the response to aldosterone in the distal nephron and other sodium transporting epithelia. The MR is a member of the nuclear receptor family of ligand-dependent transcription factors; it is unusual in being the receptor for two steroid hormones aldosterone and cortisol (which also binds to the closely related glucocorticoid receptor). Less well recognised is that progesterone also binds to the MR with high affinity. The conformation of the ligand-bound receptor is determined by the ligand including whether the conformation is agonist or antagonist. An agonist MR conformation then enables interactions with DNA, other MR (homodimerization) and coregulatory molecules to regulate gene expression. Insights into the structural determinants of an agonist response to ligand come from studies of the evolution of the MR. Progesterone is an agonist in the fish MR, but antagonist in the MR of terrestrial vertebrates; this switch results from the loss of a critical leucine that mediates a leucine:leucine interaction between helix 1 and helix 8 which enables the agonist response to progesterone. The insights into the intramolecular dynamics of activation suggest novel ways in which MR antagonism may be achieved beyond the current, progesterone-based antagonists in clinical use.

Triple-negative breast cancer (TNBC) is a highly heterogeneous disease, and molecular subtyping may result in improved diagnostic precision and targeted therapies. Our previous study classified TNBCs into four subtypes with putative therapeutic targets. Here, we conducted the FUTURE trial (ClinicalTrials.gov identifier: NCT03805399), a phase Ib/II subtyping-based and genomic biomarker-guided umbrella trial, to evaluate the efficacy of these targets. Patients with refractory metastatic TNBC were enrolled and stratified by TNBC subtypes and genomic biomarkers, and assigned to one of these seven arms: (A) pyrotinib with capecitabine, (B) androgen receptor inhibitor with CDK4/6 inhibitor, (C) anti PD-1 with nab-paclitaxel, (D) PARP inhibitor included, (E) and (F) anti-VEGFR included, or (G) mTOR inhibitor with nab-paclitaxel. The primary end point was the objective response rate (ORR). We enrolled 69 refractory metastatic TNBC patients with a median of three previous lines of therapy (range, 1–8). Objective response was achieved in 20 (29.0%, 95% confidence interval (CI): 18.7%–41.2%) of the 69 intention-to-treat (ITT) patients. Our results showed that immunotherapy (arm C), in particular, achieved the highest ORR (52.6%, 95% CI: 28.9%–75.6%) in the ITT population. Arm E demonstrated favorable ORR (26.1%, 95% CI: 10.2%–48.4% in the ITT population) but with more high grade (= 3) adverse events. Somatic mutations of TOP2Aand CD8 immunohistochemical score may have the potential to predict immunotherapy response in the immunomodulatory subtype of TNBC. In conclusion, the phase Ib/II FUTURE trial suggested a new concept for TNBC treatment, demonstrating the clinical benefit of subtyping-based targeted therapy for refractory metastatic TNBC.

Healing skin wounds with anatomic and functional integrity, especially under chronic pathological conditions, remain an enormous challenge. Due to their outstanding regenerative potential, mesenchymal stem cells (MSCs) have been explored in many studies to determine the healing ability for difficult-to-treat diseases. In this article, we review current animal studies and clinical trials of MSC-based therapy for chronic wounds, and discuss major challenges that confront future clinical applications. We found that a wealth of animal studies have revealed the versatile roles and the benefits of MSCs for chronic wound healing. MSC treatment results in enhanced angiogenesis, facilitated reepithelialization, improved granulation, and accelerated wound closure. There are some evidences of the transdifferentiation of MSCs into skin cells. However, the healing effect of MSCs depends primarily on their paracrine actions, which alleviate the harsh microenvironment of chronic wounds and regulate local cellular responses. Consistent with the findings of preclinical studies, some clinical trials have shown improved wound healing after transplantation of MSCs in chronic wounds, mainly lower extremity ulcers, pressure sores, and radiation burns. However, there are some limitations in these clinical trials, especially a small number of patients and imperfect methodology. Therefore, to better define the safety and efficiency of MSC-based wound therapy, large-scale controlled multicenter trials are needed in the future. In addition, to build a robust pool of clinical evidence, standardized protocols, especially the cultivation and quality control of MSCs, are recommended. Altogether, based on current data, MSC-based therapy represents a promising treatment option for chronic wounds.Impact statementChronic wounds persist as a significant health care problem, particularly with increasing number of patients and the lack of efficient treatments. The main goal of this article is to provide an overview of current status of mesenchymal stem cell (MSC)-based therapy for chronic wounds. The roles of MSCs in skin wound healing, as revealed in a large number of animal studies, are detailed. A critical view is made on the clinical application of MSCs for lower extremity ulcers, pressure sores, and radiation burns. Main challenges that confront future clinical applications are discussed, which hopefully contribute to innovations in MSC-based wound treatment.

The article informs about reproductive energy, the aquatic invertebrate Bryozoa bloom buds of larvae that wiggle and bubble out from their own body, and Bryozoa also support marine biodiversity by building habitats for other species. Topics include anchor each other to rock shelves and branches, creating gelatinous lanterns of nourishment for the underwater community; and reallocate energy resources to collapse the sizes of their collective skeletal structure.

Although cellular therapy has been proposed for inflammation‐related disorders such as periodontitis for decades, clinical application has been unsuccessful. One explanation for these disappointing results is that the functions of stem cells are substantially compromised when they are transplanted into an inflammatory in vivo milieu. Considering the previous finding that P2X7 receptor (P2X7R) gene modification is able to reverse inflammation‐mediated impairment of periodontal ligament stem cells (PDLSCs), we further hypothesized that cells subjected to P2X7R gene transduction also exert influences on other cells within an in vivo milieu via an exosome‐mediated paracrine mechanism. To define the paracrine ability of P2X7R gene‐modified cells, P2X7R gene‐modified stem cell‐derived conditional medium (CM‐Ad‐P2X7) and exosomes (Exs‐Ad‐P2X7) were used to incubate PDLSCs. In an inflammatory osteogenic microenvironment, inflammation‐mediated changes in PDLSCs were substantially reduced, as shown by quantitative real‐time PCR (qRT‐PCR) analysis, Western blot analysis, alkaline phosphatase (ALP) staining/activity assays, and Alizarin red staining. In addition, the Agilent miRNA microarray system combined with qRT‐PCR analysis revealed that miR‐3679‐5p, miR‐6515‐5p, and miR‐6747‐5p were highly expressed in Exs‐Ad‐P2X7. Further functional tests and luciferase reporter assays revealed that miR‐3679‐5p and miR‐6747‐5p bound directly to the GREM‐1 protein, while miR‐6515‐5p bound to the GREM‐1 protein indirectly; these effects combined to rescue inflammation‐compromised PDLSCs from dysfunction. Thus, in addition to maintaining their robust functionality under inflammatory conditions, P2X7R gene‐modified stem cells may exert positive influences on their neighbors via a paracrine mechanism, pointing to a novel strategy for modifying the harsh local microenvironment to accommodate stem cells and promote improved tissue regeneration. The potential mechanism involved in P2X7R‐mediated rescue of inflammation‐compromised periodontal ligament stem cells from dysfunction.