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Despite the success of immune checkpoint blockade (ICB) therapy in cancer management, ICB-based immunotherapy of triple-negative breast cancer (TNBC) still suffers from immunosuppressive tumor microenvironment (ITM). To break through the bottleneck of TNBC immunotherapy, a self-cascaded unimolecular prodrug consisting of an acidic pH-activatable doxorubicin and an aggregation-induced emission luminogen (AIEgen) photosensitizer coupled to a caspase-3-responsive peptide was engineered. The generated prodrug, could not only release doxorubicin initiatively in acidic tumor microenvironment, but also activate apoptosis-related caspase-3. The activated caspase-3 could in turn trigger release and in situ aggregation of photosensitizers. Importantly, the unimolecular prodrug exhibits a renal clearance pathway similar to small molecules in vivo, while the aggregated AIEgens prolong tumor retention for long-term fluorescence imaging and repeatable photodynamic therapy (PDT) by only one single-dose injection. Furthermore, the tumor-detained PDT boosts both immunogenic cell death of TNBC cells and maturation of dendritic cells. Finally, the combination of repeatable PDT with ICB therapy further promotes the proliferation and intratumoral infiltration of cytotoxic T lymphocytes, and effectively suppresses tumor growth and pulmonary metastasis. This prodrug is a proof-of-concept that confirms the first self-cascaded chemo-PDT strategy to reverse the ITM and boost the ICB-mediated TNBC immunotherapy.

The carbon emission at the embodied phase is a complex combination, extending the life cycle of the building, defining the process of the embodied phase scientifically and finding out the direct and indirect carbon emission sources in the embodied phase. Building materials have the characteristics of “low carbon surface, hidden high carbon.” Emission factor calculation method is used to establish carbon emission model for building materials. Considering the effect of design optimization on the carbon emissions of the whole life cycle of the building, a low carbon level system is set up to optimize the target of low carbon design. In the construction phase, the carbon emission sources, emission boundary, and calculation model are determined according to the subdivisional engineering division method. Through a series of process decomposition, the total amount of carbon emissions at the embodied phase can be obtained, and the carbon emission quota list at the embodied phase can be compiled to provide technical support for the carbon trading mechanism of the building.

In large-scale distributed machine learning (DML), the network performance between machines significantly impacts the speed of iterative training. In this paper we propose BML , a scalable, high-performance and fault-tolerant DML network architecture on top of Ethernet and commodity devices. BML builds on BCube topology, and runs a fully-distributed gradient synchronization algorithm. Compared to a Fat-Tree network with the same size, a BML network is expected to take much less time for gradient synchronization, for both low theoretical synchronization time and its benefit to RDMA transport. With server/link failures, the performance of BML degrades in a graceful way. Experiments of MNIST and VGG-19 benchmarks on a testbed with 9 dual-GPU servers show that, BML reduces the job completion time of DML training by up to 56.4% compared with Fat-Tree running state-of-the-art gradient synchronization algorithm.

Dimerizations of fulvene metal tricarbonyl complexes of the type (C

In central nervous system vascular endothelial cells, signaling via the partially redundant ligands WNT7A and WNT7B requires two co-activator proteins, GPR124 and RECK. WNT7A and RECK have been shown previously to play a role in limb development, but the mechanism of RECK action in this context is unknown. The roles of WNT7B and GPR124 in limb development have not been investigated. Using combinations of conventional and/or conditional loss-of-function alleles for mouse Wnt7a, Wnt7b, Gpr124 and Reck, including a Reck allele that codes for a protein that is specifically defective in WNT7A/WNT7B signaling, we show that reductions in ligand and/or co-activator function synergize to cause reduced and dysmorphic limb bone growth. Two additional limb phenotypes – loss of distal Lmx1b expression and ectopic growth of nail-like structures – occur with reduced Wnt7a/Wnt7b gene copy number and, respectively, with Reck mutations and with combined Reck and Gpr124 mutations. A third limb phenotype – bleeding into a digit – occurs with the most severe combinations of Wnt7a/Wnt7b, Reck and Gpr124 mutations. These data imply that the WNT7A/WNT7B-FRIZZLED-LRP5/LRP6-GPR124-RECK signaling system functions as an integral unit in limb development.

We use Gaia DR3 data to study the Collinder 132-Gulliver 21 region via the machine learning algorithm StarGO, and find eight subgroups of stars (ASCC 32, Collinder 132 gp 1--6, Gulliver 21) located in close proximity. Three co-moving populations were identified among these eight subgroups: (i) a coeval 25 Myr-old moving group (Collinder 132); (ii) an intermediate-age (50--100 Myr) group; and (iii) the 275 Myr-old dissolving cluster Gulliver 21. These three populations form parallel diagonal stripe-shape over-densities in the U--V distribution, which differ from open clusters and stellar groups in the solar neighborhood. We name this kinematic structure the Collinder 132-Gulliver 21 stream, as it extends over 270 pc in the 3D space. The oldest population Gulliver21 is spatially surrounded by the Collinder 132 moving group and the intermediate-age group. Stars in the Collinder 132-Gulliver 21 stream have an age difference up to 250 Myr. Metallicity information shows a variation of 0.3 dex between the youngest and oldest populations. The formation of the Collinder132-Gulliver 21 stream involves both star formation and dynamical heating. The youngest population (Collinder 132 moving group) with homogeneous metallicity is probably formed through filamentary star formation. The intermediate-age and the oldest population were then scatted by the Galactic bar or spiral structure resonance to intercept Collinder 132's orbit. Without mutual interaction between each population, the three populations are flying by each other currently and will become distinct three groups again in approximately ~50Myr., Accepted to ApJL, 15 pages, 7 figures

Tumor-derived alkaline phosphatase (ALP) is over-expressed in metastatic prostate cancer. The development of selective probes for ALP detection is therefore critical for early diagnosis and therapy of metastatic prostate cancer. Herein, we develop a mitochondria-targeted near-infrared activatable fluorescent/photoacoustic (NIR FL/PA) probe for the selective detection of prostate cancer-derived ALP and aggregation-enhanced photothermal therapy. Upon dephosphorylation, the probes are activated and they provide a red-shifted strong absorption and emission in the NIR window and thus enable NIR FL and PA imaging of ALP activity in tumor tissues. Particularly, the activated probes self-assemble in situ into a supramolecular network structure which induces cell apoptosis and significantly enhances the photothermal therapy efficacy.

We identify members of 65 open clusters in the solar neighborhood using the machine-learning algorithm StarGO based on Gaia EDR3 data. After adding members of twenty clusters from previous studies (Pang et al. 2021a,b; Li et al. 2021) we obtain 85 clusters, and study their morphology and kinematics. We classify the substructures outside the tidal radius into four categories: filamentary (f1) and fractal (f2) for clusters $100$ Myr. The kinematical substructures of f1-type clusters are elongated; these resemble the disrupted cluster Group X. Kinematic tails are distinct in t-type clusters, especially Pleiades. We identify 29 hierarchical groups in four young regions (Alessi 20, IC 348, LP 2373, LP 2442); ten among these are new. The hierarchical groups form filament networks. Two regions (Alessi 20, LP 2373) exhibit global "orthogonal" expansion (stellar motion perpendicular to the filament), which might cause complete dispersal. Infalling-like flows (stellar motion along the filament) are found in UBC 31 and related hierarchical groups in the IC 348 region. Stellar groups in the LP 2442 region (LP 2442 gp 1-5) are spatially well-mixed but kinematically coherent. A merging process might be ongoing in the LP 2442 subgroups. For younger systems ($\lesssim30$ Myr), the mean axis ratio, cluster mass and half-mass radius tend to increase with age values. These correlations between structural parameters may imply two dynamical processes occurring in the hierarchical formation scenario in young stellar groups: (1) filament dissolution and (2) sub-group mergers., Accepted to ApJ, 33 pages, 14 figures. OC 3D interactive visualization included on http://3doc-morphology.lowell.edu

With the booming development of artificial intelligence (AI), a series of relevant applications are emerging and promoting an all-rounded reform of the industry. As the major technology of AI, machine learning (ML) shows great potential in solving network challenges. Network optimization, in return, brings significant performance gains for ML applications, in particular distributed machine learning. In this paper, we conduct a survey on combining ML technologies with network research.

Because of the lack of specific targets, the highly aggressive triple negative breast cancer (TNBC) is unable to benefit from endocrine therapy or conventional targeting therapy. Even worse, current diagnostic and therapeutic approaches have limited value for TNBC. Therefore, developing TNBC-specific theranostic probes for accurate diagnosis and further selective therapy will build a powerful toolbox for TNBC management. In this contribution, we developed a sequential strategy to enhance the specificity of TNBC theranostics. In this theranostic system, a versatile nanoprobe (Pep-SQ@USPIO) was integrated legitimately for the fibronectin-targeting MR imaging and CTSB-activatable fluorescence imaging, followed with enhanced photodynamic therapy (PDT) of TNBC. First, the fibronectin overexpressed in the extracellular matrix (ECM) of TNBC was used as a biomarker for targeting theranostics using the Cys-Arg-Glu-Lys-Ala (CREKA) peptide. For another, the fluorescence and PDT capacity of self-developed squaraine photosensitizer (SQ) were prequenched by ultrasmall superparamagnetic iron oxide (USPIO), an MR imaging contrast agent. Once the linker, Gly-Phe-Leu-Gly (GFLG) peptide, was selectively cleaved by TNBC-derived CTSB, the liberated SQ photosensitizer allowed light-up fluorescence imaging and enhanced PDT of TNBC. Remarkably, this research demonstrates that tumor-ECM-targeting and endogenous enzyme-activated nanoprobes open a new avenue for TNBC theranostics.

Various squaraine dyes have been developed for biological imaging. Nevertheless, squaraine dyes with emission in the second window (NIR-II, 1000-1700 nm) have few reports largely due to the short of a simple and universal design strategy. In this contribution, molecular engineering strategy is explored to develop squaraine dyes with NIR-II emission. First, NIR-I squaraine dye SQ2 is constructed by the ethyl-grafted 1,8-naphtholactam as donor units and square acid as acceptor unit in a donor-acceptor-donor (D-A-D) structure. To red-shift the fluorescence emission into NIR-II window, malonitrile, as a forceful electron-withdrawing group, is introduced to strengthen square acid acceptor. As a result, the fluorescence spectrum of acceptor-engineered squaraine dye SQ1 exhibits a significant red-shift into NIR-II window. To translate NIR-II fluorophores SQ1 into effective theranostic agents, fibronectin-targeting SQ1 nanoprobe was constructed and showed excellent NIR-II imaging performance in angiography and tumor imaging, including lung metastatic foci in deep tissue. Furthermore, SQ1 nanoprobe can be used for photoacoustic imaging and photothermal ablation of tumors. This research demonstrates that the donor-acceptor engineering strategy is feasible and effective to develop NIR-II squaraine dyes.

International audience; A numerical study of a turbulent buoyant helium jet developing in a two-vented cavity is conducted based on a well-resolved numerical simulation. A sufficiently large exterior region is modelled in the computational domain to approach the natural inlet/outlet conditions of the vents, leading to a good agreement between the numerical results and available experimental particle image velocimetry (PIV) measurements. For a release of helium with a flow rate of 5 Nl.min-1 in an air-filled cavity about 15 cm high, the flow structure and the helium dispersion are analysed illustrating the strong confinement effect enhanced by a cross-flow from the lower vent. By tracking the jet axis deviation and comparing the classic plume description in terms of global fluxes estimated from DNS results to the Morton et al.’ theory [1], we quantify the effect of the confinement and the cross-flow on the flow structure. Finally, we highlight a blocking zone at mid-cavity height originated from confinement, where helium accumulates.

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Triple-negative breast cancer (TNBC), as the most tough subtype in breast cancer, has the worst outcome, and developing effective and safe strategies for patients undergone TNBC are urgently needed. Recently, phototheranostics, including optical imaging and phototherapy have shown a great potential in TNBC management. However, most of the phototheranostic probes, as ‘always-on’ agents, lead to high imaging background and nonspecific phototoxicity in adjacent healthy tissues. Herein, a toolbox of wavelength-adjustable butterfly molecules and gold nanorods (GNRs)-based peptide nanoassemblies (GPNAs) were achieved through simple synthesis and stepwise self-assembly for the targeted optical imaging and phototherapeutic of TNBC. Specifically, the self-assembled GPNAs were not only nonfluorescent but also photodynamic-inactivated, which significantly reduces background fluorescence and phototoxicity in adjacent healthy tissue. Extradomain-B fibronectin, as a biomarker of TNBC, can selectively disassemble peptide-conjugated butterfly molecules (ZD2-SQ) from GPNAs and liberate extremely bright NIR fluorescence in high signal-to-background ratio (SBR) and specific photodynamic therapy (PDT) capability while GNRs hold robust photoacoustic (PA) and CT imaging signals as internal reference and convert NIR light into heat energy for photothermal therapy (PTT) of TNBC. This research offers a novel general strategy for the development of activated molecular probes for specific phototheranostics of TNBC.

The dorsal surface of the mouse tongue is covered by ~7000 papillae, asymmetric epithelial protrusions that are precisely oriented to create a stereotyped macroscopic pattern. Within the context of this large-scale pattern, neighboring papillae exhibit a high degree of local order that minimizes the differences in their orientations. We show here that the orientations of lingual papillae are under the control of the core planar cell polarity (PCP) genes Vangl1, Vangl2, and Celsr1. Using K14-Cre and Nkx2.5-Cre to induce conditional knockout of Vangl1 and/or Vangl2 in the tongue epithelium, we observe more severe disruptions to local order among papillae with inactivation of larger numbers of Vangl genes, a greater role for Vangl2 than Vangl1, and a more severe phenotype with the Vangl2 Looptail (Lp) allele than the Vangl2 null allele, consistent with a dominant negative mode of action of the Vangl2Lp allele. Interestingly, Celsr1−/− tongues show disruption of both local and global order, with many papillae in the anterior tongue showing a reversed orientation. To quantify each of these phenotypes, we have developed and applied three procedures for sampling the orientations of papillae and assessing the degree of order on different spatial scales. The experiments reported here establish the dorsal surface of the mouse tongue as a favorable system for studying PCP control of epithelial patterning.

Un panache forcé d'un mélange hélium - air se développant dans une cavité avec deux évents est modélisé numériquement par simulations numériques directes. La configuration géométrique est choisie de façon à ce qu'une distribution bi-couche du mélange hélium - air se forme dans la cavité, ce qui est une hypothèse couramment posée dans les modèles industriels théoriques. Nous réalisons une série de calcul pour différentes sections horizontales afin d'identifier une géométrie minimale pour laquelle le panache d'hélium et la couche de mélange homogène se situant en partie haute de la cavité ne sont pas influencés par les parois latérales. Les résultats sont analysés en terme de structure d'écoulements et de distribution d'hélium dans la cavité, mais aussi de débits massiques d'air neuf et d'hélium traversant les évents, ceux-ci n'étant pas imposés comme condition limi

International audience; We present numerical results from direct numericalsimulations (DNS) of an air-helium buoyant jet in a two-ventedcavity. Geometrical configuration of the cavity is chosen toensure a bi-layer stratification distribution of helium, which iscommonly assumed in relevant industrial models. A series ofcomputations with different horizontal sizes of cavity isperformed to determine the optimal dimensions, for which thehelium buoyant jet and the top mixture layer are not influencedby the end walls. Results are analysed in terms of flow structureand helium concentration distribution, but also of inlet mass fluxof fresh air and of helium outlet flux, as fluxes are kept freethrough the vents. Additionally, buoyancy flux in the jetcorresponding to Morton’s theory (1956) is calculated to deduceentrainment coefficient and compared with literature.

Beta-catenin (i.e., canonical Wnt) signaling controls CNS angiogenesis and the blood-brain and blood-retina barriers. To explore the role of the Discs large/membrane-associated guanylate kinase (Dlg/MAGUK) family of scaffolding proteins in beta-catenin signaling, we studied vascular endothelial cell (EC)-specific knockout of Dlg1/SAP97. EC-specific loss of Dlg1 produces a retinal vascular phenotype that closely matches the phenotype associated with reduced beta-catenin signaling, synergizes with genetically-directed reductions in beta-catenin signaling components, and can be rescued by stabilizing beta-catenin in ECs. In reporter cells with CRISPR/Cas9-mediated inactivation of Dlg1, transfection of Dlg1 enhances beta-catenin signaling ~4 fold. Surprisingly, Frizzled4, which contains a C-terminal PDZ-binding motif that can bind to Dlg1 PDZ domains, appears to function independently of Dlg1 in vivo. These data expand the repertoire of Dlg/MAGUK family functions to include a role in beta-catenin signaling, and they suggest that proteins other than Frizzled receptors interact with Dlg1 to enhance beta-catenin signaling.

β-Catenin signaling controls the development and maintenance of the blood-brain barrier (BBB) and the blood-retina barrier (BRB), but the division of labor and degree of redundancy between the two principal ligand-receptor systems-the Norrin and Wnt7a/Wnt7b systems-are incompletely defined. Here, we present a loss-of-function genetic analysis of postnatal BBB and BRB maintenance in mice that shows striking threshold and partial redundancy effects. In particular, the combined loss of Wnt7a and Norrin or Wnt7a and Frizzled4 (Fz4) leads to anatomically localized BBB defects that are far more severe than observed with loss of Wnt7a, Norrin, or Fz4 alone. In the cerebellum, selective loss of Wnt7a in glia combined with ubiquitous loss of Norrin recapitulates the phenotype observed with ubiquitous loss of both Wnt7a and Norrin, implying that glia are the source of Wnt7a in the cerebellum. Tspan12, a coactivator of Norrin signaling in the retina, is also active in BBB maintenance but is less potent than Norrin, consistent with a model in which Tspan12 enhances the amplitude of the Norrin signal in vascular endothelial cells. Finally, in the context of a partially impaired Norrin system, the retina reveals a small contribution to BRB development from the Wnt7a/Wnt7b system. Taken together, these experiments define the extent of CNS region-specific cooperation for several components of the Norrin and Wnt7a/Wnt7b systems, and they reveal substantial regional heterogeneity in the extent to which partially redundant ligands, receptors, and coactivators maintain the BBB and BRB.