TLR4-Induced Inflammation Is a Key Promoter of Tumor Growth, Vascularization, and Metastasis

Toll-like receptor-4 (TLR4) is a powerful pathway best known for inducing inflammation in response to bacteria-produced lipopolysaccharide. TLR4 is also activated by endogenous ligands produced by host-damaged cells and a chemo-drug paclitaxel. Under normal conditions, TLR4 is expressed mainly in macrophages and, at a lower level, in epithelial, endothelial, and stromal cells. Activated TLR4 significantly increases inflammatory cytokines and enhances cell proliferation, migration, invasion, and survival. While these functions in normal cells are essential for host defense and tissue repair, TLR4 overexpression in malignant cells promotes tumor growth and metastasis. This is because pro-oncogenic effects of activated TLR4 in tumor cells are amplified by similar event in TLR4-positive tumor-associated cells including endothelial cells and their mobilized progenitors. The collective activation of multiple cell types within the tumor promotes chemoresistance and metastasis. Here, we summarize the current knowledge of the TLR4 pathway and its functional outcomes in normal and tumor cells. We also discuss its underappreciated role in supporting tumor progression through vascular activation and recruitment of endothelial progenitors. The review considers several open questions regarding the impact of TLR4-mediated pro- and antitumor effects, structural requirements for recognition of the TLR4 complex, and a potential contribution of chemotherapy to tumor spread

Taming Adaptivity in YOSO Protocols: The Modular Way

YOSO-style MPC protocols (Gentry et al., Crypto\u2721), are a promising framework where the overall computation is partitioned into small, short-lived pieces, delegated to subsets of one-time stateless parties. Such protocols enable gaining from the security benefits provided by using a large community of participants where mass corruption of a large fraction of participants is considered unlikely, while keeping the computational and communication costs manageable. However, fully realizing and analyzing YOSO-style protocols has proven to be challenging: While different components have been defined and realized in various works, there is a dearth of protocols that have reasonable efficiency and enjoy full end to end security against adaptive adversaries. The YOSO model separates the protocol design, specifying the short-lived responsibilities, from the mechanisms assigning these responsibilities to machines participating in the computation. These protocol designs must then be translated to run directly on the machines, while preserving security guarantees. We provide a versatile and modular framework for analyzing the security of YOSO-style protocols, and show how to use it to compile any protocol design that is secure against static corruptions of $t$ out of $c$ parties, into protocols that withstand adaptive corruption of $T$ out of $N$ machines (where $T/N$ is closely related to $t/c$, specifically when $t/c<0.5$, we tolerate $T/N \leq 0.29$) at overall communication cost that is comparable to that of the traditional protocol even when $c << N$. Furthermore, we demonstrate how to minimize the use of costly non-committing encryption, thereby keeping the computational and communication overhead manageable even in practical terms, while still providing end to end security analysis. Combined with existing approaches for transforming stateful protocols into stateless ones while preserving static security (e.g. Gentry et al. 21, Kolby et al. 22), we obtain end to end security

ALMA [N \i\i ] 205 \mu m Imaging Spectroscopy of the Lensed Submillimeter galaxy ID 141 at redshift 4.24

We present the Atacama Large Millimeter/submillimeter Array (ALMA) observation of the Sub-millimeter galaxy (SMG) ID 141 at z=4.24 in the [N II] 205 $\mu$m line (hereafter [N II]) and the underlying continuum at (rest-frame) 197.6 $\mu$m. Benefiting from lensing magnification by a galaxy pair at z=0.595, ID 141 is one of the brightest z$>4$ SMGs. At the angular resolutions of $\sim1.2''$ to $1.5''$ ($1'' \sim6.9$ kpc), our observation clearly separates, and moderately resolves the two lensed images in both continuum and line emission at $\rm S/N>5$ . Our continuum-based lensing model implies an averaged amplification factor of $\sim5.8$ and reveals that the de-lensed continuum image has the S\'ersic index $\simeq 0.95$ and the S\'ersic radius of $\sim0.18'' (\sim 1.24$ kpc). Furthermore, the reconstructed [N II] velocity field in the source plane is dominated by a rotation component with a maximum velocity of $\sim 300$ km/s at large radii, indicating a dark matter halo mass of $\sim 10^{12}M_{\odot}$. This, together with the reconstructed velocity dispersion field being smooth and modest in value ($<100$ km/s) over much of the outer parts of the galaxy, favours the interpretation of ID 141 being a disk galaxy dynamically supported by rotation. The observed [N II]/CO (7-6) and [N II]/[C II] 158 $\mu$m line luminosity ratios, which are consistent with the corresponding line ratio vs. far-infrared color correlation from local luminous infrared galaxies, imply a de-lensed star formation rate of ($1.8\pm 0.6)\times10^3M_\odot$/yr and provide an independent estimate on the size of the star-forming region $0.7^{+0.3}_{-0.3}$ kpc in radius.Comment: 13 pages, 6 figures, 2 tables, accepted by ApJ, lensing model code can be found here https://gitlab.com/cxylzlx/tiny_len

New Model of Macrophage Acquisition of the Lymphatic Endothelial Phenotype

Macrophage-derived lymphatic endothelial cell progenitors (M-LECPs) contribute to new lymphatic vessel formation, but the mechanisms regulating their differentiation, recruitment, and function are poorly understood. Detailed characterization of M-LECPs is limited by low frequency in vivo and lack of model systems allowing in-depth molecular analyses in vitro. Our goal was to establish a cell culture model to characterize inflammation-induced macrophage-to-LECP differentiation under controlled conditions.Time-course analysis of diaphragms from lipopolysaccharide (LPS)-treated mice revealed rapid mobilization of bone marrow-derived and peritoneal macrophages to the proximity of lymphatic vessels followed by widespread (∼50%) incorporation of M-LECPs into the inflamed lymphatic vasculature. A differentiation shift toward the lymphatic phenotype was found in three LPS-induced subsets of activated macrophages that were positive for VEGFR-3 and many other lymphatic-specific markers. VEGFR-3 was strongly elevated in the early stage of macrophage transition to LECPs but undetectable in M-LECPs prior to vascular integration. Similar transient pattern of VEGFR-3 expression was found in RAW264.7 macrophages activated by LPS in vitro. Activated RAW264.7 cells co-expressed VEGF-C that induced an autocrine signaling loop as indicated by VEGFR-3 phosphorylation inhibited by a soluble receptor. LPS-activated RAW264.7 macrophages also showed a 68% overlap with endogenous CD11b(+)/VEGFR-3(+) LECPs in the expression of lymphatic-specific genes. Moreover, when injected into LPS- but not saline-treated mice, GFP-tagged RAW264.7 cells massively infiltrated the inflamed diaphragm followed by integration into 18% of lymphatic vessels.We present a new model for macrophage-LECP differentiation based on LPS activation of cultured RAW264.7 cells. This system designated here as the "RAW model" mimics fundamental features of endogenous M-LECPs. Unlike native LECPs, this model is unrestricted by cell numbers, heterogeneity of population, and ability to change genetic composition for experimental purposes. As such, this model can provide a valuable tool for understanding the LECP and lymphatic biology

Single-cell genomics and regulatory networks for 388 human brains.

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into a resource comprising &gt;2.8 million nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified &gt;550,000 cell type-specific regulatory elements and &gt;1.4 million single-cell expression quantitative trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types

The JCMT BISTRO Survey: Studying the Complex Magnetic Field of L43

We present observations of polarized dust emission at 850 μm from the L43 molecular cloud, which sits in the Ophiuchus cloud complex. The data were taken using SCUBA-2/POL-2 on the James Clerk Maxwell Telescope as a part of the BISTRO large program. L43 is a dense (NH 10 22 2 ~ –1023 cm−2) complex molecular cloud with a submillimeter-bright starless core and two protostellar sources. There appears to be an evolutionary gradient along the isolated filament that L43 is embedded within, with the most evolved source closest to the Sco OB2 association. One of the protostars drives a CO outflow that has created a cavity to the southeast. We see a magnetic field that appears to be aligned with the cavity walls of the outflow, suggesting interaction with the outflow. We also find a magnetic field strength of up to ∼160 ± 30 μG in the main starless core and up to ∼90 ± 40 μG in the more diffuse, extended region. These field strengths give magnetically super- and subcritical values, respectively, and both are found to be roughly trans-Alfvénic. We also present a new method of data reduction for these denser but fainter objects like starless cores

Filamentary Network and Magnetic Field Structures Revealed with BISTRO in the High-mass Star-forming Region NGC 2264: Global Properties and Local Magnetogravitational Configurations

We report 850 μm continuum polarization observations toward the filamentary high-mass star-forming region NGC 2264, taken as part of the B-fields In STar forming Regions Observations large program on the James Clerk Maxwell Telescope. These data reveal a well-structured nonuniform magnetic field in the NGC 2264C and 2264D regions with a prevailing orientation around 30° from north to east. Field strength estimates and a virial analysis of the major clumps indicate that NGC 2264C is globally dominated by gravity, while in 2264D, magnetic, gravitational, and kinetic energies are roughly balanced. We present an analysis scheme that utilizes the locally resolved magnetic field structures, together with the locally measured gravitational vector field and the extracted filamentary network. From this, we infer statistical trends showing that this network consists of two main groups of filaments oriented approximately perpendicular to one another. Additionally, gravity shows one dominating converging direction that is roughly perpendicular to one of the filament orientations, which is suggestive of mass accretion along this direction. Beyond these statistical trends, we identify two types of filaments. The type I filament is perpendicular to the magnetic field with local gravity transitioning from parallel to perpendicular to the magnetic field from the outside to the filament ridge. The type II filament is parallel to the magnetic field and local gravity. We interpret these two types of filaments as originating from the competition between radial collapsing, driven by filament self-gravity, and longitudinal collapsing, driven by the region's global gravity

Filamentary Network and Magnetic Field Structures Revealed with BISTRO in the High-Mass Star-Forming Region NGC2264 : Global Properties and Local Magnetogravitational Configurations

We report 850 $\mu$m continuum polarization observations toward the filamentary high-mass star-forming region NGC 2264, taken as part of the B-fields In STar forming Regions Observations (BISTRO) large program on the James Clerk Maxwell Telescope (JCMT). These data reveal a well-structured non-uniform magnetic field in the NGC 2264C and 2264D regions with a prevailing orientation around 30 deg from north to east. Field strengths estimates and a virial analysis for the major clumps indicate that NGC 2264C is globally dominated by gravity while in 2264D magnetic, gravitational, and kinetic energies are roughly balanced. We present an analysis scheme that utilizes the locally resolved magnetic field structures, together with the locally measured gravitational vector field and the extracted filamentary network. From this, we infer statistical trends showing that this network consists of two main groups of filaments oriented approximately perpendicular to one another. Additionally, gravity shows one dominating converging direction that is roughly perpendicular to one of the filament orientations, which is suggestive of mass accretion along this direction. Beyond these statistical trends, we identify two types of filaments. The type-I filament is perpendicular to the magnetic field with local gravity transitioning from parallel to perpendicular to the magnetic field from the outside to the filament ridge. The type-II filament is parallel to the magnetic field and local gravity. We interpret these two types of filaments as originating from the competition between radial collapsing, driven by filament self-gravity, and the longitudinal collapsing, driven by the region's global gravity.Comment: Accepted for publication in the Astrophysical Journal. 43 pages, 32 figures, and 4 tables (including Appendix