The members of the Src family of nonreceptor tyrosine kinases (SFKs) are implicated in multiple signaling processes that regulate key cellular functions, including proliferation, migration, ...differentiation, and survival. SFKs are activated by a large number of receptors for growth factors, cytokines, steroid hormones, G protein-coupled receptors, and also by adhesion proteins and other signaling partners. Through their common modular kinase an adapter protein domains, SFKs critically contribute to diversify different signal inputs, weaving a complex and dynamic network of cellular responses. Not surprisingly, SFKs are involved in embryo development and in the maintenance of different adult tissues and organs. Conversely, dysfunction of SFKs is associated with different pathologies, including cancer. Despite the continuous research in the field, several aspects of SFKs regulation and function are still not well defined and new roles for these proteins are steadily reported. The aim of this review is to provide an update on the major regulatory mechanisms of SFKs activity, including the emerging redox-dependent pathway. We have also focused on the functional implications of SFKs in Prolactin signaling and breast cancer development, two increasingly important aspects of SFKs biology. Finally, we briefly revisited the role of SFKs during embryo development and provide insights on the involvement of these proteins in the regulation of embryonic, somatic, and breast cancer stem cells.
The applicability of any wastewater technology should be related not only to its degradation, mineralization or detoxification efficiency, but also to its environmental impacts. This could be ...particularly relevant in case of advanced oxidation processes (AOPs), which are usually highly demanding on chemicals, energy, and generating residual fluxes with specific problems and potential environmental impacts (metal ion-containing sludge, exhausted solid catalysts, etc). In this work, the life cycle assessment (LCA) has been applied for the evaluation of both homogeneous and heterogeneous Fenton processes for the treatment of a wastewater coming from a pharmaceutical industry in Toledo, Spain. The application of LCA as tool for the evaluation of AOPs is scarce found in literature, although it provides a systematic estimation of the environmental changes related to the AOP treatment, quantification of consumptions and emissions, and their effects on human health. In this work, the potential environmental impacts were calculated with Gabi 6.0 software by using ReCiPe version 1.06 and ICCP 2007 methods. Additionally, the water footprint (WF) was used in this study for the first time as tool for comparison between both AOP systems. Experimental data, directly obtained from the company and the laboratory were used to carry out the life cycle inventory (LCI) analysis, ensuring high accuracy and sensitivity of the obtained results. The obtained results showed that the recovery of the metallic sludge generated in the homogeneous Fenton process is the most contributing step to environmental impacts followed by the use of chemicals and the heat requirements. The comparison between homogeneous and heterogeneous Fenton processes revealed that the latter is a more environmental friendly alternative for the treatment of the pharmaceutical wastewater. In addition, the use of the heterogeneous process allows the reduction of the water footprint in more than 77% as compared to the homogeneous one. Besides the results regarding to both Fenton processes, this work shows the efficiency of the water footprint as a complementary parameter to the LCA for comparison between advanced wastewater treatments processes which can be intensive use of fresh water as a resource.
...it is used to determine the extent of the peritoneal disease (measured according to Peritoneal Carcinomatosis Index -PCI-) and look for findings of unresectability, determining the patient's ...possible eligibility for cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy. ...is used to determine the onco-surgical strategy with peritoneal metastases of gynaecological origin, being laparoscopy useful to choose whether the patient could be a candidate for primary cytoreduction or for interval surgery. ...it could be used to obtain biological samples for anatomopathological diagnosis if other less-invasive procedures fail.1–4 Crucially, patients who are not eligible for complete cytoreduction are unlikely to benefit from cytoreductive surgery with or without HIPEC. ...this procedure helps in avoiding unnecessary nontherapeutic laparotomies, which can lead to morbidity and negatively impact a patient's quality of life.
Phytoremediation is an in-situ remediation technology based on the ability of plants to fix pollutants from the soil. In this sense, plants such as Festuca arundinacea are a promising for heavy metal ...removal in contaminated soils. The present work studies phytoremediation for Pb removal from a contaminated soil located in Spain using F. arundinacea by applying the Life Cycle Assessment (LCA) approach. Two different options for biomass management were assessed: direct disposal in a security landfill (case 1A) and energy recovery (case 1B). For the latter option, cogeneration was simulated using SuperPro Designer 9.5. In addition, traditional treatments such as soil washing (case 2) and excavation + landfill (case 3) were evaluated in terms of environmental impacts by LCA. The former was simulated using SuperPro Designer 9.5, whereas data from literature were used for the latter to perform the LCA. Results showed that biomass disposal in a landfill was the most important contributor to the overall impact in case 1A. In contrast, biomass conditioning and cogeneration were the main steps responsible for environmental impacts in case 1B. Comparing cases 1A and 1B, the energy recovery from biomass was superior to direct landfill disposal, reducing the environmental impacts in most of the studied categories. Regarding the rest of the treatments, chemical production and soil disposal presented the most critical environmental burdens in cases 2 and 3, respectively. Finally, the comparison between the studied cases revealed that phytoextraction + energy recovery was the most environmentally friendly option for the studied conditions, reducing impacts by 30–100%.
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•LCA methodology applied to soil remediation processes.•Phytoremediation with Festuca arundinacea is efficient for Pb-contaminated soil.•Energy recovery reduces impacts regards other biomass disposal treatments.•Phytoremediation + energy recovery shows the best environmental footprint.
Lipid nanoparticles for delivering mRNA therapeutics hold immense promise for the treatment of a wide range of lung-associated diseases. However, the lack of effective methodologies capable of ...identifying the pulmonary delivery profile of chemically distinct lipid libraries poses a significant obstacle to the advancement of mRNA therapeutics. Here we report the implementation of a barcoded high-throughput screening system as a means to identify the lung-targeting efficacy of cationic, degradable lipid-like materials. We combinatorially synthesize 180 cationic, degradable lipids which are initially screened in vitro. We then use barcoding technology to quantify how the selected 96 distinct lipid nanoparticles deliver DNA barcodes in vivo. The top-performing nanoparticle formulation delivering Cas9-based genetic editors exhibits therapeutic potential for antiangiogenic cancer therapy within a lung tumor model in female mice. These data demonstrate that employing high-throughput barcoding technology as a screening tool for identifying nanoparticles with lung tropism holds potential for the development of next-generation extrahepatic delivery platforms.
Abstract
We present a set of multiwavelength mosaics and photometric catalogs in the Atacama Large Millimeter/submillimeter Array (ALMA) lensing cluster survey fields. The catalogs were built by the ...reprocessing of archival data from the Complete Hubble Archive for Galaxy Evolution compilation, taken by the Hubble Space Telescope (HST) in the Reionization Lensing Cluster Survey, Cluster Lensing And Supernova survey with Hubble, and Hubble Frontier Fields. Additionally, we have reconstructed the Spitzer Infrared Array Camera 3.6 and 4.5
μ
m mosaics, by utilizing all the available archival IPAC Infrared Science Archive/Spitzer Heritage Archive exposures. To alleviate the effect of blending in such a crowded region, we have modeled the Spitzer photometry by convolving the HST detection image with the Spitzer point-spread function using the novel
golfir
software. The final catalogs contain 218,000 sources, covering a combined area of 690 arcmin
2
, a factor of ∼2 improvement over the currently existing photometry. A large number of detected sources is a result of reprocessing of all available and sometimes deeper exposures, in conjunction with a combined optical–near-IR detection strategy. These data will serve as an important tool in aiding the search of the submillimeter galaxies in future ALMA surveys, as well as follow-ups of the HST dark and high-
z
sources with JWST. Coupled with the available HST photometry, the addition of the 3.6 and 4.5
μ
m bands will allow us to place a better constraint on the photometric redshifts and stellar masses of these objects, thus giving us an opportunity to identify high-redshift candidates for spectroscopic follow-ups and to answer the important questions regarding the Epoch of Reionization and formation of the first galaxies. The mosaics, photometric catalogs, and the best-fit physical properties are publicly available at
https://github.com/dawn-cph/alcs-clusters
.
Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable clinical success in the treatment of hematological malignancies. However, producing these bespoke cancer‐killing cells is a ...complicated ex vivo process involving leukapheresis, artificial T cell activation, and CAR construct introduction. The activation step requires the engagement of CD3/TCR and CD28 and is vital for T cell transfection and differentiation. Though antigen‐presenting cells (APCs) facilitate activation in vivo, ex vivo activation relies on antibodies against CD3 and CD28 conjugated to magnetic beads. While effective, this artificial activation adds to the complexity of CAR T cell production as the beads must be removed prior to clinical implementation. To overcome this challenge, this work develops activating lipid nanoparticles (aLNPs) that mimic APCs to combine the activation of magnetic beads and the transfection capabilities of LNPs. It is shown that aLNPs enable one‐step activation and transfection of primary human T cells with the resulting mRNA CAR T cells reducing tumor burden in a murine xenograft model, validating aLNPs as a promising platform for the rapid production of mRNA CAR T cells.
Activating lipid nanoparticles (aLNPs) combine the antigen presenting cell‐mimetic character of commonly used T cell activating beads with the mRNA transfecting capabilities of LNPs. aLNPs facilitate rapid, one‐step activation and transfection of primary human T cells with chimeric antigen receptor (CAR) mRNA without requiring activating beads, potentially reducing the complexity, cost, and time of mRNA CAR T cell production.
Colorectal cancer is a major cause of cancer death worldwide. A number of key oncogenes and tumor suppressor genes have been proposed to drive progression from healthy colonic epithelia to malignant ...tumors, including members of the Wnt/beta-catenin pathway. Recently, CpG island promoter hypermethylation was shown to cause inactivation of two extracellular Wnt inhibitors in colon cancer: secreted frizzled-related proteins (sFRPs) and Wnt inhibitory factor-1 (WIF-1). Here, we show for the first time that another extracellular Wnt inhibitor, the DICKKOPF-1 (DKK-1) gene, is transcriptionally silenced by CpG island promoter hypermethylation in colon cancer cell lines (n=9), whereas treatment with the DNA-demethylating agent 5-aza-2-deoxycytidine restored DKK-1 expression. Restoration of DKK-1 function in non-expressing cells bearing a truncated APC (Adenomatous Polyposis Coli) gene had no effect on beta-catenin/T-cell factor-dependent transcription, but induced tumor suppressor-like features such as reduced colony formation density and tumor growth inhibition in nude mice. These results suggest additional functions for DKK-1 other than inhibiting canonical Wnt signaling. In primary colorectal tumors, DKK-1 was found hypermethylated in 17% (nine of 54) of cases. Furthermore, while for both SFRP-1 and WIF-1 methylation-associated silencing occurred across the whole spectrum of colorectal tumorigenesis, DKK-1 promoter was selectively hypermethylated in advanced colorectal neoplasms (Duke's C and D tumors).
We present the first simultaneous spectral energy distribution (SED) of M87 core at a scale of 0.4 arcsec ( ∼ 32 pc) across the electromagnetic spectrum. Two separate, quiescent, and active states ...are sampled that are characterized by a similar featureless SED of power-law form, and that are thus remarkably different from that of a canonical active galactic nuclei or a radiatively inefficient accretion source. We show that the emission from a jet gives an excellent representation of the core of M87 core covering ten orders of magnitude in frequency for both the active and the quiescent phases. The inferred total jet power is, however, one to two orders of magnitude lower than the jet mechanical power reported in the literature. The maximum luminosity of a thin accretion disc allowed by the data yields an accretion rate of < 6 × 10− 5 M⊙ yr− 1, assuming 10 per cent efficiency. This power suffices to explain M87 radiative luminosity at the jet frame, it is however two to three order of magnitude below that required to account for the jet's kinetic power. The simplest explanation is variability, which requires the core power of M87 to have been two to three orders of magnitude higher in the last 200 yr. Alternatively, an extra source of power may derive from black hole spin. Based on the strict upper limit on the accretion rate, such spin power extraction requires an efficiency an order of magnitude higher than predicted from magnetohydrodynamic simulations, currently in the few hundred per cent range.
We present ALLSMOG, the APEX Low-redshift Legacy Survey for MOlecular Gas. ALLSMOG is a survey designed to observe the CO(2 − 1) emission line with the APEX telescope, in a sample of local galaxies ...(0.01 < z < 0.03), with stellar masses in the range 8.5 < log(M*/M⊙) < 10. This paper is a data release and initial analysis of the first two semesters of observations, consisting of 42 galaxies observed in CO(2 − 1). By combining these new CO(2 − 1) emission line data with archival H i data and SDSS optical spectroscopy, we compile a sample of low-mass galaxies with well-defined molecular gas masses, atomic gas masses, and gas-phase metallicities. We explore scaling relations of gas fraction and gas consumption time-scale, and test the extent to which our findings are dependent on a varying CO/H2 conversion factor. We find an increase in the H2/H i mass ratio with stellar mass which closely matches semi-analytic predictions. We find a mean molecular gas fraction for ALLSMOG galaxies of M
H2/M
* = (0.09–0.13), which decreases with stellar mass. This decrease in total gas fraction with stellar mass is in excess of some model predictions at low stellar masses. We measure a mean molecular gas consumption time-scale for ALLSMOG galaxies of 0.4–0.7 Gyr. We also confirm the non-universality of the molecular gas consumption time-scale, which varies (with stellar mass) from ∼100 Myr to ∼2 Gyr. Importantly, we find that the trends in the H2/H i mass ratio, gas fraction, and the non-universal molecular gas consumption time-scale are all robust to a range of recent metallicity-dependent CO/H2 conversion factors.
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