A Novel Mechanism of TRAF Signaling Revealed by Structural and Functional Analyses of the TRADD–TRAF2 Interaction

AbstractTRAF proteins are major mediators for the cell activation, cell survival, and antiapoptotic functions of the TNF receptor superfamily. They can be recruited to activated TNF receptors either by direct interactions with the receptors or indirectly via the adaptor protein TRADD. We now report the structure of the TRADD-TRAF2 complex, which is highly distinct from receptor–TRAF2 interactions. This interaction is significantly stronger and we show by an in vivo signaling assay that TRAF2 signaling is more readily initiated by TRADD than by direct receptor–TRAF2 interactions. TRADD is specific for TRAF1 and TRAF2, which ensures the recruitment of cIAPs for the direct inhibition of caspase activation in the signaling complex. The stronger affinity and unique specificity of the TRADD–TRAF2 interaction are crucial for the suppression of apoptosis and provide a mechanistic basis for the perturbation of TRAF recruitment in sensitizing cell death induction

Dynamics of Trophoblast Differentiation in Peri-Implantation–Stage Human Embryos

Single-cell RNA sequencing of cells from cultured human blastocysts has enabled us to define the transcriptomic landscape of placental trophoblast (TB) that surrounds the epiblast and associated embryonic tissues during the enigmatic day 8 (D8) to D12 peri-implantation period before the villous placenta forms. We analyzed the transcriptomes of 3 early placental cell types, cytoTB (CTB), syncytioTB (STB), and migratoryTB (MTB), picked manually from cultured embryos dissociated with trypsin and were able to follow sublineages that emerged from proliferating CTB at the periphery of the conceptus. A unique form of CTB with some features of STB was detectable at D8, while mature STB was at its zenith at D10. A form of MTB with a mixed MTB/CTB phenotype arose around D10. By D12, STB generation was in decline, CTB had entered a new phase of proliferation, and mature MTB cells had begun to move from the main body of the conceptus. Notably, the MTB transcriptome at D12 indicated enrichment of transcripts associated with IFN signaling, migration, and invasion and upregulation of HLA-C, HLA-E, and HLA-G. The STB, which is distinct from the STB of later villous STB, had a phenotype consistent with intense protein export and placental hormone production, as well as migration and invasion. The studies show that TB associated with human embryos is in rapid developmental flux during periimplantation period when it must invade, signal robustly to the mother to ensure that the pregnancy continues, and make first contact with the maternal immune system

Chemical and Biochemical Technologies for Environmental Infrastructure Sustainability

Lawrence K. Wang, Mu-Hao Sung Wang, Thomas Suozzo, Rebecca A. Dixon, and Terry L. Wright (2023) . Chemical and Biochemical Technologies for Environmental Infrastructure Sustainability, In: "Evolutionary Progress in Science, Technology, Engineering, Arts, and Mathematics (STEAM)", Lawrence K. Wang and Hung-ping Tsao (editors). Volume 5, Number 10A, October 2023; 5(10A), 58 pages. Lenox Institute Press, MA, USA. https://doi.org/10.17613/z30s-gj22 ..... ABSTRACT: Various highly efficient flotation processes and systems are introduced for water and wastewater infrastructure sustainability. This publication covers the following subjects: (a) Flotation types , theories, principles, and “zero velocity concept”; (b) Unit processes of mixing, coagulation, precipitation, flocculation, clarification (flotation or sedimentation), filtration, disinfection, sludge thickening and sludge dewatering; (c) Flotation rising rate, surface loading rate, and detention time; (d) Dissolved air flotation (DAF), DAF-filtration (DAFF) and sedimentation comparison; (e) Various municipal and industrial applications of DAF and DAFF; (f) Full scale rectangular and circular DAF and DAFF installations for potable water treatment and industrial effluent treatment when land space and budget are limited; (g) upgrading an existing sedimentation to a DAF-sedimentation clarifier; (h) DAF sludge thickening and screwpress sludge dewatering (Float Press); (i) Oxyozosynthesis system (oxygenation, ozonation, sludge wet oxidation, and Float Press sludge dewatering); (j) Biological or physicochemical sequencing batch reactor (SBR); (k) Recent advances in and case histories of dissolved gas flotation (DGF), primary flotation, secondary flotation, tertiary flotation, nitrification, denitrification, flotation sludge thickening, dissolved carbon dioxide flotation (DCDF), dairy wastewater treatment (WWT), and tannery WWT

An Anti-Human ICAM-1 Antibody Inhibits Rhinovirus-Induced Exacerbations of Lung Inflammation

Human rhinoviruses (HRV) cause the majority of common colds and acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Effective therapies are urgently needed, but no licensed treatments or vaccines currently exist. Of the 100 identified serotypes, ∼90% bind domain 1 of human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor, making this an attractive target for development of therapies; however, ICAM-1 domain 1 is also required for host defence and regulation of cell trafficking, principally via its major ligand LFA-1. Using a mouse anti-human ICAM-1 antibody (14C11) that specifically binds domain 1 of human ICAM-1, we show that 14C11 administered topically or systemically prevented entry of two major groups of rhinoviruses, HRV16 and HRV14, and reduced cellular inflammation, pro-inflammatory cytokine induction and virus load in vivo. 14C11 also reduced cellular inflammation and Th2 cytokine/chemokine production in a model of major group HRV-induced asthma exacerbation. Interestingly, 14C11 did not prevent cell adhesion via human ICAM-1/LFA-1 interactions in vitro, suggesting the epitope targeted by 14C11 was specific for viral entry. Thus a human ICAM-1 domain-1-specific antibody can prevent major group HRV entry and induction of airway inflammation in vivo

Natural product (L)-gossypol inhibits colon cancer cell growth by targeting RNA-binding protein Musashi-1

Musashi-1 (MSI1) is an RNA-binding protein that acts as a translation activator or repressor of target mRNAs. The best-characterized MSI1 target is Numb mRNA, whose encoded protein negatively regulates Notch signaling. Additional MSI1 targets include the mRNAs for the tumor suppressor protein APC that regulates Wnt signaling and the cyclin-dependent kinase inhibitor P21WAF−1. We hypothesized that increased expression of NUMB, P21 and APC, through inhibition of MSI1 RNA-binding activity might be an effective way to simultaneously downregulate Wnt and Notch signaling, thus blocking the growth of a broad range of cancer cells. We used a fluorescence polarization assay to screen for small molecules that disrupt the binding of MSI1 to its consensus RNA binding site. One of the top hits was (−)-gossypol (Ki = 476 ± 273 nM), a natural product from cottonseed, known to have potent anti-tumor activity and which has recently completed Phase IIb clinical trials for prostate cancer. Surface plasmon resonance and nuclear magnetic resonance studies demonstrate a direct interaction of (−)-gossypol with the RNA binding pocket of MSI1. We further showed that (−)-gossypol reduces Notch/Wnt signaling in several colon cancer cell lines having high levels of MSI1, with reduced SURVIVIN expression and increased apoptosis/autophagy. Finally, we showed that orally administered (−)-gossypol inhibits colon cancer growth in a mouse xenograft model. Our study identifies (−)-gossypol as a potential small molecule inhibitor of MSI1-RNA interaction, and suggests that inhibition of MSI1's RNA binding activity may be an effective anti-cancer strategy

Quantification of the Frequency and Multiplicity of Infection of Respiratory- and Lymph Node–Resident Dendritic Cells During Influenza Virus Infection

Background: Previous studies have demonstrated that DC differentially regulate influenza A virus (IAV)–specific CD8 T cell responses in vivo during high and low dose IAV infections. Furthermore, in vitro infection of DC with IAV at low versus high multiplicities of infection (MOI) results in altered cytokine production and a reduced ability to prime naïve CD8 T cell responses. Flow cytometric detection of IAV proteins within DC, a commonly used method for detection of cellular IAV infection, does not distinguish between the direct infection of these cells or their uptake of viral proteins from dying epithelial cells. Methods/Principal Findings: We have developed a novel, sensitive, single-cell RT-PCR–based approach to assess the infection of respiratory DC (rDC) and lymph node (LN)-resident DC (LNDC) following high and low dose IAV infections. Our results show that, while a fraction of both rDC and LNDC contain viral mRNA following IAV infection, there is little correlation between the percentage of rDC containing viral mRNA and the initial IAV inoculum dose. Instead, increasing IAV inoculums correlate with augmented rDC MOI. Conclusion/Significance: Together, our results demonstrate a novel and sensitive method for the detection of direct IAV infection at the single-cell level and suggest that the previously described ability of DC to differentially regulate IAV-specific T cell responses during high and low dose IAV infections could relate to the MOI of rDC within the LN rather than th

Heterogeneity and chemical reactivity of the remote troposphere defined by aircraft measurements

The NASA Atmospheric Tomography (ATom) mission built a photochemical climatology of air parcels based on in situ measurements with the NASA DC-8 aircraft along objectively planned profiling transects through the middle of the Pacific and Atlantic oceans. In this paper we present and analyze a data set of 10 s (2 km) merged and gap-filled observations of the key reactive species driving the chemical budgets of O3 and CH4 (O3, CH4, CO, H2O, HCHO, H2O2, CH3OOH, C2H6, higher alkanes, alkenes, aromatics, NOx, HNO3, HNO4, peroxyacetyl nitrate, other organic nitrates), consisting of 146,494 distinct air parcels from ATom deployments 1 through 4. Six models calculated the O3 and CH4 photochemical tendencies from this modeling data stream for ATom 1. We find that 80 %&ndash;90 % of the total reactivity lies in the top 50 % of the parcels; and 25 %&ndash;35 %, in the top 10 %, supporting previous model-only studies that tropospheric chemistry is driven by a fraction of all the air. In other words, accurate simulation of the least reactive 50 % of the troposphere is unimportant for global budgets. Surprisingly, the probability densities of species and reactivities averaged on a model scale (100 km) differ only slightly from the 2 km ATom data, indicating that much of the heterogeneity in tropospheric chemistry can be captured with current global chemistry models. Comparing the ATom reactivities over the tropical oceans with climatological statistics from six global chemistry models, we find generally good agreement with the reactivity rates for O3 and CH4. In the Pacific but not Atlantic, however, models distinctly underestimate O3 production below 2 km, and this can be traced lower NOX levels than observed. Attaching photochemical reactivities to measurements of chemical species allows for a richer, yet more constrained-to-what-matters, set of metrics for model evaluation.</p

Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study

Objectives To validate the clinical efficacy and practical feasibility of massively parallel maternal plasma DNA sequencing to screen for fetal trisomy 21 among high risk pregnancies clinically indicated for amniocentesis or chorionic villus sampling