Schwartzfiltenborg9640

The development of resistance to anticancer drugs is believed to cause chemotherapy failure in pancreatic cancer (PC). The efflux of anticancer drugs mediated by ATP-binding cassette (ABC) transporters is a widely accepted mechanism for chemoresistance, but for ABCA subfamily members, which are characterized by their ability to transport lipids and cholesterol, its role in chemoresistance remains unknown. Here we found that the expression of ABCA8, a member of ABCA subfamily transporters, was significantly increased in human PC cells after gemcitabine (GEM) treatment, as well as in established GEM-resistant (Gem-R) PC cells. Importantly, ABCA8 knockdown reversed the chemoresistance phenotype of Gem-R cells, whereas ABCA8 overexpression significantly decreased the sensitivity of human PC cells to GEM, both in vitro and in vivo, demonstrating an important role of ABCA8 in regulating chemosensitivity. Moreover, our results showed that treatment with taurocholic acid (TCA), an endogenous substrate of ABCA8, also induced GEM insensitivity in PC cells. We further demonstrated that ABCA8 mediates the efflux of TCA out of PC cells, and that extracellular TCA activates extracellular signal-regulated kinase (ERK) signaling via the sphingosine 1-phosphate receptor 2 (S1PR2), which is responsible for ABCA8-induced GEM ineffectiveness. Together, these findings reveal a novel TCA-related mechanism of ABCA subfamily transporter-mediated chemoresistance that goes beyond the role of a drug pump and suggest ABCA8 or the TCA-S1RP2-ERK pathway as potential targets for improving the effectiveness of and overcoming the resistance to chemotherapy in PC.Since the industrial revolution, it has been assumed that fossil-fuel combustions dominate increasing nitrogen oxide (NOx) emissions. However, it remains uncertain to the actual contribution of the non-fossil fuel NOx to total NOx emissions. Natural N isotopes of NO3- in precipitation (δ15Nw-NO3-) have been widely employed for tracing atmospheric NOx sources. Here, we compiled global δ15Nw-NO3- observations to evaluate the relative importance of fossil and non-fossil fuel NOx emissions. We found that regional differences in human activities directly influenced spatial-temporal patterns of δ15Nw-NO3- variations. Further, isotope mass-balance and bottom-up calculations suggest that the non-fossil fuel NOx accounts for 55 ± 7% of total NOx emissions, reaching up to 21.6 ± 16.6Mt yr-1 in East Asia, 7.4 ± 5.5Mt yr-1 in Europe, and 21.8 ± 18.5Mt yr-1 in North America, respectively. These results reveal the importance of non-fossil fuel NOx emissions and provide direct evidence for making strategies on mitigating atmospheric NOx pollution.Understanding the mechanism for antibody neutralization of SARS-CoV-2 is critical for the development of effective therapeutics and vaccines. We recently isolated a large number of monoclonal antibodies from SARS-CoV-2 infected individuals. Here we select the top three most potent yet variable neutralizing antibodies for in-depth structural and functional analyses. AR-C155858 Crystal structural comparisons reveal differences in the angles of approach to the receptor binding domain (RBD), the size of the buried surface areas, and the key binding residues on the RBD of the viral spike glycoprotein. One antibody, P2C-1F11, most closely mimics binding of receptor ACE2, displays the most potent neutralizing activity in vitro and conferred strong protection against SARS-CoV-2 infection in Ad5-hACE2-sensitized mice. It also occupies the largest binding surface and demonstrates the highest binding affinity to RBD. More interestingly, P2C-1F11 triggers rapid and extensive shedding of S1 from the cell-surface expressed spike glycoprotein, with only minimal such effect by the remaining two antibodies. These results offer a structural and functional basis for potent neutralization via disruption of the very first and critical steps for SARS-CoV-2 cell entry.Acute myeloid leukemia (AML) is a high remission, high relapse fatal blood cancer. Although mTORC1 is a master regulator of cell proliferation and survival, its inhibitors have not performed well as AML treatments. To uncover the dynamics of mTORC1 activity in vivo, fluorescent probes are developed to track single cell proliferation, apoptosis and mTORC1 activity of AML cells in the bone marrow of live animals and to quantify these activities in the context of microanatomical localization and intra-tumoral heterogeneity. When chemotherapy drugs commonly used clinically are given to mice with AML, apoptosis is rapid, diffuse and not preferentially restricted to anatomic sites. Dynamic measurement of mTORC1 activity indicated a decline in mTORC1 activity with AML progression. However, at the time of maximal chemotherapy response, mTORC1 signaling is high and positively correlated with a leukemia stemness transcriptional profile. Cell barcoding reveals the induction of mTORC1 activity rather than selection of mTORC1 high cells and timed inhibition of mTORC1 improved the killing of AML cells. These data define the real-time dynamics of AML and the mTORC1 pathway in association with AML growth, response to and relapse after chemotherapy. They provide guidance for timed intervention with pathway-specific inhibitors.Infectious disease prevention, control and forecasting rely on sentinel observations; however, many locations lack the capacity for routine surveillance. Here we show that, by using data from multiple sites collectively, accurate estimation and forecasting of respiratory diseases for locations without surveillance is feasible. We develop a framework to optimize surveillance sites that suppresses uncertainty propagation in a networked disease transmission model. Using influenza outbreaks from 35 US states, the optimized system generates better near-term predictions than alternate systems designed using population and human mobility. We also find that monitoring regional population centers serves as a reasonable proxy for the optimized network and could direct surveillance for diseases with limited records. The proxy method is validated using model simulations for 3,108 US counties and historical data for two other respiratory pathogens - human metapneumovirus and seasonal coronavirus - from 35 US states and can be used to guide systemic allocation of surveillance efforts.