The initial reinforcing properties of drugs of abuse, such as cocaine, are largely attributed to their ability to activate the mesolimbic dopamine system. Resulting increases in extracellular ...dopamine in the nucleus accumbens (NAc) are traditionally thought to result from cocaine's ability to block dopamine transporters (DATs). Here we demonstrate that cocaine also interacts with the immunosurveillance receptor complex, Toll-like receptor 4 (TLR4), on microglial cells to initiate central innate immune signaling. Disruption of cocaine signaling at TLR4 suppresses cocaine-induced extracellular dopamine in the NAc, as well as cocaine conditioned place preference and cocaine self-administration. These results provide a novel understanding of the neurobiological mechanisms underlying cocaine reward/reinforcement that includes a critical role for central immune signaling, and offer a new target for medication development for cocaine abuse treatment.
Metastases remain the major cause of death from cancer. Recent molecular advances have highlighted the importance of metabolic alterations in cancer cells, including the Warburg effect that describes ...an increased glycolysis in cancer cells. However, how this altered metabolism contributes to tumour metastasis remains elusive. Here, we report that phosphorylation-induced activation of lactate dehydrogenase A (LDHA), an enzyme that catalyses the interconversion of pyruvate and lactate, promotes cancer cell invasion, anoikis resistance and tumour metastasis. We demonstrate that LDHA is phosphorylated at tyrosine 10 by upstream kinases, HER2 and Src. Targeting HER2 or Src attenuated LDH activity as well as invasive potential in head and neck cancer and breast cancer cells. Inhibition of LDH activity by small hairpin ribonucleic acid or expression of phospho-deficient LDHA Y10F sensitized the cancer cells to anoikis induction and resulted in attenuated cell invasion and elevated reactive oxygen species, whereas such phenotypes were reversed by its product lactate or antioxidant N-acetylcysteine, suggesting that Y10 phosphorylation-mediated LDHA activity promotes cancer cell invasion and anoikis resistance through redox homeostasis. In addition, LDHA knockdown or LDHA Y10F rescue expression in human cancer cells resulted in decreased tumour metastasis in xenograft mice. Furthermore, LDHA phosphorylation at Y10 positively correlated with progression of metastatic breast cancer in clinical patient tumour samples. Our findings demonstrate that LDHA phosphorylation and activation provide pro-invasive, anti-anoikis and pro-metastatic advantages to cancer cells, suggesting that Y10 phosphorylation of LDHA may represent a promising therapeutic target and a prognostic marker for metastatic human cancers.
Complex tissues contain multiple cell types that are hierarchically organized within morphologically and functionally distinct compartments. Construction of engineered tissues with optimized tissue ...architecture has been limited by tissue fabrication techniques, which do not enable versatile microscale organization of multiple cell types in tissues of size adequate for physiological studies and tissue therapies. Here we present an 'Intaglio-Void/Embed-Relief Topographic molding' method for microscale organization of many cell types, including induced pluripotent stem cell-derived progeny, within a variety of synthetic and natural extracellular matrices and across tissues of sizes appropriate for in vitro, pre-clinical, and clinical studies. We demonstrate that compartmental placement of non-parenchymal cells relative to primary or induced pluripotent stem cell-derived hepatocytes, compartment microstructure, and cellular composition modulate hepatic functions. Configurations found to sustain physiological function in vitro also result in survival and function in mice for at least 4 weeks, demonstrating the importance of architectural optimization before implantation.
We present a hierarchical Bayesian method for atmospheric trace gas inversions. This method is used to estimate emissions of trace gases as well as "hyper-parameters" that characterize the ...probability density functions (PDFs) of the a priori emissions and model-measurement covariances. By exploring the space of "uncertainties in uncertainties", we show that the hierarchical method results in a more complete estimation of emissions and their uncertainties than traditional Bayesian inversions, which rely heavily on expert judgment. We present an analysis that shows the effect of including hyper-parameters, which are themselves informed by the data, and show that this method can serve to reduce the effect of errors in assumptions made about the a priori emissions and model-measurement uncertainties. We then apply this method to the estimation of sulfur hexafluoride (SF6) emissions over 2012 for the regions surrounding four Advanced Global Atmospheric Gases Experiment (AGAGE) stations. We find that improper accounting of model representation uncertainties, in particular, can lead to the derivation of emissions and associated uncertainties that are unrealistic and show that those derived using the hierarchical method are likely to be more representative of the true uncertainties in the system. We demonstrate through this SF6 case study that this method is less sensitive to outliers in the data and to subjective assumptions about a priori emissions and model-measurement uncertainties than traditional methods.
The global extent and distribution of forest trees is central to our understanding of the terrestrial biosphere. We provide the first spatially continuous map of forest tree density at a global ...scale. This map reveals that the global number of trees is approximately 3.04 trillion, an order of magnitude higher than the previous estimate. Of these trees, approximately 1.39 trillion exist in tropical and subtropical forests, with 0.74 trillion in boreal regions and 0.61 trillion in temperate regions. Biome-level trends in tree density demonstrate the importance of climate and topography in controlling local tree densities at finer scales, as well as the overwhelming effect of humans across most of the world. Based on our projected tree densities, we estimate that over 15 billion trees are cut down each year, and the global number of trees has fallen by approximately 46% since the start of human civilization.
While much effort has been made to characterize influenza A pdm09 virus (pH1N1), the flu that was responsible for the fourth influenza pandemic, there is a lack of study on the composition of ...bacteria that lead to secondary infection. In this study, we recruited pneumonia patients with and without pH1N1 infection and characterized their oropharyngeal microbiota by the unbiased high-throughput sequencing method. While there were no significant differences in common bacterial pneumonia-causative agents (Acinetobacter and Streptococcus species), previously unreported Pseudomonas species equipped with chemotaxis and flagellar assembly genes significantly increased (>20-fold) in the pH1N1-infected group. Bacillus and Ralstonia species that also increased significantly (5–10-fold) were also found to possess similar signaling and motility genes. In contrast, no such genes were found in oral commensal Prevotella, Veillonella and Neisseria species, which decreased significantly, or in either Acinetobacter or 10 out of 21 Streptococcus species, including Streptococcus pneumoniae. Our results support the notion that pH1N1 infection provides a niche for previously unnoticed potential respiratory pathogens that were able to access the lower respiratory tract with weakened immunity.
Abstract
Fast radio burst (FRB) source FRB 20180916B exhibits a 16.33-day periodicity in its burst activity. It is as of yet unclear what proposed mechanism produces the activity, but polarization ...information is a key diagnostic. Here we report on the polarization properties of 44 bursts from FRB 20180916B detected between 2018 December and 2021 December by CHIME/FRB, the FRB project on the Canadian Hydrogen Intensity Mapping Experiment. In contrast to previous observations, we find significant variations in the Faraday rotation measure (RM) of FRB 20180916B. Over the 9-month period 2021 April and 2021 December we observe an apparent secular increase in RM of ∼50 rad m
−2
(a fractional change of over 40%) that is accompanied by a possible drift of the emitting band to lower frequencies. This interval displays very little variation in the dispersion measure (ΔDM ≲ 0.8 pc cm
−3
), which indicates that the observed RM evolution is likely produced from coherent changes in the Faraday-active medium’s magnetic field. Burst-to-burst RM variations appear unrelated to the activity cycle phase. The degree of linear polarization of our burst sample (≳80%) is consistent with the negligible depolarization expected for this source in the 400–800 MHz bandpass of CHIME. FRB 20180916B joins other repeating FRBs in displaying substantial RM evolution. This is consistent with the notion that repeater progenitors may be associated with young stellar populations by their preferential occupation of dynamic magnetized environments commonly found in supernova remnants, in pulsar wind nebulae, or near high-mass stellar companions.
Glaucoma is a major cause of blindness and is frequently associated with elevated intraocular pressure. The trabecular meshwork (TM), the tissue that primarily regulates intraocular pressure, is ...known to have reduced cellularity in glaucoma. Thus, stem cells, if properly delivered to the TM, may offer a novel therapeutic option for intraocular pressure control in glaucoma patients. For this purpose, targeted delivery of stem cells to the TM is desired. Here, we used magnetic nanoparticles (Prussian blue nanocubes PBNCs) to label mesenchymal stem cells and to magnetically steer them to the TM following injection into the eye's anterior chamber. PBNC-labeled stem cells showed increased delivery to the TM vs. unlabeled cells after only 15-minute exposure to a magnetic field. Further, PBNC-labeled mesenchymal stem cells could be delivered to the entire circumference of the TM, which was not possible without magnetic steering. PBNCs did not affect mesenchymal stem cell viability or multipotency. We conclude that this labeling approach allows for targeted, relatively high-efficiency delivery of stem cells to the TM in clinically translatable time-scales, which are necessary steps towards regenerative medicine therapies for control of ocular hypertension in glaucoma patients.
•FRP tubes filled with seawater and sea sand concrete (SWSSC) is studied.•A theoretical model for SWSSC-filled FRP tubes in compression is proposed.•The orthotropic behaviour of FRP tubes is properly ...accounted for in the model.•A simplified method is proposed to determine the load shared by the FRP tube.•The interaction between the FRP tube and the SWSSC is explicitly modelled.
The use of FRP with seawater and sea sand concrete (SWSSC) holds great potential for marine and coastal infrastructure, and concrete-filled FRP tubular columns are among the attractive forms of structural members for such applications. This paper presents a theoretical model for the compressive behaviour of seawater and sea sand concrete-filled circular FRP tubular stub columns. FRP tubes can be manufactured to possess considerable strength and stiffness in the longitudinal direction, so the behaviour of concrete-filled FRP tubes differed substantially from that of concrete columns with an FRP wrap (also referred to as “concrete-filled FRP wraps”) which commonly contains fibres only in the hoop direction. Many theoretical models have been proposed for concrete-filled FRP wraps, but very limited work has been conducted on the theoretical modelling of concrete-filled FRP tubes. In the present study, an existing dilation model for concrete-filled FRP wraps is combined with a biaxial stress analysis of the FRP tube so that the effect of the Poisson’s ratio of the FRP tube is properly accounted for. In order to predict the buckling of the FRP tube, a maximum strain buckling failure criterion is proposed and is shown to be in reasonable agreement with the experimental results. Moreover, the load carried by the FRP tube is studied, and a simplified model is proposed to determine the load shared by the FRP tube during the entire loading process. Finally, a theoretical model for SWSSC-filled FRP tubular columns is proposed, in which the behaviour of both the concrete and the FRP tube as well as their interactions are explicitly modelled (i.e., an analysis-oriented model). The proposed model gives reasonably close predictions of the existing experimental data.
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