More Like this

1. Cleavage of the Perlecan-Semaphorin 3A-Plexin A1-Neuropilin-1 (PSPN) Complex by Matrix Metalloproteinase 7/Matrilysin Triggers Prostate Cancer Cell Dyscohesion and Migration

   https://doi.org/10.3390/ijms22063218  

   Tellman, Tristen V.; Cruz, Lissette A.; Grindel, Brian J.; Farach-Carson, Mary C. (March 2021, International Journal of Molecular Sciences)

   null (Ed.)

   The Perlecan-Semaphorin 3A-Plexin A1-Neuropilin-1 (PSPN) Complex at the cell surface of prostate cancer (PCa) cells influences cell–cell cohesion and dyscohesion. We investigated matrix metalloproteinase-7/matrilysin (MMP-7)’s ability to digest components of the PSPN Complex in bone metastatic PCa cells using in silico analyses and in vitro experiments. Results demonstrated that in addition to the heparan sulfate proteoglycan, perlecan, all components of the PSPN Complex were degraded by MMP-7. To investigate the functional consequences of PSPN Complex cleavage, we developed a preformed microtumor model to examine initiation of cell dispersion after MMP-7 digestion. We found that while perlecan fully decorated with glycosaminoglycan limited dispersion of PCa microtumors, MMP-7 initiated rapid dyscohesion and migration even with perlecan present. Additionally, we found that a bioactive peptide (PLN4) found in perlecan domain IV in a region subject to digestion by MMP-7 further enhanced cell dispersion along with MMP-7. We found that digestion of the PSPN Complex with MMP-7 destabilized cell–cell junctions in microtumors evidenced by loss of co-registration of E-cadherin and F-actin. We conclude that MMP-7 plays a key functional role in PCa cell transition from a cohesive, indolent phenotype to a dyscohesive, migratory phenotype favoring production of circulating tumor cells and metastasis to bone. 

   more » « less
2. Blood substitution therapy rescues the brain of mice from ischemic damage

   https://doi.org/10.1038/s41467-020-17930-x  

   Ren, Xuefang; Hu, Heng; Farooqi, Imran; Simpkins, James W. (August 2020, Nature Communications)

   Abstract Acute stroke causes complex, pathological, and systemic responses that have not been treatable by any single medication. In this study, using a murine transient middle cerebral artery occlusion stroke model, a novel therapeutic strategy is proposed, where blood replacement (BR) robustly reduces infarctions and improves neurological deficits in mice. Our analyses of immune cell subsets suggest that BR therapy substantially decreases neutrophils in blood following a stroke. Electrochemiluminescence detection demonstrates that BR therapy reduces cytokine storm in plasma and ELISA demonstrates reduced levels of matrix metalloproteinase-9 (MMP-9) in the plasma and brains at different time points post-stroke. Further, we have demonstrated that the addition of MMP-9 to the blood diminishes the protective effect of the BR therapy. Our study is the first to show that BR therapy leads to profoundly improved stroke outcomes in mice and that the improved outcomes are mediated via MMP-9. These results offer new insights into the mechanisms of stroke damage. 

   more » « less
3. Review of Learning-Based Longitudinal Motion Planning for Autonomous Vehicles: Research Gaps Between Self-Driving and Traffic Congestion

   https://doi.org/10.1177/03611981211035764  

   Zhou, Hao; Laval, Jorge; Zhou, Anye; Wang, Yu; Wu, Wenchao; Qing, Zhu; Peeta, Srinivas (July 2021, Transportation Research Record: Journal of the Transportation Research Board)

   Self-driving technology companies and the research community are accelerating the pace of use of machine learning longitudinal motion planning (mMP) for autonomous vehicles (AVs). This paper reviews the current state of the art in mMP, with an exclusive focus on its impact on traffic congestion. The paper identifies the availability of congestion scenarios in current datasets, and summarizes the required features for training mMP. For learning methods, the major methods in both imitation learning and non-imitation learning are surveyed. The emerging technologies adopted by some leading AV companies, such as Tesla, Waymo, and Comma.ai, are also highlighted. It is found that: (i) the AV industry has been mostly focusing on the long tail problem related to safety and has overlooked the impact on traffic congestion, (ii) the current public self-driving datasets have not included enough congestion scenarios, and mostly lack the necessary input features/output labels to train mMP, and (iii) although the reinforcement learning approach can integrate congestion mitigation into the learning goal, the major mMP method adopted by industry is still behavior cloning, whose capability to learn a congestion-mitigating mMP remains to be seen. Based on the review, the study identifies the research gaps in current mMP development. Some suggestions for congestion mitigation for future mMP studies are proposed: (i) enrich data collection to facilitate the congestion learning, (ii) incorporate non-imitation learning methods to combine traffic efficiency into a safety-oriented technical route, and (iii) integrate domain knowledge from the traditional car-following theory to improve the string stability of mMP. 

   more » « less
4. Replacement and Parallel Simplification of Nonhomologous Proteinases Maintain Venom Phenotypes in Rear-Fanged Snakes

   https://doi.org/10.1093/molbev/msaa192  

   Bayona-Serrano, Juan David; Viala, Vincent Louis; Rautsaw, Rhett M; Schramer, Tristan D; Barros-Carvalho, Gesiele A; Nishiyama, Milton Yutaka; Freitas-de-Sousa, Luciana A; Moura-da-Silva, Ana Maria; Parkinson, Christopher L; Grazziotin, Felipe Gobbi; et al (July 2020, Molecular Biology and Evolution)

   True, John (Ed.)

   Abstract Novel phenotypes are commonly associated with gene duplications and neofunctionalization, less documented are the cases of phenotypic maintenance through the recruitment of novel genes. Proteolysis is the primary toxic character of many snake venoms, and ADAM metalloproteinases, named snake venom metalloproteinases (SVMPs), are largely recognized as the major effectors of this phenotype. However, by investigating original transcriptomes from 58 species of advanced snakes (Caenophidia) across their phylogeny, we discovered that a different enzyme, matrix metalloproteinase (MMP), is actually the dominant venom component in three tribes (Tachymenini, Xenodontini, and Conophiini) of rear-fanged snakes (Dipsadidae). Proteomic and functional analyses of these venoms further indicate that MMPs are likely playing an “SVMP-like” function in the proteolytic phenotype. A detailed look into the venom-specific sequences revealed a new highly expressed MMP subtype, named snake venom MMP (svMMP), which originated independently on at least three occasions from an endogenous MMP-9. We further show that by losing ancillary noncatalytic domains present in its ancestors, svMMPs followed an evolutionary path toward a simplified structure during their expansion in the genomes, thus paralleling what has been proposed for the evolution of their Viperidae counterparts, the SVMPs. Moreover, we inferred an inverse relationship between the expression of svMMPs and SVMPs along the evolutionary history of Xenodontinae, pointing out that one type of enzyme may be substituting for the other, whereas the general (metallo)proteolytic phenotype is maintained. These results provide rare evidence on how relevant phenotypic traits can be optimized via natural selection on nonhomologous genes, yielding alternate biochemical components. 

   more » « less
5. Quasi‐F‐splittings in birational geometry II

   https://doi.org/10.1112/plms.12593  

   Kawakami, Tatsuro; Takamatsu, Teppei; Tanaka, Hiromu; Witaszek, Jakub; Yobuko, Fuetaro; Yoshikawa, Shou (April 2024, Proceedings of the London Mathematical Society)

   Abstract Over an algebraically closed field of characteristic , we prove that three‐dimensional ‐factorial affine klt varieties are quasi‐‐split. Furthermore, we show that the bound on the characteristic is optimal. 

   more » « less