@article{RN142, author = {Adebowale, K. and Guerriero, J. L. and Mitragotri, S.}, title = {Dynamics of macrophage tumor infiltration}, journal = {Applied Physics Reviews}, volume = {10}, number = {4}, note = {U0qa5 Times Cited:0 Cited References Count:58}, abstract = {Long-term remission in cancer patients treated with ex vivo bona fide M1-induced macrophages has been poor, and the reasons behind this are not understood. Injected M1 macrophages must physically migrate to tumors to execute their role that leads to a therapeutic benefit. However, the trafficking of macrophages to tumors has not been rigorously studied. We hypothesized that trafficking capabilities of macrophages are impacted when naive M0 macrophages are converted into an M1 phenotype for macrophage therapy. To test this, we developed a three-dimensional assay comprising a tumor spheroid and macrophages to quantify macrophage tumor transport. Cell migration, permeability, and kinetics of tumor entry were quantitatively defined and compared between macrophage phenotypes. Our results demonstrate that compared to M0 macrophages, M1 macrophages migrate less efficiently toward the tumor spheroid and exhibit a fivefold lower tumor permeability. Live imaging data combined with unsupervised machine learning algorithms reveal that macrophage migration correlates with their shape transitions. Our studies highlight the importance of transport considerations in determining the efficacy of cell therapies. This study quantitatively demonstrates that the transport properties of macrophages in tumors depend on their phenotype.}, keywords = {monocyte-derived macrophages in-vivo adoptive immunotherapy 3d culture migration tumorigenesis mechanisms plasticity cells}, ISSN = {1931-9401}, DOI = {Artn 041402 10.1063/5.0160924}, url = {://WOS:001081926500001}, year = {2023}, type = {Journal Article} } @article{RN144, author = {Ahrendsen, J. T. and Nong, Y. and Huo, Y. and Steele, J. and Anderson, M. P.}, title = {CD8 cytotoxic T-cell infiltrates and cellular damage in the hypothalamus in human obesity}, journal = {Acta Neuropathol Commun}, volume = {11}, number = {1}, pages = {163}, note = {Ahrendsen, Jared T Nong, Yi Huo, Yuda Steele, Jasmine Anderson, Matthew P eng U54 HD090255/HD/NICHD NIH HHS/ R01 MH112714/MH/NIMH NIH HHS/ R01 MH114858/MH/NIMH NIH HHS/ R21 MH100868/MH/NIMH NIH HHS/ R21 HD079249/HD/NICHD NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England 2023/10/10 Acta Neuropathol Commun. 2023 Oct 9;11(1):163. doi: 10.1186/s40478-023-01659-x.}, abstract = {Rare cases of paraneoplastic obesity in children suggest sporadic obesity might also arise from an adaptive immune cell-mediated mechanism. Since the hypothalamus is a central regulator of feeding behavior and energy expenditure, we quantified lymphocytic inflammation in this region in a cohort of obese and non-obese human post-mortem brains. We report that CD8-positive cytotoxic T-cells are increased in hypothalamic median eminence/arcuate nucleus (ME/Arc) and bed nucleus of the stria terminalis in 40% of obese compared to non-obese patients, but not in other hypothalamic nuclei or brain regions. CD8 T-cells were most abundant in individuals with concurrent obesity and diabetes. Markers of cytotoxic T-cell induced damage, activated caspase 3 and poly-ADP ribose, were also elevated in the ME/Arc of obese patients. To provoke CD8 cytotoxic T-cell infiltrates in ventromedial region of hypothalamus in mice we performed stereotactic injections of an adeno-associated virus expressing immunogenic green fluorescent protein or saline. AAV but not saline injections triggered hypothalamic CD8 T-cell infiltrates associated with a rapid weight gain in mice recapitulating the findings in human obesity. This is the first description of the neuropathology of human obesity and when combined with its reconstitution in a mouse model suggests adaptive immunity may drive as much as 40% of the human condition.}, keywords = {Animals Humans Mice Arcuate Nucleus of Hypothalamus/metabolism CD8-Positive T-Lymphocytes Hypothalamus/metabolism *Pediatric Obesity/metabolism T-Lymphocytes CD8 T cell Hypothalamus Inflammation Obesity}, ISSN = {2051-5960 (Electronic) 2051-5960 (Linking)}, DOI = {10.1186/s40478-023-01659-x}, url = {https://www.ncbi.nlm.nih.gov/pubmed/37814324}, year = {2023}, type = {Journal Article} } @article{RN143, author = {Dingal, Pcdp and Carte, A. N. and Montague, T. G. and Lim Suan, M. B., Jr. and Schier, A. F.}, title = {Molecular mechanisms controlling the biogenesis of the TGF-beta signal Vg1}, journal = {Proc Natl Acad Sci U S A}, volume = {120}, number = {43}, pages = {e2307203120}, note = {Dingal, P C Dave P Carte, Adam N Montague, Tessa G Lim Suan, Medel B Jr Schier, Alexander F eng DP1-HD094764/HHS | National Institutes of Health (NIH)/ UT Dallas Startup Fund/University of Texas at Dallas (UTD)/ 2023/10/16 Proc Natl Acad Sci U S A. 2023 Oct 24;120(43):e2307203120. doi: 10.1073/pnas.2307203120. Epub 2023 Oct 16.}, abstract = {The TGF-beta signals Vg1 (Dvr1/Gdf3) and Nodal form heterodimers to induce vertebrate mesendoderm. The Vg1 proprotein is a monomer retained in the endoplasmic reticulum (ER) and is processed and secreted upon heterodimerization with Nodal, but the mechanisms underlying Vg1 biogenesis are largely elusive. Here, we clarify the mechanisms underlying Vg1 retention, processing, secretion, and signaling and introduce a Synthetic Processing (SynPro) system that enables the programmed cleavage of ER-resident and extracellular proteins. First, we find that Vg1 can be processed by intra- or extracellular proteases. Second, Vg1 can be processed without Nodal but requires Nodal for secretion and signaling. Third, Vg1-Nodal signaling activity requires Vg1 processing, whereas Nodal can remain unprocessed. Fourth, Vg1 employs exposed cysteines, glycosylated asparagines, and BiP chaperone-binding motifs for monomer retention in the ER. These observations suggest two mechanisms for rapid mesendoderm induction: Chaperone-binding motifs help store Vg1 as an inactive but ready-to-heterodimerize monomer in the ER, and the flexibility of Vg1 processing location allows efficient generation of active heterodimers both intra- and extracellularly. These results establish SynPro as an in vivo processing system and define molecular mechanisms and motifs that facilitate the generation of active TGF-beta heterodimers.}, keywords = {Nodal Vg1 processing retention zebrafish}, ISSN = {1091-6490 (Electronic) 0027-8424 (Linking)}, DOI = {10.1073/pnas.2307203120}, url = {https://www.ncbi.nlm.nih.gov/pubmed/37844219}, year = {2023}, type = {Journal Article} } @article{RN146, author = {Lafuente-Gomez, N. and de Lazaro, I. and Dhanjani, M. and Garcia-Soriano, D. and Sobral, M. C. and Salas, G. and Mooney, D. J. and Somoza, A.}, title = {Multifunctional magnetic nanoparticles elicit anti-tumor immunity in a mouse melanoma model}, journal = {Mater Today Bio}, volume = {23}, pages = {100817}, note = {Lafuente-Gomez, Nuria de Lazaro, Irene Dhanjani, Monica Garcia-Soriano, David Sobral, Miguel C Salas, Gorka Mooney, David J Somoza, Alvaro eng England 2023/10/12 Mater Today Bio. 2023 Sep 24;23:100817. doi: 10.1016/j.mtbio.2023.100817. eCollection 2023 Dec.}, abstract = {Immunotherapy has emerged as a promising strategy to eradicate cancer cells. Particularly, the development of cancer vaccines to induce a potent and sustained antigen-specific T cell response has become a center of attention. Herein, we describe a novel immunotherapy based on magnetic nanoparticles (MNP) covalently modified with the OVA(254-267) antigen and a CpG oligonucleotide via disulfide bonds. The MNP-CpG-COVA significantly enhances dendritic cell activation and CD8(+) T cell antitumoral response against B16-OVA melanoma cells in vitro. Notably, the immune response induced by the covalently modified MNP is more potent and sustained over time than that triggered by the free components, highlighting the advantage of nanoformulations in immunotherapies. What is more, the nanoparticles are stable in the blood after in vivo administration and induce potent levels of systemic tumor-specific effector CD8 + T cells. Overall, our findings highlight the potential of covalently functionalized MNP to induce robust immune responses against mouse melanoma.}, keywords = {Cancer immunotherapy Cancer vaccine Magnetic nanoparticles Nanomedicine}, ISSN = {2590-0064 (Electronic) 2590-0064 (Linking)}, DOI = {10.1016/j.mtbio.2023.100817}, url = {https://www.ncbi.nlm.nih.gov/pubmed/37822453}, year = {2023}, type = {Journal Article} } @article{RN147, author = {Mizes, K. G. C. and Lindsey, J. and Escola, G. S. and Olveczky, B. P.}, title = {Dissociating the contributions of sensorimotor striatum to automatic and visually guided motor sequences}, journal = {Nat Neurosci}, volume = {26}, number = {10}, pages = {1791-1804}, note = {Mizes, Kevin G C Lindsey, Jack Escola, G Sean Olveczky, Bence P eng R01 NS105349/NS/NINDS NIH HHS/ Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. 2023/09/05 Nat Neurosci. 2023 Oct;26(10):1791-1804. doi: 10.1038/s41593-023-01431-3. Epub 2023 Sep 4.}, abstract = {The ability to sequence movements in response to new task demands enables rich and adaptive behavior. However, such flexibility is computationally costly and can result in halting performances. Practicing the same motor sequence repeatedly can render its execution precise, fast and effortless, that is, 'automatic'. The basal ganglia are thought to underlie both types of sequence execution, yet whether and how their contributions differ is unclear. We parse this in rats trained to perform the same motor sequence instructed by cues and in a self-initiated overtrained, or 'automatic,' condition. Neural recordings in the sensorimotor striatum revealed a kinematic code independent of the execution mode. Although lesions reduced the movement speed and affected detailed kinematics similarly, they disrupted high-level sequence structure for automatic, but not visually guided, behaviors. These results suggest that the basal ganglia are essential for 'automatic' motor skills that are defined in terms of continuous kinematics, but can be dispensable for discrete motor sequences guided by sensory cues.}, keywords = {Rats Animals *Corpus Striatum/physiology *Basal Ganglia/physiology Movement/physiology Neostriatum Motor Skills Psychomotor Performance/physiology}, ISSN = {1546-1726 (Electronic) 1097-6256 (Linking)}, DOI = {10.1038/s41593-023-01431-3}, url = {https://www.ncbi.nlm.nih.gov/pubmed/37667040}, year = {2023}, type = {Journal Article} } @article{RN141, author = {Xiong, T. and Tarikere, S. and Rosser, N. and Li, X. and Yago, M. and Mallet, J.}, title = {A polygenic explanation for Haldane's rule in butterflies}, journal = {Proc Natl Acad Sci U S A}, volume = {120}, number = {44}, pages = {e2300959120}, note = {Xiong, Tianzhu Tarikere, Shreeharsha Rosser, Neil Li, Xueyan Yago, Masaya Mallet, James eng Internal Funding/Harvard University Department of Organismic and Evolutionary Biology/ 1764269/The Quantitative Biology Initiatives at Harvard; The NSF-Simons Center for Mathematical and Statistical Analysis of Biology at Harvard/ Grant in Aid of Research/Sigma Xi, The Scientific Research Honor Society/ 32070482/National Natural Science Foundation of China/ 21H02215/JSPS KAKENHI Grant/ 2023/10/19 Proc Natl Acad Sci U S A. 2023 Oct 31;120(44):e2300959120. doi: 10.1073/pnas.2300959120. Epub 2023 Oct 19.}, abstract = {Two robust rules have been discovered about animal hybrids: Heterogametic hybrids are more unfit (Haldane's rule), and sex chromosomes are disproportionately involved in hybrid incompatibility (the large-X/Z effect). The exact mechanisms causing these rules in female heterogametic taxa such as butterflies are unknown but are suggested by theory to involve dominance on the sex chromosome. We investigate hybrid incompatibilities adhering to both rules in Papilio and Heliconius butterflies and show that dominance theory cannot explain our data. Instead, many defects coincide with unbalanced multilocus introgression between the Z chromosome and all autosomes. Our polygenic explanation predicts both rules because the imbalance is likely greater in heterogametic females, and the proportion of introgressed ancestry is more variable on the Z chromosome. We also show that mapping traits polygenic on a single chromosome in backcrosses can generate spurious large-effect QTLs. This mirage is caused by statistical linkage among polygenes that inflates estimated effect sizes. By controlling for statistical linkage, most incompatibility QTLs in our hybrid crosses are consistent with a polygenic basis. Since the two genera are very distantly related, polygenic hybrid incompatibilities are likely common in butterflies.}, keywords = {Animals Female *Butterflies/genetics Hybridization, Genetic Models, Genetic Sex Chromosomes Haldane's rule Lepidoptera Qtl hybrid incompatibility polygenic trait}, ISSN = {1091-6490 (Electronic) 0027-8424 (Linking)}, DOI = {10.1073/pnas.2300959120}, url = {https://www.ncbi.nlm.nih.gov/pubmed/37856563}, year = {2023}, type = {Journal Article} } @article{RN145, author = {Yang, X. and Qi, Y. and Wang, C. and Zwang, T. J. and Rommelfanger, N. J. and Hong, G. and Lieber, C. M.}, title = {Laminin-coated electronic scaffolds with vascular topography for tracking and promoting the migration of brain cells after injury}, journal = {Nat Biomed Eng}, volume = {7}, number = {10}, pages = {1282-1292}, note = {Yang, Xiao Qi, Yue Wang, Chonghe Zwang, Theodore J Rommelfanger, Nicholas J Hong, Guosong Lieber, Charles M eng 1R21DA043985-01/U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA)/ 1DP1EB025835-01/U.S. Department of Health & Human Services | NIH | National Institute of Biomedical Imaging and Bioengineering (NIBIB)/ England 2023/10/10 Nat Biomed Eng. 2023 Oct;7(10):1282-1292. doi: 10.1038/s41551-023-01101-6. Epub 2023 Oct 9.}, abstract = {In the adult brain, neural stem cells are largely restricted into spatially discrete neurogenic niches, and hence areas of neuron loss during neurodegenerative disease or following a stroke or traumatic brain injury do not typically repopulate spontaneously. Moreover, understanding neural activity accompanying the neural repair process is hindered by a lack of minimally invasive devices for the chronic measurement of the electrophysiological dynamics in damaged brain tissue. Here we show that 32 individually addressable platinum microelectrodes integrated into laminin-coated branched polymer scaffolds stereotaxically injected to span a hydrogel-filled cortical lesion and deeper regions in the brains of mice promote neural regeneration while allowing for the tracking of migrating host brain cells into the lesion. Chronic measurements of single-unit activity and neural-circuit analyses revealed the establishment of spiking activity in new neurons in the lesion and their functional connections with neurons deeper in the brain. Electronic implants mimicking the topographical and surface properties of brain vasculature may aid the stimulation and tracking of neural-circuit restoration following injury.}, ISSN = {2157-846X (Electronic) 2157-846X (Linking)}, DOI = {10.1038/s41551-023-01101-6}, url = {https://www.ncbi.nlm.nih.gov/pubmed/37814007}, year = {2023}, type = {Journal Article} }