[Research Articles] GLP-1 receptor agonists synergize with DYRK1A inhibitors to potentiate functional human {beta} cell regeneration
Glucagon-like peptide-1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 inhibitors are widely prescribed diabetes drugs due to their ability to stimulate insulin secretion from remaining β cells and to reduce caloric intake. Unfortunately, they fail to increase human β cell proliferation. Small-molecule inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) are able to induce adult human β cell proliferation, but rates are modest (~2%), and their specificity to β cells is limited. Here, we provide evidence that combining any member of the GLP1R agonist class with any member of the DYR...
Source: Science Translational Medicine - February 12, 2020 Category: Biomedical Science Authors: Ackeifi, C., Wang, P., Karakose, E., Manning Fox, J. E., Gonzalez, B. J., Liu, H., Wilson, J., Swartz, E., Berrouet, C., Li, Y., Kumar, K., MacDonald, P. E., Sanchez, R., Thorens, B., DeVita, R., Homann, D., Egli, D., Scott, D. K., Garcia-Ocana, A., Stewa Tags: Research Articles Source Type: research

[Editors' Choice] A spring-like renewal in the lungs
Epithelial cells with a low mutation burden expand after smoking cessation. (Source: Science Translational Medicine)
Source: Science Translational Medicine - February 12, 2020 Category: Biomedical Science Authors: Naxerova, K. Tags: Editors ' Choice Source Type: research

[Editors' Choice] Maybe not an overreaction
A mathematical simulation of coronavirus COVID-19 estimated the number of infections to be far worse than reported. (Source: Science Translational Medicine)
Source: Science Translational Medicine - February 12, 2020 Category: Biomedical Science Authors: Han, L.-H. Tags: Editors ' Choice Source Type: research

[Research Articles] Elevated plasma {beta}-hydroxybutyrate predicts adverse outcomes and disease progression in patients with arrhythmogenic cardiomyopathy
Sudden death could be the first symptom of patients with arrhythmogenic cardiomyopathy (AC), a disease for which clinical indicators predicting adverse progression remain lacking. Recent findings suggest that metabolic dysregulation is present in AC. We performed this study to identify metabolic indicators that predicted major adverse cardiac events (MACEs) in patients with AC and their relatives. Comparing explanted hearts from patients with AC and healthy donors, we identified deregulated metabolic pathways using quantitative proteomics. Right ventricles (RVs) from patients with AC displayed elevated ketone metabolic enz...
Source: Science Translational Medicine - February 12, 2020 Category: Biomedical Science Authors: Song, J.-P., Chen, L., Chen, X., Ren, J., Zhang, N.-N., Tirasawasdichai, T., Hu, Z.-L., Hua, W., Hu, Y.-R., Tang, H.-R., Chen, H.-S. V., Hu, S.-S. Tags: Research Articles Source Type: research

[Focus] Two drugs converged in a pancreatic {beta} cell
Combining a DYRK1A inhibitor and GLP-1 receptor agonist boosts human pancreatic β cell proliferation and glucose homeostasis in vivo (Ackeifi et al., this issue). (Source: Science Translational Medicine)
Source: Science Translational Medicine - February 12, 2020 Category: Biomedical Science Authors: Scavuzzo, M. A., Borowiak, M. Tags: Focus Source Type: research

[Research Articles] Mannose receptor (CD206) activation in tumor-associated macrophages enhances adaptive and innate antitumor immune responses
Solid tumors elicit a detectable immune response including the infiltration of tumor-associated macrophages (TAMs). Unfortunately, this immune response is co-opted into contributing toward tumor growth instead of preventing its progression. We seek to reestablish an antitumor immune response by selectively targeting surface receptors and endogenous signaling processes of the macrophage subtypes driving cancer progression. RP-182 is a synthetic 10-mer amphipathic analog of host defense peptides that selectively induces a conformational switch of the mannose receptor CD206 expressed on TAMs displaying an M2-like phenotype. R...
Source: Science Translational Medicine - February 12, 2020 Category: Biomedical Science Authors: Jaynes, J. M., Sable, R., Ronzetti, M., Bautista, W., Knotts, Z., Abisoye-Ogunniyan, A., Li, D., Calvo, R., Dashnyam, M., Singh, A., Guerin, T., White, J., Ravichandran, S., Kumar, P., Talsania, K., Chen, V., Ghebremedhin, A., Karanam, B., Bin Salam, A., Tags: Research Articles Source Type: research

[Research Articles] JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function
Janus kinase (JAK)–mediated cytokine signaling has emerged as an important therapeutic target for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). Accordingly, JAK inhibitors compose a new class of drugs, among which tofacitinib and baricitinib have been approved for the treatment of RA. Periarticular bone erosions contribute considerably to the pathogenesis of RA. However, although the immunomodulatory aspect of JAK inhibition (JAKi) is well defined, the current knowledge of how JAKi influences bone homeostasis is limited. Here, we assessed the effects of the JAK inhibitors tofacitinib and b...
Source: Science Translational Medicine - February 12, 2020 Category: Biomedical Science Authors: Adam, S., Simon, N., Steffen, U., Andes, F. T., Scholtysek, C., Müller, D. I. H., Weidner, D., Andreev, D., Kleyer, A., Culemann, S., Hahn, M., Schett, G., Krönke, G., Frey, S., Hueber, A. J. Tags: Research Articles Source Type: research

[Research Articles] Bilirubin enhances the activity of ASIC channels to exacerbate neurotoxicity in neonatal hyperbilirubinemia in mice
In this study, we found that the concentration of the cell death marker, lactate dehydrogenase (LDH) in cerebrospinal fluid (CSF), is elevated in infants with both hyperbilirubinemia and acidosis and showed stronger correlation with the severity of acidosis rather than increased bilirubin concentration. In mouse neonatal neurons, bilirubin exhibits limited toxicity but robustly potentiates the activity of acid-sensing ion channels (ASICs), resulting in increases in intracellular Ca2+ concentration, spike firings, and cell death. Furthermore, neonatal conditioning with concurrent hyperbilirubinemia and hypoxia-induced acido...
Source: Science Translational Medicine - February 12, 2020 Category: Biomedical Science Authors: Lai, K., Song, X.-L., Shi, H.-S., Qi, X., Li, C.-Y., Fang, J., Wang, F., Maximyuk, O., Krishtal, O., Xu, T.-L., Li, X.-Y., Ni, K., Li, W.-P., Shi, H.-B., Wang, L.-Y., Yin, S.-K. Tags: Research Articles Source Type: research

[Editors' Choice] The tick tock of toxicity
A cell-intrinsic circadian program diminishes neutrophil toxicity to protect organs from excessive inflammation. (Source: Science Translational Medicine)
Source: Science Translational Medicine - February 12, 2020 Category: Biomedical Science Authors: Hurley, J. M. Tags: Editors ' Choice Source Type: research

[Research Articles] Engineered probiotics for local tumor delivery of checkpoint blockade nanobodies
Checkpoint inhibitors have revolutionized cancer therapy but only work in a subset of patients and can lead to a multitude of toxicities, suggesting the need for more targeted delivery systems. Because of their preferential colonization of tumors, microbes are a natural platform for the local delivery of cancer therapeutics. Here, we engineer a probiotic bacteria system for the controlled production and intratumoral release of nanobodies targeting programmed cell death–ligand 1 (PD-L1) and cytotoxic T lymphocyte–associated protein-4 (CTLA-4) using a stabilized lysing release mechanism. We used computational mod...
Source: Science Translational Medicine - February 12, 2020 Category: Biomedical Science Authors: Gurbatri, C. R., Lia, I., Vincent, R., Coker, C., Castro, S., Treuting, P. M., Hinchliffe, T. E., Arpaia, N., Danino, T. Tags: Research Articles Source Type: research

[Research Resources] Immune system development varies according to age, location, and anemia in African children
Children from low- and middle-income countries, where there is a high incidence of infectious disease, have the greatest need for the protection afforded by vaccination, but vaccines often show reduced efficacy in these populations. An improved understanding of how age, infection, nutrition, and genetics influence immune ontogeny and function is key to informing vaccine design for this at-risk population. We sought to identify factors that shape immune development in children under 5 years of age from Tanzania and Mozambique by detailed immunophenotyping of longitudinal blood samples collected during the RTS,S malaria vacc...
Source: Science Translational Medicine - February 5, 2020 Category: Biomedical Science Authors: Hill, D. L., Carr, E. J., Rutishauser, T., Moncunill, G., Campo, J. J., Innocentin, S., Mpina, M., Nhabomba, A., Tumbo, A., Jairoce, C., Moll, H. A., van Zelm, M. C., Dobano, C., Daubenberger, C., Linterman, M. A. Tags: Research Resources Source Type: research

[Editors' Choice] Lets switch on AAV!
RNA switches expand the reach of AAV vectors. (Source: Science Translational Medicine)
Source: Science Translational Medicine - February 5, 2020 Category: Biomedical Science Authors: Ronzitti, G. Tags: Editors ' Choice Source Type: research

[Editors' Choice] Undressing drug reactions, one cell at a time
Single-cell transcriptomic analysis allowed successful treatment of a patient with refractory severe drug-induced hypersensitivity syndrome. (Source: Science Translational Medicine)
Source: Science Translational Medicine - February 5, 2020 Category: Biomedical Science Authors: Kulkarni, R. P. Tags: Editors ' Choice Source Type: research

[Editors' Choice] Livening up pertussis vaccine development
Vaccination with a Bordetella pertussis live attenuated vaccine induces a beneficial TH1 cell bias and broadly targeting functional antibodies in humans. (Source: Science Translational Medicine)
Source: Science Translational Medicine - February 5, 2020 Category: Biomedical Science Authors: Boyle, M. Tags: Editors ' Choice Source Type: research

[Research Articles] The prolactin receptor long isoform regulates nociceptor sensitization and opioid-induced hyperalgesia selectively in females
Pain is more prevalent in women for reasons that remain unclear. We have identified a mechanism of injury-free nociceptor sensitization and opioid-induced hyperalgesia (OIH) promoted by prolactin (PRL) in females. PRL signals through mutually inhibitory long (PRLR-L) and short (PRLR-S) receptor isoforms, and PRLR-S activation induces neuronal excitability. PRL and PRLR expression were higher in females. CRISPR-mediated editing of PRLR-L promoted nociceptor sensitization and allodynia in naìˆve, uninjured female mice that depended on circulating PRL. Opioids, but not trauma-induced nerve injury, decreased PRLR-L promoting ...
Source: Science Translational Medicine - February 5, 2020 Category: Biomedical Science Authors: Chen, Y., Moutal, A., Navratilova, E., Kopruszinski, C., Yue, X., Ikegami, M., Chow, M., Kanazawa, I., Bellampalli, S. S., Xie, J., Patwardhan, A., Rice, K., Fields, H., Akopian, A., Neugebauer, V., Dodick, D., Khanna, R., Porreca, F. Tags: Research Articles Source Type: research

[Research Articles] Osteoclast-mediated bone resorption is controlled by a compensatory network of secreted and membrane-tethered metalloproteinases
Osteoclasts actively remodel both the mineral and proteinaceous components of bone during normal growth and development as well as pathologic states ranging from osteoporosis to bone metastasis. The cysteine proteinase cathepsin K confers osteoclasts with potent type I collagenolytic activity; however, cathepsin K–null mice, as well as cathepsin K–mutant humans, continue to remodel bone and degrade collagen by as-yet-undefined effectors. Here, we identify a cathepsin K–independent collagenolytic system in osteoclasts that is composed of a functionally redundant network of the secreted matrix metalloprotei...
Source: Science Translational Medicine - February 5, 2020 Category: Biomedical Science Authors: Zhu, L., Tang, Y., Li, X.-Y., Keller, E. T., Yang, J., Cho, J.-S., Feinberg, T. Y., Weiss, S. J. Tags: Research Articles Source Type: research

[Research Articles] APOE genotype regulates pathology and disease progression in synucleinopathy
In this study, we generated A53T αSyn transgenic mice (A53T) on Apoe knockout (A53T/EKO) or human APOE knockin backgrounds (A53T/E2, E3, and E4). At 12 months of age, A53T/E4 mice accumulated higher amounts of brainstem detergent-insoluble phosphorylated αSyn compared to A53T/EKO and A53T/E3; detergent-insoluble αSyn in A53T/E2 mice was undetectable. By immunohistochemistry, A53T/E4 mice displayed a higher burden of phosphorylated αSyn and reactive gliosis compared to A53T/E2 mice. A53T/E2 mice exhibited increased survival and improved motor performance compared to other APOE genotypes. In a complem...
Source: Science Translational Medicine - February 5, 2020 Category: Biomedical Science Authors: Davis, A. A., Inman, C. E., Wargel, Z. M., Dube, U., Freeberg, B. M., Galluppi, A., Haines, J. N., Dhavale, D. D., Miller, R., Choudhury, F. A., Sullivan, P. M., Cruchaga, C., Perlmutter, J. S., Ulrich, J. D., Benitez, B. A., Kotzbauer, P. T., Holtzman, D Tags: Research Articles Source Type: research

[Research Articles] APOE4 exacerbates {alpha}-synuclein pathology and related toxicity independent of amyloid
The apolipoprotein E (APOE) 4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease mainly by driving amyloid-β pathology. Recently, APOE4 has also been found to be a genetic risk factor for Lewy body dementia (LBD), which includes dementia with Lewy bodies and Parkinson’s disease dementia. How APOE4 drives risk of LBD and whether it has a direct effect on α-synuclein pathology are not clear. Here, we generated a mouse model of synucleinopathy using an adeno-associated virus gene delivery of α-synuclein in human APOE-targeted replacement mice expressing APOE2, APOE3, or...
Source: Science Translational Medicine - February 5, 2020 Category: Biomedical Science Authors: Zhao, N., Attrebi, O. N., Ren, Y., Qiao, W., Sonustun, B., Martens, Y. A., Meneses, A. D., Li, F., Shue, F., Zheng, J., Van Ingelgom, A. J., Davis, M. D., Kurti, A., Knight, J. A., Linares, C., Chen, Y., Delenclos, M., Liu, C.-C., Fryer, J. D., Asmann, Y. Tags: Research Articles Source Type: research

[Research Articles] Distinct immune phenotypes in infants developing asthma during childhood
Early exposure to environmental triggers may elicit trajectories to chronic inflammatory disease through deregulated immune responses. To address relations between early immune competence and development of childhood asthma, we performed functional immune profiling of 186 parameters in blood of 541 18-month-old infants and examined links between their response phenotype and development of transient or persistent disease at 6 years of age. An abnormal neutrophil-linked antiviral response was associated with increased risk of transient asthma. Children who exhibited persistent asthma at year 6 showed enhanced interleukin-5 (...
Source: Science Translational Medicine - February 5, 2020 Category: Biomedical Science Authors: Thysen, A. H., Waage, J., Larsen, J. M., Rasmussen, M. A., Stokholm, J., Chawes, B., Fink, N. R., Pedersen, T. M., Wolsk, H., Thorsteinsdottir, S., Litman, T., Renz, H., Bonnelykke, K., Bisgaard, H., Brix, S. Tags: Research Articles Source Type: research

[Research Articles] Mixed chimerism and acceptance of kidney transplants after immunosuppressive drug withdrawal
In conclusion, persistent mixed chimerism established in fully HLA- or haplotype-matched patients allowed for complete or partial IS drug withdrawal without rejection. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 29, 2020 Category: Biomedical Science Authors: Busque, S., Scandling, J. D., Lowsky, R., Shizuru, J., Jensen, K., Waters, J., Wu, H.-H., Sheehan, K., Shori, A., Choi, O., Pham, T., Fernandez Vina, M. A., Hoppe, R., Tamaresis, J., Lavori, P., Engleman, E. G., Meyer, E., Strober, S. Tags: Research Articles Source Type: research

[Research Articles] A dual apolipoprotein C-II mimetic-apolipoprotein C-III antagonist peptide lowers plasma triglycerides
We describe a strategy for lowering triglycerides (TGs) with an apolipoprotein C-II (apoC-II) mimetic peptide called D6PV that activates lipoprotein lipase (LPL), the main plasma TG-hydrolyzing enzyme, and antagonizes the TG-raising effect of apoC-III. The design of D6PV was motivated by a combination of all-atom molecular dynamics simulation of apoC-II on the Anton 2 supercomputer, structural prediction programs, and biophysical techniques. Efficacy of D6PV was assessed ex vivo in human HTG plasma and was found to be more potent than full-length apoC-II in activating LPL. D6PV markedly lowered TG by more than 80% within a...
Source: Science Translational Medicine - January 29, 2020 Category: Biomedical Science Authors: Wolska, A., Lo, L., Sviridov, D. O., Pourmousa, M., Pryor, M., Ghosh, S. S., Kakkar, R., Davidson, M., Wilson, S., Pastor, R. W., Goldberg, I. J., Basu, D., Drake, S. K., Cougnoux, A., Wu, M. J., Neher, S. B., Freeman, L. A., Tang, J., Amar, M., Devalaraj Tags: Research Articles Source Type: research

[Research Articles] Different human resting memory CD4+ T cell subsets show similar low inducibility of latent HIV-1 proviruses
The latent reservoir of HIV-1 in resting CD4+ T cells is a major barrier to cure. It is unclear whether the latent reservoir resides principally in particular subsets of CD4+ T cells, a finding that would have implications for understanding its stability and developing curative therapies. Recent work has shown that proliferation of HIV-1–infected CD4+ T cells is a major factor in the generation and persistence of the latent reservoir and that latently infected T cells that have clonally expanded in vivo can proliferate in vitro without producing virions. In certain CD4+ memory T cell subsets, the provirus may be in a...
Source: Science Translational Medicine - January 29, 2020 Category: Biomedical Science Authors: Kwon, K. J., Timmons, A. E., Sengupta, S., Simonetti, F. R., Zhang, H., Hoh, R., Deeks, S. G., Siliciano, J. D., Siliciano, R. F. Tags: Research Articles Source Type: research

[Research Articles] Preclinical efficacy of the GPER-selective agonist G-1 in mouse models of obesity and diabetes
In conclusion, this work demonstrates that GPER-selective agonism is a viable therapeutic approach against obesity, diabetes, and associated metabolic abnormalities in multiple preclinical male and female models. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 29, 2020 Category: Biomedical Science Authors: Sharma, G., Hu, C., Staquicini, D. I., Brigman, J. L., Liu, M., Mauvais-Jarvis, F., Pasqualini, R., Arap, W., Arterburn, J. B., Hathaway, H. J., Prossnitz, E. R. Tags: Research Articles Source Type: research

[Research Articles] Mapping global variation in dengue transmission intensity
Intervention planning for dengue requires reliable estimates of dengue transmission intensity. However, current maps of dengue risk provide estimates of disease burden or the boundaries of endemicity rather than transmission intensity. We therefore developed a global high-resolution map of dengue transmission intensity by fitting environmentally driven geospatial models to geolocated force of infection estimates derived from cross-sectional serological surveys and routine case surveillance data. We assessed the impact of interventions on dengue transmission and disease using Wolbachia-infected mosquitoes and the Sanofi-Pas...
Source: Science Translational Medicine - January 29, 2020 Category: Biomedical Science Authors: Cattarino, L., Rodriguez-Barraquer, I., Imai, N., Cummings, D. A. T., Ferguson, N. M. Tags: Research Articles Source Type: research

[Editors' Choice] Immunomodulation in the front, bone-binding in the back
Zoledronic acid–tethered nanoparticles bind remodeling bone, polarize macrophages, and reduce osteoclasts to prevent breast cancer–induced osteolysis. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 29, 2020 Category: Biomedical Science Authors: Kerr, B. A. Tags: Editors ' Choice Source Type: research

[Editors' Choice] Unfolding the mystery of UPR in astrocytes
Activation of the unfolded protein response in astrocytes leads to a distinct reactive state detrimental to neuronal health in prion disease. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 29, 2020 Category: Biomedical Science Authors: Gallardo, G. Tags: Editors ' Choice Source Type: research

[Editors' Choice] Airway macrophages reveal their origins
Airway macrophages are derived from recipient circulating monocytes after transplant. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 29, 2020 Category: Biomedical Science Authors: Dakin, S. G. Tags: Editors ' Choice Source Type: research

[Research Articles] Immune correlates of tuberculosis disease and risk translate across species
In this study, we have provided an in-depth identification of the conserved and diversified gene/immune pathways in TB models of nonhuman primate and diversity outbred mouse and human TB. Our results show that prominent differentially expressed genes/pathways induced during TB disease progression are conserved in genetically diverse mice, macaques, and humans. In addition, using gene-deficient inbred mouse models, we have addressed the functional role of individual genes comprising the gene signature of disease progression seen in humans with Mtb infection. We show that genes representing specific immune pathways can be pr...
Source: Science Translational Medicine - January 29, 2020 Category: Biomedical Science Authors: Ahmed, M., Thirunavukkarasu, S., Rosa, B. A., Thomas, K. A., Das, S., Rangel-Moreno, J., Lu, L., Mehra, S., Mbandi, S. K., Thackray, L. B., Diamond, M. S., Murphy, K. M., Means, T., Martin, J., Kaushal, D., Scriba, T. J., Mitreva, M., Khader, S. A. Tags: Research Articles Source Type: research

[Research Articles] Long-gap peripheral nerve repair through sustained release of a neurotrophic factor in nonhuman primates
This study demonstrates the efficacious bridging of a long peripheral nerve gap in a nonhuman primate model using an acellular, biodegradable nerve conduit. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 22, 2020 Category: Biomedical Science Authors: Fadia, N. B., Bliley, J. M., DiBernardo, G. A., Crammond, D. J., Schilling, B. K., Sivak, W. N., Spiess, A. M., Washington, K. M., Waldner, M., Liao, H.-T., James, I. B., Minteer, D. M., Tompkins-Rhoades, C., Cottrill, A. R., Kim, D.-Y., Schweizer, R., Bo Tags: Research Articles Source Type: research

[Research Articles] PI4KIII{beta} is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma
Heightened secretion of protumorigenic effector proteins is a feature of malignant cells. Yet, the molecular underpinnings and therapeutic implications of this feature remain unclear. Here, we identify a chromosome 1q region that is frequently amplified in diverse cancer types and encodes multiple regulators of secretory vesicle biogenesis and trafficking, including the Golgi-dedicated enzyme phosphatidylinositol (PI)-4-kinase IIIβ (PI4KIIIβ). Molecular, biochemical, and cell biological studies show that PI4KIIIβ-derived PI-4-phosphate (PI4P) synthesis enhances secretion and accelerates lung adenocarcinoma p...
Source: Science Translational Medicine - January 22, 2020 Category: Biomedical Science Authors: Tan, X., Banerjee, P., Pham, E. A., Rutaganira, F. U. N., Basu, K., Bota-Rabassedas, N., Guo, H.-F., Grzeskowiak, C. L., Liu, X., Yu, J., Shi, L., Peng, D. H., Rodriguez, B. L., Zhang, J., Zheng, V., Duose, D. Y., Solis, L. M., Mino, B., Raso, M. G., Behr Tags: Research Articles Source Type: research

[Editors' Choice] Angling for a bug-inspired method of coating therapeutics onto microneedles
Mimicking the microstructures on the surface of European true bugs may help optimize loading of therapeutics onto transdermal microneedle patches. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 22, 2020 Category: Biomedical Science Authors: OCearbhaill, E. Tags: Editors ' Choice Source Type: research

[Editors' Choice] Neurodevelopment and risk for ADHD and depression
Childhood brain connectivity predicts psychiatric difficulties four years later. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 22, 2020 Category: Biomedical Science Authors: Gee, D. G. Tags: Editors ' Choice Source Type: research

[Editors' Choice] Hitting a double to treat cancer
Simultaneous targeting of polyamine and methionine pathways may be a promising strategy to treat prostate cancer. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 22, 2020 Category: Biomedical Science Authors: El-Kenawi, A. Tags: Editors ' Choice Source Type: research

[Research Articles] Pan-viral protection against arboviruses by activating skin macrophages at the inoculation site
Arthropod-borne viruses (arboviruses) are important human pathogens for which there are no specific antiviral medicines. The abundance of genetically distinct arbovirus species, coupled with the unpredictable nature of their outbreaks, has made the development of virus-specific treatments challenging. Instead, we have defined and targeted a key aspect of the host innate immune response to virus at the arthropod bite that is common to all arbovirus infections, potentially circumventing the need for virus-specific therapies. Using mouse models and human skin explants, we identify innate immune responses by dermal macrophages...
Source: Science Translational Medicine - January 22, 2020 Category: Biomedical Science Authors: Bryden, S. R., Pingen, M., Lefteri, D. A., Miltenburg, J., Delang, L., Jacobs, S., Abdelnabi, R., Neyts, J., Pondeville, E., Major, J., Müller, M., Khalid, H., Tuplin, A., Varjak, M., Merits, A., Edgar, J., Graham, G. J., Shams, K., McKimmie, C. S Tags: Research Articles Source Type: research

[Research Articles] The IDH-TAU-EGFR triad defines the neovascular landscape of diffuse gliomas
Gliomas that express the mutated isoforms of isocitrate dehydrogenase 1/2 (IDH1/2) have better prognosis than wild-type (wt) IDH1/2 gliomas. However, how these mutant (mut) proteins affect the tumor microenvironment is still a pending question. Here, we describe that the transcription of microtubule-associated protein TAU (MAPT), a gene that has been classically associated with neurodegenerative diseases, is epigenetically controlled by the balance between wt and mut IDH1/2 in mouse and human gliomas. In IDH1/2 mut tumors, we found high expression of TAU that decreased with tumor progression. Furthermore, MAPT was almost a...
Source: Science Translational Medicine - January 22, 2020 Category: Biomedical Science Authors: Gargini, R., Segura-Collar, B., Herranz, B., Garcia-Escudero, V., Romero-Bravo, A., Nunez, F. J., Garcia-Perez, D., Gutierrez-Guaman, J., Ayuso-Sacido, A., Seoane, J., Perez-Nunez, A., Sepulveda-Sanchez, J. M., Hernandez-Lain, A., Castro, M. G., Garcia-Es Tags: Research Articles Source Type: research

[Focus] Deep phenotyping during pregnancy for predictive and preventive medicine
Deep phenotyping during pregnancy offers an opportunity to define the antecedents of lifelong health and wellness, and to improve pregnancy outcomes. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 22, 2020 Category: Biomedical Science Authors: Paquette, A. G., Hood, L., Price, N. D., Sadovsky, Y. Tags: Focus Source Type: research

[Research Articles] Gene therapy delivering a paraoxonase 1 variant offers long-term prophylactic protection against nerve agents in mice
Chemical warfare nerve agents are organophosphorus chemical compounds that induce cholinergic crisis, leaving little or no time for medical intervention to prevent death. The current chemical treatment regimen may prevent death but does not prevent postexposure complications such as brain damage and permanent behavioral abnormalities. In the present study, we have demonstrated an adeno-associated virus 8 (AAV8)–mediated paraoxonase 1 variant IF-11 (PON1-IF11) gene therapy that offers asymptomatic prophylactic protection to mice against multiple lethal doses of G-type chemical warfare nerve agents, namely, tabun, sari...
Source: Science Translational Medicine - January 22, 2020 Category: Biomedical Science Authors: Betapudi, V., Goswami, R., Silayeva, L., Doctor, D. M., Chilukuri, N. Tags: Research Articles Source Type: research

[Research Articles] Stromal cell protein kinase C-{beta} inhibition enhances chemosensitivity in B cell malignancies and overcomes drug resistance
Overcoming drug resistance remains a key challenge to cure patients with acute and chronic B cell malignancies. Here, we describe a stromal cell–autonomous signaling pathway, which contributes to drug resistance of malignant B cells. We show that protein kinase C (PKC)–β–dependent signals from bone marrow–derived stromal cells markedly decrease the efficacy of cytotoxic therapies. Conversely, small-molecule PKC-β inhibitors antagonize prosurvival signals from stromal cells and sensitize tumor cells to targeted and nontargeted chemotherapy, resulting in enhanced cytotoxicity and prolonged s...
Source: Science Translational Medicine - January 15, 2020 Category: Biomedical Science Authors: Park, E., Chen, J., Moore, A., Mangolini, M., Santoro, A., Boyd, J. R., Schjerven, H., Ecker, V., Buchner, M., Williamson, J. C., Lehner, P. J., Gasparoli, L., Williams, O., Bloehdorn, J., Stilgenbauer, S., Leitges, M., Egle, A., Schmidt-Supprian, M., Fri Tags: Research Articles Source Type: research

[Research Articles] Intratumoral expression of IL-7 and IL-12 using an oncolytic virus increases systemic sensitivity to immune checkpoint blockade
The immune status of the tumor microenvironment is a key indicator in determining the antitumor effectiveness of immunotherapies. Data support the role of activation and expansion of tumor-infiltrating lymphocytes (TILs) in increasing the benefit of immunotherapies in patients with solid tumors. We found that intratumoral injection of a tumor-selective oncolytic vaccinia virus encoding interleukin-7 (IL-7) and IL-12 into tumor-bearing immunocompetent mice activated the inflammatory immune status of previously poorly immunogenic tumors and resulted in complete tumor regression, even in distant tumor deposits. Mice achieving...
Source: Science Translational Medicine - January 15, 2020 Category: Biomedical Science Authors: Nakao, S., Arai, Y., Tasaki, M., Yamashita, M., Murakami, R., Kawase, T., Amino, N., Nakatake, M., Kurosaki, H., Mori, M., Takeuchi, M., Nakamura, T. Tags: Research Articles Source Type: research

[Research Articles] {beta}-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3{beta}/tau cascade
The brain noradrenergic system is critical for normal cognition and is affected at early stages in Alzheimer’s disease (AD). Here, we reveal a previously unappreciated direct role of norepinephrine signaling in connecting β-amyloid (Aβ) and tau, two key pathological components of AD pathogenesis. Our results show that Aβ oligomers bind to an allosteric site on α2A adrenergic receptor (α2AAR) to redirect norepinephrine-elicited signaling to glycogen synthase kinase 3β (GSK3β) activation and tau hyperphosphorylation. This norepinephrine-dependent mechanism sensitizes pathological GS...
Source: Science Translational Medicine - January 15, 2020 Category: Biomedical Science Authors: Zhang, F., Gannon, M., Chen, Y., Yan, S., Zhang, S., Feng, W., Tao, J., Sha, B., Liu, Z., Saito, T., Saido, T., Keene, C. D., Jiao, K., Roberson, E. D., Xu, H., Wang, Q. Tags: Research Articles Source Type: research

[Research Articles] Engraftment of rare, pathogenic donor hematopoietic mutations in unrelated hematopoietic stem cell transplantation
Clonal hematopoiesis is associated with various age-related morbidities. Error-corrected sequencing (ECS) of human blood samples, with a limit of detection of ≥0.0001, has demonstrated that nearly every healthy individual>50 years old harbors rare hematopoietic clones below the detection limit of standard high-throughput sequencing. If these rare mutations confer survival or proliferation advantages, then the clone(s) could expand after a selective pressure such as chemotherapy, radiotherapy, or chronic immunosuppression. Given these observations and the lack of quantitative data regarding clonal hematopoiesis in ado...
Source: Science Translational Medicine - January 15, 2020 Category: Biomedical Science Authors: Wong, W. H., Bhatt, S., Trinkaus, K., Pusic, I., Elliott, K., Mahajan, N., Wan, F., Switzer, G. E., Confer, D. L., DiPersio, J., Pulsipher, M. A., Shah, N. N., Sees, J., Bystry, A., Blundell, J. R., Shaw, B. E., Druley, T. E. Tags: Research Articles Source Type: research

[Research Articles] Human umbilical cord perivascular cells improve human pancreatic islet transplant function by increasing vascularization
Islet transplantation is an efficacious therapy for type 1 diabetes; however, islets from multiple donor pancreata are required, and a gradual attrition in transplant function is seen. Here, we manufactured human umbilical cord perivascular mesenchymal stromal cells (HUCPVCs) to Good Manufacturing Practice (GMP) standards. HUCPVCs showed a stable phenotype while undergoing rapid ex vivo expansion at passage 2 (p2) to passage 4 (p4) and produced proregenerative factors, strongly suppressing T cell responses in the resting state and in response to inflammation. Transplanting an islet equivalent (IEQ):HUCPVC ratio of 1:30 und...
Source: Science Translational Medicine - January 15, 2020 Category: Biomedical Science Authors: Forbes, S., Bond, A. R., Thirlwell, K. L., Burgoyne, P., Samuel, K., Noble, J., Borthwick, G., Colligan, D., McGowan, N. W. A., Lewis, P. S., Fraser, A. R., Mountford, J. C., Carter, R. N., Morton, N. M., Turner, M. L., Graham, G. J., Campbell, J. D. M. Tags: Research Articles Source Type: research

[Editors' Choice] Organoid optimization: Engineering a better cell therapy to treat type 1 diabetes
Islet organoids reaggregated in endothelialized collagen constructs improve engraftment and function in the subcutaneous space in diabetic mice. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 15, 2020 Category: Biomedical Science Authors: Weaver, J. D. Tags: Editors ' Choice Source Type: research

[Editors' Choice] The "cancer flu shot"?
Direct injection of an influenza vaccine into tumors in mice increases immune infiltration and prolongs survival. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 15, 2020 Category: Biomedical Science Authors: Jeyasekharan, A. D. Tags: Editors ' Choice Source Type: research

[Editors' Choice] Weighing in on asthma
Immune activation and microbiota alterations are accentuated in obese asthmatics. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 15, 2020 Category: Biomedical Science Authors: Brunner, P. M. Tags: Editors ' Choice Source Type: research

[Research Articles] Cerebellar oscillations driven by synaptic pruning deficits of cerebellar climbing fibers contribute to tremor pathophysiology
Essential tremor (ET) is one of the most common movement disorders and the prototypical disorder for abnormal rhythmic movements. However, the pathophysiology of tremor generation in ET remains unclear. Here, we used autoptic cerebral tissue from patients with ET, clinical data, and mouse models to report that synaptic pruning deficits of climbing fiber (CF)–to–Purkinje cell (PC) synapses, which are related to glutamate receptor delta 2 (GluR2) protein insufficiency, cause excessive cerebellar oscillations and might be responsible for tremor. The CF-PC synaptic pruning deficits were correlated with the reductio...
Source: Science Translational Medicine - January 15, 2020 Category: Biomedical Science Authors: Pan, M.-K., Li, Y.-S., Wong, S.-B., Ni, C.-L., Wang, Y.-M., Liu, W.-C., Lu, L.-Y., Lee, J.-C., Cortes, E. P., Vonsattel, J.-P. G., Sun, Q., Louis, E. D., Faust, P. L., Kuo, S.-H. Tags: Research Articles Source Type: research

[Errata] Erratum for the Research Article: " Reduced non-rapid eye movement sleep is associated with tau pathology in early Alzheimers disease " by B. P. Lucey, A. McCullough, E. C. Landsness, C. D. Toedebusch, J. S. McLeland, A. M. Zaza, A. M. Fagan, L. McCue, C. Xiong, J. C. Morris, T. L. S. Benzinger, D. M. Holtzman
(Source: Science Translational Medicine)
Source: Science Translational Medicine - January 8, 2020 Category: Biomedical Science Tags: Errata Source Type: research

[Research Articles] A class of costimulatory CD28-bispecific antibodies that enhance the antitumor activity of CD3-bispecific antibodies
T cell activation is initiated upon binding of the T cell receptor (TCR)/CD3 complex to peptide–major histocompatibility complexes ("signal 1"); activation is enhanced by engagement of a second "costimulatory" receptor, such as the CD28 receptor on T cells binding to its cognate ligand(s) on the target cell ("signal 2"). CD3-based bispecific antibodies act by replacing conventional signal 1, linking T cells to tumor cells by binding a tumor-specific antigen (TSA) with one arm of the bispecific and bridging to TCR/CD3 with the other. Although some of these so-called TSAxCD3 bispecifics ha...
Source: Science Translational Medicine - January 8, 2020 Category: Biomedical Science Authors: Skokos, D., Waite, J. C., Haber, L., Crawford, A., Hermann, A., Ullman, E., Slim, R., Godin, S., Ajithdoss, D., Ye, X., Wang, B., Wu, Q., Ramos, I., Pawashe, A., Canova, L., Vazzana, K., Ram, P., Herlihy, E., Ahmed, H., Oswald, E., Golubov, J., Poon, P., Tags: Research Articles Source Type: research

[Research Articles] HDAC inhibition improves cardiopulmonary function in a feline model of diastolic dysfunction
This study assessed the effects of histone deacetylase (HDAC) inhibition on cardiopulmonary structure, function, and metabolism in a large mammalian model of pressure overload recapitulating features of diastolic dysfunction common to human HFpEF. Male domestic short-hair felines (n = 31, aged 2 months) underwent a sham procedure (n = 10) or loose aortic banding (n = 21), resulting in slow-progressive pressure overload. Two months after banding, animals were treated daily with suberoylanilide hydroxamic acid (b + SAHA, 10 mg/kg, n = 8), a Food and Drug Administration–approved pan-HDAC inhibitor, or vehicle (b + veh, ...
Source: Science Translational Medicine - January 8, 2020 Category: Biomedical Science Authors: Wallner, M., Eaton, D. M., Berretta, R. M., Liesinger, L., Schittmayer, M., Gindlhuber, J., Wu, J., Jeong, M. Y., Lin, Y. H., Borghetti, G., Baker, S. T., Zhao, H., Pfleger, J., Blass, S., Rainer, P. P., von Lewinski, D., Bugger, H., Mohsin, S., Graier, W Tags: Research Articles Source Type: research

[Research Articles] Nucleoside-modified mRNA vaccination partially overcomes maternal antibody inhibition of de novo immune responses in mice
Maternal antibodies provide short-term protection to infants against many infections. However, they can inhibit de novo antibody responses in infants elicited by infections or vaccination, leading to increased long-term susceptibility to infectious diseases. Thus, there is a need to develop vaccines that are able to elicit protective immune responses in the presence of antigen-specific maternal antibodies. Here, we used a mouse model to demonstrate that influenza virus–specific maternal antibodies inhibited de novo antibody responses in mouse pups elicited by influenza virus infection or administration of conventiona...
Source: Science Translational Medicine - January 8, 2020 Category: Biomedical Science Authors: Willis, E., Pardi, N., Parkhouse, K., Mui, B. L., Tam, Y. K., Weissman, D., Hensley, S. E. Tags: Research Articles Source Type: research