[Viewpoint] Continuous health monitoring: An opportunity for precision health
Continuous health monitoring and integrated diagnostic devices, worn on the body and used in the home, will help to identify and prevent early manifestations of disease. However, challenges lie ahead in validating new health monitoring technologies and in optimizing data analytics to extract actionable conclusions from continuously obtained health data. (Source: Science Translational Medicine)
Source: Science Translational Medicine - June 9, 2021 Category: Biomedical Science Authors: Gambhir, S. S., Ge, T. J., Vermesh, O., Spitler, R., Gold, G. E. Tags: Viewpoint Source Type: research

[Research Articles] Therapeutic liver repopulation by transient acetaminophen selection of gene-modified hepatocytes
Gene therapy by integrating vectors is promising for monogenic liver diseases, especially in children where episomal vectors remain transient. However, reaching the therapeutic threshold with genome-integrating vectors is challenging. Therefore, we developed a method to expand hepatocytes bearing therapeutic transgenes. The common fever medicine acetaminophen becomes hepatotoxic via cytochrome p450 metabolism. Lentiviral vectors with transgenes linked in cis to a Cypor shRNA were administered to neonatal mice. Hepatocytes lacking the essential cofactor of Cyp enzymes, NADPH-cytochrome p450 reductase (Cypor), were selected ...
Source: Science Translational Medicine - June 9, 2021 Category: Biomedical Science Authors: Vonada, A., Tiyaboonchai, A., Nygaard, S., Posey, J., Peters, A. M., Winn, S. R., Cantore, A., Naldini, L., Harding, C. O., Grompe, M. Tags: Research Articles Source Type: research

[Research Articles] Plasmodium falciparum Pf77 and male development gene 1 as vaccine antigens that induce potent transmission-reducing antibodies
Malaria vaccines that disrupt the Plasmodium life cycle in mosquitoes and reduce parasite transmission in endemic areas are termed transmission-blocking vaccines (TBVs). Despite decades of research, there are only a few Plasmodium falciparum antigens that indisputably and reproducibly demonstrate transmission-blocking immunity. So far, only two TBV candidates have advanced to phase 1/2 clinical testing with limited success. By applying an unbiased transcriptomics-based approach, we have identified Pf77 and male development gene 1 (PfMDV-1) as two P. falciparum TBV antigens that, upon immunization, induced antibodies that c...
Source: Science Translational Medicine - June 9, 2021 Category: Biomedical Science Authors: Tripathi, A. K., Oakley, M. S., Verma, N., Mlambo, G., Zheng, H., Meredith, S. M., Essuman, E., Puri, A., Skelton, R. A., Takeda, K., Majam, V., Quakyi, I. A., Locke, E., Morin, M., Miura, K., Long, C. A., Kumar, S. Tags: Research Articles Source Type: research

[Research Articles] A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression
Nitrous oxide at 50% inhaled concentration has been shown to improve depressive symptoms in patients with treatment-resistant major depression (TRMD). Whether a lower concentration of 25% nitrous oxide provides similar efficacy and persistence of antidepressant effects while reducing the risk of adverse side effects is unknown. In this phase 2 clinical trial (NCT03283670), 24 patients with severe TRMD were randomly assigned in a crossover fashion to three treatments consisting of a single 1-hour inhalation with (i) 50% nitrous oxide, (ii) 25% nitrous oxide, or (iii) placebo (air/oxygen). The primary outcome was the change ...
Source: Science Translational Medicine - June 9, 2021 Category: Biomedical Science Authors: Nagele, P., Palanca, B. J., Gott, B., Brown, F., Barnes, L., Nguyen, T., Xiong, W., Salloum, N. C., Espejo, G. D., Lessov-Schlaggar, C. N., Jain, N., Cheng, W. W. L., Komen, H., Yee, B., Bolzenius, J. D., Janski, A., Gibbons, R., Zorumski, C. F., Conway, Tags: Research Articles Source Type: research

[Research Articles] High titers and low fucosylation of early human anti-SARS-CoV-2 IgG promote inflammation by alveolar macrophages
Patients diagnosed with coronavirus disease 2019 (COVID-19) become critically ill primarily around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early-phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein–specific immunoglobulin G (IgG) in serum of critically ill COVID-19 patients induces excessive inflammatory responses by human alveolar macrophages. We identified that this excessive inflammatory response is dependent on two antibody features that...
Source: Science Translational Medicine - June 2, 2021 Category: Biomedical Science Authors: Hoepel, W., Chen, H.-J., Geyer, C. E., Allahverdiyeva, S., Manz, X. D., de Taeye, S. W., Aman, J., Mes, L., Steenhuis, M., Griffith, G. R., Bonta, P. I., Brouwer, P. J. M., Caniels, T. G., van der Straten, K., Golebski, K., Jonkers, R. E., Larsen, M. D., Tags: Research Articles Source Type: research

[Research Articles] Rebalancing expression of HMGB1 redox isoforms to counteract muscular dystrophy
Muscular dystrophies (MDs) are a group of genetic diseases characterized by progressive muscle wasting associated to oxidative stress and persistent inflammation. It is essential to deepen our knowledge on the mechanism connecting these two processes because current treatments for MDs have limited efficacy and/or are associated with side effects. Here, we identified the alarmin high-mobility group box 1 (HMGB1) as a functional link between oxidative stress and inflammation in MDs. The oxidation of HMGB1 cysteines switches its extracellular activities from the orchestration of tissue regeneration to the exacerbation of infl...
Source: Science Translational Medicine - June 2, 2021 Category: Biomedical Science Authors: Careccia, G., Saclier, M., Tirone, M., Ruggieri, E., Principi, E., Raffaghello, L., Torchio, S., Recchia, D., Canepari, M., Gorzanelli, A., Ferrara, M., Castellani, P., Rubartelli, A., Rovere-Querini, P., Casalgrandi, M., Preti, A., Lorenzetti, I., Bruno, Tags: Research Articles Source Type: research

[Research Articles] COVID-19-related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters
We report evidence that the olfactory neuroepithelium is a major site of SARS-CoV2 infection with multiple cell types, including olfactory sensory neurons, support cells, and immune cells, becoming infected. SARS-CoV-2 replication in the olfactory neuroepithelium was associated with local inflammation. Furthermore, we showed that SARS-CoV-2 induced acute anosmia and ageusia in golden Syrian hamsters, lasting as long as the virus remained in the olfactory epithelium and the olfactory bulb. Last, olfactory mucosa sampling from patients showing long-term persistence of COVID-19–associated anosmia revealed the presence o...
Source: Science Translational Medicine - June 2, 2021 Category: Biomedical Science Authors: de Melo, G. D., Lazarini, F., Levallois, S., Hautefort, C., Michel, V., Larrous, F., Verillaud, B., Aparicio, C., Wagner, S., Gheusi, G., Kergoat, L., Kornobis, E., Donati, F., Cokelaer, T., Hervochon, R., Madec, Y., Roze, E., Salmon, D., Bourhy, H., Lecu Tags: Research Articles Source Type: research

[Research Articles] Cis P-tau underlies vascular contribution to cognitive impairment and dementia and can be effectively targeted by immunotherapy in mice
Compelling evidence supports vascular contributions to cognitive impairment and dementia (VCID) including Alzheimer’s disease (AD), but the underlying pathogenic mechanisms and treatments are not fully understood. Cis P-tau is an early driver of neurodegeneration resulting from traumatic brain injury, but its role in VCID remains unclear. Here, we found robust cis P-tau despite no tau tangles in patients with VCID and in mice modeling key aspects of clinical VCID, likely because of the inhibition of its isomerase Pin1 by DAPK1. Elimination of cis P-tau in VCID mice using cis-targeted immunotherapy, brain-specific Pin...
Source: Science Translational Medicine - June 2, 2021 Category: Biomedical Science Authors: Qiu, C., Albayram, O., Kondo, A., Wang, B., Kim, N., Arai, K., Tsai, C.-Y., Bassal, M. A., Herbert, M. K., Washida, K., Angeli, P., Kozono, S., Stucky, J. E., Baxley, S., Lin, Y.-M., Sun, Y., Rotenberg, A., Caldarone, B. J., Bigio, E. H., Chen, X., Tenen, Tags: Research Articles Source Type: research

[Research Articles] A nanofibrous encapsulation device for safe delivery of insulin-producing cells to treat type 1 diabetes
Transplantation of stem cell–derived β (SC-β) cells represents a promising therapy for type 1 diabetes (T1D). However, the delivery, maintenance, and retrieval of these cells remain a challenge. Here, we report the design of a safe and functional device composed of a highly porous, durable nanofibrous skin and an immunoprotective hydrogel core. The device consists of electrospun medical-grade thermoplastic silicone-polycarbonate-urethane and is soft but tough (~15 megapascal at a rupture strain of >2). Tuning the nanofiber size to less than ~500 nanometers prevented cell penetration while maintaining max...
Source: Science Translational Medicine - June 2, 2021 Category: Biomedical Science Authors: Wang, X., Maxwell, K. G., Wang, K., Bowers, D. T., Flanders, J. A., Liu, W., Wang, L.-H., Liu, Q., Liu, C., Naji, A., Wang, Y., Wang, B., Chen, J., Ernst, A. U., Melero-Martin, J. M., Millman, J. R., Ma, M. Tags: Research Articles Source Type: research

[Research Articles] First exposure to the pandemic H1N1 virus induced broadly neutralizing antibodies targeting hemagglutinin head epitopes
Broadly neutralizing antibodies are critical for protection against both drifted and shifted influenza viruses. Here, we reveal that first exposure to the 2009 pandemic H1N1 influenza virus recalls memory B cells that are specific to the conserved receptor-binding site (RBS) or lateral patch epitopes of the hemagglutinin (HA) head domain. Monoclonal antibodies (mAbs) generated against these epitopes are broadly neutralizing against H1N1 viruses spanning 40 years of viral evolution and provide potent protection in vivo. Lateral patch-targeting antibodies demonstrated near universal binding to H1 viruses, and RBS-binding ant...
Source: Science Translational Medicine - June 2, 2021 Category: Biomedical Science Authors: Guthmiller, J. J., Han, J., Li, L., Freyn, A. W., Liu, S. T. H., Stovicek, O., Stamper, C. T., Dugan, H. L., Tepora, M. E., Utset, H. A., Bitar, D. J., Hamel, N. J., Changrob, S., Zheng, N.-Y., Huang, M., Krammer, F., Nachbagauer, R., Palese, P., Ward, A. Tags: Research Articles Source Type: research

[Research Articles] The brain penetrant PPAR{gamma} agonist leriglitazone restores multiple altered pathways in models of X-linked adrenoleukodystrophy
X-linked adrenoleukodystrophy (X-ALD), a potentially fatal neurometabolic disorder with no effective pharmacological treatment, is characterized by clinical manifestations ranging from progressive spinal cord axonopathy [adrenomyeloneuropathy (AMN)] to severe demyelination and neuroinflammation (cerebral ALD-cALD), for which molecular mechanisms are not well known. Leriglitazone is a recently developed brain penetrant full PPAR agonist that could modulate multiple biological pathways relevant for neuroinflammatory and neurodegenerative diseases, and particularly for X-ALD. We found that leriglitazone decreased oxidative st...
Source: Science Translational Medicine - June 2, 2021 Category: Biomedical Science Authors: Rodriguez-Pascau, L., Vilalta, A., Cerrada, M., Traver, E., Forss-Petter, S., Weinhofer, I., Bauer, J., Kemp, S., Pina, G., Pascual, S., Meya, U., Musolino, P. L., Berger, J., Martinell, M., Pizcueta, P. Tags: Research Articles Source Type: research

[Research Articles] Depleting plasmacytoid dendritic cells reduces local type I interferon responses and disease activity in patients with cutaneous lupus
Plasmacytoid dendritic cells (pDCs) not only are specialized in their capacity to secrete large amounts of type I interferon (IFN) but also serve to enable both innate and adaptive immune responses through expression of additional proinflammatory cytokines, chemokines, and costimulatory molecules. Persistent activation of pDCs has been demonstrated in a number of autoimmune diseases. To evaluate the potential benefit of depleting pDCs in autoimmunity, a monoclonal antibody targeting the pDC-specific marker immunoglobulin-like transcript 7 was generated. This antibody, known as VIB7734, which was engineered for enhanced eff...
Source: Science Translational Medicine - May 26, 2021 Category: Biomedical Science Authors: Karnell, J. L., Wu, Y., Mittereder, N., Smith, M. A., Gunsior, M., Yan, L., Casey, K. A., Henault, J., Riggs, J. M., Nicholson, S. M., Sanjuan, M. A., Vousden, K. A., Werth, V. P., Drappa, J., Illei, G. G., Rees, W. A., Ratchford, J. N., VIB7734 Trial Inv Tags: Research Articles Source Type: research

[Research Articles] Hexose-6-phosphate dehydrogenase blockade reverses prostate cancer drug resistance in xenograft models by glucocorticoid inactivation
Prostate cancer resistance to next-generation hormonal treatment with enzalutamide is a major problem and eventuates into disease lethality. Biologically active glucocorticoids that stimulate glucocorticoid receptor (GR) have an 11β-OH moiety, and resistant tumors exhibit loss of 11β-HSD2, the oxidative (11β-OH -> 11-keto) enzyme that normally inactivates glucocorticoids, allowing elevated tumor glucocorticoids to drive resistance by stimulating GR. Here, we show that up-regulation of hexose-6-phosphate dehydrogenase (H6PD) protein occurs in prostate cancer tissues of men treated with enzalutamide, human-...
Source: Science Translational Medicine - May 26, 2021 Category: Biomedical Science Authors: Li, J., Berk, M., Alyamani, M., Sabharwal, N., Goins, C., Alvarado, J., Baratchian, M., Zhu, Z., Stauffer, S., Klein, E. A., Sharifi, N. Tags: Research Articles Source Type: research

[Research Articles] Transient receptor potential canonical 5 mediates inflammatory mechanical and spontaneous pain in mice
Tactile and spontaneous pains are poorly managed symptoms of inflammatory and neuropathic injury. Here, we found that transient receptor potential canonical 5 (TRPC5) is a chief contributor to both of these sensations in multiple rodent pain models. Use of TRPC5 knockout mice and inhibitors revealed that TRPC5 selectively contributes to the mechanical hypersensitivity associated with CFA injection, skin incision, chemotherapy induced peripheral neuropathy, sickle cell disease, and migraine, all of which were characterized by elevated concentrations of lysophosphatidylcholine (LPC). Accordingly, exogenous application of LPC...
Source: Science Translational Medicine - May 26, 2021 Category: Biomedical Science Authors: Sadler, K. E., Moehring, F., Shiers, S. I., Laskowski, L. J., Mikesell, A. R., Plautz, Z. R., Brezinski, A. N., Mecca, C. M., Dussor, G., Price, T. J., McCorvy, J. D., Stucky, C. L. Tags: Research Articles Source Type: research

[Research Articles] PAC1 receptor-mediated clearance of tau in postsynaptic compartments attenuates tau pathology in mouse brain
Accumulation of pathological tau in synapses has been identified as an early event in Alzheimer’s disease (AD) and correlates with cognitive decline in patients with AD. Tau is a cytosolic axonal protein, but under disease conditions, tau accumulates in postsynaptic compartments and presynaptic terminals, due to missorting within neurons, transsynaptic transfer between neurons, or a failure of clearance pathways. Using subcellular fractionation of brain tissue from rTg4510 tau transgenic mice with tauopathy and human postmortem brain tissue from patients with AD, we found accumulation of seed-competent tau predominan...
Source: Science Translational Medicine - May 26, 2021 Category: Biomedical Science Authors: Schaler, A. W., Runyan, A. M., Clelland, C. L., Sydney, E. J., Fowler, S. L., Figueroa, H. Y., Shioda, S., Santa-Maria, I., Duff, K. E., Myeku, N. Tags: Research Articles Source Type: research