[Research Articles] Chop/Ddit3 depletion in {beta} cells alleviates ER stress and corrects hepatic steatosis in mice
Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia, hyperinsulinemia, and insulin resistance (IR). During the early phase of T2D, insulin synthesis and secretion by pancreatic β cells is enhanced, which can lead to proinsulin misfolding that aggravates endoplasmic reticulum (ER) protein homeostasis in β cells. Moreover, increased circulating insulin may contribute to fatty liver disease. Medical interventions aimed at alleviating ER stress in β cells while maintaining optimal insulin secretion are therefore an attractive therapeutic strategy for T2D. Previously, we demonstrated that...
Source: Science Translational Medicine - July 28, 2021 Category: Biomedical Science Authors: Yong, J., Parekh, V. S., Reilly, S. M., Nayak, J., Chen, Z., Lebeaupin, C., Jang, I., Zhang, J., Prakash, T. P., Sun, H., Murray, S., Guo, S., Ayala, J. E., Satin, L. S., Saltiel, A. R., Kaufman, R. J. Tags: Research Articles Source Type: research

[Research Articles] Blockade of the CD93 pathway normalizes tumor vasculature to facilitate drug delivery and immunotherapy
The immature and dysfunctional vascular network within solid tumors poses a substantial obstacle to immunotherapy because it creates a hypoxic tumor microenvironment that actively limits immune cell infiltration. The molecular basis underpinning this vascular dysfunction is not fully understood. Using genome-scale receptor array technology, we showed here that insulin-like growth factor binding protein 7 (IGFBP7) interacts with its receptor CD93, and we subsequently demonstrated that this interaction contributes to abnormal tumor vasculature. Both CD93 and IGFBP7 were up-regulated in tumor-associated endothelial cells. IGF...
Source: Science Translational Medicine - July 28, 2021 Category: Biomedical Science Authors: Sun, Y., Chen, W., Torphy, R. J., Yao, S., Zhu, G., Lin, R., Lugano, R., Miller, E. N., Fujiwara, Y., Bian, L., Zheng, L., Anand, S., Gao, F., Zhang, W., Ferrara, S. E., Goodspeed, A. E., Dimberg, A., Wang, X.-J., Edil, B. H., Barnett, C. C., Schulick, R. Tags: Research Articles Source Type: research

[Research Articles] PARIS farnesylation prevents neurodegeneration in models of Parkinsons disease
Accumulation of the parkin-interacting substrate (PARIS; ZNF746), due to inactivation of parkin, contributes to Parkinson’s disease (PD) through repression of peroxisome proliferator-activated receptor- coactivator-1α (PGC-1α; PPARGC1A) activity. Here, we identify farnesol as an inhibitor of PARIS. Farnesol promoted the farnesylation of PARIS, preventing its repression of PGC-1α via decreasing PARIS occupancy on the PPARGC1A promoter. Farnesol prevented dopaminergic neuronal loss and behavioral deficits via farnesylation of PARIS in PARIS transgenic mice, ventral midbrain transduction of AAV-PARIS, ...
Source: Science Translational Medicine - July 28, 2021 Category: Biomedical Science Authors: Jo, A., Lee, Y., Kam, T.-I., Kang, S.-U., Neifert, S., Karuppagounder, S. S., Khang, R., Kang, H., Park, H., Chou, S.-C., Oh, S., Jiang, H., Swing, D. A., Ham, S., Pirooznia, S., Umanah, G. K. E., Mao, X., Kumar, M., Ko, H. S., Kang, H. C., Lee, B. D., Le Tags: Research Articles Source Type: research

[Research Articles] An ACE inhibitor reduces bactericidal activity of human neutrophils in vitro and impairs mouse neutrophil activity in vivo
Angiotensin-converting enzyme inhibitors (ACEIs) are used by millions of patients to treat hypertension, diabetic kidney disease, and heart failure. However, these patients are often at increased risk of infection. To evaluate the impact of ACEIs on immune responses to infection, we compared the effect of an ACEI versus an angiotensin receptor blocker (ARB) on neutrophil antibacterial activity. ACEI exposure reduced the ability of murine neutrophils to kill methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Klebsiella pneumoniae in vitro. In vivo, ACEI-treated mice infected with MRSA had increa...
Source: Science Translational Medicine - July 28, 2021 Category: Biomedical Science Authors: Cao, D.-Y., Giani, J. F., Veiras, L. C., Bernstein, E. A., Okwan-Duodu, D., Ahmed, F., Bresee, C., Tourtellotte, W. G., Karumanchi, S. A., Bernstein, K. E., Khan, Z. Tags: Research Articles Source Type: research

[Research Articles] Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS
Alterations in the components [nucleoporins (Nups)] and function of the nuclear pore complex (NPC) have been implicated as contributors to the pathogenesis of genetic forms of neurodegeneration including C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). We hypothesized that Nup alterations and the consequential loss of NPC function may lie upstream of TDP-43 dysfunction and mislocalization widely observed in ALS, FTD, and related neurodegenerative diseases. Here, we provide evidence that CHMP7, a critical mediator of NPC quality control, is increased in nuclei of C9orf72 and sporadic ALS induced plur...
Source: Science Translational Medicine - July 28, 2021 Category: Biomedical Science Authors: Coyne, A. N., Baskerville, V., Zaepfel, B. L., Dickson, D. W., Rigo, F., Bennett, F., Lusk, C. P., Rothstein, J. D. Tags: Research Articles Source Type: research

[Research Articles] Targeting multiple cell death pathways extends the shelf life and preserves the function of human and mouse neutrophils for transfusion
Clinical outcomes from granulocyte transfusion (GTX) are disadvantaged by the short shelf life and compromised function of donor neutrophils. Spontaneous neutrophil death is heterogeneous and mediated by multiple pathways. Leveraging mechanistic knowledge and pharmacological screening, we identified a combined treatment, caspases–lysosomal membrane permeabilization–oxidant–necroptosis inhibition plus granulocyte colony-stimulating factor (CLON-G), which altered neutrophil fate by simultaneously targeting multiple cell death pathways. CLON-G prolonged human and mouse neutrophil half-life in vitro from less...
Source: Science Translational Medicine - July 28, 2021 Category: Biomedical Science Authors: Fan, Y., Teng, Y., Loison, F., Pang, A., Kasorn, A., Shao, X., Zhang, C., Ren, Q., Yu, H., Zheng, Y., Cancelas, J. A., Manis, J., Chai, L., Park, S.-Y., Zhao, L., Xu, Y., Feng, S., Silberstein, L. E., Ma, F., Luo, H. R. Tags: Research Articles Source Type: research

[Research Articles] The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance
The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low prop...
Source: Science Translational Medicine - July 21, 2021 Category: Biomedical Science Authors: Murithi, J. M., Pascal, C., Bath, J., Boulenc, X., Gnädig, N. F., Pasaje, C. F. A., Rubiano, K., Yeo, T., Mok, S., Klieber, S., Desert, P., Jimenez-Diaz, M. B., Marfurt, J., Rouillier, M., Cherkaoui-Rbati, M. H., Gobeau, N., Wittlin, S., Uhlemann, Tags: Research Articles Source Type: research

[Research Articles] A resident stromal cell population actively restrains innate immune response in the propagation phase of colitis pathogenesis in mice
Inflammatory bowel disease (IBD) affects 0.3% of the global population, yet the etiology remains poorly understood. Anti-inflammation therapy has shown great success, but only 60% of patients with IBD benefit from it, indicating that new targets are needed. Here, we report the discovery of an intrinsic counter regulatory mechanism in colitis pathogenesis that may be targeted for IBD treatment. In response to microbial invasion, resident Vimentin+ stromal cells, connective tissue cells genetically marked by Twist2, are activated during the propagation phase of the disease, but not during initiation and resolution phases, an...
Source: Science Translational Medicine - July 21, 2021 Category: Biomedical Science Authors: Gao, L., Yu, Q., Zhang, H., Wang, Z., Zhang, T., Xiang, J., Yu, S., Zhang, S., Wu, H., Xu, Y., Wang, Z., Shen, L., Shu, G., Chen, Y.-G., Liu, H., Shen, L., Li, B. Tags: Research Articles Source Type: research

[Research Articles] Erythropoietin promotes abdominal aortic aneurysms in mice through angiogenesis and inflammatory infiltration
Abdominal aortic aneurysm (AAA) is a potentially fatal vascular disease, but the underlying mechanisms remain unknown. Here, we tested the hypothesis that erythropoietin (EPO) may promote the formation of AAA. We found that EPO dose-dependently promoted the formation of AAA in both Apoe–/– (66.7%) and wild-type (WT) (60%) mice receiving a high dose of EPO. EPO monoclonal antibodies given to Apoe–/– mice receiving angiotensin II (AngII) stimulation resulted in a markedly lower incidence of AAA (from 86.7 to 20%, P
Source: Science Translational Medicine - July 21, 2021 Category: Biomedical Science Authors: Zhang, M., Sui, W., Cheng, C., Xue, F., Tian, Z., Cheng, J., Zhang, J., Zhang, T., Zhang, J., Wang, W., Xiong, W., Hao, P., Ma, J., Xu, X., Wang, S., Sun, S., Zhang, M., Zhang, Y., Zhang, C. Tags: Research Articles Source Type: research

[Research Articles] Toward predicting CYP2D6-mediated variable drug response from CYP2D6 gene sequencing data
Pharmacogenomics is a key component of personalized medicine that promises safer and more effective drug treatment by individualizing drug choice and dose based on genetic profiles. In clinical practice, genetic biomarkers are used to categorize patients into *-alleles to predict CYP450 enzyme activity and adjust drug dosages accordingly. However, this approach leaves a large part of variability in drug response unexplained. Here, we present a proof-of-concept approach that uses continuous-scale (instead of categorical) assignments to predict enzyme activity. We used full CYP2D6 gene sequences obtained with long-read ampli...
Source: Science Translational Medicine - July 21, 2021 Category: Biomedical Science Authors: van der Lee, M., Allard, W. G., Vossen, R. H. A. M., Baak-Pablo, R. F., Menafra, R., Deiman, B. A. L. M., Deenen, M. J., Neven, P., Johansson, I., Gastaldello, S., Ingelman-Sundberg, M., Guchelaar, H.-J., Swen, J. J., Anvar, S. Y. Tags: Research Articles Source Type: research

[Research Articles] Dynamic loading of human engineered heart tissue enhances contractile function and drives a desmosome-linked disease phenotype
The role that mechanical forces play in shaping the structure and function of the heart is critical to understanding heart formation and the etiology of disease but is challenging to study in patients. Engineered heart tissues (EHTs) incorporating human induced pluripotent stem cell (hiPSC)–derived cardiomyocytes have the potential to provide insight into these adaptive and maladaptive changes. However, most EHT systems cannot model both preload (stretch during chamber filling) and afterload (pressure the heart must work against to eject blood). Here, we have developed a new dynamic EHT (dyn-EHT) model that enables u...
Source: Science Translational Medicine - July 21, 2021 Category: Biomedical Science Authors: Bliley, J. M., Vermeer, M. C. S. C., Duffy, R. M., Batalov, I., Kramer, D., Tashman, J. W., Shiwarski, D. J., Lee, A., Teplenin, A. S., Volkers, L., Coffin, B., Hoes, M. F., Kalmykov, A., Palchesko, R. N., Sun, Y., Jongbloed, J. D. H., Bomer, N., de Boer, Tags: Research Articles Source Type: research

[Research Articles] A small-molecule activator of the unfolded protein response eradicates human breast tumors in mice
Metastatic estrogen receptor α (ERα)–positive breast cancer is presently incurable. Seeking to target these drug-resistant cancers, we report the discovery of a compound, called ErSO, that activates the anticipatory unfolded protein response (a-UPR) and induces rapid and selective necrosis of ERα-positive breast cancer cell lines in vitro. We then tested ErSO in vivo in several preclinical orthotopic and metastasis mouse models carrying different xenografts of human breast cancer lines or patient-derived breast tumors. In multiple orthotopic models, ErSO treatment given either orally or intraperiton...
Source: Science Translational Medicine - July 21, 2021 Category: Biomedical Science Authors: Boudreau, M. W., Duraki, D., Wang, L., Mao, C., Kim, J. E., Henn, M. A., Tang, B., Fanning, S. W., Kiefer, J., Tarasow, T. M., Bruckheimer, E. M., Moreno, R., Mousses, S., Greene, G. L., Roy, E. J., Park, B. H., Fan, T. M., Nelson, E. R., Hergenrother, P. Tags: Research Articles Source Type: research

[Reports] Serum neurofilament light protein correlates with unfavorable clinical outcomes in hospitalized patients with COVID-19
Brain imaging studies of patients with COVID-19 show evidence of macro- and microhemorrhagic lesions, multifocal white matter hyperintensities, and lesions consistent with posterior reversible leukoencephalopathy. Imaging studies, however, are subject to selection bias, and prospective studies are challenging to scale. Here, we evaluated whether serum neurofilament light chain (NFL), a neuroaxonal injury marker, could predict the extent of neuronal damage in a cohort of 142 hospitalized patients with COVID-19. NFL was elevated in the serum of patients with COVID-19 compared to healthy controls, including those without over...
Source: Science Translational Medicine - July 14, 2021 Category: Biomedical Science Authors: Prudencio, M., Erben, Y., Marquez, C. P., Jansen-West, K. R., Franco-Mesa, C., Heckman, M. G., White, L. J., Dunmore, J. A., Cook, C. N., Lilley, M. T., Song, Y., Harlow, C. F., Oskarsson, B., Nicholson, K. A., Wszolek, Z. K., Hickson, L. J., OHoro, J. C. Tags: Reports Source Type: research

[Research Articles] Ebola vaccine-induced protection in nonhuman primates correlates with antibody specificity and Fc-mediated effects
Although substantial progress has been made with Ebola virus (EBOV) vaccine measures, the immune correlates of vaccine-mediated protection remain uncertain. Here, five mucosal vaccine vectors based on human and avian paramyxoviruses provided nonhuman primates with varying degrees of protection, despite expressing the same EBOV glycoprotein (GP) immunogen. Each vaccine produced antibody responses that differed in Fc-mediated functions and isotype composition, as well as in magnitude and coverage toward GP and its conformational and linear epitopes. Differences in the degree of protection and comprehensive characterization o...
Source: Science Translational Medicine - July 14, 2021 Category: Biomedical Science Authors: Meyer, M., Gunn, B. M., Malherbe, D. C., Gangavarapu, K., Yoshida, A., Pietzsch, C., Kuzmina, N. A., Saphire, E. O., Collins, P. L., Crowe, J. E., Zhu, J. J., Suchard, M. A., Brining, D. L., Mire, C. E., Cross, R. W., Geisbert, J. B., Samal, S. K., Anders Tags: Research Articles Source Type: research

[Research Articles] Losartan prevents tumor-induced hearing loss and augments radiation efficacy in NF2 schwannoma rodent models
Hearing loss is one of the most common symptoms of neurofibromatosis type 2 (NF2) caused by vestibular schwannomas (VSs). Fibrosis in the VS tumor microenvironment (TME) is associated with hearing loss in patients with NF2. We hypothesized that reducing the fibrosis using losartan, an FDA-approved antihypertensive drug that blocks fibrotic and inflammatory signaling, could improve hearing. Using NF2 mouse models, we found that losartan treatment normalized the TME by (i) reducing neuroinflammatory IL-6/STAT3 signaling and preventing hearing loss, (ii) normalizing tumor vasculature and alleviating neuro-edema, and (iii) inc...
Source: Science Translational Medicine - July 14, 2021 Category: Biomedical Science Authors: Wu, L., Vasilijic, S., Sun, Y., Chen, J., Landegger, L. D., Zhang, Y., Zhou, W., Ren, J., Early, S., Yin, Z., Ho, W. W., Zhang, N., Gao, X., Lee, G. Y., Datta, M., Sagers, J. E., Brown, A., Muzikansky, A., Stemmer-Rachamimov, A., Zhang, L., Plotkin, S. R. Tags: Research Articles Source Type: research

[Research Articles] Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer
Lung and bladder cancers are mostly incurable because of the early development of drug resistance and metastatic dissemination. Hence, improved therapies that tackle these two processes are urgently needed to improve clinical outcome. We have identified RSK4 as a promoter of drug resistance and metastasis in lung and bladder cancer cells. Silencing this kinase, through either RNA interference or CRISPR, sensitized tumor cells to chemotherapy and hindered metastasis in vitro and in vivo in a tail vein injection model. Drug screening revealed several floxacin antibiotics as potent RSK4 activation inhibitors, and trovafloxaci...
Source: Science Translational Medicine - July 14, 2021 Category: Biomedical Science Authors: Chrysostomou, S., Roy, R., Prischi, F., Thamlikitkul, L., Chapman, K. L., Mufti, U., Peach, R., Ding, L., Hancock, D., Moore, C., Molina-Arcas, M., Mauri, F., Pinato, D. J., Abrahams, J. M., Ottaviani, S., Castellano, L., Giamas, G., Pascoe, J., Moonamale Tags: Research Articles Source Type: research

[Research Articles] Key epidemiological drivers and impact of interventions in the 2020 SARS-CoV-2 epidemic in England
We fitted a model of SARS-CoV-2 transmission in care homes and the community to regional surveillance data for England. Compared with other approaches, our model provides a synthesis of multiple surveillance data streams into a single coherent modeling framework, allowing transmission and severity to be disentangled from features of the surveillance system. Of the control measures implemented, only national lockdown brought the reproduction number (Rteff) below 1 consistently; if introduced 1 week earlier, it could have reduced deaths in the first wave from an estimated 48,600 to 25,600 [95% credible interval (CrI): 15,900...
Source: Science Translational Medicine - July 14, 2021 Category: Biomedical Science Authors: Knock, E. S., Whittles, L. K., Lees, J. A., Perez-Guzman, P. N., Verity, R., FitzJohn, R. G., Gaythorpe, K. A. M., Imai, N., Hinsley, W., Okell, L. C., Rosello, A., Kantas, N., Walters, C. E., Bhatia, S., Watson, O. J., Whittaker, C., Cattarino, L., Boony Tags: Research Articles Source Type: research

[Research Articles] Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade
Molecular and cellular effects of radiotherapy on tumor microenvironment (TME) can help prime and propagate antitumor immunity. We hypothesized that delivering radiation to all tumor sites could augment response to immunotherapies. We tested an approach to enhance response to immune checkpoint inhibitors (ICIs) by using targeted radionuclide therapy (TRT) to deliver radiation semiselectively to tumors. NM600, an alkylphosphocholine analog that preferentially accumulates in most tumor types, chelates a radioisotope and semiselectively delivers it to the TME for therapeutic or diagnostic applications. Using serial 86Y-NM600 ...
Source: Science Translational Medicine - July 14, 2021 Category: Biomedical Science Authors: Patel, R. B., Hernandez, R., Carlson, P., Grudzinski, J., Bates, A. M., Jagodinsky, J. C., Erbe, A., Marsh, I. R., Arthur, I., Aluicio-Sarduy, E., Sriramaneni, R. N., Jin, W. J., Massey, C., Rakhmilevich, A. L., Vail, D., Engle, J. W., Le, T., Kim, K., Be Tags: Research Articles Source Type: research

[Research Articles] Pan-caspase inhibition as a potential host-directed immunotherapy against MRSA and other bacterial skin infections
Staphylococcus aureus causes most skin infections in humans, and the emergence of methicillin-resistant S. aureus (MRSA) strains is a serious public health threat. There is an urgent clinical need for nonantibiotic immunotherapies to treat MRSA infections and prevent the spread of antibiotic resistance. Here, we investigated the pan-caspase inhibitor quinoline–valine–aspartic acid–difluorophenoxymethyl ketone (Q-VD-OPH) for efficacy against MRSA skin infection in mice. A single systemic dose of Q-VD-OPH decreased skin lesion sizes and reduced bacterial burden compared with vehicle-treated or untreated mic...
Source: Science Translational Medicine - July 7, 2021 Category: Biomedical Science Authors: Alphonse, M. P., Rubens, J. H., Ortines, R. V., Orlando, N. A., Patel, A. M., Dikeman, D., Wang, Y., Vuong, I., Joyce, D. P., Zhang, J., Mumtaz, M., Liu, H., Liu, Q., Youn, C., Patrick, G. J., Ravipati, A., Miller, R. J., Archer, N. K., Miller, L. S. Tags: Research Articles Source Type: research

[Research Articles] A recombinant commensal bacteria elicits heterologous antigen-specific immune responses during pharyngeal carriage
The human nasopharynx contains a stable microbial ecosystem of commensal and potentially pathogenic bacteria, which can elicit protective primary and secondary immune responses. Experimental intranasal infection of human adults with the commensal Neisseria lactamica produced safe, sustained pharyngeal colonization. This has potential utility as a vehicle for sustained release of antigen to the human mucosa, but commensals in general are thought to be immunologically tolerated. Here, we show that engineered N. lactamica, chromosomally transformed to express a heterologous vaccine antigen, safely induces systemic, antigen-sp...
Source: Science Translational Medicine - July 7, 2021 Category: Biomedical Science Authors: Laver, J. R., Gbesemete, D., Dale, A. P., Pounce, Z. C., Webb, C. N., Roche, E. F., Guy, J. M., Berreen, G., Belogiannis, K., Hill, A. R., Ibrahim, M. M., Ahmed, M., Cleary, D. W., Pandey, A. K., Humphries, H. E., Allen, L., de Graaf, H., Maiden, M. C., F Tags: Research Articles Source Type: research

[Editorial] Increasing threats from SARS-CoV-2 variants: Time to establish global surveillance
(Source: Science Translational Medicine)
Source: Science Translational Medicine - July 7, 2021 Category: Biomedical Science Authors: Layne, S. P., Taubenberger, J. K. Tags: Editorial Source Type: research

[Research Articles] Genome-encoded cytoplasmic double-stranded RNAs, found in C9ORF72 ALS-FTD brain, propagate neuronal loss
We report the presence of cytoplasmic double-stranded RNA (cdsRNA), an established trigger of innate immunity, in ALS-FTD brains carrying C9ORF72 intronic hexanucleotide expansions that included genomically encoded expansions of the G4C2 repeat sequences. The presence of cdsRNA in human brains was coincident with cytoplasmic TAR DNA binding protein 43 (TDP-43) inclusions, a pathologic hallmark of ALS/FTD. Introducing cdsRNA into cultured human neural cells induced type I interferon (IFN-I) signaling and death that was rescued by FDA-approved JAK inhibitors. In mice, genomically encoded dsRNAs expressed exclusively in a neu...
Source: Science Translational Medicine - July 7, 2021 Category: Biomedical Science Authors: Rodriguez, S., Sahin, A., Schrank, B. R., Al-Lawati, H., Costantino, I., Benz, E., Fard, D., Albers, A. D., Cao, L., Gomez, A. C., Evans, K., Ratti, E., Cudkowicz, M., Frosch, M. P., Talkowski, M., Sorger, P. K., Hyman, B. T., Albers, M. W. Tags: Research Articles Source Type: research

[Research Articles] Down-regulation of A20 promotes immune escape of lung adenocarcinomas
Inflammation is a well-known driver of lung tumorigenesis. One strategy by which tumor cells escape tight homeostatic control is by decreasing the expression of the potent anti-inflammatory protein tumor necrosis factor alpha–induced protein 3 (TNFAIP3), also known as A20. We observed that tumor cell intrinsic loss of A20 markedly enhanced lung tumorigenesis and was associated with reduced CD8+ T cell–mediated immune surveillance in patients with lung cancer and in mouse models. In mice, we observed that this effect was completely dependent on increased cellular sensitivity to interferon- (IFN-) signaling by ab...
Source: Science Translational Medicine - July 7, 2021 Category: Biomedical Science Authors: Breitenecker, K., Homolya, M., Luca, A. C., Lang, V., Trenk, C., Petroczi, G., Mohrherr, J., Horvath, J., Moritsch, S., Haas, L., Kurnaeva, M., Eferl, R., Stoiber, D., Moriggl, R., Bilban, M., Obenauf, A. C., Ferran, C., Dome, B., Laszlo, V., Gyorffy, B., Tags: Research Articles Source Type: research

[Reports] Undiagnosed SARS-CoV-2 seropositivity during the first 6 months of the COVID-19 pandemic in the United States
Asymptomatic SARS-CoV-2 infection and delayed implementation of diagnostics have led to poorly defined viral prevalence rates in the United States and elsewhere. To address this, we analyzed seropositivity in 9089 adults in the United States who had not been diagnosed previously with COVID-19. Individuals with characteristics that reflected the U.S. population (n = 27,716) were selected by quota sampling from 462,949 volunteers. Enrolled participants (n = 11,382) provided medical, geographic, demographic, and socioeconomic information and dried blood samples. Survey questions coincident with the Behavioral Risk Factor Surv...
Source: Science Translational Medicine - July 7, 2021 Category: Biomedical Science Authors: Kalish, H., Klumpp-Thomas, C., Hunsberger, S., Baus, H. A., Fay, M. P., Siripong, N., Wang, J., Hicks, J., Mehalko, J., Travers, J., Drew, M., Pauly, K., Spathies, J., Ngo, T., Adusei, K. M., Karkanitsa, M., Croker, J. A., Li, Y., Graubard, B. I., Czajkow Tags: Reports Source Type: research

[Research Articles] Bacterial cytoplasmic membranes synergistically enhance the antitumor activity of autologous cancer vaccines
Cancer vaccines based on resected tumors from patients have gained great interest as an individualized cancer treatment strategy. However, eliciting a robust therapeutic effect with personalized vaccines remains a challenge because of the weak immunogenicity of autologous tumor antigens. Utilizing exogenous prokaryotic constituents that act as adjuvants to enhance immunogenicity is a promising strategy to overcome this limitation. However, nonspecific stimulation of the immune system may elicit an undesirable immunopathological state. To specifically trigger sufficient antitumor reactivity without notable adverse effects, ...
Source: Science Translational Medicine - July 7, 2021 Category: Biomedical Science Authors: Chen, L., Qin, H., Zhao, R., Zhao, X., Lin, L., Chen, Y., Lin, Y., Li, Y., Qin, Y., Li, Y., Liu, S., Cheng, K., Chen, H., Shi, J., Anderson, G. J., Wu, Y., Zhao, Y., Nie, G. Tags: Research Articles Source Type: research

[Research Articles] Multicellular modeling of ciliopathy by combining iPS cells and microfluidic airway-on-a-chip technology
Mucociliary clearance is an essential lung function that facilitates the removal of inhaled pathogens and foreign matter unidirectionally from the airway tract and is innately achieved by coordinated ciliary beating of multiciliated cells. Should ciliary function become disturbed, mucus can accumulate in the airway causing subsequent obstruction and potentially recurrent pneumonia. However, it has been difficult to recapitulate unidirectional mucociliary flow using human-derived induced pluripotent stem cells (iPSCs) in vitro and the mechanism governing the flow has not yet been elucidated, hampering the proper humanized a...
Source: Science Translational Medicine - July 7, 2021 Category: Biomedical Science Authors: Sone, N., Konishi, S., Igura, K., Tamai, K., Ikeo, S., Korogi, Y., Kanagaki, S., Namba, T., Yamamoto, Y., Xu, Y., Takeuchi, K., Adachi, Y., Chen-Yoshikawa, T. F., Date, H., Hagiwara, M., Tsukita, S., Hirai, T., Torisawa, Y.-s., Gotoh, S. Tags: Research Articles Source Type: research

[Research Articles] Antibodies elicited by mRNA-1273 vaccination bind more broadly to the receptor binding domain than do those from SARS-CoV-2 infection
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with mutations in key antibody epitopes has raised concerns that antigenic evolution could erode adaptive immunity elicited by prior infection or vaccination. The susceptibility of immunity to viral evolution is shaped in part by the breadth of epitopes targeted by antibodies elicited by vaccination or natural infection. To investigate how human antibody responses to vaccines are influenced by viral mutations, we used deep mutational scanning to compare the specificity of polyclonal antibodies elicited by either two doses of the mRNA-127...
Source: Science Translational Medicine - June 30, 2021 Category: Biomedical Science Authors: Greaney, A. J., Loes, A. N., Gentles, L. E., Crawford, K. H. D., Starr, T. N., Malone, K. D., Chu, H. Y., Bloom, J. D. Tags: Research Articles Source Type: research

[Research Articles] Inhibiting DNA-PK induces glioma stem cell differentiation and sensitizes glioblastoma to radiation in mice
Glioblastoma (GBM), a lethal primary brain tumor, contains glioma stem cells (GSCs) that promote malignant progression and therapeutic resistance. SOX2 is a core transcription factor that maintains the properties of stem cells, including GSCs, but mechanisms associated with posttranslational SOX2 regulation in GSCs remain elusive. Here, we report that DNA-dependent protein kinase (DNA-PK) governs SOX2 stability through phosphorylation, resulting in GSC maintenance. Mass spectrometric analyses of SOX2-binding proteins showed that DNA-PK interacted with SOX2 in GSCs. The DNA-PK catalytic subunit (DNA-PKcs) was preferentially...
Source: Science Translational Medicine - June 30, 2021 Category: Biomedical Science Authors: Fang, X., Huang, Z., Zhai, K., Huang, Q., Tao, W., Kim, L., Wu, Q., Almasan, A., Yu, J. S., Li, X., Stark, G. R., Rich, J. N., Bao, S. Tags: Research Articles Source Type: research

[Research Articles] Gene therapy knockdown of Hippo signaling induces cardiomyocyte renewal in pigs after myocardial infarction
Human heart failure, a leading cause of death worldwide, is a prominent example of a chronic disease that may result from poor cell renewal. The Hippo signaling pathway is an inhibitory kinase cascade that represses adult heart muscle cell (cardiomyocyte) proliferation and renewal after myocardial infarction in genetically modified mice. Here, we investigated an adeno-associated virus 9 (AAV9)–based gene therapy to locally knock down the Hippo pathway gene Salvador (Sav) in border zone cardiomyocytes in a pig model of ischemia/reperfusion-induced myocardial infarction. Two weeks after myocardial infarction, when pigs...
Source: Science Translational Medicine - June 30, 2021 Category: Biomedical Science Authors: Liu, S., Li, K., Wagner Florencio, L., Tang, L., Heallen, T. R., Leach, J. P., Wang, Y., Grisanti, F., Willerson, J. T., Perin, E. C., Zhang, S., Martin, J. F. Tags: Research Articles Source Type: research

[Research Articles] Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance toward self-nucleic acids, autoantibody production, interferon expression and signaling, and a defect in the regulatory T (Treg) cell compartment. In this work, we identified that platelets from patients with active SLE preferentially interacted with Treg cells via the P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1) axis. Selectin interaction with PSGL-1 blocked the regulatory and suppressive properties of Treg cells and particularly follicular Treg cells by triggering Syk phosphorylation and an increase in intracy...
Source: Science Translational Medicine - June 30, 2021 Category: Biomedical Science Authors: Scherlinger, M., Guillotin, V., Douchet, I., Vacher, P., Boizard-Moracchini, A., Guegan, J.-P., Garreau, A., Merillon, N., Vermorel, A., Ribeiro, E., Machelart, I., Lazaro, E., Couzi, L., Duffau, P., Barnetche, T., Pellegrin, J.-L., Viallard, J.-F., Saleh Tags: Research Articles Source Type: research

[Research Articles] Circulating proteins protect against renal decline and progression to end-stage renal disease in patients with diabetes
Diabetic kidney disease (DKD) and its major clinical manifestation, progressive renal decline that leads to end-stage renal disease (ESRD), are a major health burden for individuals with diabetes. The disease process that underlies progressive renal decline comprises factors that increase risk as well as factors that protect against this outcome. Using untargeted proteomic profiling of circulating proteins from individuals in two independent cohorts with type 1 and type 2 diabetes and varying stages of DKD followed for 7 to 15 years, we identified three elevated plasma proteins—fibroblast growth factor 20 (OR, 0.69; ...
Source: Science Translational Medicine - June 30, 2021 Category: Biomedical Science Authors: Md Dom, Z. I., Satake, E., Skupien, J., Krolewski, B., ONeil, K., Willency, J. A., Dillon, S. T., Wilson, J. M., Kobayashi, H., Ihara, K., Libermann, T. A., Pragnell, M., Duffin, K. L., Krolewski, A. S. Tags: Research Articles Source Type: research

[Research Articles] Neutrophils initiate and exacerbate Stevens-Johnson syndrome and toxic epidermal necrolysis
We describe a mechanism by which neutrophils triggered inflammation during early phases of SJS/TEN. Skin-infiltrating CD8+ T cells produced lipocalin-2 in a drug-specific manner, which triggered the formation of neutrophil extracellular traps (NETs) in early lesional skin. Neutrophils undergoing NETosis released LL-37, an antimicrobial peptide, which induced formyl peptide receptor 1 (FPR1) expression by keratinocytes. FPR1 expression caused keratinocytes to be vulnerable to necroptosis that caused further release of LL-37 by necroptotic keratinocytes and induced FPR1 expression on surrounding keratinocytes, which likely a...
Source: Science Translational Medicine - June 30, 2021 Category: Biomedical Science Authors: Kinoshita, M., Ogawa, Y., Hama, N., Ujiie, I., Hasegawa, A., Nakajima, S., Nomura, T., Adachi, J., Sato, T., Koizumi, S., Shimada, S., Fujita, Y., Takahashi, H., Mizukawa, Y., Tomonaga, T., Nagao, K., Abe, R., Kawamura, T. Tags: Research Articles Source Type: research

[Research Articles] Paired box 6 programs essential exocytotic genes in the regulation of glucose-stimulated insulin secretion and glucose homeostasis
The paired box 6 (PAX6) transcription factor is crucial for normal pancreatic islet development and function. Heterozygous mutations of PAX6 are associated with impaired insulin secretion and early-onset diabetes mellitus in humans. However, the molecular mechanism of PAX6 in controlling insulin secretion in human beta cells and its pathophysiological role in type 2 diabetes (T2D) remain ambiguous. We investigated the molecular pathway of PAX6 in the regulation of insulin secretion and the potential therapeutic value of PAX6 in T2D by using human pancreatic beta cell line EndoC-βH1, the db/db mouse model, and primary ...
Source: Science Translational Medicine - June 30, 2021 Category: Biomedical Science Authors: So, W. Y., Liu, W. N., Teo, A. K. K., Rutter, G. A., Han, W. Tags: Research Articles Source Type: research

[Research Articles] Reactivation of the tumor suppressor PTEN by mRNA nanoparticles enhances antitumor immunity in preclinical models
Increasing clinical evidence has demonstrated that the deletion or mutation of tumor suppressor genes such as the gene-encoding phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in cancer cells may correlate with an immunosuppressive tumor microenvironment (TME) and poor response or resistance to immune checkpoint blockade (ICB) therapy. It is largely unknown whether the restoration of functional PTEN may modulate the TME and improve the tumor’s sensitivity to ICB therapy. Here, we demonstrate that mRNA delivery by polymeric nanoparticles can effectively induce expression of PTEN in Pten-mutated melanoma...
Source: Science Translational Medicine - June 23, 2021 Category: Biomedical Science Authors: Lin, Y.-X., Wang, Y., Ding, J., Jiang, A., Wang, J., Yu, M., Blake, S., Liu, S., Bieberich, C. J., Farokhzad, O. C., Mei, L., Wang, H., Shi, J. Tags: Research Articles Source Type: research

[Research Resource] A biliary immune landscape map of primary sclerosing cholangitis reveals a dominant network of neutrophils and tissue-resident T cells
This study uncovers the immunological niche of human bile ducts, defines a local immune network between neutrophils and biliary-resident T cells in PSC, and provides a resource for future studies of the immune responses in biliary disorders. (Source: Science Translational Medicine)
Source: Science Translational Medicine - June 23, 2021 Category: Biomedical Science Authors: Zimmer, C. L., von Seth, E., Buggert, M., Strauss, O., Hertwig, L., Nguyen, S., Wong, A. Y. W., Zotter, C., Berglin, L., Michaëlsson, J., Hansson, M. R., Arnelo, U., Sparrelid, E., Ellis, E. C. S., Söderholm, J. D., Keita, A. V., Holm, K., Tags: Research Resource Source Type: research

[Research Articles] The TLR7 agonist vesatolimod induced a modest delay in viral rebound in HIV controllers after cessation of antiretroviral therapy
Toll-like receptor 7 (TLR7) agonists, in combination with other therapies, can induce sustained control of simian-human immunodeficiency virus (SHIV) or simian immunodeficiency virus (SIV) in nonhuman primates. Here, we report the results of a randomized, double-blind, placebo-controlled phase 1b clinical trial of an oral TLR7 agonist, vesatolimod, in HIV-1–infected controllers on antiretroviral therapy (ART). We randomized participants 2:1 to receive vesatolimod (n = 17) or placebo (n = 8) once every other week for a total of 10 doses while continuing on ART. ART was then interrupted, and the time to viral rebound w...
Source: Science Translational Medicine - June 23, 2021 Category: Biomedical Science Authors: SenGupta, D., Brinson, C., DeJesus, E., Mills, A., Shalit, P., Guo, S., Cai, Y., Wallin, J. J., Zhang, L., Humeniuk, R., Begley, R., Geleziunas, R., Mellors, J., Wrin, T., Jones, N., Milush, J., Ferre, A. L., Shacklett, B. L., Laird, G. M., Moldt, B., Ven Tags: Research Articles Source Type: research

[Research Articles] Functional human IgA targets a conserved site on malaria sporozoites
This study reveals a role for circulating IgA in malaria and identifies the amino terminus of the circumsporozoite protein as a target of functional antibodies. (Source: Science Translational Medicine)
Source: Science Translational Medicine - June 23, 2021 Category: Biomedical Science Authors: Tan, J., Cho, H., Pholcharee, T., Pereira, L. S., Doumbo, S., Doumtabe, D., Flynn, B. J., Schön, A., Kanatani, S., Aylor, S. O., Oyen, D., Vistein, R., Wang, L., Dillon, M., Skinner, J., Peterson, M., Li, S., Idris, A. H., Molina-Cruz, A., Zhao, M Tags: Research Articles Source Type: research

[Research Articles] A self-amplifying loop of YAP and SHH drives formation and expansion of heterotopic ossification
Heterotopic ossification (HO) occurs as a common complication after injury or in genetic disorders. The mechanisms underlying HO remain incompletely understood, and there are no approved prophylactic or secondary treatments available. Here, we identify a self-amplifying, self-propagating loop of Yes-associated protein (YAP)–Sonic hedgehog (SHH) as a core molecular mechanism underlying diverse forms of HO. In mouse models of progressive osseous heteroplasia (POH), a disease caused by null mutations in GNAS, we found that Gnas–/– mesenchymal cells secreted SHH, which induced osteoblast differentiation of th...
Source: Science Translational Medicine - June 23, 2021 Category: Biomedical Science Authors: Cong, Q., Liu, Y., Zhou, T., Zhou, Y., Xu, R., Cheng, C., Chung, H. S., Yan, M., Zhou, H., Liao, Z., Gao, B., Bocobo, G. A., Covington, T. A., Song, H. J., Su, P., Yu, P. B., Yang, Y. Tags: Research Articles Source Type: research

[Research Articles] Hepatocyte TLR4 triggers inter-hepatocyte Jagged1/Notch signaling to determine NASH-induced fibrosis
Aberrant hepatocyte Notch activity is critical to the development of nonalcoholic steatohepatitis (NASH)–induced liver fibrosis, but mechanisms underlying Notch reactivation in developed liver are unclear. Here, we identified that increased expression of the Notch ligand Jagged1 (JAG1) tracked with Notch activation and nonalcoholic fatty liver disease (NAFLD) activity score (NAS) in human liver biopsy specimens and mouse NASH models. The increase in Jag1 was mediated by hepatocyte Toll-like receptor 4 (TLR4)–nuclear factor B (NF-B) signaling in pericentral hepatocytes. Hepatocyte-specific Jag1 overexpression ex...
Source: Science Translational Medicine - June 23, 2021 Category: Biomedical Science Authors: Yu, J., Zhu, C., Wang, X., Kim, K., Bartolome, A., Dongiovanni, P., Yates, K. P., Valenti, L., Carrer, M., Sadowski, T., Qiang, L., Tabas, I., Lavine, J. E., Pajvani, U. B. Tags: Research Articles Source Type: research

[Research Articles] Plasma from patients with bacterial sepsis or severe COVID-19 induces suppressive myeloid cell production from hematopoietic progenitors in vitro
Bacterial sepsis and severe COVID-19 share similar clinical manifestations and are both associated with dysregulation of the myeloid cell compartment. We previously reported an expanded CD14+ monocyte state, MS1, in patients with bacterial sepsis and validated expansion of this cell subpopulation in publicly available transcriptomics data. Here, using published datasets, we show that the gene expression program associated with MS1 correlated with sepsis severity and was up-regulated in monocytes from patients with severe COVID-19. To examine the ontogeny and function of MS1 cells, we developed a cellular model for inducing...
Source: Science Translational Medicine - June 16, 2021 Category: Biomedical Science Authors: Reyes, M., Filbin, M. R., Bhattacharyya, R. P., Sonny, A., Mehta, A., Billman, K., Kays, K. R., Pinilla-Vera, M., Benson, M. E., Cosimi, L. A., Hung, D. T., Levy, B. D., Villani, A.-C., Sade-Feldman, M., Baron, R. M., Goldberg, M. B., Blainey, P. C., Haco Tags: Research Articles Source Type: research

[Research Articles] A helicase-primase drug candidate with sufficient target tissue exposure affects latent neural herpes simplex virus infections
More than 50% of the world population is chronically infected with herpesviruses. Herpes simplex virus (HSV) infections are the cause of herpes labialis (cold sores), genital herpes, and sight-impairing keratitis. Less frequently, life-threatening disseminated disease (encephalitis and generalized viremia) can also occur, mainly in immunocompromised patients and newborns. After primary infection, HSV persists for life in a latent state in trigeminal or sacral ganglia and, triggered by diverse stimuli, disease recurs in more than 30% of patients up to several times a year. Current therapy with nucleoside analogs targeting t...
Source: Science Translational Medicine - June 16, 2021 Category: Biomedical Science Authors: Gege, C., Bravo, F. J., Uhlig, N., Hagmaier, T., Schmachtenberg, R., Elis, J., Burger-Kentischer, A., Finkelmeier, D., Hamprecht, K., Grunwald, T., Bernstein, D. I., Kleymann, G. Tags: Research Articles Source Type: research

[Research Articles] A randomized controlled trial to isolate the effects of fasting and energy restriction on weight loss and metabolic health in lean adults
Intermittent fasting may impart metabolic benefits independent of energy balance by initiating fasting-mediated mechanisms. This randomized controlled trial examined 24-hour fasting with 150% energy intake on alternate days for 3 weeks in lean, healthy individuals (0:150; n = 12). Control groups involved a matched degree of energy restriction applied continuously without fasting (75% energy intake daily; 75:75; n = 12) or a matched pattern of fasting without net energy restriction (200% energy intake on alternate days; 0:200; n = 12). Primary outcomes were body composition, components of energy balance, and postprandial me...
Source: Science Translational Medicine - June 16, 2021 Category: Biomedical Science Authors: Templeman, I., Smith, H. A., Chowdhury, E., Chen, Y.-C., Carroll, H., Johnson-Bonson, D., Hengist, A., Smith, R., Creighton, J., Clayton, D., Varley, I., Karagounis, L. G., Wilhelmsen, A., Tsintzas, K., Reeves, S., Walhin, J.-P., Gonzalez, J. T., Thompson Tags: Research Articles Source Type: research

[Research Articles] Macrophage depletion induces edema through release of matrix-degrading proteases and proteoglycan deposition
In this study, we examined molecular and cellular events associated with edema formation in mice and human patients with cancer treated with a CSF1R blocking antibody. Extended antibody treatment of mice caused marked body weight gain, an indicator of enhanced body fluid retention. This was associated with an increase of extracellular matrix–remodeling metalloproteinases (MMPs), namely MMP2 and MMP3, and enhanced deposition of hyaluronan (HA) and proteoglycans, leading to skin thickening. Discontinuation of anti-CSF1R treatment or blockade of MMP activity restored unaltered body weight and normal skin morphology in t...
Source: Science Translational Medicine - June 16, 2021 Category: Biomedical Science Authors: Bissinger, S., Hage, C., Wagner, V., Maser, I.-P., Brand, V., Schmittnaegel, M., Jegg, A.-M., Cannarile, M., Watson, C., Klaman, I., Rieder, N., Gonzalez Loyola, A., Petrova, T. V., Cassier, P. A., Gomez-Roca, C., Sibaud, V., De Palma, M., Hoves, S., Ries Tags: Research Articles Source Type: research

[Research Articles] Enhancing proteasomal processing improves survival for a peptide vaccine used to treat glioblastoma
We examined 20 peptides in silico and experimentally, which showed that a tyrosine substitution (Y6-pepVIII) maximizes proteasome cleavage and survival in a subcutaneous tumor model in mice. In an intracranial glioma model, Y6-pepVIII showed a 62 and 31% improvement in median survival compared to control animals and pepVIII-vaccinated mice. Y6-pepVIII vaccination altered tumor-infiltrating lymphocyte subsets and expression of PD-1 on intratumoral T cells. Combination with anti–PD-1 therapy cured 45% of the Y6-pepVIII–vaccinated mice but was ineffective for pepVIII-treated mice. Liquid chromatography–tande...
Source: Science Translational Medicine - June 16, 2021 Category: Biomedical Science Authors: Fidanza, M., Gupta, P., Sayana, A., Shanker, V., Pahlke, S.-M., Vu, B., Krantz, F., Azameera, A., Wong, N., Anne, N., Xia, Y., Rong, J., Anne, A., Skirboll, S., Lim, M., Wong, A. J. Tags: Research Articles Source Type: research

[Research Articles] Development of {beta}-globin gene correction in human hematopoietic stem cells as a potential durable treatment for sickle cell disease
Sickle cell disease (SCD) is the most common serious monogenic disease with 300,000 births annually worldwide. SCD is an autosomal recessive disease resulting from a single point mutation in codon six of the β-globin gene (HBB). Ex vivo β-globin gene correction in autologous patient-derived hematopoietic stem and progenitor cells (HSPCs) may potentially provide a curative treatment for SCD. We previously developed a CRISPR-Cas9 gene targeting strategy that uses high-fidelity Cas9 precomplexed with chemically modified guide RNAs to induce recombinant adeno-associated virus serotype 6 (rAAV6)–mediated HBB gen...
Source: Science Translational Medicine - June 16, 2021 Category: Biomedical Science Authors: Lattanzi, A., Camarena, J., Lahiri, P., Segal, H., Srifa, W., Vakulskas, C. A., Frock, R. L., Kenrick, J., Lee, C., Talbott, N., Skowronski, J., Cromer, M. K., Charlesworth, C. T., Bak, R. O., Mantri, S., Bao, G., DiGiusto, D., Tisdale, J., Wright, J. F., Tags: Research Articles Source Type: research

[Research Articles] Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury
Acetaminophen (N-acetyl-p-aminophenol; APAP) toxicity is a common cause of liver damage. In the mouse model of APAP-induced liver injury (AILI), interleukin 11 (IL11) is highly up-regulated and administration of recombinant human IL11 (rhIL11) has been shown to be protective. Here, we demonstrate that the beneficial effect of rhIL11 in the mouse model of AILI is due to its inhibition of endogenous mouse IL11 activity. Our results show that species-matched IL11 behaves like a hepatotoxin. IL11 secreted from APAP-damaged human and mouse hepatocytes triggered an autocrine loop of NADPH oxidase 4 (NOX4)–dependent cell de...
Source: Science Translational Medicine - June 9, 2021 Category: Biomedical Science Authors: Widjaja, A. A., Dong, J., Adami, E., Viswanathan, S., Ng, B., Pakkiri, L. S., Chothani, S. P., Singh, B. K., Lim, W. W., Zhou, J., Shekeran, S. G., Tan, J., Lim, S. Y., Goh, J., Wang, M., Holgate, R., Hearn, A., Felkin, L. E., Yen, P. M., Dear, J. W., Dru Tags: Research Articles Source Type: research

[Research Articles] An MD2-perturbing peptide has therapeutic effects in rodent and rhesus monkey models of stroke
Studies have failed to translate more than 1000 experimental treatments from bench to bedside, leaving stroke as the second leading cause of death in the world. Thrombolysis within 4.5 hours is the recommended therapy for stroke and cannot be performed until neuroimaging is used to distinguish ischemic stroke from hemorrhagic stroke. Therefore, finding a common and critical therapeutic target for both ischemic and hemorrhagic stroke is appealing. Here, we report that the expression of myeloid differentiation protein 2 (MD2), which is traditionally regarded to be expressed only in microglia in the normal brain, was markedly...
Source: Science Translational Medicine - June 9, 2021 Category: Biomedical Science Authors: Fang, Z., Wu, D., Deng, J., Yang, Q., Zhang, X., Chen, J., Wang, S., Hu, S., Hou, W., Ning, S., Ding, Y., Fan, Z., Jiang, Z., Kang, J., Liu, Y., Miao, J., Ji, X., Dong, H., Xiong, L. Tags: Research Articles Source Type: research

[Research Articles] A single-shot Lassa vaccine induces long-term immunity and protects cynomolgus monkeys against heterologous strains
A safe and protective Lassa virus vaccine is crucially needed in Western Africa to stem the recurrent outbreaks of Lassa virus infections in Nigeria and the emergence of Lassa virus in previously unaffected countries, such as Benin and Togo. Major challenges in developing a Lassa virus vaccine include the high diversity of circulating strains and their reemergence from 1 year to another. To address each of these challenges, we immunized cynomolgus monkeys with a measles virus vector expressing the Lassa virus glycoprotein and nucleoprotein of the prototypic Lassa virus strain Josiah (MeV-NP). To evaluate vaccine efficacy a...
Source: Science Translational Medicine - June 9, 2021 Category: Biomedical Science Authors: Mateo, M., Reynard, S., Journeaux, A., Germain, C., Hortion, J., Carnec, X., Picard, C., Baillet, N., Borges-Cardoso, V., Merabet, O., Vallve, A., Barron, S., Jourjon, O., Lacroix, O., Duthey, A., Dirheimer, M., Jouvion, G., Moreau, P.-H., Fellmann, L., C Tags: Research Articles Source Type: research

[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