[Research Articles] The Uppsala APP deletion causes early onset autosomal dominant Alzheimers disease by altering APP processing and increasing amyloid {beta} fibril formation
Point mutations in the amyloid precursor protein gene (APP) cause familial Alzheimer’s disease (AD) by increasing generation or altering conformation of amyloid β (Aβ). Here, we describe the Uppsala APP mutation (690–695), the first reported deletion causing autosomal dominant AD. Affected individuals have an age at symptom onset in their early forties and suffer from a rapidly progressing disease course. Symptoms and biomarkers are typical of AD, with the exception of normal cerebrospinal fluid (CSF) Aβ42 and only slightly pathological amyloid–positron emission tomography signals. Mass spe...
Source: Science Translational Medicine - August 11, 2021 Category: Biomedical Science Authors: Pagnon de la Vega, M., Giedraitis, V., Michno, W., Kilander, L., Güner, G., Zielinski, M., Löwenmark, M., Brundin, R., Danfors, T., Söderberg, L., Alafuzoff, I., Nilsson, L. N. G., Erlandsson, A., Willbold, D., Müller, S. A Tags: Research Articles Source Type: research
[Research Articles] Reduced pannexin 1-IL-33 axis function in donor livers increases risk of MRSA infection in liver transplant recipients
Liver transplantation patients are at increased risk for methicillin-resistant Staphylococcus aureus (MRSA) infection, but the molecular mechanism remains unclear. We found that genetic predisposition to low pannexin 1 (PANX1) expression in donor livers was associated with MRSA infection in human liver transplantation recipients. Using Panx1 and Il-33-knockout mice for liver transplantation models with MRSA tail vein injection, we demonstrated that Panx1 deficiency increased MRSA-induced liver injury and animal death. We found that decreased PANX1 expression in the liver led to reduced release of adenosine triphosphate (AT...
Source: Science Translational Medicine - August 11, 2021 Category: Biomedical Science Authors: Li, H., Yu, X., Shi, B., Zhang, K., Yuan, L., Liu, X., Wang, P., Lv, J., Meng, G., Xuan, Q., Wu, W., Li, B., Peng, X., Qin, X., Liu, W., Zhong, L., Peng, Z. Tags: Research Articles Source Type: research
[Research Articles] Engineering sperm-binding IgG antibodies for the development of an effective nonhormonal female contraception
Many women risk unintended pregnancy because of medical contraindications or dissatisfaction with contraceptive methods, including real and perceived side effects associated with the use of exogenous hormones. We pursued direct vaginal delivery of sperm-binding monoclonal antibodies (mAbs) that can limit progressive sperm motility in the female reproductive tract as a strategy for effective nonhormonal contraception. Here, motivated by the greater agglutination potencies of polyvalent immunoglobulins but the bioprocessing ease and stability of immunoglobulin G (IgG), we engineered a panel of sperm-binding IgGs with 6 to 10...
Source: Science Translational Medicine - August 11, 2021 Category: Biomedical Science Authors: Shrestha, B., Schaefer, A., Zhu, Y., Saada, J., Jacobs, T. M., Chavez, E. C., Omsted, S. S., Cruz-Teran, C. A., Vaca, G. B., Vincent, K., Moench, T. R., Lai, S. K. Tags: Research Articles Source Type: research
[Research Articles] Overcoming microenvironmental resistance to PD-1 blockade in genetically engineered lung cancer models
Immune checkpoint blockade (ICB) with PD-1 or PD-L1 antibodies has been approved for the treatment of non–small cell lung cancer (NSCLC). However, only a minority of patients respond, and sustained remissions are rare. Both chemotherapy and antiangiogenic drugs may improve the efficacy of ICB in mouse tumor models and patients with cancer. Here, we used genetically engineered mouse models of KrasG12D/+;p53–/– NSCLC, including a mismatch repair–deficient variant (KrasG12D/+;p53–/–;Msh2–/–) with higher mutational burden, and longitudinal imaging to study tumor response and resi...
Source: Science Translational Medicine - August 11, 2021 Category: Biomedical Science Authors: Martinez-Usatorre, A., Kadioglu, E., Boivin, G., Cianciaruso, C., Guichard, A., Torchia, B., Zangger, N., Nassiri, S., Keklikoglou, I., Schmittnaegel, M., Ries, C. H., Meylan, E., De Palma, M. Tags: Research Articles Source Type: research
[Research Articles] A recombinant spike protein subunit vaccine confers protective immunity against SARS-CoV-2 infection and transmission in hamsters
Multiple safe and effective vaccines that elicit immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are necessary to respond to the ongoing coronavirus disease 2019 (COVID-19) pandemic. Here, we developed a protein subunit vaccine composed of spike ectodomain protein (StriFK) plus a nitrogen bisphosphonate–modified zinc-aluminum hybrid adjuvant (FH002C). StriFK-FH002C generated substantially higher neutralizing antibody titers in mice, hamsters, and cynomolgus monkeys than those observed in plasma isolated from COVID-19 convalescent individuals. StriFK-FH002C also induced both TH1- ...
Source: Science Translational Medicine - August 11, 2021 Category: Biomedical Science Authors: Wu, Y., Huang, X., Yuan, L., Wang, S., Zhang, Y., Xiong, H., Chen, R., Ma, J., Qi, R., Nie, M., Xu, J., Zhang, Z., Chen, L., Wei, M., Zhou, M., Cai, M., Shi, Y., Zhang, L., Yu, H., Hong, J., Wang, Z., Hong, Y., Yue, M., Li, Z., Chen, D., Zheng, Q., Li, S. Tags: Research Articles Source Type: research
[Research Articles] Formyl peptide receptor 1 signaling potentiates inflammatory brain injury
Acute brain insults elicit pronounced inflammation that amplifies brain damage in intracerebral hemorrhage (ICH). We profiled perihematomal tissue from patients with ICH, generating a molecular landscape of the injured brain, and identified formyl peptide receptor 1 (FPR1) as the most abundantly increased damage-associated molecular pattern (DAMP) receptor, predominantly expressed by microglia. Circulating mitochondrial N-formyl peptides, endogenous ligands of FPR1, were augmented and correlated with the magnitude of brain edema in patients with ICH. Interactions of formyl peptides with FPR1 activated microglia, boosted ne...
Source: Science Translational Medicine - August 4, 2021 Category: Biomedical Science Authors: Li, Z., Li, Y., Han, J., Zhu, Z., Li, M., Liu, Q., Wang, Y., Shi, F.-D. Tags: Research Articles Source Type: research
[Research Articles] Perturbed BMP signaling and denervation promote muscle wasting in cancer cachexia
Most patients with advanced solid cancers exhibit features of cachexia, a debilitating syndrome characterized by progressive loss of skeletal muscle mass and strength. Because the underlying mechanisms of this multifactorial syndrome are incompletely defined, effective therapeutics have yet to be developed. Here, we show that diminished bone morphogenetic protein (BMP) signaling is observed early in the onset of skeletal muscle wasting associated with cancer cachexia in mouse models and in patients with cancer. Cancer-mediated factors including Activin A and IL-6 trigger the expression of the BMP inhibitor Noggin in muscle...
Source: Science Translational Medicine - August 4, 2021 Category: Biomedical Science Authors: Sartori, R., Hagg, A., Zampieri, S., Armani, A., Winbanks, C. E., Viana, L. R., Haidar, M., Watt, K. I., Qian, H., Pezzini, C., Zanganeh, P., Turner, B. J., Larsson, A., Zanchettin, G., Pierobon, E. S., Moletta, L., Valmasoni, M., Ponzoni, A., Attar, S., Tags: Research Articles Source Type: research
[Research Articles] Dual targeting of CTLA-4 and CD47 on Treg cells promotes immunity against solid tumors
Blockade of CD47, the "do not eat me" signal, has limited effects in solid tumors despite its potent antitumor effects in hematopoietic malignancies. Taking advantage of the high expression of cytotoxic T lymphocyte–associated protein 4 (CTLA-4) on Treg cells and abundant Fc receptor–expressing active phagocytes inside the tumor microenvironment (TME), we designed and tested a heterodimer combining an anti–CTLA-4 antibody, which targets Treg cells, with the CD47 ligand, signal regulatory protein α (SIRPα), to selectively block CD47 on intratumoral Treg cells. We hypothesized that heterodimer t...
Source: Science Translational Medicine - August 4, 2021 Category: Biomedical Science Authors: Zhang, A., Ren, Z., Tseng, K.-F., Liu, X., Li, H., Lu, C., Cai, Y., Minna, J. D., Fu, Y.-X. Tags: Research Articles Source Type: research
[Research Articles] A high-throughput cell- and virus-free assay shows reduced neutralization of SARS-CoV-2 variants by COVID-19 convalescent plasma
The detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–specific antibodies in the serum of an individual indicates previous infection or vaccination. However, it provides limited insight into the protective nature of this immune response. Neutralizing antibodies recognizing the viral spike protein are more revealing, yet their measurement traditionally requires virus- and cell-based systems that are costly, time-consuming, inflexible, and potentially biohazardous. Here, we present a cell-free quantitative neutralization assay based on the competitive inhibition of trimeric SARS-CoV-2 spike prot...
Source: Science Translational Medicine - August 4, 2021 Category: Biomedical Science Authors: Fenwick, C., Turelli, P., Pellaton, C., Farina, A., Campos, J., Raclot, C., Pojer, F., Cagno, V., Nussle, S. G., DAcremont, V., Fehr, J., Puhan, M., Pantaleo, G., Trono, D. Tags: Research Articles Source Type: research
[Research Articles] Unfolded protein response inhibitors cure group A streptococcal necrotizing fasciitis by modulating host asparagine
Group A streptococcus (GAS) is among the top 10 causes of mortality from an infectious disease, producing mild to invasive life-threatening manifestations. Necrotizing fasciitis (NF) is characterized by a rapid GAS spread into fascial planes followed by extensive tissue destruction. Despite prompt treatments of antibiotic administration and tissue debridement, mortality from NF is still high. Moreover, there is no effective vaccine against GAS, and early diagnosis of NF is problematic because its clinical presentations are not specific. Thus, there is a genuine need for effective treatments against GAS NF. Previously, we r...
Source: Science Translational Medicine - August 4, 2021 Category: Biomedical Science Authors: Anand, A., Sharma, A., Ravins, M., Biswas, D., Ambalavanan, P., Lim, K. X. Z., Tan, R. Y. M., Johri, A. K., Tirosh, B., Hanski, E. Tags: Research Articles Source Type: research
[Focus] Identifying and targeting the Achilles heel of a recalcitrant cancer
Targeting replication stress response proteins in small cell lung cancer activates the innate immune cGAS-STING pathway leading to augmentation of immunotherapy’s antitumor response. (Source: Science Translational Medicine)
Source: Science Translational Medicine - August 4, 2021 Category: Biomedical Science Authors: Sen, T. Tags: Focus Source Type: research
[Research Articles] TGF{beta}2 and TGF{beta}3 isoforms drive fibrotic disease pathogenesis
Transforming growth factor–β (TGFβ) is a key driver of fibrogenesis. Three TGFβ isoforms (TGFβ1, TGFβ2, and TGFβ3) in mammals have distinct functions in embryonic development; however, the postnatal pathological roles and activation mechanisms of TGFβ2 and TGFβ3 have not been well characterized. Here, we show that the latent forms of TGFβ2 and TGFβ3 can be activated by integrin-independent mechanisms and have lower activation thresholds compared to TGFβ1. Unlike TGFB1, TGFB2 and TGFB3 expression is increased in human lung and liver fibrotic tissues compared to he...
Source: Science Translational Medicine - August 4, 2021 Category: Biomedical Science Authors: Sun, T., Huang, Z., Liang, W.-C., Yin, J., Lin, W. Y., Wu, J., Vernes, J.-M., Lutman, J., Caplazi, P., Jeet, S., Wong, T., Wong, M., DePianto, D. J., Morshead, K. B., Sun, K.-H., Modrusan, Z., Vander Heiden, J. A., Abbas, A. R., Zhang, H., Xu, M., NDiaye, Tags: Research Articles Source Type: research
[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
