Abstract:
:The AAA+ adenosine triphosphatase (ATPase) Thorase plays a critical role in controlling synaptic plasticity by regulating the expression of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Bidirectional sequencing of exons of ATAD1, the gene encoding Thorase, in a cohort of patients with schizophrenia and healthy controls revealed rare Thorase variants. These variants caused defects in glutamatergic signaling by impairing AMPAR internalization and recycling in mouse primary cortical neurons. This contributed to increased surface expression of the AMPAR subunit GluA2 and enhanced synaptic transmission. Heterozygous Thorase-deficient mice engineered to express these Thorase variants showed altered synaptic transmission and several behavioral deficits compared to heterozygous Thorase-deficient mice expressing wild-type Thorase. These behavioral impairments were rescued by the competitive AMPAR antagonist Perampanel, a U.S. Food and Drug Administration-approved drug. These findings suggest that Perampanel may be useful for treating disorders involving compromised AMPAR-mediated glutamatergic neurotransmission.
journal_name
Sci Transl Medjournal_title
Science translational medicineauthors
Umanah GKE,Pignatelli M,Yin X,Chen R,Crawford J,Neifert S,Scarffe L,Behensky AA,Guiberson N,Chang M,Ma E,Kim JW,Castro CC,Mao X,Chen L,Andrabi SA,Pletnikov MV,Pulver AE,Avramopoulos D,Bonci A,Valle D,Dawson TM,doi
10.1126/scitranslmed.aah4985subject
Has Abstractpub_date
2017-12-13 00:00:00issue
420eissn
1946-6234issn
1946-6242pii
9/420/eaah4985journal_volume
9pub_type
杂志文章abstract::Current HIV vaccines are only partially efficacious, presenting an opportunity to identify correlates of protection and, thereby, potential insight into mechanisms that prevent HIV acquisition. Two independent preclinical challenge studies in nonhuman primates (NHPs) previously showed partial efficacy of a mosaic aden...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aaw4236
更新日期:2019-08-28 00:00:00
abstract::Elevated serum levels of both total and allergen-specific immunoglobulin E (IgE) correlate with atopic diseases such as allergic rhinitis and allergic asthma. Neutralization of IgE by anti-IgE antibodies can effectively treat allergic asthma. Preclinical studies indicate that targeting membrane IgE-positive cells with...
journal_title:Science translational medicine
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1126/scitranslmed.3008961
更新日期:2014-07-02 00:00:00
abstract::Adoptive cell transfer of ex vivo expanded regulatory T cells (Tregs) has shown immense potential in animal models of auto- and alloimmunity. However, the effective translation of such Treg therapies to the clinic has been slow. Because Treg homeostasis is known to require continuous T cell receptor (TCR) ligation and...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aaw4744
更新日期:2020-11-11 00:00:00
abstract::In recent years, there has been a growing focus on the unreliability of published biomedical and clinical research. To introduce effective new scientific contributors to the culture of health care, we propose a "datathon" or "hackathon" model in which participants with disparate, but potentially synergistic and comple...
journal_title:Science translational medicine
pub_type: 杂志文章,评审
doi:10.1126/scitranslmed.aad9072
更新日期:2016-04-06 00:00:00
abstract::The neurotransmitter glutamate is the primary excitatory neurotransmitter in mammalian brain and is responsible for most corticocortical and corticofugal neurotransmission. Disturbances in glutamatergic function have been implicated in the pathophysiology of several neuropsychiatric disorders-including schizophrenia, ...
journal_title:Science translational medicine
pub_type: 杂志文章,评审
doi:10.1126/scitranslmed.3002804
更新日期:2011-09-28 00:00:00
abstract::EphB receptors regulate the proliferation and positioning of intestinal stem and progenitor cells. In addition, they can act as tumor promoters for adenoma development but suppress progression to invasive carcinoma. We used imatinib to abrogate Abl kinase activity in Apc(Min/+) mice and in mice with LGR5(+) stem cells...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3010567
更新日期:2015-04-01 00:00:00
abstract::Short-term starvation (or fasting) protects normal cells, mice, and potentially humans from the harmful side effects of a variety of chemotherapy drugs. Here, we show that treatment with starvation conditions sensitized yeast cells (Saccharomyces cerevisiae) expressing the oncogene-like RAS2(val19) to oxidative stress...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3003293
更新日期:2012-03-07 00:00:00
abstract::Defects in tumor-intrinsic interferon (IFN) signaling result in failure of immune checkpoint blockade (ICB) against cancer, but these tumors may still maintain sensitivity to T cell-based adoptive cell therapy (ACT). We generated models of IFN signaling defects in B16 murine melanoma observed in patients with acquired...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.abb0152
更新日期:2020-10-14 00:00:00
abstract::In current clinical practice, uterine contractions are monitored via a tocodynamometer or an intrauterine pressure catheter, both of which provide crude information about contractions. Although electrohysterography/electromyography can measure uterine electrical activity, this method lacks spatial specificity and thus...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aau1428
更新日期:2019-03-13 00:00:00
abstract::Physiologically relevant ALK (anaplastic lymphoma kinase) expression was not detected in human and mouse monocytes and macrophages, suggesting that the effects of bioactive compounds on stimulator of interferon genes (STING) activation may not depend on ALK. ...
journal_title:Science translational medicine
pub_type: 评论,杂志文章
doi:10.1126/scitranslmed.aar4321
更新日期:2018-12-12 00:00:00
abstract::Misuse of prescription opioids, opioid addiction, and overdose underscore the urgent need for developing addiction-free effective medications for treating severe pain. Mu opioid peptide (MOP) receptor agonists provide very effective pain relief. However, severe side effects limit their use in the clinical setting. Ago...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aar3483
更新日期:2018-08-29 00:00:00
abstract::Restoring reverse cholesterol transport ameliorates the B cell hyperexpansion and autoimmune disease found to be associated with accumulation of cholesterol in CD11c+ antigen-presenting cells. ...
journal_title:Science translational medicine
pub_type: 评论,杂志文章
doi:10.1126/scitranslmed.aal4997
更新日期:2017-01-25 00:00:00
abstract::Elucidating the factors that impinge on the stability of bacterial communities in the vagina may help in predicting the risk of diseases that affect women's health. Here, we describe the temporal dynamics of the composition of vaginal bacterial communities in 32 reproductive-age women over a 16-week period. The analys...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3003605
更新日期:2012-05-02 00:00:00
abstract::Diseases of failed inflammation resolution are common and largely incurable. Therapeutic induction of inflammation resolution is an attractive strategy to bring about healing without increasing susceptibility to infection. However, therapeutic targeting of inflammation resolution has been hampered by a lack of underst...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3007672
更新日期:2014-02-26 00:00:00
abstract::Local delivery of anticancer agents has the potential to maximize treatment efficacy and minimize the acute and long-term systemic toxicities. Here, we used unsupervised systematic evolution of ligands by exponential enrichment to identify four RNA aptamers that specifically recognized mouse and human myeloid cells in...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aav9760
更新日期:2020-06-17 00:00:00
abstract::Recent studies have established the involvement of the fat mass and obesity-associated gene (FTO) in metabolic disorders such as obesity and diabetes. However, the precise molecular mechanism by which FTO regulates metabolism remains unknown. Here, we used a structure-based virtual screening of U.S. Food and Drug Admi...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aau7116
更新日期:2019-04-17 00:00:00
abstract::Osteoarthritis (OA) is a common degenerative condition that afflicts more than 70% of the population between 55 and 77 years of age. Although its prevalence is rising globally with aging of the population, current therapy is limited to symptomatic relief and, in severe cases, joint replacement surgery. We report that ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3005409
更新日期:2013-03-13 00:00:00
abstract::Therapeutic intravesical instillation of bacillus Calmette-Guérin (BCG) is effective at triggering inflammation and eliciting successful tumor immunity in patients with non-muscle invasive bladder cancer, with 50 to 70% clinical response. Therapeutic success relies on repeated instillations of live BCG administered as...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3003586
更新日期:2012-06-06 00:00:00
abstract::Clinical advancement of the bioartificial liver is hampered by the lack of expandable human hepatocytes and appropriate bioreactors and carriers to encourage hepatic cells to function during extracorporeal circulation. We have recently developed an efficient approach for derivation of expandable liver progenitor-like ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aba5146
更新日期:2020-07-08 00:00:00
abstract::Protein replacement therapies for rare monogenic diseases have a higher probability of regulatory approval compared with biologics, small molecules, and grant-funded orphan drugs. ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3005007
更新日期:2013-03-27 00:00:00
abstract::Metastasis is the major cause of cancer mortality. A more thorough understanding of the mechanisms driving this complex multistep process will aid in the identification and characterization of therapeutically targetable genetic drivers of disease progression. We demonstrate that KLF6-SV1, an oncogenic splice variant o...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3004688
更新日期:2013-01-23 00:00:00
abstract::The Commentary of Mills and Sykes in Science Translational Medicine presented their thesis on the advent of high-throughput technologies and the dangers they may represent for the future of biomedical research. In response, we argue that true progress on the diagnosis and treatment of common human diseases will requir...
journal_title:Science translational medicine
pub_type: 评论,杂志文章
doi:10.1126/scitranslmed.3000882
更新日期:2010-03-31 00:00:00
abstract::Vaccines directed against the blood stages of Plasmodium falciparum malaria are intended to prevent the parasite from invading and replicating within host cells. No blood-stage malaria vaccine has shown clinical efficacy in humans. Most malaria vaccine antigens are parasite surface proteins that have evolved extensive...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3000257
更新日期:2009-10-14 00:00:00
abstract::Hutchinson-Gilford progeria syndrome (HGPS) is caused by a point mutation in the LMNA gene that activates a cryptic donor splice site and yields a truncated form of prelamin A called progerin. Small amounts of progerin are also produced during normal aging. Studies with mouse models of HGPS have allowed the recent dev...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3002847
更新日期:2011-10-26 00:00:00
abstract::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 inhibitor...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aaw9996
更新日期:2020-02-12 00:00:00
abstract::We outline the fundamental properties of a highly participatory rapid learning system that can be developed in part from meaningful use of electronic health records (EHRs). Future widespread adoption of EHRs will make increasing amounts of medical information available in computable form. Secured and trusted use of th...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3001456
更新日期:2010-11-10 00:00:00
abstract::Emerging viral diseases pose ongoing health threats, particularly in an era of globalization; however, new biomedical research technologies such as genome sequencing and structure-based vaccine and drug design have improved our ability to respond to viral threats. ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3009872
更新日期:2014-09-10 00:00:00
abstract::The proinflammatory cytokine interleukin-1β (IL-1β) plays a central role in the pathogenesis and the course of inflammatory skin diseases, including psoriasis. Posttranscriptional activation of IL-1β is mediated by inflammasomes; however, the mechanisms triggering IL-1β processing remain unknown. Recently, cytosolic D...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3002001
更新日期:2011-05-11 00:00:00
abstract::Mycosis fungoides (MF), the most common cutaneous T cell lymphoma (CTCL) is a malignancy of skin-tropic memory T cells. Most MF cases present as early stage (stage I A/B, limited to the skin), and these patients typically have a chronic, indolent clinical course. However, a small subset of early-stage cases develop pr...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aar5894
更新日期:2018-05-09 00:00:00
abstract::Promising therapies for cartilage repair are translated through large animal models toward human application. To guide this work, regulatory agencies publish recommendations ("guidance documents") to direct pivotal large animal studies. These are meant to aid in study design, outline metrics for judging efficacy, and ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aac7019
更新日期:2015-10-21 00:00:00