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Elizabeth A Whitcomb, Yien Che Tsai, Johnvesly Basappa, Ke Liu, Aurélie K Le Feuvre, Allan M Weissman, Allen Taylor
Ubiquitinylation drives many cellular processes by targeting proteins for proteasomal degradation. Ubiquitin conjugation enzymes promote ubiquitinylation and, thus, degradation of protein substrates. Ubiquitinylation is a well-known posttranslational modification controlling cell-cycle transitions and levels or/and activation levels of ubiquitin-conjugating enzymes change during development and cell cycle. Progression through the cell cycle is tightly controlled by CDK inhibitors such as p27Kip1 . Here we show that, in contrast to promoting its degradation, the ubiquitin-conjugating enzyme UBCH7/UBE2L3 specifically protects p27Kip1 from degradation...
August 16, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Jie Yang, Mengru Zhang, Hongshik Ahn, Qing Zhang, Tony B Jin, Ien A Li, Matthew Nemesure, Nandita Joshi, Haoran Jiang, Jeffrey M Miller, Robert Todd Ogden, Eva Petkova, Matthew S Milak, Mary Elizabeth Sublette, Gregory M Sullivan, Madhukar H Trivedi, Myrna Weissman, Patrick J McGrath, Maurizio Fava, Benji T Kurian, Diego A Pizzagalli, Crystal M Cooper, Melvin McInnis, Maria A Oquendo, Joseph John Mann, Ramin V Parsey, Christine DeLorenzo
This study aimed to identify biomarkers of major depressive disorder (MDD), by relating neuroimage-derived measures to binary (MDD/control), ordinal (severe MDD/mild MDD/control), or continuous (depression severity) outcomes. To address MDD heterogeneity, factors (severity of psychic depression, motivation, anxiety, psychosis, and sleep disturbance) were also used as outcomes. A multisite, multimodal imaging (diffusion MRI [dMRI] and structural MRI [sMRI]) cohort (52 controls and 147 MDD patients) and several modeling techniques-penalized logistic regression, random forest, and support vector machine (SVM)-were used...
August 16, 2018: Human Brain Mapping
Mingye Feng, Kristopher D Marjon, Fangfang Zhu, Rachel Weissman-Tsukamoto, Aaron Levett, Katie Sullivan, Kevin S Kao, Maxim Markovic, Paul A Bump, Hannah M Jackson, Timothy S Choi, Jing Chen, Allison M Banuelos, Jie Liu, Phung Gip, Lei Cheng, Denong Wang, Irving L Weissman
Macrophage-mediated programmed cell removal (PrCR) is a process essential for the clearance of unwanted (damaged, dysfunctional, aged, or harmful) cells. The detection and recognition of appropriate target cells by macrophages is a critical step for successful PrCR, but its molecular mechanisms have not been delineated. Here using the models of tissue turnover, cancer immunosurveillance, and hematopoietic stem cells, we show that unwanted cells such as aging neutrophils and living cancer cells are susceptible to "labeling" by secreted calreticulin (CRT) from macrophages, enabling their clearance through PrCR...
August 10, 2018: Nature Communications
Ofira Zloto, Irina S Barequet, Alon Weissman, Orit Ezra Nimni, Yoav Berger, Noa Avni-Zauberman
PURPOSE: To examine the clinical characteristics, treatments, and prognosis of all cases of infectious keratitis resistant to conventional therapy and treated by photo-activated chromophore for keratitis corneal cross-linking (PACK-CXL) in one institution between 2012 and 2016. METHODS: A database search of patients who underwent PACK-CXL (ultraviolet-A for 10 minutes for irradiance of 9 mW/cm2 ) for infectious keratitis unresponsive to medical treatment at a tertiary care hospital was conducted...
August 1, 2018: Journal of Refractive Surgery
Nicholas T Ingolia, Jeffrey A Hussmann, Jonathan S Weissman
The translation of messenger RNA (mRNA) into protein and the folding of the resulting protein into an active form are prerequisites for virtually every cellular process and represent the single largest investment of energy by cells. Ribosome profiling-based approaches have revolutionized our ability to monitor every step of protein synthesis in vivo, allowing one to measure the rate of protein synthesis across the proteome, annotate the protein coding capacity of genomes, monitor localized protein synthesis, and explore cotranslational folding and targeting...
July 23, 2018: Cold Spring Harbor Perspectives in Biology
Max A Horlbeck, Albert Xu, Min Wang, Neal K Bennett, Chong Y Park, Derek Bogdanoff, Britt Adamson, Eric D Chow, Martin Kampmann, Tim R Peterson, Ken Nakamura, Michael A Fischbach, Jonathan S Weissman, Luke A Gilbert
Seminal yeast studies have established the value of comprehensively mapping genetic interactions (GIs) for inferring gene function. Efforts in human cells using focused gene sets underscore the utility of this approach, but the feasibility of generating large-scale, diverse human GI maps remains unresolved. We developed a CRISPR interference platform for large-scale quantitative mapping of human GIs. We systematically perturbed 222,784 gene pairs in two cancer cell lines. The resultant maps cluster functionally related genes, assigning function to poorly characterized genes, including TMEM261, a new electron transport chain component...
August 9, 2018: Cell
Theodore L Roth, Cristina Puig-Saus, Ruby Yu, Eric Shifrut, Julia Carnevale, P Jonathan Li, Joseph Hiatt, Justin Saco, Paige Krystofinski, Han Li, Victoria Tobin, David N Nguyen, Michael R Lee, Amy L Putnam, Andrea L Ferris, Jeff W Chen, Jean-Nicolas Schickel, Laurence Pellerin, David Carmody, Gorka Alkorta-Aranburu, Daniela Del Gaudio, Hiroyuki Matsumoto, Montse Morell, Ying Mao, Min Cho, Rolen M Quadros, Channabasavaiah B Gurumurthy, Baz Smith, Michael Haugwitz, Stephen H Hughes, Jonathan S Weissman, Kathrin Schumann, Jonathan H Esensten, Andrew P May, Alan Ashworth, Gary M Kupfer, Siri Atma W Greeley, Rosa Bacchetta, Eric Meffre, Maria Grazia Roncarolo, Neil Romberg, Kevan C Herold, Antoni Ribas, Manuel D Leonetti, Alexander Marson
Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4 . The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6 . Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function...
July 2018: Nature
Joshua M Liao, Judy A Shea, Arlene Weissman, Amol S Navathe
We surveyed a national sample of internal medicine physicians in March-May 2017 to explore their beliefs about the newly implemented Merit-based Incentive Payment System (MIPS). Respondents believed that their efforts in the four focus areas identified in the survey would ultimately improve the value of care. When informed that those areas represented the four MIPS domains, the majority remained positive about the likely impact on value. However, expectations varied by physicians' characteristics and sense of control over the desired outcomes, and many respondents believed that unintended consequences could occur...
July 2018: Health Affairs
Weihan Li, Voytek Okreglak, Jirka Peschek, Philipp Kimmig, Meghan Zubradt, Jonathan S Weissman, Peter Walter
The endoplasmic reticulum (ER) protein folding capacity is balanced with the protein folding burden to prevent accumulation of un- or misfolded proteins. The ER membrane-resident kinase/RNase Ire1 maintains ER protein homeostasis through two fundamentally distinct processes. First, Ire1 can initiate a transcriptional response through a non-conventional mRNA splicing reaction to increase the ER folding capacity. Second, Ire1 can decrease the ER folding burden through selective mRNA decay. In Saccharomyces cerevisiae and Schizosaccharomyces pombe, the two Ire1 functions have been evolutionarily separated...
July 9, 2018: ELife
Veronika L Tchesnokova, Elena Rechkina, Lydia Larson, Kendra Ferrier, Jamie Lee Weaver, David W Schroeder, Rosemary She, Susan M Butler-Wu, Maria E Aguero-Rosenfeld, Danielle Zerr, Ferric C Fang, James Ralston, Kim Riddell, Delia Scholes, Scott Weissman, Kaveri Parker, Brad Spellberg, James R Johnson, Evgeni V Sokurenko
We describe the rapid and ongoing emergence across multiple US cities of a new multidrug-resistant E. coli clone - ST1193, resistant to fluoroquinolones (100%), trimethoprim/sulfamethoxazole (55%) and tetracycline (53%). ST1193 is associated with younger adults (age < 40 years) and currently comprises a quarter of fluoroquinolone-resistant clinical E. coli urine isolates.
June 29, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Hao Shao, Xiaokai Li, Michael A Moses, Luke A Gilbert, Chakrapani Kalyanaraman, Zapporah T Young, Margarita Chernova, Sara N Journey, Jonathan S Weissman, Byron Hann, Matthew P Jacobson, Len Neckers, Jason E Gestwicki
Cancer cells rely on the chaperone heat shock protein 70 (Hsp70) for survival and proliferation. Recently, benzothiazole rhodacyanines have been shown to bind an allosteric site on Hsp70, interrupting its binding to nucleotide-exchange factors (NEFs) and promoting cell death in breast cancer cell lines. However, proof-of-concept molecules, such as JG-98, have relatively modest potency (EC50 ≈ 0.7-0.4 μM) and are rapidly metabolized in animals. Here, we explored this chemical series through structure- and property-based design of ∼300 analogs, showing that the most potent had >10-fold improved EC50 values (∼0...
July 26, 2018: Journal of Medicinal Chemistry
Ulf-Peter Guenther, David E Weinberg, Meghan M Zubradt, Frank A Tedeschi, Brittany N Stawicki, Leah L Zagore, Gloria A Brar, Donny D Licatalosi, David P Bartel, Jonathan S Weissman, Eckhard Jankowsky
The conserved and essential DEAD-box RNA helicase Ded1p from yeast and its mammalian orthologue DDX3 are critical for the initiation of translation1 . Mutations in DDX3 are linked to tumorigenesis2-4 and intellectual disability5 , and the enzyme is targeted by a range of viruses6 . How Ded1p and its orthologues engage RNAs during the initiation of translation is unknown. Here we show, by integrating transcriptome-wide analyses of translation, RNA structure and Ded1p-RNA binding, that the effects of Ded1p on the initiation of translation are connected to near-cognate initiation codons in 5' untranslated regions...
July 2018: Nature
Rebecca T Hahn, Jonathon Leipsic, Pamela S Douglas, Wael A Jaber, Neil J Weissman, Philippe Pibarot, Philipp Blanke, Jae K Oh
OBJECTIVES: This study aims to establish parameters for identifying normal function for each of the 3 iterations of balloon-expandable valves and 2 iterations of self-expanding valves. BACKGROUND: Expected transthoracic echocardiographic Doppler-derived hemodynamic data for transcatheter aortic valves inform pre-implant decision-making and post-implanted monitoring of longitudinal valve function. METHODS: We collected the Echocardiography Core Lab measured mean gradients and effective orifice area (EOA) from discharge or 30-day echocardiograms from randomized trials; the PARTNER (Placement of Aortic Transcatheter Valves) trials for the balloon-expandable valves and the Medtronic CoreValve US Pivotal trial and Medtronic CoreValve Evolut R United States IDE Clinical Study for the self-expanding valves...
June 8, 2018: JACC. Cardiovascular Imaging
Joel S Weissman, Eric G Campbell, I Glenn Cohen, Holly Fernandez Lynch, Emily A Largent, Avni Gupta, Ronen Rozenblum, Melissa Abraham, Karen Spikes, Maureen Fagan, Martie Carnie
Patient-centered outcomes research (PCOR) is becoming increasingly common. However, there is little evidence regarding what novel ethical challenges, if any, are posed by PCOR with relevance to institutional review board (IRB) oversight and human subjects protections. This article reports the results of a national survey of all IRB chairpersons from research-intensive institutions in the United States. Findings address the responsibilities of IRBs and the challenges associated with PCOR review and oversight...
June 1, 2018: Journal of Empirical Research on Human Research Ethics: JERHRE
Juliet Okoroh, Samuel Essoun, Anthony Seddoh, Hobart Harris, Joel S Weissman, Lydia Dsane-Selby, Robert Riviello
BACKGROUND: Approximately 150 million people suffer from financial catastrophe annually because of out-of-pocket expenditures (OOPEs) on health. Although the National Health Insurance Scheme (NHIS) of Ghana was designed to promote universal health coverage, OOPEs as a proportion of total health expenditures remains elevated at 26%, exceeding the WHO's recommendations of less than 15-20%. To determine whether enrollment in the NHIS reduces the likelihood of OOPEs and catastrophic health expenditures (CHEs) in Ghana, we undertook a systematic review of the published literature...
June 7, 2018: BMC Health Services Research
Matthew J Shurtleff, Daniel N Itzhak, Jeffrey A Hussmann, Nicole T Schirle Oakdale, Elizabeth A Costa, Martin Jonikas, Jimena Weibezahn, Katerina D Popova, Calvin H Jan, Pavel Sinitcyn, Shruthi S Vembar, Hilda Hernandez, Jürgen Cox, Alma L Burlingame, Jeffrey Brodsky, Adam Frost, Georg Hh Borner, Jonathan S Weissman
The endoplasmic reticulum (ER) supports biosynthesis of proteins with diverse transmembrane domain (TMD) lengths and hydrophobicity. Features in transmembrane domains such as charged residues in ion channels are often functionally important, but could pose a challenge during cotranslational membrane insertion and folding. Our systematic proteomic approaches in both yeast and human cells revealed that the ER membrane protein complex (EMC) binds to and promotes the biogenesis of a range of multipass transmembrane proteins, with a particular enrichment for transporters...
May 29, 2018: ELife
Gunsagar S Gulati, Matthew P Murphy, Owen Marecic, Michael Lopez, Rachel E Brewer, Lauren S Koepke, Anoop Manjunath, Ryan C Ransom, Ankit Salhotra, Irving L Weissman, Michael T Longaker, Charles K F Chan
There are limited methods available to study skeletal stem, progenitor, and progeny cell activity in normal and diseased contexts. Most protocols for skeletal stem cell isolation are based on the extent to which cells adhere to plastic or whether they express a limited repertoire of surface markers. Here, we describe a flow cytometry-based approach that does not require in vitro selection and that uses eight surface markers to distinguish and isolate mouse skeletal stem cells (mSSCs); bone, cartilage, and stromal progenitors (mBCSPs); and five downstream differentiated subtypes, including chondroprogenitors, two types of osteoprogenitors, and two types of hematopoiesis-supportive stroma...
June 2018: Nature Protocols
Zhou Yu, Lauren E Surface, Chong Yon Park, Max A Horlbeck, Gregory A Wyant, Monther Abu-Remaileh, Timothy R Peterson, David M Sabatini, Jonathan S Weissman, Erin K O'Shea
Nitrogen-containing-bisphosphonates (N-BPs) are a class of drugs widely prescribed to treat osteoporosis and other bone-related diseases. Although previous studies have established that N-BPs function by inhibiting the mevalonate pathway in osteoclasts, the mechanism by which N-BPs enter the cytosol from the extracellular space to reach their molecular target is not understood. Here, we implemented a CRISPRi-mediated genome-wide screen and identified SLC37A3 (solute carrier family 37 member A3) as a gene required for the action of N-BPs in mammalian cells...
May 10, 2018: ELife
Norbert Pardi, Michael J Hogan, Martin S Naradikian, Kaela Parkhouse, Derek W Cain, Letitia Jones, M Anthony Moody, Hans P Verkerke, Arpita Myles, Elinor Willis, Celia C LaBranche, David C Montefiori, Jenna L Lobby, Kevin O Saunders, Hua-Xin Liao, Bette T Korber, Laura L Sutherland, Richard M Scearce, Peter T Hraber, István Tombácz, Hiromi Muramatsu, Houping Ni, Daniel A Balikov, Charles Li, Barbara L Mui, Ying K Tam, Florian Krammer, Katalin Karikó, Patricia Polacino, Laurence C Eisenlohr, Thomas D Madden, Michael J Hope, Mark G Lewis, Kelly K Lee, Shiu-Lok Hu, Scott E Hensley, Michael P Cancro, Barton F Haynes, Drew Weissman
T follicular helper (Tfh) cells are required to develop germinal center (GC) responses and drive immunoglobulin class switch, affinity maturation, and long-term B cell memory. In this study, we characterize a recently developed vaccine platform, nucleoside-modified, purified mRNA encapsulated in lipid nanoparticles (mRNA-LNPs), that induces high levels of Tfh and GC B cells. Intradermal vaccination with nucleoside-modified mRNA-LNPs encoding various viral surface antigens elicited polyfunctional, antigen-specific, CD4+ T cell responses and potent neutralizing antibody responses in mice and nonhuman primates...
June 4, 2018: Journal of Experimental Medicine
Seung Woo Cho, Jin Xu, Ruping Sun, Maxwell R Mumbach, Ava C Carter, Y Grace Chen, Kathryn E Yost, Jeewon Kim, Jing He, Stephanie A Nevins, Suet-Feung Chin, Carlos Caldas, S John Liu, Max A Horlbeck, Daniel A Lim, Jonathan S Weissman, Christina Curtis, Howard Y Chang
Noncoding mutations in cancer genomes are frequent but challenging to interpret. PVT1 encodes an oncogenic lncRNA, but recurrent translocations and deletions in human cancers suggest alternative mechanisms. Here, we show that the PVT1 promoter has a tumor-suppressor function that is independent of PVT1 lncRNA. CRISPR interference of PVT1 promoter enhances breast cancer cell competition and growth in vivo. The promoters of the PVT1 and the MYC oncogenes, located 55 kb apart on chromosome 8q24, compete for engagement with four intragenic enhancers in the PVT1 locus, thereby allowing the PVT1 promoter to regulate pause release of MYC transcription...
May 31, 2018: Cell
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