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Human Islets Expressing Hnf1a Variant Have Defective Beta Cell Transcriptional Regulatory Networks, Rachana Haliyur, Sambra D. Redick, David M. Harlan, Alvin C. Powers Jan 2019

Human Islets Expressing Hnf1a Variant Have Defective Beta Cell Transcriptional Regulatory Networks, Rachana Haliyur, Sambra D. Redick, David M. Harlan, Alvin C. Powers

Open Access Articles

Using an integrated approach to characterize the pancreatic tissue and isolated islets from a 33-year-old with 17 years of type 1 diabetes (T1D), we found that donor islets contained beta cells without insulitis and lacked glucose-stimulated insulin secretion despite a normal insulin response to cAMP-evoked stimulation. With these unexpected findings for T1D, we sequenced the donor DNA and found a pathogenic heterozygous variant in the gene encoding hepatocyte nuclear factor-1alpha (HNF1A). In one of the first studies of human pancreatic islets with a disease-causing HNF1A variant associated with the most common form of monogenic diabetes, we found that HNF1A dysfunction ...


General Population Normative Data For The Eortc Qlq-C30 Health-Related Quality Of Life Questionnaire Based On 15,386 Persons Across 13 European Countries, Canada And The Unites States, S. Nolte, G. Liegl, M. A. Petersen, N. K. Aaronson, A. Costantini, P. M. Fayers, M. Groenvold, B. Holzner, C. D. Johnson, G Kemmler, K. A. Tomaszewski, A. Waldmann, T. E. Young, Matthias S. F. Rose Jan 2019

General Population Normative Data For The Eortc Qlq-C30 Health-Related Quality Of Life Questionnaire Based On 15,386 Persons Across 13 European Countries, Canada And The Unites States, S. Nolte, G. Liegl, M. A. Petersen, N. K. Aaronson, A. Costantini, P. M. Fayers, M. Groenvold, B. Holzner, C. D. Johnson, G Kemmler, K. A. Tomaszewski, A. Waldmann, T. E. Young, Matthias S. F. Rose

Open Access Articles

OBJECTIVE: The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 health-related quality of life questionnaire is one of the most widely used cancer-specific health-related quality of life questionnaires worldwide. General population norm data can facilitate the interpretation of QLQ-C30 data obtained from cancer patients. This study aimed at systematically collecting norm data from the general population to develop European QLQ-C30 norm scores and to generate comparable norm data for individual countries in Europe and North America.

METHODS: We collected QLQ-C30 data from the general population across 11 European Union (EU) countries, Russia, Turkey, Canada and United States (n ...


Establishing The European Norm For The Health-Related Quality Of Life Domains Of The Computer-Adaptive Test Eortc Cat Core, G. Liegl, M. A. Petersen, M. Groenvold, N. K. Aaronson, A. Costantini, P. M. Fayers, B. Holzner, C. D. Johnson, G. Kemmler, K. A. Tomaszewski, A. Waldmann, T. E. Young, Matthias S. F. Rose, S. Nolte Jan 2019

Establishing The European Norm For The Health-Related Quality Of Life Domains Of The Computer-Adaptive Test Eortc Cat Core, G. Liegl, M. A. Petersen, M. Groenvold, N. K. Aaronson, A. Costantini, P. M. Fayers, B. Holzner, C. D. Johnson, G. Kemmler, K. A. Tomaszewski, A. Waldmann, T. E. Young, Matthias S. F. Rose, S. Nolte

Open Access Articles

OBJECTIVE: The computer-adaptive test (CAT) of the European Organisation for Research and Treatment of Cancer (EORTC), the EORTC CAT Core, assesses the same 15 domains as the EORTC QLQ-C30 health-related quality of life questionnaire but with increased precision, efficiency, measurement range and flexibility. CAT parameters for estimating scores have been established based on clinical data from cancer patients. This study aimed at establishing the European Norm for each CAT domain based on general population data.

METHODS: We collected representative general population data across 11 European Union (EU) countries, Russia, Turkey, Canada and the United States (n > /= 1000/country; stratified by ...


Culturally Adaptive Storytelling Intervention Versus Didactic Intervention To Improve Hypertension Control In Vietnam- 12 Month Follow Up Results: A Cluster Randomized Controlled Feasibility Trial, Hoa L. Nguyen, Duc A. Ha, Robert J. Goldberg, Catarina I. Kiefe, German Chiriboga, Ha N. Ly, Cuong K. Nguyen, Ngoc T. Phan, Nguyen C. Vu, Quang P. Nguyen, Jeroan J. Allison Dec 2018

Culturally Adaptive Storytelling Intervention Versus Didactic Intervention To Improve Hypertension Control In Vietnam- 12 Month Follow Up Results: A Cluster Randomized Controlled Feasibility Trial, Hoa L. Nguyen, Duc A. Ha, Robert J. Goldberg, Catarina I. Kiefe, German Chiriboga, Ha N. Ly, Cuong K. Nguyen, Ngoc T. Phan, Nguyen C. Vu, Quang P. Nguyen, Jeroan J. Allison

Open Access Articles

INTRODUCTION: Vietnam is experiencing an epidemiologic transition with an increased prevalence of non-communicable diseases. The country needs novel, large-scale, and sustainable interventions to improve hypertension control. We report the 12 month follow-up results of a cluster randomized feasibility trial in Hung Yen province, Vietnam, which evaluated the feasibility and acceptability of two community-based interventions to improve hypertension control: a "storytelling" and a didactic intervention.

METHODS: The storytelling intervention included stories in the patients' own words about coping with hypertension and didactic content about the importance of healthy lifestyle behaviors in controlling elevated blood pressure levels. The didactic intervention included only ...


Toll-Like Receptor-4 Disruption Suppresses Adipose Tissue Remodeling And Increases Survival In Cancer Cachexia Syndrome, Felipe Henriques, Magno A. Lopes, Felipe O. Franco, Pamela Knobl, Kaltinaitis B. Santos, Luana L. Bueno, Victor A. Correa, Alexander H. Bedard, Adilson L. Guilherme, Alexander Birbrair, Sidney B. Peres, Stephen R. Farmer, Miguel L. Batista Jr. Dec 2018

Toll-Like Receptor-4 Disruption Suppresses Adipose Tissue Remodeling And Increases Survival In Cancer Cachexia Syndrome, Felipe Henriques, Magno A. Lopes, Felipe O. Franco, Pamela Knobl, Kaltinaitis B. Santos, Luana L. Bueno, Victor A. Correa, Alexander H. Bedard, Adilson L. Guilherme, Alexander Birbrair, Sidney B. Peres, Stephen R. Farmer, Miguel L. Batista Jr.

Open Access Articles

Cancer-induced cachexia, characterized by systemic inflammation, body weight loss, adipose tissue (AT) remodeling and muscle wasting, is a malignant metabolic syndrome with undefined etiology. Here, we show that both genetic ablation and pharmacological inhibition of TLR4 were able to attenuate the main clinical markers of cachexia in mice bearing Lewis lung carcinoma (LLC). AT remodelling was not found in LLC tumor-bearing (TB) TLR4(-/-) mice due to reduced macrophage infiltration and adipocyte atrophy. TLR4(-/-) mice were also resistant to cold-induced browning of subcutaneous AT (scAT). Importantly, pharmacological inhibition of TLR4 (Atorvastatin) reproduced the main protective effect against AT remodeling found in ...


Hla-Do Modulates The Diversity Of The Mhc-Ii Self-Peptidome, Padma P. Nanaware, Mollie M. Jurewicz, John D. Leszyk, Scott A. Shaffer, Lawrence J. Stern Dec 2018

Hla-Do Modulates The Diversity Of The Mhc-Ii Self-Peptidome, Padma P. Nanaware, Mollie M. Jurewicz, John D. Leszyk, Scott A. Shaffer, Lawrence J. Stern

Open Access Articles

Presentation of antigenic peptides on MHC-II molecules is essential for tolerance to self and for initiation of immune responses against foreign antigens. DO (HLA-DO in humans, H2-O in mice) is a non-classical MHC-II protein that has been implicated in control of autoimmunity and regulation of neutralizing antibody responses to viruses. These effects likely are related to a role of DO in selecting MHC-II epitopes, but previous studies examining the effect of DO on presentation of selected CD4 T cell epitopes have been contradictory. To understand how DO modulates MHC-II antigen presentation, we characterized the full spectrum of peptides presented by ...


Protective Versus Pathologic Pre-Exposure Cytokine Profiles In Dengue Virus Infection, Heather Friberg, Coreen M. Beaumier, Sangshin Park, Pamela P. Pazoles, Timothy P. Endy, Anuja Mathew, Jeffrey R. Currier, Richard G. Jarman, Kathryn B. Anderson, Steven Hatch, Stephen J. Thomas, Alan L. Rothman Dec 2018

Protective Versus Pathologic Pre-Exposure Cytokine Profiles In Dengue Virus Infection, Heather Friberg, Coreen M. Beaumier, Sangshin Park, Pamela P. Pazoles, Timothy P. Endy, Anuja Mathew, Jeffrey R. Currier, Richard G. Jarman, Kathryn B. Anderson, Steven Hatch, Stephen J. Thomas, Alan L. Rothman

Open Access Articles

BACKGROUND: Hyperendemic circulation of all four types of dengue virus (DENV-1-4) has expanded globally, fueling concern for increased incidence of severe dengue. While the majority of DENV infections are subclinical, epidemiologic studies suggest that type-cross-reactive immunity can influence disease outcome in subsequent infections. The mechanisms controlling these differential clinical outcomes remain poorly defined.

METHODOLOGY/PRINCIPAL FINDINGS: Blood samples were collected from a cohort of school-aged Thai children who subsequently experienced a subclinical DENV infection or developed dengue illness. PBMC collected prior to infection were stimulated in vitro with DENV and the secretion of 30 cytokines was measured using a multiplexed ...


Cpla2alpha-/- Sympathetic Neurons Exhibit Increased Membrane Excitability And Loss Of N-Type Ca2+ Current Inhibition By M1 Muscarinic Receptor Signaling, Liwang Liu, Joseph V. Bonventre, Ann R. Rittenhouse Dec 2018

Cpla2alpha-/- Sympathetic Neurons Exhibit Increased Membrane Excitability And Loss Of N-Type Ca2+ Current Inhibition By M1 Muscarinic Receptor Signaling, Liwang Liu, Joseph V. Bonventre, Ann R. Rittenhouse

Open Access Articles

Group IVa cytosolic phospholipase A2 (cPLA2alpha) mediates GPCR-stimulated arachidonic acid (AA) release from phosphatidylinositol 4,5-bisphosphate (PIP2) located in plasma membranes. We previously found in superior cervical ganglion (SCG) neurons that PLA2 activity is required for voltage-independent N-type Ca2+ (N-) current inhibition by M1 muscarinic receptors (M1Rs). These findings are at odds with an alternative model, previously observed for M-current inhibition, where PIP2 dissociation from channels and subsequent metabolism by phospholipase C suffices for current inhibition. To resolve cPLA2alpha's importance, we have investigated its role in mediating voltage-independent N-current inhibition (~40%) that follows application of the muscarinic agonist oxotremorine-M ...


Membrane Protein Nanoparticles: The Shape Of Things To Come, Kailene S. Simon, Naomi L. Pollock, Sarah C. Lee Dec 2018

Membrane Protein Nanoparticles: The Shape Of Things To Come, Kailene S. Simon, Naomi L. Pollock, Sarah C. Lee

Open Access Articles

The use of styrene-maleic acid (SMA) for the purification of a wide range of membrane proteins (MPs) from both prokaryotic and eukaryotic sources has begun to make an impact in the field of MP biology. This method is growing in popularity as a means to purify and thoroughly investigate the structure and function of MPs and biological membranes. The amphiphilic SMA copolymer can effectively extract MPs directly from a native lipid bilayer to form discs approximately 10 nm in diameter. The resulting lipid particles, or styrene-maleic acid lipid particles (SMALPs), contain SMA, protein and membrane lipid. MPs purified in SMALPs ...


Stakeholder Engagement In Developing An Electronic Clinical Support Tool For Tobacco Prevention In Adolescent Primary Care, Ramzi G. Salloum, Ryan P. Theis, Lori Pbert, Matthew J. Gurka, Maribeth Porter, Diana Lee, Elizabeth A. Shenkman, Lindsay A. Thompson Dec 2018

Stakeholder Engagement In Developing An Electronic Clinical Support Tool For Tobacco Prevention In Adolescent Primary Care, Ramzi G. Salloum, Ryan P. Theis, Lori Pbert, Matthew J. Gurka, Maribeth Porter, Diana Lee, Elizabeth A. Shenkman, Lindsay A. Thompson

Open Access Articles

Following guideline recommendations to promote tobacco prevention in adolescent primary care, we developed a patient-facing clinical support tool. The electronic tool screens patients for use and susceptibility to conventional and alternative tobacco products, and promotes patient(-)provider communication. The purpose of this paper is to describe the iterative stakeholder engagement process used in the development of the tool. During the pre-testing phase, we consulted with scientists, methodologists, clinicians, and Citizen Scientists. Throughout the development phase, we engaged providers from three clinics in focus groups. Usability testing was conducted via in-depth, cognitive interviewing of adolescent patients. Citizen Scientists (n = 7) played ...


Intron-Containing Rna From The Hiv-1 Provirus Activates Type I Interferon And Inflammatory Cytokines, Sean M. Mccauley, Kyusik Kim, Anetta Nowosielska, Ann Dauphin, Leonid Yurkovetskiy, William E. Diehl, Jeremy Luban Dec 2018

Intron-Containing Rna From The Hiv-1 Provirus Activates Type I Interferon And Inflammatory Cytokines, Sean M. Mccauley, Kyusik Kim, Anetta Nowosielska, Ann Dauphin, Leonid Yurkovetskiy, William E. Diehl, Jeremy Luban

Open Access Articles

HIV-1-infected people who take drugs that suppress viremia to undetectable levels are protected from developing AIDS. Nonetheless, HIV-1 establishes proviruses in long-lived CD4(+) memory T cells, and perhaps other cell types, that preclude elimination of the virus even after years of continuous antiviral therapy. Here we show that the HIV-1 provirus activates innate immune signaling in isolated dendritic cells, macrophages, and CD4(+) T cells. Immune activation requires transcription from the HIV-1 provirus and expression of CRM1-dependent, Rev-dependent, RRE-containing, unspliced HIV-1 RNA. If rev is provided in trans, all HIV-1 coding sequences are dispensable for activation except those cis-acting sequences required ...


Orbit: A New Paradigm For Genetic Engineering Of Mycobacterial Chromosomes, Kenan C. Murphy, Samantha J. Nelson, Subhalaxmi Nambi, Kadamba Papavinasasundaram, Christina E. Baer, Christopher M. Sassetti Dec 2018

Orbit: A New Paradigm For Genetic Engineering Of Mycobacterial Chromosomes, Kenan C. Murphy, Samantha J. Nelson, Subhalaxmi Nambi, Kadamba Papavinasasundaram, Christina E. Baer, Christopher M. Sassetti

Open Access Articles

Two efficient recombination systems were combined to produce a versatile method for chromosomal engineering that obviates the need to prepare double-stranded DNA (dsDNA) recombination substrates. A synthetic "targeting oligonucleotide" is incorporated into the chromosome via homologous recombination mediated by the phage Che9c RecT annealase. This oligonucleotide contains a site-specific recombination site for the directional Bxb1 integrase (Int), which allows the simultaneous integration of a "payload plasmid" that contains a cognate recombination site and a selectable marker. The targeting oligonucleotide and payload plasmid are cotransformed into a RecT- and Int-expressing strain, and drug-resistant homologous recombinants are selected in a single step ...


The Caenorhabditis Elegans Oxidative Stress Response Requires The Nhr-49 Transcription Factor, Queenie Hu, Dayana R. D'Amora, Lesley T. Macneil, Albertha J. M. Walhout, Terrance J. Kubiseski Dec 2018

The Caenorhabditis Elegans Oxidative Stress Response Requires The Nhr-49 Transcription Factor, Queenie Hu, Dayana R. D'Amora, Lesley T. Macneil, Albertha J. M. Walhout, Terrance J. Kubiseski

Open Access Articles

The overproduction of reactive oxygen species (ROS) in cells can lead to the development of diseases associated with aging. We have previously shown that C. elegans BRAP-2 (Brca1 associated binding protein 2) regulates phase II detoxification genes such as gst-4, by increasing SKN-1 activity. Previously, a transcription factor (TF) RNAi screen was conducted to identify potential activators that are required to induce gst-4 expression in brap-2(ok1492) mutants. The lipid metabolism regulator NHR-49/HNF4 was among 18 TFs identified. Here, we show that knockdown of nhr-49 suppresses the activation of gst-4 caused by brap-2 inactivation and that gain-of-function alleles of ...


Conserved Mrna-Granule Component Scd6 Targets Dhh1 To Repress Translation Initiation And Activates Dcp2-Mediated Mrna Decay In Vivo, Quira Zeidan, Feng He, Fan Zhang, Hongen Zhang, Allan Jacobson, Alan G. Hinnebusch Dec 2018

Conserved Mrna-Granule Component Scd6 Targets Dhh1 To Repress Translation Initiation And Activates Dcp2-Mediated Mrna Decay In Vivo, Quira Zeidan, Feng He, Fan Zhang, Hongen Zhang, Allan Jacobson, Alan G. Hinnebusch

Open Access Articles

Scd6 protein family members are evolutionarily conserved components of translationally silent mRNA granules. Yeast Scd6 interacts with Dcp2 and Dhh1, respectively a subunit and a regulator of the mRNA decapping enzyme, and also associates with translation initiation factor eIF4G to inhibit translation in cell extracts. However, the role of Scd6 in mRNA turnover and translational repression in vivo is unclear. We demonstrate that tethering Scd6 to a GFP reporter mRNA reduces mRNA abundance via Dcp2 and suppresses reporter mRNA translation via Dhh1. Thus, in a dcp2Delta mutant, tethered Scd6 reduces GFP protein expression with little effect on mRNA abundance, whereas ...


Designing Shared Decision-Making Interventions For Dissemination And Sustainment: Can Implementation Science Help Translate Shared Decision Making Into Routine Practice, Andy S. Tan L, Kathleen M. Mazor, Daniel Mcdonald, Stella J. Lee, Demetria Mcneal, Daniel D. Matlock, Russell E. Glasgow Dec 2018

Designing Shared Decision-Making Interventions For Dissemination And Sustainment: Can Implementation Science Help Translate Shared Decision Making Into Routine Practice, Andy S. Tan L, Kathleen M. Mazor, Daniel Mcdonald, Stella J. Lee, Demetria Mcneal, Daniel D. Matlock, Russell E. Glasgow

Open Access Articles

Shared decision making (SDM) is not widely practiced in routine care due to a variety of organizational, provider, patient, and contextual factors. This article explores how implementation science-which encourages attention to the multilevel contextual factors that influence the adoption, implementation, and sustainment of health care practices-can provide useful insights for increasing SDM use in routine practice. We engaged with stakeholders representing different organizations and geographic locations over three phases: 1) multidisciplinary workgroup meeting comprising researchers and clinicians (n = 11); 2) survey among a purposive sample of 47 patient advocates, clinicians, health care system leaders, funders, policymakers, and researchers; and 3 ...


General Decapping Activators Target Different Subsets Of Inefficiently Translated Mrnas, Feng He, Alper Celik, Chan Wu, Allan Jacobson Dec 2018

General Decapping Activators Target Different Subsets Of Inefficiently Translated Mrnas, Feng He, Alper Celik, Chan Wu, Allan Jacobson

Open Access Articles

The Dcp1-Dcp2 decapping enzyme and the decapping activators Pat1, Dhh1, and Lsm1 regulate mRNA decapping, but their mechanistic integration is unknown. We analyzed the gene expression consequences of deleting PAT1, LSM1, or DHH1, or the DCP2 C-terminal domain, and found that: i) the Dcp2 C-terminal domain is an effector of both negative and positive regulation; ii) rather than being global activators of decapping, Pat1, Lsm1, and Dhh1 directly target specific subsets of yeast mRNAs and loss of the functions of each of these factors has substantial indirect consequences for genome-wide mRNA expression; and iii) transcripts targeted by Pat1, Lsm1, and ...


Nmecas9 Is An Intrinsically High-Fidelity Genome-Editing Platform, Nadia Amrani, Xin D. Gao, Pengpeng Liu, Alireza Edraki, Aamir Mir, Raed Ibraheim, Ankit Gupta, Kanae E. Sasaki, Tong Wu, Thomas G. Fazzio, Lihua Julie Zhu, Scot A. Wolfe, Erik J. Sontheimer Dec 2018

Nmecas9 Is An Intrinsically High-Fidelity Genome-Editing Platform, Nadia Amrani, Xin D. Gao, Pengpeng Liu, Alireza Edraki, Aamir Mir, Raed Ibraheim, Ankit Gupta, Kanae E. Sasaki, Tong Wu, Thomas G. Fazzio, Lihua Julie Zhu, Scot A. Wolfe, Erik J. Sontheimer

Open Access Articles

BACKGROUND: The development of CRISPR genome editing has transformed biomedical research. Most applications reported thus far rely upon the Cas9 protein from Streptococcus pyogenes SF370 (SpyCas9). With many RNA guides, wildtype SpyCas9 can induce significant levels of unintended mutations at near-cognate sites, necessitating substantial efforts toward the development of strategies to minimize off-target activity. Although the genome-editing potential of thousands of other Cas9 orthologs remains largely untapped, it is not known how many will require similarly extensive engineering to achieve single-site accuracy within large genomes. In addition to its off-targeting propensity, SpyCas9 is encoded by a relatively large open reading ...


Trisomy Silencing By Xist Normalizes Down Syndrome Cell Pathogenesis Demonstrated For Hematopoietic Defects In Vitro, Jen-Chieh Chiang, Jun Jiang, Peter E. Newburger, Jeanne B. Lawrence Dec 2018

Trisomy Silencing By Xist Normalizes Down Syndrome Cell Pathogenesis Demonstrated For Hematopoietic Defects In Vitro, Jen-Chieh Chiang, Jun Jiang, Peter E. Newburger, Jeanne B. Lawrence

Open Access Articles

We previously demonstrated that an integrated XIST transgene can broadly repress one chromosome 21 in Down syndrome (DS) pluripotent cells. Here we address whether trisomy-silencing can normalize cell function and development sufficiently to correct cell pathogenesis, tested in an in vitro model of human fetal hematopoiesis, for which DS cellular phenotypes are best known. XIST induction in four transgenic clones reproducibly corrected over-production of megakaryocytes and erythrocytes, key to DS myeloproliferative disorder and leukemia. A contrasting increase in neural stem and iPS cells shows cell-type specificity, supporting this approach successfully rebalances the hematopoietic developmental program. Given this, we next used ...


Explantation Of Infected Thoracic Endovascular Aortic Repair, Emily Y. Fan, Dejah R. Judelson, Andres Schanzer Dec 2018

Explantation Of Infected Thoracic Endovascular Aortic Repair, Emily Y. Fan, Dejah R. Judelson, Andres Schanzer

Open Access Articles

Prosthetic graft infection is a rare and serious complication of thoracic endovascular aortic repair associated with high mortality and posing unique challenges for treatment. The prosthetic graft infection is often identified late as patients present with mild nonspecific symptoms. We describe the successful medical management and surgical explantation of an infected thoracic endograft with an aorta-bronchial fistula, using an inline reconstruction with an antibiotic-soaked synthetic graft. In this report, we provide an example of a patient with an infected thoracic endograft and how inline reconstruction combined with appropriate medical management is an acceptable treatment strategy.


Potent Cas9 Inhibition In Bacterial And Human Cells By Acriic4 And Acriic5 Anti-Crispr Proteins, Jooyoung Lee, Aamir Mir, Alireza Edraki, Bianca Garcia, Nadia Amrani, Hannah E. Lou, Ildar Gainetdinov, April Pawluk, Raed Ibraheim, Xin D. Gao, Pengpeng Liu, Alan R. Davidson, Karen L. Maxwell, Erik J. Sontheimer Dec 2018

Potent Cas9 Inhibition In Bacterial And Human Cells By Acriic4 And Acriic5 Anti-Crispr Proteins, Jooyoung Lee, Aamir Mir, Alireza Edraki, Bianca Garcia, Nadia Amrani, Hannah E. Lou, Ildar Gainetdinov, April Pawluk, Raed Ibraheim, Xin D. Gao, Pengpeng Liu, Alan R. Davidson, Karen L. Maxwell, Erik J. Sontheimer

Open Access Articles

In their natural settings, CRISPR-Cas systems play crucial roles in bacterial and archaeal adaptive immunity to protect against phages and other mobile genetic elements, and they are also widely used as genome engineering technologies. Previously we discovered bacteriophage-encoded Cas9-specific anti-CRISPR (Acr) proteins that serve as countermeasures against host bacterial immunity by inactivating their CRISPR-Cas systems (A. Pawluk, N. Amrani, Y. Zhang, B. Garcia, et al., Cell 167:1829-1838.e9, 2016, https://doi.org/10.1016/j.cell.2016.11.017). We hypothesized that the evolutionary advantages conferred by anti-CRISPRs would drive the widespread occurrence of these proteins in nature (K ...


Randomized Controlled Trial Of Individualized Treatment Summary And Survivorship Care Plans For Hematopoietic Cell Transplantation Survivors, Navneet S. Majhail, Jan Cerny Dec 2018

Randomized Controlled Trial Of Individualized Treatment Summary And Survivorship Care Plans For Hematopoietic Cell Transplantation Survivors, Navneet S. Majhail, Jan Cerny

Open Access Articles

Survivorship care plans may facilitate long-term care for cancer survivors, but their effectiveness has not been established in hematopoietic cell transplantation recipients. We evaluated the impact of individualized survivorship care plans on patient-reported outcomes among transplant survivors. Adult (>/=18 years at transplant) survivors who were 1-5 years post-transplantation, proficient in English, and without relapse or secondary cancers were eligible for this multicenter randomized trial. Care plans were developed based on risk-factors and treatment exposures using patient data routinely submitted by transplant centers to the Center for International Blood and Marrow Transplant Research and published guidelines for long-term follow-up of transplant ...


Molecular Mechanisms Directing Spine Outgrowth And Synaptic Partner Selection In Caenorhabditis Elegans, Devyn Oliver, Kellianne Alexander, Michael M. Francis Dec 2018

Molecular Mechanisms Directing Spine Outgrowth And Synaptic Partner Selection In Caenorhabditis Elegans, Devyn Oliver, Kellianne Alexander, Michael M. Francis

Open Access Articles

The development of the nervous system requires precise outgrowth, extension, and wiring of both axons and dendrites to generate properly functioning neural circuits. The molecular mechanisms that shape neurite development, in particular dendritic development, remain incompletely understood. Dendrites are often highly branched and coated with actin-filled, thorny protrusions, called dendritic spines, that allow for increased numbers of synaptic contacts with neighboring neurons. Disruptions in dendritic spine development have been implicated in many neurological disorders such as autism, schizophrenia, and Alzheimer's disease. Although the development of dendritic spines is vital for cognitive function, understanding the mechanisms driving their outgrowth and ...


Ectopic High Endothelial Venules In Pancreatic Ductal Adenocarcinoma: A Unique Site For Targeted Delivery, Baharak Bahmani, Mayuko Uehara, Farideh Ordikhani, Xiaofei Li, Liwei Jiang, Naima Banouni, Takaharu Ichimura, Vivek Kasinath, Siawosh K. Eskandari, Nasim Annabi, Jonathan S. Bromberg, Leonard D. Shultz, Dale L. Greiner, Reza Abdi Dec 2018

Ectopic High Endothelial Venules In Pancreatic Ductal Adenocarcinoma: A Unique Site For Targeted Delivery, Baharak Bahmani, Mayuko Uehara, Farideh Ordikhani, Xiaofei Li, Liwei Jiang, Naima Banouni, Takaharu Ichimura, Vivek Kasinath, Siawosh K. Eskandari, Nasim Annabi, Jonathan S. Bromberg, Leonard D. Shultz, Dale L. Greiner, Reza Abdi

Open Access Articles

BACKGROUND: Nanomedicine offers an excellent opportunity to tackle treatment-refractory malignancies by enhancing the delivery of therapeutics to the tumor site. High endothelial venules (HEVs) are found primarily in lymph nodes or formed de novo in peripheral tissues during inflammatory responses. They express peripheral node addressin (PNAd), which is recognized by the monoclonal antibody MECA79.

METHODS: Here, we demonstrated that HEVs form de novo in human pancreatic ductal adenocarcinoma (PDAC). We engineered MECA79 coated nanoparticles (MECA79-NPs) that recognize these ectopic HEVs in PDAC.

FINDINGS: The trafficking of MECA79-NPs following intravenous delivery to human PDAC implanted in a humanized mouse model was ...


Real-World Comparative Effectiveness Of Tocilizumab Monotherapy Vs. Tumor Necrosis Factor Inhibitors With Methotrexate In Patients With Rheumatoid Arthritis, Leslie R. Harrold, George W. Reed, Jennie Best, Steve Zlotnick, Joel M. Kremer Dec 2018

Real-World Comparative Effectiveness Of Tocilizumab Monotherapy Vs. Tumor Necrosis Factor Inhibitors With Methotrexate In Patients With Rheumatoid Arthritis, Leslie R. Harrold, George W. Reed, Jennie Best, Steve Zlotnick, Joel M. Kremer

Open Access Articles

INTRODUCTION: Controlled clinical studies have shown that the efficacy of tocilizumab (TCZ) monotherapy is superior to that of tumor necrosis factor inhibitor (TNFi) monotherapy and comparable to that of TCZ plus methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). This study compared the real-world effectiveness of TCZ monotherapy vs. TNFis plus MTX in US patients with RA.

METHODS: TCZ-naive patients from the Corrona RA registry with prior exposure to > /= 1 TNFi who initiated TCZ monotherapy or TNFi + MTX were included. Outcomes included mean change in Clinical Disease Activity Index (CDAI), achievement of low disease activity (LDA; CDAI < /= 10), achievement of modified American College of Rheumatology (mACR) 20/50 responses, and mean change in modified Health Assessment Questionnaire (mHAQ) at 6 months. Patients initiating TNFi + MTX were grouped by MTX dose ( < /= 10 mg; > 10 to ...


Magnitude And Impact Of Multiple Chronic Conditions With Advancing Age In Older Adults Hospitalized With Acute Myocardial Infarction, Mayra Tisminetzky, Hoa L. Nguyen, Jerry H. Gurwitz, David D. Mcmanus, Joel M. Gore, Sonal Singh, Jorge L. Yarzebski, Robert J. Goldberg Dec 2018

Magnitude And Impact Of Multiple Chronic Conditions With Advancing Age In Older Adults Hospitalized With Acute Myocardial Infarction, Mayra Tisminetzky, Hoa L. Nguyen, Jerry H. Gurwitz, David D. Mcmanus, Joel M. Gore, Sonal Singh, Jorge L. Yarzebski, Robert J. Goldberg

Open Access Articles

BACKGROUND: To examine age-specific differences in the frequency and impact of cardiac and non-cardiac conditions among patients aged 65years and older hospitalized with acute myocardial infarction (AMI).

METHODS: Study population consisted of 3863 adults hospitalized with AMI at 11 medical centers in central Massachusetts on a biennial basis between 2001 and 2011. The presence of 11 chronic conditions (five cardiac and six non-cardiac) was based on the review of hospital medical records.

RESULTS: Participants' median age was 79years, 49% were men, and had an average of three chronic conditions (average of cardiac conditions: 2.6 and average of non-cardiac conditions ...


Stress-Responsive And Metabolic Gene Regulation Are Altered In Low S-Adenosylmethionine, Wei Ding, Daniel P. Higgins, Dilip K. Yadav, Adwait A. Godbole, Read Pukkila-Worley, Amy K. Walker Nov 2018

Stress-Responsive And Metabolic Gene Regulation Are Altered In Low S-Adenosylmethionine, Wei Ding, Daniel P. Higgins, Dilip K. Yadav, Adwait A. Godbole, Read Pukkila-Worley, Amy K. Walker

Open Access Articles

S-adenosylmethionine (SAM) is a donor which provides the methyl groups for histone or nucleic acid modification and phosphatidylcholine production. SAM is hypothesized to link metabolism and chromatin modification, however, its role in acute gene regulation is poorly understood. We recently found that Caenorhabditis elegans with reduced SAM had deficiencies in H3K4 trimethylation (H3K4me3) at pathogen-response genes, decreasing their expression and limiting pathogen resistance. We hypothesized that SAM may be generally required for stress-responsive transcription. Here, using genetic assays, we show that transcriptional responses to bacterial or xenotoxic stress fail in C. elegans with low SAM, but that expression of heat ...


Improving Efficiency In Neuroimaging Research Through Application Of Lean Principles, Alexandra Roy, Julia Colpitts, Kara Becker, Judson A. Brewer, Remko Van Lutterveld Nov 2018

Improving Efficiency In Neuroimaging Research Through Application Of Lean Principles, Alexandra Roy, Julia Colpitts, Kara Becker, Judson A. Brewer, Remko Van Lutterveld

Open Access Articles

INTRODUCTION: "Lean" is a set of management principles which focus on increasing value and efficiency by reducing or avoiding waste (e.g., overproduction, defects, inventory, transportation, waiting, motion, over processing). It has been applied to manufacturing, education, and health care, leading to optimized process flow, increased efficiency and increased team empowerment. However, to date, it has not been applied to neuroimaging research.

METHODS: Lean principles, such as Value stream mapping (e.g. a tool with which steps in the workflow can be identified on which to focus improvement efforts), 5S (e.g. an organizational method to boost workplace efficiency and ...


Relationships Between Intensity, Duration, Cumulative Dose, And Timing Of Smoking With Age At Menopause: A Pooled Analysis Of Individual Data From 17 Observational Studies, Dongshan Zhu, Sybil L. Crawford, Gita D. Mishra Nov 2018

Relationships Between Intensity, Duration, Cumulative Dose, And Timing Of Smoking With Age At Menopause: A Pooled Analysis Of Individual Data From 17 Observational Studies, Dongshan Zhu, Sybil L. Crawford, Gita D. Mishra

Open Access Articles

BACKGROUND: Cigarette smoking is associated with earlier menopause, but the impact of being a former smoker and any dose-response relationships on the degree of smoking and age at menopause have been less clear. If the toxic impact of cigarette smoking on ovarian function is irreversible, we hypothesized that even former smokers might experience earlier menopause, and variations in intensity, duration, cumulative dose, and age at start/quit of smoking might have varying impacts on the risk of experiencing earlier menopause.

METHODS AND FINDINGS: A total of 207,231 and 27,580 postmenopausal women were included in the cross-sectional and prospective ...


Genome-Wide Crispr Screens For Shiga Toxins And Ricin Reveal Golgi Proteins Critical For Glycosylation, Songhai Tian, Khaja Muneeruddin, Mei Yuk Choi, Liang Tao, Robiul H. Bhuiyan, Yuhsuke Ohmi, Keiko Furukawa, Koichi Furukawa, Sebastian Boland, Scott A. Shaffer, Rosalyn M. Adam, Min Dong Nov 2018

Genome-Wide Crispr Screens For Shiga Toxins And Ricin Reveal Golgi Proteins Critical For Glycosylation, Songhai Tian, Khaja Muneeruddin, Mei Yuk Choi, Liang Tao, Robiul H. Bhuiyan, Yuhsuke Ohmi, Keiko Furukawa, Koichi Furukawa, Sebastian Boland, Scott A. Shaffer, Rosalyn M. Adam, Min Dong

Open Access Articles

Glycosylation is a fundamental modification of proteins and membrane lipids. Toxins that utilize glycans as their receptors have served as powerful tools to identify key players in glycosylation processes. Here, we carried out Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9-mediated genome-wide loss-of-function screens using two related bacterial toxins, Shiga-like toxins (Stxs) 1 and 2, which use a specific glycolipid, globotriaosylceramide (Gb3), as receptors, and the plant toxin ricin, which recognizes a broad range of glycans. The Stxs screens identified major glycosyltransferases (GTs) and transporters involved in Gb3 biosynthesis, while the ricin screen identified GTs and transporters involved in N-linked ...


Effects Of Age, Race, And Ethnicity On The Optic Nerve And Peripapillary Region Using Spectral-Domain Oct 3d Volume Scans, Linda Yi-Chieh Poon, Hussein Antar, Edem Tsikata, Rong Guo, Georgia Papadogeorgou, Madeline Freeman, Ziad Khoueir, Ramon Lee, Eric Shieh, Huseyin Simavli, Christian John Que, Johannes F. De Boer, Teresa C. Chen Nov 2018

Effects Of Age, Race, And Ethnicity On The Optic Nerve And Peripapillary Region Using Spectral-Domain Oct 3d Volume Scans, Linda Yi-Chieh Poon, Hussein Antar, Edem Tsikata, Rong Guo, Georgia Papadogeorgou, Madeline Freeman, Ziad Khoueir, Ramon Lee, Eric Shieh, Huseyin Simavli, Christian John Que, Johannes F. De Boer, Teresa C. Chen

Open Access Articles

Purpose: To evaluate the effects of age, race, and ethnicity on the optic nerve and peripapillary retina using spectral-domain optical coherence tomography (SD-OCT) three-dimensional (3D) volume scans in normal subjects.

Methods: This is a cross-sectional study performed at a single institution in Boston. All patients received retinal nerve fiber layer (RNFL) scans and an optic nerve 3D volume scan. The SD-OCT software calculated peripapillary RNFL thickness, retinal thickness (RT), and retinal volume (RV). Custom-designed software calculated neuroretinal rim minimum distance band (MDB) thickness and area.

Results: There were 272 normal subjects, including 175 whites, 40 blacks, 40 Asians, and 17 ...