Deconvolution of Blood Microarray Data Identifies Cellular Activation Patterns in Systemic Lupus Erythematosus

Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease with a complex spectrum of cellular and molecular characteristics including several dramatic changes in the populations of peripheral leukocytes. These changes include general leukopenia, activation of B and T cells, and maturation of granulocytes. The manifestation of SLE in peripheral blood is central to the disease but is incompletely understood. A technique for rigorously characterizing changes in mixed populations of cells, microarray expression deconvolution, has been applied to several areas of biology but not to SLE or to blood. Here we demonstrate that microarray expression deconvolution accurately quantifies the constituents of real blood samples and mixtures of immune-derived cell lines. We characterize a broad spectrum of peripheral leukocyte cell types and states in SLE to uncover novel patterns including: specific activation of NK and T helper lymphocytes, relationships of these patterns to each other, and correlations to clinical variables and measures. The expansion and activation of monocytes, NK cells, and T helper cells in SLE at least partly underlie this disease's prominent interferon signature. These and other patterns of leukocyte dynamics uncovered here correlate with disease severity and treatment, suggest potential new treatments, and extend our understanding of lupus pathology as a complex autoimmune disease involving many arms of the immune system

Maximizing Adherence and Gaining New Information For Your Chronic Obstructive Pulmonary Disease (MAGNIFY COPD):Study Protocol for the Pragmatic, Cluster Randomized Trial Evaluating the Impact of Dual Bronchodilator with Add-On Sensor and Electronic Monitoring on Clinical Outcomes

Background: Poor treatment adherence in COPD patients is associated with poor clinical outcomes and increased healthcare burden. Personalized approaches for adherence management, supported with technology-based interventions, may offer benefits to patients and providers but are currently unproven in terms of clinical outcomes as opposed to adherence outcomes. Methods: Maximizing Adherence and Gaining New Information For Your COPD (MAGNIFY COPD study), a pragmatic cluster randomized trial, aims to evaluate the impact of an adherence technology package (interventional package), comprising an adherence review, ongoing provision of a dual bronchodilator but with an add-on inhaler sensor device and a connected mobile application. This will compare time to treatment failure and other clinical outcomes in patients identified at high risk of exacerbations with historic poor treatment adherence as measured by prescription collection to mono/dual therapy over one year (1312 patients) versus usual care. Treatment failure is defined as the first occurrence of one of the following: (1) moderate/severe COPD exacerbation, (2) prescription of triple therapy (inhaled corticosteroid/long-acting β2-agonist/long-acting muscarinic antagonist [ICS/LABA/LAMA]), (3) prescription of additional chronic therapy for COPD, or (4) respiratory-related death. Adherence, moderate/severe exacerbations, respiratory-related healthcare resource utilization and costs, and intervention package acceptance rate will also be assessed. Eligible primary care practices (N=176) participating in the Optimum Patient Care Quality Improvement Program will be randomized (1:1) to either adherence support cluster arm (suitable patients already receiving or initiated Ultibro® Breezhaler® [indacaterol/glycopyrronium] will be offered interventional package) or the control cluster arm (suitable patients continue to receive usual clinical care). Patients will be identified and outcomes collected from anonymized electronic medical records within the Optimum Patient Care Research Database. On study completion, electronic medical record data will be re-extracted to analyze outcomes in both study groups. Registration Number: ISRCTN10567920. Conclusion: MAGNIFY will explore patient benefits of technology-based interventions for electronic adherence monitoring

Homozygous microdeletion of exon 5 in ZNF277 in a girl with specific language impairment

Peer reviewedPublisher PD

CMIP and ATP2C2 Modulate Phonological Short-Term Memory in Language Impairment

Specific language impairment (SLI) is a common developmental disorder characterized by difficulties in language acquisition despite otherwise normal development and in the absence of any obvious explanatory factors. We performed a high-density screen of SLI1, a region of chromosome 16q that shows highly significant and consistent linkage to nonword repetition, a measure of phonological short-term memory that is commonly impaired in SLI. Using two independent language-impaired samples, one family-based (211 families) and another selected from a population cohort on the basis of extreme language measures (490 cases), we detected association to two genes in the SLI1 region: that encoding c-maf-inducing protein (CMIP, minP = 5.5 × 10−7 at rs6564903) and that encoding calcium-transporting ATPase, type2C, member2 (ATP2C2, minP = 2.0 × 10−5 at rs11860694). Regression modeling indicated that each of these loci exerts an independent effect upon nonword repetition ability. Despite the consistent findings in language-impaired samples, investigation in a large unselected cohort (n = 3612) did not detect association. We therefore propose that variants in CMIP and ATP2C2 act to modulate phonological short-term memory primarily in the context of language impairment. As such, this investigation supports the hypothesis that some causes of language impairment are distinct from factors that influence normal language variation. This work therefore implicates CMIP and ATP2C2 in the etiology of SLI and provides molecular evidence for the importance of phonological short-term memory in language acquisition

Exploring movement patterns and changing distributions of baleen whales in the western North Atlantic using a decade of passive acoustic data

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Davis, G. E., Baumgartner, M. F., Corkeron, P. J., Bell, J., Berchok, C., Bonnell, J. M., Thornton, J. B., Brault, S., Buchanan, G. A., Cholewiak, D. M., Clark, C. W., Delarue, J., Hatch, L. T., Klinck, H., Kraus, S. D., Martin, B., Mellinger, D. K., Moors-Murphy, H., Nieukirk, S., Nowacek, D. P., Parks, S. E., Parry, D., Pegg, N., Read, A. J., Rice, A. N., Risch, D., Scott, A., Soldevilla, M. S., Stafford, K. M., Stanistreet, J. E., Summers, E., Todd, S., & Van Parijs, S. M. Exploring movement patterns and changing distributions of baleen whales in the western North Atlantic using a decade of passive acoustic data. Global Change Biology, (2020): 1-30, doi:10.1111/gcb.15191.Six baleen whale species are found in the temperate western North Atlantic Ocean, with limited information existing on the distribution and movement patterns for most. There is mounting evidence of distributional shifts in many species, including marine mammals, likely because of climate‐driven changes in ocean temperature and circulation. Previous acoustic studies examined the occurrence of minke (Balaenoptera acutorostrata ) and North Atlantic right whales (NARW; Eubalaena glacialis ). This study assesses the acoustic presence of humpback (Megaptera novaeangliae ), sei (B. borealis ), fin (B. physalus ), and blue whales (B. musculus ) over a decade, based on daily detections of their vocalizations. Data collected from 2004 to 2014 on 281 bottom‐mounted recorders, totaling 35,033 days, were processed using automated detection software and screened for each species' presence. A published study on NARW acoustics revealed significant changes in occurrence patterns between the periods of 2004–2010 and 2011–2014; therefore, these same time periods were examined here. All four species were present from the Southeast United States to Greenland; humpback whales were also present in the Caribbean. All species occurred throughout all regions in the winter, suggesting that baleen whales are widely distributed during these months. Each of the species showed significant changes in acoustic occurrence after 2010. Similar to NARWs, sei whales had higher acoustic occurrence in mid‐Atlantic regions after 2010. Fin, blue, and sei whales were more frequently detected in the northern latitudes of the study area after 2010. Despite this general northward shift, all four species were detected less on the Scotian Shelf area after 2010, matching documented shifts in prey availability in this region. A decade of acoustic observations have shown important distributional changes over the range of baleen whales, mirroring known climatic shifts and identifying new habitats that will require further protection from anthropogenic threats like fixed fishing gear, shipping, and noise pollution.We thank Chris Pelkie, David Wiley, Michael Thompson, Chris Tessaglia‐Hymes, Eric Matzen, Chris Tremblay, Lance Garrison, Anurag Kumar, John Hildebrand, Lynne Hodge, Russell Charif, Kathleen Dudzinski, and Ann Warde for help with project planning, field work support, and data management. For all the support and advice, thanks to the NEFSC Protected Species Branch, especially the passive acoustics group, Josh Hatch, and Leah Crowe. We thank the field and crew teams on all the ships that helped in the numerous deployments and recoveries. This research was funded and supported by many organizations, specified by projects as follows: data recordings from region 1 were provided by K. Stafford (funding: National Science Foundation #NSF‐ARC 0532611). Region 2 data: D. K. Mellinger and S. Nieukirk, National Oceanic and Atmospheric Administration (NOAA) PMEL contribution #5055 (funding: NOAA and the Office of Naval Research #N00014–03–1–0099, NOAA #NA06OAR4600100, US Navy #N00244‐08‐1‐0029, N00244‐09‐1‐0079, and N00244‐10‐1‐0047). Region 3A data: D. Risch (funding: NOAA and Navy N45 programs). Region 3 data: H. Moors‐Murphy and Fisheries and Oceans Canada (2005–2014 data), and the Whitehead Lab of Dalhousie University (eastern Scotian Shelf data; logistical support by A. Cogswell, J. Bartholette, A. Hartling, and vessel CCGS Hudson crew). Emerald Basin and Roseway Basin Guardbuoy data, deployment, and funding: Akoostix Inc. Region 3 Emerald Bank and Roseway Basin 2004 data: D. K. Mellinger and S. Nieukirk, NOAA PMEL contribution #5055 (funding: NOAA). Region 4 data: S. Parks (funding: NOAA and Cornell University) and E. Summers, S. Todd, J. Bort Thornton, A. N. Rice, and C. W. Clark (funding: Maine Department of Marine Resources, NOAA #NA09NMF4520418, and #NA10NMF4520291). Region 5 data: S. M. Van Parijs, D. Cholewiak, L. Hatch, C. W. Clark, D. Risch, and D. Wiley (funding: National Oceanic Partnership Program (NOPP), NOAA, and Navy N45). Region 6 data: S. M. Van Parijs and D. Cholewiak (funding: Navy N45 and Bureau of Ocean and Energy Management (BOEM) Atlantic Marine Assessment Program for Protected Species [AMAPPS] program). Region 7 data: A. N. Rice, H. Klinck, A. Warde, B. Martin, J. Delarue, and S. Kraus (funding: New York State Department of Environmental Conservation, Massachusetts Clean Energy Center, and BOEM). Region 8 data: G. Buchanan, and K. Dudzinski (funding: New Jersey Department of Environmental Protection and the New Jersey Clean Energy Fund) and A. N. Rice, C. W. Clark, and H. Klinck (funding: Center for Conservation Bioacoustics at Cornell University and BOEM). Region 9 data: J. E. Stanistreet, J. Bell, D. P. Nowacek, A. J. Read, and S. M. Van Parijs (funding: NOAA and US Fleet Forces Command). Region 10 data: L. Garrison, M. Soldevilla, C. W. Clark, R. A. Chariff, A. N. Rice, H. Klinck, J. Bell, D. P. Nowacek, A. J. Read, J. Hildebrand, A. Kumar, L. Hodge, and J. E. Stanistreet (funding: US Fleet Forces Command, BOEM, NOAA, and NOPP). Region 11 data: C. Berchok as part of a collaborative project led by the Fundacion Dominicana de Estudios Marinos, Inc. (Dr. Idelisa Bonnelly de Calventi; funding: The Nature Conservancy [Elianny Dominguez]) and D. Risch (funding: World Wildlife Fund, NOAA, and Dutch Ministry of Economic Affairs)

Functional Studies on the IBD Susceptibility Gene IL23R Implicate Reduced Receptor Function in the Protective Genetic Variant R381Q

Genome-wide association studies (GWAS) in several populations have demonstrated significant association of the IL23R gene with IBD (Crohn's disease (CD) and ulcerative colitis (UC)) and psoriasis, suggesting that perturbation of the IL-23 signaling pathway is relevant to the pathophysiology of these diseases. One particular variant, R381Q (rs11209026), confers strong protection against development of CD. We investigated the effects of this variant in primary T cells from healthy donors carrying IL23RR381 and IL23RQ381 haplotypes. Using a proprietary anti-IL23R antibody, ELISA, flow cytometry, phosphoflow and real-time RT-PCR methods, we examined IL23R expression and STAT3 phosphorylation and activation in response to IL-23. IL23RQ381 was associated with reduced STAT3 phosphorylation upon stimulation with IL-23 and decreased number of IL-23 responsive T-cells. We also observed slightly reduced levels of proinflammatory cytokine secretion in IL23RQ381 positive donors. Our study shows conclusively that IL23RQ381 is a loss-of-function allele, further strengthening the implication from GWAS results that the IL-23 pathway is pathogenic in human disease. This data provides an explanation for the protective role of R381Q in CD and may lead to the development of improved therapeutics for autoimmune disorders like CD

Identification of Kinases Regulating Prostate Cancer Cell Growth Using an RNAi Phenotypic Screen

As prostate cancer progresses to castration-resistant disease, there is an increase in signal transduction activity. Most castration-resistant prostate tumors continue to express the androgen receptor (AR) as well as androgen-responsive genes, despite the near absence of circulating androgen in these patients. The AR is regulated not only by its cognate steroid hormone, but also by interactions with a constellation of co-regulatory and signaling molecules. Thus, the elevated signaling activity that occurs during progression to castration resistance can affect prostate cancer cell growth either through the AR or independent of the AR. In order to identify signaling pathways that regulate prostate cancer cell growth, we screened a panel of shRNAs targeting 673 human kinases against LNCaP prostate cancer cells grown in the presence and absence of hormone. The screen identified multiple shRNA clones against known and novel gene targets that regulate prostate cancer cell growth. Based on the magnitude of effect on growth, we selected six kinases for further study: MAP3K11, DGKD, ICK, CIT, GALK2, and PSKH1. Knockdown of these kinases decreased cell growth in both androgen-dependent and castration-resistant prostate cancer cells. However, these kinases had different effects on basal or androgen-induced transcriptional activity of AR target genes. MAP3K11 knockdown most consistently altered transcription of AR target genes, suggesting that MAP3K11 affected its growth inhibitory effect by modulating the AR transcriptional program. Consistent with MAP3K11 acting on the AR, knockdown of MAP3K11 inhibited AR Ser 650 phosphorylation, further supporting stress kinase regulation of AR phosphorylation. This study demonstrates the applicability of lentiviral-based shRNA for conducting phenotypic screens and identifies MAP3K11, DGKD, ICK, CIT, GALK2, and PSKH1 as regulators of prostate cancer cell growth. The thorough evaluation of these kinase targets will pave the way for developing more effective treatments for castration-resistant prostate cancer

Regulation of human endometrial function: mechanisms relevant to uterine bleeding

This review focuses on the complex events that occur in the endometrium after progesterone is withdrawn (or blocked) and menstrual bleeding ensues. A detailed understanding of these local mechanisms will enhance our knowledge of disturbed endometrial/uterine function – including problems with excessively heavy menstrual bleeding, endometriosis and breakthrough bleeding with progestin only contraception. The development of novel strategies to manage these clinically significant problems depends on such new understanding as does the development of new contraceptives which avoid the endometrial side effect of breakthrough bleeding