541 research outputs found
Genomic organization and evolution of the ULBP genes in cattle
BACKGROUND: The cattle UL16-binding protein 1 (ULBP1) and ULBP2 genes encode members of the MHC Class I superfamily that have homology to the human ULBP genes. Human ULBP1 and ULBP2 interact with the NKG2D receptor to activate effector cells in the immune system. The human cytomegalovirus UL16 protein is known to disrupt the ULBP-NKG2D interaction, thereby subverting natural killer cell-mediated responses. Previous Southern blotting experiments identified evidence of increased ULBP copy number within the genomes of ruminant artiodactyls. On the basis of these observations we hypothesized that the cattle ULBPs evolved by duplication and sequence divergence to produce a sufficient number and diversity of ULBP molecules to deliver an immune activation signal in the presence of immunogenic peptides. Given the importance of the ULBPs in antiviral immunity in other species, our goal was to determine the copy number and genomic organization of the ULBP genes in the cattle genome. RESULTS: Sequencing of cattle bacterial artificial chromosome genomic inserts resulted in the identification of 30 cattle ULBP loci existing in two gene clusters. Evidence of extensive segmental duplication and approximately 14 Kbp of novel repetitive sequences were identified within the major cluster. Ten ULBPs are predicted to be expressed at the cell surface. Substitution analysis revealed 11 outwardly directed residues in the predicted extracellular domains that show evidence of positive Darwinian selection. These positively selected residues have only one residue that overlaps with those proposed to interact with NKG2D, thus suggesting the interaction with molecules other than NKG2D. CONCLUSION: The ULBP loci in the cattle genome apparently arose by gene duplication and subsequent sequence divergence. Substitution analysis of the ULBP proteins provided convincing evidence for positive selection on extracellular residues that may interact with peptide ligands. These results support our hypothesis that the cattle ULBPs evolved under adaptive diversifying selection to avoid interaction with a UL16-like molecule whilst preserving the NKG2D binding site. The large number of ULBPs in cattle, their extensive diversification, and the high prevalence of bovine herpesvirus infections make this gene family a compelling target for studies of antiviral immunity
Laboratory Focus on Improving the Culture of Biosafety: Statewide Risk Assessment of Clinical Laboratories That Process Specimens for Microbiologic Analysis
The Wisconsin State Laboratory of Hygiene challenged Wisconsin laboratories to examine their biosafety practices and improve their culture of biosafety. One hundred three clinical and public health laboratories completed a questionnaire-based, microbiology-focused biosafety risk assessment. Greater than 96% of the respondents performed activities related to specimen processing, direct microscopic examination, and rapid nonmolecular testing, while approximately 60% performed culture interpretation. Although they are important to the assessment of risk, data specific to patient occupation, symptoms, and travel history were often unavailable to the laboratory and, therefore, less contributory to a microbiology-focused biosafety risk assessment than information on the specimen source and test requisition. Over 88% of the respondents complied with more than three-quarters of the mitigation control measures listed in the survey. Facility assessment revealed that subsets of laboratories that claim biosafety level 1, 2, or 3 status did not possess all of the biosafety elements considered minimally standard for their respective classifications. Many laboratories reported being able to quickly correct the minor deficiencies identified. Task assessment identified deficiencies that trended higher within the general (not microbiology-specific) laboratory for core activities, such as packaging and shipping, direct microscopic examination, and culture modalities solely involving screens for organism growth. For traditional microbiology departments, opportunities for improvement in the cultivation and management of highly infectious agents, such as acid-fast bacilli and systemic fungi, were revealed. These results derived from a survey of a large cohort of small- and large-scale laboratories suggest the necessity for continued microbiology-based understanding of biosafety practices, vigilance toward biosafety, and enforcement of biosafety practices throughout the laboratory setting
Spectral Energy Distributions of Local Luminous And Ultraluminous Infrared Galaxies
Luminous and ultraluminous infrared galaxies ((U)LIRGs) are the most extreme
star forming galaxies in the universe. The local (U)LIRGs provide a unique
opportunity to study their multi-wavelength properties in detail for comparison
to their more numerous counterparts at high redshifts. We present common large
aperture photometry at radio through X-ray wavelengths, and spectral energy
distributions (SEDs) for a sample of 53 nearby LIRGs and 11 ULIRGs spanning log
(LIR/Lsun) = 11.14-12.57 from the flux-limited Great Observatories All-sky LIRG
Survey (GOALS). The SEDs for all objects are similar in that they show a broad,
thermal stellar peak and a dominant FIR thermal dust peak, where nuLnu(60um) /
nuLnu(V) increases from ~2-30 with increasing LIR. When normalized at
IRAS-60um, the largest range in the luminosity ratio,
R(lambda)=log[nuLnu(lambda)/nuLnu(60um)] observed over the full sample is seen
in the Hard X-rays (HX=2-10 keV). A small range is found in the Radio (1.4GHz),
where the mean ratio is largest. Total infrared luminosities, LIR(8-1000um),
dust temperatures, and dust masses were computed from fitting thermal dust
emission modified blackbodies to the mid-infrared (MIR) through submillimeter
SEDs. The new results reflect an overall ~0.02 dex lower luminosity than the
original IRAS values. Total stellar masses were computed by fitting stellar
population synthesis models to the observed near-infrared (NIR) through
ultraviolet (UV) SEDs. Mean stellar masses are found to be log(M/Msun) =
10.79+/-0.40. Star formation rates have been determined from the infrared
(SFR_IR~45Msun/yr) and from the monochromatic UV luminosities
(SFR_UV~1.3Msun/yr), respectively. Multiwavelength AGN indicators have be used
to select putative AGN: about 60% of the ULIRGs would have been classified as
an AGN by at least one of the selection criteria.Comment: 39 pages, including 12 figures and 11 tables; accepted for
publication in ApJ
Soluble Antigen Arrays for Selective Desensitization of Insulin-Reactive B Cells
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Molecular Pharmaceutics, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.molpharmaceut.8b01250.Autoimmune diseases are believed to be highly dependent on loss of immune tolerance to self-antigens. Currently, no treatments have been successful clinically in inducing autoantigen-specific tolerance, including efforts to utilize antigen-specific immunotherapy (ASIT) to selectively correct the aberrant autoimmunity. Soluble antigen arrays (SAgAs) represent a novel autoantigen delivery system composed of a linear polymer, hyaluronic acid (HA), displaying multiple copies of conjugated autoantigen. We have previously reported that Soluble Antigen Arrays proteolipid protein (SAgAPLP) induced tolerance to a specific multiple sclerosis (MS) autoantigen, proteolipid peptide (PLP). Utilizing SAgA technology, we have developed a new ASIT as a possible type 1 diabetes (T1D) therapeutic by conjugating human insulin to HA, known as Soluble Antigen Array Insulin (SAgAIns). Three types were synthesized: low valency lvSAgAIns (2 insulins per HA), medium valency mvSAgAIns (4 insulins per HA) and, high valency hvSAgAIns (9 insulins per HA) to determine if valency differentially modulates the ex vivo activity of insulin-binding B cells (IBCs). Extensive biophysical characterization was performed for the SAgA molecules. SAgAIns molecules were successfully used to affect the biologic activity of IBCs by inducing desensitization of the B cell antigen receptors (BCR). SAgAIns bound specifically to insulin-reactive B cells without blocking epitopes recognized by antibodies against the Fc regions of membrane immunoglobulin or CD79 transducer components of the BCR. Pre-incubation of IBCs (125Tg) with SAgAIns, but not HA alone, rendered the IBCs refractory to re-stimulation. SAgAIns induced a decrease in BCR expression and IP3R-mediated intracellular calcium release. Surprisingly, SAgAIns binding to BCR on the surface of IBCs induced the observed effects at both high and low SAgAIns valency. Future studies aim to test the effects of SAgAIns on disease progression in the VH125.NOD mouse model of T1D.NIH T32 GM00854
Omnidirectional Transfer for Quasilinear Lifelong Learning
In biological learning, data are used to improve performance not only on the
current task, but also on previously encountered and as yet unencountered
tasks. In contrast, classical machine learning starts from a blank slate, or
tabula rasa, using data only for the single task at hand. While typical
transfer learning algorithms can improve performance on future tasks, their
performance on prior tasks degrades upon learning new tasks (called
catastrophic forgetting). Many recent approaches for continual or lifelong
learning have attempted to maintain performance given new tasks. But striving
to avoid forgetting sets the goal unnecessarily low: the goal of lifelong
learning, whether biological or artificial, should be to improve performance on
all tasks (including past and future) with any new data. We propose
omnidirectional transfer learning algorithms, which includes two special cases
of interest: decision forests and deep networks. Our key insight is the
development of the omni-voter layer, which ensembles representations learned
independently on all tasks to jointly decide how to proceed on any given new
data point, thereby improving performance on both past and future tasks. Our
algorithms demonstrate omnidirectional transfer in a variety of simulated and
real data scenarios, including tabular data, image data, spoken data, and
adversarial tasks. Moreover, they do so with quasilinear space and time
complexity
Adenylyl cyclase mRNA localizes to the posterior of polarized DICTYOSTELIUM cells during chemotaxis
In Dictyostelium discoideum, vesicular transport of the adenylyl cyclase A (ACA) to the posterior of polarized cells is essential to relay exogenous 3′,5′-cyclic adenosine monophosphate (cAMP) signals during chemotaxis and for the collective migration of cells in head-to-tail arrangements called streams. Using fluorescence in situ hybridization (FISH), we discovered that the ACA mRNA is asymmetrically distributed at the posterior of polarized cells. Using both standard estimators and Monte Carlo simulation methods, we found that the ACA mRNA enrichment depends on the position of the cell within a stream, with the posterior localization of ACA mRNA being strongest for cells at the end of a stream. By monitoring the recovery of ACA-YFP after cycloheximide (CHX) treatment, we observed that ACA mRNA and newly synthesized ACA-YFP first emerge as fluorescent punctae that later accumulate to the posterior of cells. We also found that the ACA mRNA localization requires 3′ ACA cis-acting elements. Together, our findings suggest that the asymmetric distribution of ACA mRNA allows the local translation and accumulation of ACA protein at the posterior of cells. These data represent a novel functional role for localized translation in the relay of chemotactic signal during chemotaxis.https://doi.org/10.1186/s12860-017-0139-
The Stellar Halos of Massive Elliptical Galaxies
We use the Mitchell Spectrograph (formerly VIRUS-P) on the McDonald
Observatory 2.7m Harlan J. Smith Telescope to search for the chemical
signatures of massive elliptical galaxy assembly. The Mitchell Spectrograph is
an integral-field spectrograph with a uniquely wide field of view (107x107 sq
arcsec), allowing us to achieve remarkably high signal-to-noise ratios of
~20-70 per pixel in radial bins of 2-2.5 times the effective radii of the eight
galaxies in our sample. Focusing on a sample of massive elliptical galaxies
with stellar velocity dispersions sigma* > 150 km/s, we study the radial
dependence in the equivalent widths (EWs) of key metal absorption lines. By
twice the effective radius, the Mgb EWs have dropped by ~50%, and only a weak
correlation between sigma* and Mgb EW remains. The Mgb EWs at large radii are
comparable to those seen in the centers of elliptical galaxies that are
approximately an order of magnitude less massive. We find that the well-known
metallicity gradients often observed within an effective radius continue
smoothly to 2.5R_e, while the abundance ratio gradients remain flat. Much like
the halo of the Milky Way, the stellar halos of our galaxies have low
metallicities and high alpha-abundance ratios, as expected for very old stars
formed in small stellar systems. Our observations support a picture in which
the outer parts of massive elliptical galaxies are built by the accretion of
much smaller systems whose star formation history was truncated at early times.Comment: To appear in ApJ, 15 pages, 9 figure
Lipidomic profiling identifies signatures of metabolic risk
BACKGROUND: Metabolic syndrome (MetS), the clustering of metabolic risk factors, is associated with cardiovascular disease risk. We sought to determine if dysregulation of the lipidome may contribute to metabolic risk factors. METHODS: We measured 154 circulating lipid species in 658 participants from the Framingham Heart Study (FHS) using liquid chromatography-tandem mass spectrometry and tested for associations with obesity, dysglycemia, and dyslipidemia. Independent external validation was sought in three independent cohorts. Follow-up data from the FHS were used to test for lipid metabolites associated with longitudinal changes in metabolic risk factors. RESULTS: Thirty-nine lipids were associated with obesity and eight with dysglycemia in the FHS. Of 32 lipids that were available for replication for obesity and six for dyslipidemia, 28 (88%) replicated for obesity and five (83%) for dysglycemia. Four lipids were associated with longitudinal changes in body mass index and four were associated with changes in fasting blood glucose in the FHS. CONCLUSIONS: We identified and replicated several novel lipid biomarkers of key metabolic traits. The lipid moieties identified in this study are involved in biological pathways of metabolic risk and can be explored for prognostic and therapeutic utility.The Framingham Heart Study is funded by National Institutes of Health (NIH) contract N01-HC-25195. This study was made possible by a CRADA between BG Medicine, Inc., Boston University, and the NHLBI, and the laboratory work for this research was supported by the Division of Intramural Research of the National Heart, Lung, and Blood Institute (NHLBI). Analytical work was funded by the Division of Intramural Research of NHLBI as well as the Center for Information Technology, NIH, Bethesda, MD. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.
The PESA study is supported by a non-competitive unrestricted grant shared between the National Center for Cardiovascular Research Carlos III (CNIC) and the Bank of Santander. The PESA study is a noncommercial study independent of the health and pharmaceutical industry. The CNIC is supported by the Spanish Ministry of Science, Innovation and Universities, the Instituto de Salud Carlos III, and the proCNIC Foundation. The study was partially funded by a grant from AstraZeneca (TANSNIP project). JMO is supported by the US Department of Agriculture, under agreement no. 8050-51000-098-00D. MPO and MJ acknowledge an Institute of Health Carlos III grant (PI 17-00134). This research was in part funded by the Spanish Ministry of Economy and Competitiveness, Institute of Health Carlos III (PI14/00328), co-financed by FEDER funds from the European Union ('A way to built Europe'), and the Generalitat of Catalonia, Department of Health(SLT002/16/00250) and Department of Business and Knowledge(2017SGR696) to R.P. MJ is a Serra Hunter Fellow.S
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