The Signal Sequence Coding Region Promotes Nuclear Export of mRNA

In eukaryotic cells, most mRNAs are exported from the nucleus by the transcription export (TREX) complex, which is loaded onto mRNAs after their splicing and capping. We have studied in mammalian cells the nuclear export of mRNAs that code for secretory proteins, which are targeted to the endoplasmic reticulum membrane by hydrophobic signal sequences. The mRNAs were injected into the nucleus or synthesized from injected or transfected DNA, and their export was followed by fluorescent in situ hybridization. We made the surprising observation that the signal sequence coding region (SSCR) can serve as a nuclear export signal of an mRNA that lacks an intron or functional cap. Even the export of an intron-containing natural mRNA was enhanced by its SSCR. Like conventional export, the SSCR-dependent pathway required the factor TAP, but depletion of the TREX components had only moderate effects. The SSCR export signal appears to be characterized in vertebrates by a low content of adenines, as demonstrated by genome-wide sequence analysis and by the inhibitory effect of silent adenine mutations in SSCRs. The discovery of an SSCR-mediated pathway explains the previously noted amino acid bias in signal sequences and suggests a link between nuclear export and membrane targeting of mRNAs

Exploring Hyperons and Hypernuclei with Lattice QCD

In this work we outline a program for lattice QCD that would provide a first step toward understanding the strong and weak interactions of strange baryons. The study of hypernuclear physics has provided a significant amount of information regarding the structure and weak decays of light nuclei containing one or two Lambda's, and Sigma's. From a theoretical standpoint, little is known about the hyperon-nucleon interaction, which is required input for systematic calculations of hypernuclear structure. Furthermore, the long-standing discrepancies in the P-wave amplitudes for nonleptonic hyperon decays remain to be understood, and their resolution is central to a better understanding of the weak decays of hypernuclei. We present a framework that utilizes Luscher's finite-volume techniques in lattice QCD to extract the scattering length and effective range for Lambda-N scattering in both QCD and partially-quenched QCD. The effective theory describing the nonleptonic decays of hyperons using isospin symmetry alone, appropriate for lattice calculations, is constructed.Comment: 24 pages, 7 figure

Genus Two Partition and Correlation Functions for Fermionic Vertex Operator Superalgebras I

We define the partition and $n$-point correlation functions for a vertex operator superalgebra on a genus two Riemann surface formed by sewing two tori together. For the free fermion vertex operator superalgebra we obtain a closed formula for the genus two continuous orbifold partition function in terms of an infinite dimensional determinant with entries arising from torus Szeg\"o kernels. We prove that the partition function is holomorphic in the sewing parameters on a given suitable domain and describe its modular properties. Using the bosonized formalism, a new genus two Jacobi product identity is described for the Riemann theta series. We compute and discuss the modular properties of the generating function for all $n$-point functions in terms of a genus two Szeg\"o kernel determinant. We also show that the Virasoro vector one point function satisfies a genus two Ward identity.Comment: A number of typos have been corrected, 39 pages. To appear in Commun. Math. Phy

The FIREBIRD Instrument for Relativistic Electrons: Enabling Technologies for a Fast High-Sensitivity, Low-Power Space Weather Radiation Payload

Miniaturized instrument payloads on small satellite and nanosatellite platforms that are deployed in low Earth orbit are demonstrating cost effective weather monitoring platforms with increased temporal and spatial resolution compared to larger weather satellites. The NASA Earth Decadal Survey [1] states that improving the revisit time of microwave radiometers would significantly improve weather forecasting. Radiometers such as the Advanced Technology Microwave Sounder (ATMS) on Suomi National Polar-orbiting Partnership (Suomi-NPP) and the Joint Polar Satellite System-1 (JPSS-1), now NOAA-20, provide an average revisit rate of 7.6 hours; however, a constellation of six CubeSats in three orbital Low Earth Orbit (LEO) planes with microwave radiometers such as the Time-Resolved Observations of Precipitations structure and storm Intensity with a Constellation of Smallsats (TROPICS) mission would provide a refresh rate of better than 60 minutes. In order to effectively use CubeSats in a constellation as a weather monitoring platform, calibration must be used to provide measurements consistent with state of the art measurements, such as ATMS that has a NeDT at 300K of 0.5-3.0K [2]. In this work, we use the Joint Center for Satellite Data Assimilation (JCSDA) Community Radiative Transfer Model (CRTM) to simulate brightness temperatures (https://www.jcsda.noaa.gov/projects_crtm.php), which are used to assess miniaturized microwave radiometer radiometric biases. CRTM is a fast radiative transfer model that uses Fortran functions, structure variables, and coefficient data of the modeled sensor to simulate radiances. The user inputs surface characteristics, scan angles, and atmospheric profiles from sources such as radiosondes, Numerical Weather Prediction (NWP) models, and Global Positioning System Radio Occultation (GPSRO) measurements. The output of CRTM is a simulated brightness temperature that is used to correct radiometric biases in order to meet required instrument NeDT performance. We use radiosonde, GPSRO, and NWP ERA-5 atmospheric profiles in CRTM and compare the results to ATMS brightness temperatures and find an average difference in brightness temperature of 1.95 K, which is comparable to ATMS Integrated Calibration/Validation System (https://www.star.nesdis.noaa.gov/icvs/status_NPP_ATMS.php) reports which show channel bias variations of up to 2 K. We take a similar approach to provide calibration for the Micro-sized Microwave Atmospheric Satellite-2A (MicroMAS-2A), a 3U CubeSat that was launched on January 11th, 2018. MicroMAS-2A carries a 1U 10-channel passive microwave radiometer that provides imagery near 90 and 206 GHz, temperature sounding near 118 GHz, and moisture sounding near 183 GHz. We develop an approach for comparing MicroMas-2A brightness temperatures to radiosonde, GPSRO, and NWP ERA5 atmospheric profiles. Due to the scarcity of GPSRO and radiosonde profiles near the MicroMAS-2A data segments, we determine that NWP models will be the best option for radiance validation. After the next stage of calibration of MicroMAS-2A is completed, we will compare CRTM simulated radiances from ERA profiles to the initial sensor data, with expected results of channel bias variations of \u3c 2 K

Priming by Chemokines Restricts Lateral Mobility of the Adhesion Receptor LFA-1 and Restores Adhesion to ICAM-1 Nano-Aggregates on Human Mature Dendritic Cells

LFA-1 is a leukocyte specific β2 integrin that plays a major role in regulating adhesion and migration of different immune cells. Recent data suggest that LFA-1 on mature dendritic cells (mDCs) may function as a chemokine-inducible anchor during homing of DCs through the afferent lymphatics into the lymph nodes, by transiently switching its molecular conformational state. However, the role of LFA-1 mobility in this process is not yet known, despite that the importance of lateral organization and dynamics for LFA-1-mediated adhesion regulation is broadly recognized. Using single particle tracking approaches we here show that LFA-1 exhibits higher mobility on resting mDCs compared to monocytes. Lymphoid chemokine CCL21 stimulation of the LFA-1 high affinity state on mDCs, led to a significant reduction of mobility and an increase on the fraction of stationary receptors, consistent with re-activation of the receptor. Addition of soluble monomeric ICAM-1 in the presence of CCL21 did not alter the diffusion profile of LFA-1 while soluble ICAM-1 nano-aggregates in the presence of CCL21 further reduced LFA-1 mobility and readily bound to the receptor. Overall, our results emphasize the importance of LFA-1 lateral mobility across the membrane on the regulation of integrin activation and its function as adhesion receptor. Importantly, our data show that chemokines alone are not sufficient to trigger the high affinity state of the integrin based on the strict definition that affinity refers to the adhesion capacity of a single receptor to its ligand in solution. Instead our data indicate that nanoclustering of the receptor, induced by multi-ligand binding, is required to maintain stable cell adhesion once LFA-1 high affinity state is transiently triggered by inside-out signals.Peer ReviewedPostprint (published version

The External Genitalia Score (EGS): A European Multicenter Validation Study

CONTEXT: Standardized description of external genitalia is needed in the assessment of children with atypical genitalia. OBJECTIVES: To validate the External Genitalia Score (EGS), to present reference values for preterm and term babies up to 24 months and correlate obtained scores with anogenital distances (AGDs). DESIGN, SETTING: A European multicenter (n = 8) validation study was conducted from July 2016 to July 2018. PATIENTS AND METHODS: EGS is based on the external masculinization score but uses a gradual scale from female to male (range, 0-12) and terminology appropriate for both sexes. The reliability of EGS and AGDs was determined by the interclass correlation coefficient (ICC). Cross-sectional data were obtained in 686 term babies (0-24 months) and 181 preterm babies, and 111 babies with atypical genitalia. RESULTS: The ICC of EGS in typical and atypical genitalia is excellent and good, respectively. Median EGS (10th to 90th centile) in males < 28 weeks gestation is 10 (8.6-11.5); in males 28-32 weeks 11.5 (9.2-12); in males 33-36 weeks 11.5 (10.5-12) and in full-term males 12 (10.5-12). In all female babies, EGS is 0 (0-0). The mean (SD) lower/upper AGD ratio (AGDl/u) is 0.45 (0.1), with significant difference between AGDl/u in males 0.49 (0.1) and females 0.39 (0.1) and intermediate values in differences of sex development (DSDs) 0.43 (0.1). The AGDl/u correlates with EGS in males with typical genitalia and in atypical genitalia. CONCLUSIONS: EGS is a reliable and valid tool to describe external genitalia in premature and term babies up to 24 months. EGS correlates with AGDl/u in males. It facilitates standardized assessment, clinical decision-making and multicenter research

2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137753/1/acr23274.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137753/2/acr23274_am.pd

2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137769/1/art40149.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137769/2/art40149_am.pd