Molecular Characterization of a Novel Intracellular ADP-Ribosyl Cyclase

Background. ADP-ribosyl cyclases are remarkable enzymes capable of catalyzing multiple reactions including the synthesis of the novel and potent intracellular calcium mobilizing messengers, cyclic ADP-ribose and NAADP. Not all ADP-ribosyl cyclases however have been characterized at the molecular level. Moreover, those that have are located predominately at the outer cell surface and thus away from their cytosolic substrates. Methodology/Principal Findings. Here we report the molecular cloning of a novel expanded family of ADP-ribosyl cyclases from the sea urchin, an extensively used model organism for the study of inositol trisphosphate-independent calcium mobilization. We provide evidence that one of the isoforms (SpARC1) is a soluble protein that is targeted exclusively to the endoplasmic reticulum lumen when heterologously expressed. Catalytic activity of the recombinant protein was readily demonstrable in crude cell homogenates, even under conditions where luminal continuity was maintained. Conclusions/Significance. Our data reveal a new intracellular location for ADP-ribosyl cyclases and suggest that production of calcium mobilizing messengers may be compartmentalized

The Yeast Nuclear Pore Complex and Transport Through It

Exchange of macromolecules between the nucleus and cytoplasm is a key regulatory event in the expression of a cell’s genome. This exchange requires a dedicated transport system: (1) nuclear pore complexes (NPCs), embedded in the nuclear envelope and composed of proteins termed nucleoporins (or “Nups”), and (2) nuclear transport factors that recognize the cargoes to be transported and ferry them across the NPCs. This transport is regulated at multiple levels, and the NPC itself also plays a key regulatory role in gene expression by influencing nuclear architecture and acting as a point of control for various nuclear processes. Here we summarize how the yeast Saccharomyces has been used extensively as a model system to understand the fundamental and highly conserved features of this transport system, revealing the structure and function of the NPC; the NPC’s role in the regulation of gene expression; and the interactions of transport factors with their cargoes, regulatory factors, and specific nucleoporins

A case of nocardiosis in a patient with ulcerative colitis on chronic corticosteroids, infliximab, and upadacitinib

Key Clinical Message Immunosuppression, malnutrition, and underlying infection can unmask obscure infections which can be challenging to identify. Early diagnosis and treatment of infections in immunosuppressed patients are essential due to high morbidity and mortality. Abstract The immunosuppressive effects of treatment for ulcerative colitis (UC), including chronic corticosteroids, anti‐TNF agents, and JAK inhibitors, can impact the spread of latent or obscure infections. Clinicians should have a low threshold for pursuing aggressive diagnostic and therapeutic intervention in patients who show signs of clinical deterioration while on immunosuppressing medications. Our unique case highlights an immunosuppressed patient with UC who developed Nocardiosis after initiation of upadacitinib while hospitalized for concurrent UC flare and Clostridium difficile infection

High Spectral Resolution Infrared and Raman Lidar Observations for the ARM Program: Clear and Cloudy Sky Applications

This grant began with the development of the Atmospheric Emitted Radiance Interferometer (AERI) for ARM. The AERI has provided highly accurate and reliable observations of downwelling spectral radiance (Knuteson et al. 2004a, 2004b) for application to radiative transfer, remote sensing of boundary layer temperature and water vapor, and cloud characterization. One of the major contributions of the ARM program has been its success in improving radiation calculation capabilities for models and remote sensing that evolved from the multi-year, clear-sky spectral radiance comparisons between AERI radiances and line-by-line calculations (Turner et al. 2004). This effort also spurred us to play a central role in improving the accuracy of water vapor measurements, again helping ARM lead the way in the community (Turner et al. 2003a, Revercomb et al. 2003). In order to add high-altitude downlooking AERI-like observations over the ARM sites, we began the development of an airborne AERI instrument that has become known as the Scanning High-resolution Interferometer Sounder (Scanning-HIS). This instrument has become an integral part of the ARM Unmanned Aerospace Vehicle (ARM-UAV) program. It provides both a cross-track mapping view of the earth and an uplooking view from the 12-15 km altitude of the Scaled Composites Proteus aircraft when flown over the ARM sites for IOPs. It has successfully participated in the first two legs of the “grand tour” of the ARM sites (SGP and NSA), resulting in a very good comparison with AIRS observations in 2002 and in an especially interesting data set from the arctic during the Mixed-Phase Cloud Experiment (M-PACE) in 2004. More specifically, our major achievements for ARM include 1. Development of the Atmospheric Emitted Radiance Interferometer (AERI) to function like a satellite on the ground for ARM, providing a steady stream of accurately calibrated spectral radiances for Science Team clear sky and cloud applications (Knuteson et al. 2004a), 2. Detailed radiometric calibration and characterization of AERI radiances, with uncertainty estimates established from complete error analyses and proven by inter-comparison tests (Knuteson et al. 2004b), 3. AERI data quality assessment and maintenance over the extended time frames needed to support ARM (Dedecker et al., 2005) 4. Key role in the radiative transfer model improvements from the AERI/LBLRTM QME (Turner et al. 2004) and AERI-ER especially from the SHEBA experiment (Tobin et al. 1999), 5. Contributed scientific and programmatic leadership leading to significant water vapor accuracy improvements and uncertainty assessments for the low to mid troposphere (Turner et al. 2003a, Revercomb et al. 2003), 6. Leadership of the ARM assessment of the accuracy of water vapor observations from radiosondes, Raman Lidar and in situ aircraft observations in the upper troposphere and lower stratosphere (Tobin et al. 2002, Ferrare et al. 2004), 7. New techniques for characterizing clouds from AERI (DeSlover et al. 1999, Turner 2003b, Turner et al. 2003b), 8. Initial design and development of the Scanning-HIS aircraft instrument and application to ARM UAV Program missions (Revercomb et al. 2005), and 9. Coordinated efforts leading to the use of ARM observations as a key validation tool for the high resolution Atmospheric IR Sounder on the NASA Aqua platform (Tobin et al. 2005a) 10. Performed ARM site and global clear sky radiative closure studies that shows closure of top-of-atmosphere flux at the level of ~1 W/m2 (Moy et al 2008 and Section 3 of this appendix) 11. Performed studies to characterize SGP site cirrus cloud property retrievals and assess impacts on computed fluxes and heating rate profiles (Borg et al. 2008 and Section 2 of this appendix)

Regular and low-dose aspirin, other non-steroidal anti-inflammatory medications and prospective risk of HER2-defined breast cancer: the California Teachers Study

Abstract Background Regular users of aspirin may have reduced risk of breast cancer. Few studies have addressed whether risk reduction pertains to specific breast cancer subtypes defined jointly by hormone receptor (estrogen and progesterone receptor) and human epidermal growth factor receptor 2 (HER2) expression. This study assessed the prospective risk of breast cancer (overall and by subtype) according to use of aspirin and other non-steroidal anti-inflammatory medications (NSAIDs) in a cohort of female public school professionals in California. Methods In 1995 − 1996, participants in the California Teachers Study completed a baseline questionnaire on family history of cancer and other conditions, use of NSAIDs, menstrual and reproductive history, self-reported weight and height, living environment, diet, alcohol use, and physical activity. In 2005–2006, 57,164 participants provided some updated information, including use of NSAIDs and 1457 of these participants developed invasive breast cancer before January 2013. Multivariable Cox proportional hazards regression models provided hazard rate ratios (HRR) for the association between NSAID use and risk of invasive breast cancer as well as hormone receptor- and HER2-defined subtypes. Results Developing breast cancer was associated inversely with taking three or more tablets of low-dose aspirin per week (23% of participants). Among women reporting this exposure, the HRR was 0.84 (95% confidence interval (CI) 0.72–0.98) compared to those not taking NSAIDs and this was particularly evident in women with the hormone receptor-positive/HER2-negative subtype (HRR = 0.80, 95% CI 0.66–0.96). Use of three or more tablets of “other” NSAIDs was marginally associated with lower risk of breast cancer (HRR = 0.79, 95% CI 0.62–1.00). Other associations with NSAIDs were generally null. Conclusion Our observation of reduced risk of breast cancer, among participants who took three or more tablets of low-dose aspirin weekly, is consistent with other reports looking at aspirin without differentiation by dose. This is the first report to suggest that the reduction in risk occurs for low-dose aspirin and not for regular-dose aspirin and only among women with the hormone receptor-positive/HER2-negative subtype. This preliminary study builds on previous knowledge and further supports the need for formal cancer chemoprevention studies of low-dose aspirin

De Novo Bone Induction by Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2) in Maxillary Sinus Floor Augmentation

This phase II study was designed to evaluate 2 concentrations of recombinant human bone morphogenetic protein-2 (rhBMP-2) for safety and efficacy in inducing adequate bone for endosseous dental implant in patients requiring staged maxillary sinus floor augmentation. Patients were treated with rhBMP-2 (via an absorbable collagen sponge [ACS]), at concentrations of 0.75 mg/mL (n = 18), 1.50 mg/mL (n = 17), or with bone graft (n = 13). Bone induction was assessed by alveolar ridge height, width, and density measurements from computed tomography scans obtained before and 4 months after treatment and 6 months post-functional loading of dental implants (density only). Mean increases in alveolar ridge height at 4 months after treatment were similar among the groups; 11.3 mm, 9.5 mm, and 10.2 mm, respectively, in the bone graft, 0.75 mg/mL, and 1.50 mg/mL rhBMP-2/ACS treatment groups. Mean increases in alveolar ridge width (buccal to lingual) at the crest of the ridge were statistically different among the treatment groups; 4.7 mm, 2.0 mm, and 2.0 mm, respectively, in the bone graft, 0.75 mg/mL, and 1.50 mg/mL treatment groups ( P ≤ .01 vs 0.75 mg/mL; P < .01 vs 1.50 mg/mL). At 4 months postoperative new bone density was statistically different among the treatment groups; 350 mg/cc, 84 mg/cc, and 134 mg/cc for the bone graft, 0.75 mg/mL, and 1.50 mg/mL rhBMP-2/ACS treatment groups, respectively ( P = .003 vs 0.75 mg/mL, P = .0137 vs 1.50 mg/mL, P = .0188; 1.50 mg/mL vs 0.75 mg/mL). Core bone biopsies obtained at the time of dental implant placement confirmed normal bone formation. The proportion of patients who received dental implants that were functionally loaded and remained functional at 36 months post-functional loading was 62%, 67%, and 76% in the bone graft, 0.75 mg/mL, and 1.50 mg/mL rhBMP-2/ACS treatment groups, respectively. This study is the first randomized controlled trial demonstrating de novo organ tissue growth in humans from a recombinant human protein. rhBMP-2/ACS safely induced adequate bone for the placement and functional loading of endosseous dental implants in patients requiring staged maxillary sinus floor augmentation

Assessing an electronic self-report method for improving quality of ethnicity and race data in the Veterans Health Administration.

ObjectiveEvaluate self-reported electronic screening (eScreening) in a VA Transition Care Management Program (TCM) to improve the accuracy and completeness of administrative ethnicity and race data.Materials and methodsWe compared missing, declined, and complete (neither missing nor declined) rates between (1) TCM-eScreening (ethnicity and race entered into electronic tablet directly by patient using eScreening), (2) TCM-EHR (Veteran-completed paper form plus interview, data entered by staff), and (3) Standard-EHR (multiple processes, data entered by staff). The TCM-eScreening (n = 7113) and TCM-EHR groups (n = 7113) included post-9/11 Veterans. Standard-EHR Veterans included all non-TCM Gulf War and post-9/11 Veterans at VA San Diego (n = 92 921).ResultsEthnicity: TCM-eScreening had lower rates of missingness than TCM-EHR and Standard-EHR (3.0% vs 5.3% and 8.6%, respectively, P &lt; .05), but higher rates of "decline to answer" (7% vs 0.5% and 1.2%, P &lt; .05). TCM-EHR had higher data completeness than TCM-eScreening and Standard-EHR (94.2% vs 90% and 90.2%, respectively, P &lt; .05). Race: No differences between TCM-eScreening and TCM-EHR for missingness (3.5% vs 3.4%, P &gt; .05) or data completeness (89.9% vs 91%, P &gt; .05). Both had better data completeness than Standard-EHR (P &lt; .05), which despite the lowest rate of "decline to answer" (3%) had the highest missingness (10.3%) and lowest overall completeness (86.6%). There was strong agreement between TCM-eScreening and TCM-EHR for ethnicity (Kappa = .92) and for Asian, Black, and White Veteran race (Kappas = .87 to .97), but lower agreement for American Indian/Alaska Native (Kappa = .59) and Native Hawaiian/Other Pacific Islander (Kappa = .50) Veterans.ConculsionseScreening is a promising method for improving ethnicity and race data accuracy and completeness in VA