Investigation of Colorado front range winter storms using a nonhydrostatic mesoscale numerical model designed for operational use

Fall 1993.Also issued as author's sdissertation (Ph.D.) -- Colorado State University, 1993.Includes bibliographical references.State-of-the-art data sources such as Doppler radar, automated surface observations, wind profiler, digital satellite, and aircraft reports are for the first time providing the capability to generate real-time, operational three-dimensional gridded data sets with sufficient spatial and temporal resolutions to diagnose the structure and evolution of mesoscale systems. A prototype data assimilation system of this type, called the Local Analysis and Prediction System (LAPS), is being developed at the National Oceanic and Atmospheric System's Forecast Systems Laboratory (FSL). The investigation utilizes the three-dimensional LAPS analyses for initialization of the full physics, nonhydrostatic Regional Atmospheric Modeling System (RAMS) model developed at the Colorado State University to create a system capable of generating operational mesoscale predictions. The LAPS/RAMS system structured for operational use can add significant value to existing operational model output and can provide an improved scientific understanding of mesoscale weather events. The results a.re presented through two case study analyses, the 7 January 1992 Colorado Front Range blizzard and the 8-9 March 1992 eastern Colorado snowstorm. Both cases a.re ideal for this investigation due to the significant mesoscale variation observed in the precipitation and flow structure. The case study results demonstrate the ability to successfully detect and predict mesoscale features using a mesoscale numerical model initialized with high resolution (10 km horizontal grid interval), non­ homogeneous data. Conceptual models of the two snowstorms are developed by utilizing the RAMS model output in combination with observations and other larger domain model simulations. The strong influence of the Colorado topography on the resultant flow is suggested by the generation of a lee vortex that frequently develops east of the Front Range and south of the Cheyenne Ridge in stable, northwest synoptic flow. The lee vortex, often called the "Longmont anticyclone", exhibits surface flow characteristics that are similar to results from low Froude number flow around an isolated obstacle. A series of numerical experiments using RAMS with idealized topography and horizontally homogeneous initial conditions are presented to investigate typical low Froude number flow characteristics in the vicinity of barriers representative of the Colorado topography. The results are compared to the findings of previous investigations and to the case study observations and numerical predictions. The findings suggest that the Colorado orography significantly altered the low-level flow in both case studies resulting in mesoscale variation of observed precipitation. Improved representation of the topography by the model led to the majority of the forecast improvement

CAUSES OF SIMULTANEOUS LEE AND UPWIND RECORD SNOWFALL AND EXTRAORDINARY SNOWFALL VARIATION IN A ROCKY MOUNTAIN BLIZZARD

We describe our investigation of an extreme snowfall event in the Colorado Rocky Mountains during Mar 2003. This event was characterized by extraordinary micro-scale snowfall variability and record snowfall both upwind and in the lee of the 3000 m north-south oriented barrier. We utilize observational analysis and numerical sensitivity tests with the MM5 mesoscale model to test our hypotheses. Stunning micro-scale snowfall variability observed in-situ and visualized by satellite is found to be a consequence of local terrain-induced warming and reduced microphysical efficiency and the amplified influence of this effect due to the relatively warm temperatures accompanying this storm. Record snowfall (2 m) downwind of the barrier simultaneous with record snowfall (2.2 m) upwind is very rare climatologically, and is found to be caused, in effect, by the exceptional synoptic dimensions of this storm. A rare combination of, 1) moist, deep inflow, 2) a reversal of the mid-latitude westerlies to the tropopause overlying a well-developed barrier jet for an extended period and, 3) static stability favoring cross-barrier microphysical production and hydrometeor transport rather than drying, are implicated

Human GUCY2C-Targeted Chimeric Antigen Receptor (CAR)-Expressing T Cells Eliminate Colorectal Cancer Metastases.

One major hurdle to the success of adoptive T-cell therapy is the identification of antigens that permit effective targeting of tumors in the absence of toxicities to essential organs. Previous work has demonstrated that T cells engineered to express chimeric antigen receptors (CAR-T cells) targeting the murine homolog of the colorectal cancer antigen GUCY2C treat established colorectal cancer metastases, without toxicity to the normal GUCY2C-expressing intestinal epithelium, reflecting structural compartmentalization of endogenous GUCY2C to apical membranes comprising the intestinal lumen. Here, we examined the utility of a human-specific, GUCY2C-directed single-chain variable fragment as the basis for a CAR construct targeting human GUCY2C-expressing metastases. Human GUCY2C-targeted murine CAR-T cells promoted antigen-dependent T-cell activation quantified by activation marker upregulation, cytokine production, and killing of GUCY2C-expressing, but not GUCY2C-deficient, cancer cells in vitro. GUCY2C CAR-T cells provided long-term protection against lung metastases of murine colorectal cancer cells engineered to express human GUCY2C in a syngeneic mouse model. GUCY2C murine CAR-T cells recognized and killed human colorectal cancer cells endogenously expressing GUCY2C, providing durable survival in a human xenograft model in immunodeficient mice. Thus, we have identified a human GUCY2C-specific CAR-T cell therapy approach that may be developed for the treatment of GUCY2C-expressing metastatic colorectal cancer

Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients.

Background: The colorectal cancer antigen GUCY2C exhibits unique split tolerance, evoking antigen-specific CD8+, but not CD4+, T-cell responses that deliver anti-tumor immunity without autoimmunity in mice. Here, the cancer vaccine Ad5-GUCY2C-PADRE was evaluated in a first-in-man phase I clinical study of patients with early-stage colorectal cancer to assess its safety and immunological efficacy. Methods: Ten patients with surgically-resected stage I or stage II (pN0) colon cancer received a single intramuscular injection of 1011 viral particles (vp) of Ad5-GUCY2C-PADRE. Safety assessment and immunomonitoring were carried out for 6 months following immunization. This trial employed continual monitoring of both efficacy and toxicity of subjects as joint primary outcomes. Results: All patients receiving Ad5-GUCY2C-PADRE completed the study and none developed adverse events greater than grade 1. Antibody responses to GUCY2C were detected in 10% of patients, while 40% exhibited GUCY2C-specific T-cell responses. GUCY2C-specific responses were exclusively CD8+ cytotoxic T cells, mimicking pre-clinical studies in mice in which GUCY2C-specific CD4+ T cells are eliminated by self-tolerance, while CD8+ T cells escape tolerance and mediate antitumor immunity. Moreover, pre-existing neutralizing antibodies (NAbs) to the Ad5 vector were associated with poor vaccine-induced responses, suggesting that Ad5 NAbs oppose GUCY2C immune responses to the vaccine in patients and supported by mouse studies. Conclusions: Split tolerance to GUCY2C in cancer patients can be exploited to safely generate antigen-specific cytotoxic CD8+, but not autoimmune CD4+, T cells by Ad5-GUCY2C-PADRE in the absence of pre-existing NAbs to the viral vector. TRIAL REGISTRATION: This trial (NCT01972737) was registered at ClinicalTrials.gov on October 30th, 2013. https://clinicaltrials.gov/ct2/show/NCT01972737

CAUSES OF SIMULTANEOUS LEE AND UPWIND RECORD SNOWFALL AND EXTRAORDINARY SNOWFALL VARIATION IN A ROCKY MOUNTAIN BLIZZARD

We describe our investigation of an extreme snowfall event in the Colorado Rocky Mountains during Mar 2003. This event was characterized by extraordinary micro-scale snowfall variability and record snowfall both upwind and in the lee of the 3000 m north-south oriented barrier. We utilize observational analysis and numerical sensitivity tests with the MM5 mesoscale model to test our hypotheses. Stunning micro-scale snowfall variability observed in-situ and visualized by satellite is found to be a consequence of local terrain-induced warming and reduced microphysical efficiency and the amplified influence of this effect due to the relatively warm temperatures accompanying this storm. Record snowfall (2 m) downwind of the barrier simultaneous with record snowfall (2.2 m) upwind is very rare climatologically, and is found to be caused, in effect, by the exceptional synoptic dimensions of this storm. A rare combination of, 1) moist, deep inflow, 2) a reversal of the mid-latitude westerlies to the tropopause overlying a well-developed barrier jet for an extended period and, 3) static stability favoring cross-barrier microphysical production and hydrometeor transport rather than drying, are implicated

The dedicated iron deficiency anaemia clinic – a fifteen-year experience

Objective : To report our cumulative experience from a dedicated IDA clinic over the last 15 years – with particular emphasis on referral rate, uptake of investigation, impact on endoscopy services, diagnostic yield of GI investigation, and the issue of recurrent IDA. Method : A series of analyses of a register of 2808 referrals to the Poole IDA clinic between 2004 and 2018. Results : The study population of 2808 had a sex ratio of 1.9 (F/M) and a median age of 72 years (IQR : 60 - 79). A rising referral rate over the study period appears to be plateauing at around 2 cases per 1000 population per annum. On the basis of a snapshot audit, investigation of IDA may now account for over 20% of all diagnostic endoscopies. Overall, 86% of cases underwent examination of the upper and lower GI tract. Significant GI pathology was identified in 27% of the investigated cohort. Adenocarcinoma of the upper or lower GI tract was found in 8.3%, the majority in the right colon. The prevalence of recurrent IDA was estimated at 12.4%, and the results of investigation of this sub-group are reported. Conclusion : Unexplained IDA is common, particularly in those over 60 years, and may be the first indication of underlying GI malignancy in over 8% of cases. Unresolved challenges include accommodating the resulting endoscopy workload, establishing a risk / benefit ratio for investigating those with major co-morbidities, and the management of recurrent IDA

Search for the standard model Higgs boson in the H to ZZ to 2l 2nu channel in pp collisions at sqrt(s) = 7 TeV

A search for the standard model Higgs boson in the H to ZZ to 2l 2nu decay channel, where l = e or mu, in pp collisions at a center-of-mass energy of 7 TeV is presented. The data were collected at the LHC, with the CMS detector, and correspond to an integrated luminosity of 4.6 inverse femtobarns. No significant excess is observed above the background expectation, and upper limits are set on the Higgs boson production cross section. The presence of the standard model Higgs boson with a mass in the 270-440 GeV range is excluded at 95% confidence level.Comment: Submitted to JHE

Measurement of the t t-bar production cross section in the dilepton channel in pp collisions at sqrt(s) = 7 TeV

The t t-bar production cross section (sigma[t t-bar]) is measured in proton-proton collisions at sqrt(s) = 7 TeV in data collected by the CMS experiment, corresponding to an integrated luminosity of 2.3 inverse femtobarns. The measurement is performed in events with two leptons (electrons or muons) in the final state, at least two jets identified as jets originating from b quarks, and the presence of an imbalance in transverse momentum. The measured value of sigma[t t-bar] for a top-quark mass of 172.5 GeV is 161.9 +/- 2.5 (stat.) +5.1/-5.0 (syst.) +/- 3.6(lumi.) pb, consistent with the prediction of the standard model.Comment: Replaced with published version. Included journal reference and DO

Search for anomalous t t-bar production in the highly-boosted all-hadronic final state

A search is presented for a massive particle, generically referred to as a Z', decaying into a t t-bar pair. The search focuses on Z' resonances that are sufficiently massive to produce highly Lorentz-boosted top quarks, which yield collimated decay products that are partially or fully merged into single jets. The analysis uses new methods to analyze jet substructure, providing suppression of the non-top multijet backgrounds. The analysis is based on a data sample of proton-proton collisions at a center-of-mass energy of 7 TeV, corresponding to an integrated luminosity of 5 inverse femtobarns. Upper limits in the range of 1 pb are set on the product of the production cross section and branching fraction for a topcolor Z' modeled for several widths, as well as for a Randall--Sundrum Kaluza--Klein gluon. In addition, the results constrain any enhancement in t t-bar production beyond expectations of the standard model for t t-bar invariant masses larger than 1 TeV.Comment: Submitted to the Journal of High Energy Physics; this version includes a minor typo correction that will be submitted as an erratu

Combined search for the quarks of a sequential fourth generation

Results are presented from a search for a fourth generation of quarks produced singly or in pairs in a data set corresponding to an integrated luminosity of 5 inverse femtobarns recorded by the CMS experiment at the LHC in 2011. A novel strategy has been developed for a combined search for quarks of the up and down type in decay channels with at least one isolated muon or electron. Limits on the mass of the fourth-generation quarks and the relevant Cabibbo-Kobayashi-Maskawa matrix elements are derived in the context of a simple extension of the standard model with a sequential fourth generation of fermions. The existence of mass-degenerate fourth-generation quarks with masses below 685 GeV is excluded at 95% confidence level for minimal off-diagonal mixing between the third- and the fourth-generation quarks. With a mass difference of 25 GeV between the quark masses, the obtained limit on the masses of the fourth-generation quarks shifts by about +/- 20 GeV. These results significantly reduce the allowed parameter space for a fourth generation of fermions.Comment: Replaced with published version. Added journal reference and DO