HOW IS THE NEW KIDNEY ALLOCATION SYSTEM WORKING? INSIGHTS FROM HIGHLY SENSITIZED AND PEDIATRIC PATIENTS

The Kidney Allocation System (KAS) was implemented on December 4, 2014, and was the largest policy change to how deceased donor kidneys are allocated in the United States in the last two decades. Since policy change can have unintended consequences, we sought to critically examine how KAS has impacted kidney transplant candidates and recipients. This dissertation focuses on two unique transplant populations: highly sensitized (HS, calculated panel reactive antibody [cPRA] ≥80%) and pediatric (age <18) patients. First, one explicit goal of KAS was to improve the likelihood that a HS kidney transplant candidate would receive a deceased donor kidney transplant (DDKT), and we sought to quantify the extent to which KAS accomplished this goal (Chapter 2). Using national data, we found that candidates with the highest levels of sensitization had a significantly higher DDKT rate post-KAS (for example, cPRA 98% candidates had a 1.77-fold higher DDKT rate). We then sought to understand how other transplant modalities were being used to transplant the HS (Chapter 3). We used national data from 39,907 HS candidates and found that HS candidates were 2.25-fold more likely to utilize kidney paired donation but 18% less likely to utilize non-kidney paired donation living donor kidney transplantation in the post-KAS era compared to earlier eras. We then studied how KAS impacted pediatric DDKT recipient outcomes, in light of concerns that fewer pediatric donor kidneys were being allocated to pediatric DDKT recipients (Chapter 4). We used national data from 1,887 pediatric DDKT candidates and found that post-KAS pediatric DDKT recipients had a 41% lower risk of graft loss than pre-KAS recipients. We then studied changes in offer and acceptance patterns under KAS (Chapter 5). Using national data from 3,642 pediatric DDKT candidates, we found that post-KAS candidates were 20% more likely to receive offers from donors age 18-34 with KDPI ≤35%, but were also 23% less likely to accept kidneys from those same high-quality donors. Our results will be used by pediatric and adult nephrologists, transplant surgeons, and policy-makers to understand how KAS has impacted HS and pediatric candidates and recipients to better inform any potential policy changes

Notes on Lung Development in South African Ghost Frogs (Anura: Heleophrynidae)

Lungs are a prototypical trait of most tetrapods, but some amphibians have become secondarily lungless over evolutionary time. Anuran (frog) tadpoles offer an opportunity to examine lung loss from an evolutionary perspective, because there are many independent instances where lungs are not inflated until adulthood, and so are functionally lost. Lung loss is typically associated with living in fast-flowing streams, and so we examined larval lung development in the stream specialist family Heleophrynidae. We find that one genus, Hadromophryne Van Dijk, 2008, has large lungs as tadpole, while the other genus, Heleophryne Sclater, 1898, has much smaller, stunted lung buds. We further speculate how this information changes our understanding of how the specialised torrent form has evolved in this specialised group

Supernova Ia and Galaxy Cluster Gas Mass Fraction Constraints on Dark Energy

We use the Riess et al.(2004) supernova Ia apparent magnitude versus redshift data and the Allen et al.(2004) galaxy cluster gas mass fraction versus redshift data to constrain dark energy models. These data provide complementary constraints that when combined together ignificantly restrict model parameters and favor lowly-evolving dark energy density models, close to the Einstein cosmological constant limit of dark energy.Comment: 13 pages, 4 figure

Ab initio Study of Ground-State CS Photodissociation Via Highly Excited Electronic States

Photodissociation by ultraviolet radiation is the key destruction pathway for CS in photon-dominated regions, such as diffuse clouds. However, the large uncertainties of photodissociation cross sections and rates of CS, resulting from a lack of both laboratory experiments and theoretical calculations, limit the accuracy of calculated abundances of S-bearing molecules by modern astrochemical models. Here we show a detailed \textit{ab initio} study of CS photodissociation. Accurate potential energy curves of CS electronic states were obtained by choosing an active space CAS(8,10) in MRCI+Q/aug-cc-pV(5+d)Z calculation with additional diffuse functions, with a focus on the $B$ and C\,^1\Sigma^+ states. Cross sections for both direct photodissociation and predissociation from the vibronic ground state were calculated by applying the coupled-channel method. We found that the $C-X$ $(0-0)$ transition has extremely strong absorption due to a large transition dipole moment in the Franck-Condon region and the upper state is resonant with several triplet states via spin-orbit couplings, resulting in predissociation to the main atomic products C $(^3P)$ and S $(^1D)$. Our new calculations show the photodissociation rate under the standard interstellar radiation field is 2.9\ee{-9}\,s$^{-1}$, with a 57\% contribution from $C-X$ $(0-0)$ transition. This value is larger than that adopted by the Leiden photodissociation and photoionization database by a factor of 3.0. Our accurate \textit{ab initio} calculations will allow more secure determination of S-bearing molecules in astrochemical models.Comment: 23 pages, 14 figure

Induction of viral mimicry upon loss of DHX9 and ADAR1 in breast cancer cells

UNLABELLED: Detection of viral double-stranded RNA (dsRNA) is an important component of innate immunity. However, many endogenous RNAs containing double-stranded regions can be misrecognized and activate innate immunity. The IFN-inducible ADAR1-p150 suppresses dsRNA sensing, an essential function for adenosine deaminase acting on RNA 1 (ADAR1) in many cancers, including breast. Although ADAR1-p150 has been well established in this role, the functions of the constitutively expressed ADAR1-p110 isoform are less understood. We used proximity labeling to identify putative ADAR1-p110-interacting proteins in breast cancer cell lines. Of the proteins identified, the RNA helicase DHX9 was of particular interest. Knockdown of DHX9 in ADAR1-dependent cell lines caused cell death and activation of the dsRNA sensor PKR. In ADAR1-independent cell lines, combined knockdown of DHX9 and ADAR1, but neither alone, caused activation of multiple dsRNA sensing pathways leading to a viral mimicry phenotype. Together, these results reveal an important role for DHX9 in suppressing dsRNA sensing by multiple pathways. SIGNIFICANCE: These findings implicate DHX9 as a suppressor of dsRNA sensing. In some cell lines, loss of DHX9 alone is sufficient to cause activation of dsRNA sensing pathways, while in other cell lines DHX9 functions redundantly with ADAR1 to suppress pathway activation

Evaluation of Jobsite Cylinder Curing Practices for the Alabama Concrete Industry

The effect of initial curing temperature and duration on the 28-day compressive strength of concrete was experimentally evaluated. Concrete cylinders were cured at six initial curing temperatures (60, 68, 78, 84, 90, and 100 \u2070F) for three different initial curing durations (24, 48, and 72 hours). After the initial curing duration was complete, the cylinders were moved to final curing in a moist cure room that maintained a temperature of 73.5 \ub1 3.5 \ub0F until compressive strength testing at 28 days. Eight different concretes were produced at elevated temperatures to simulate summer placement conditions. The results confirm that as the initial curing temperature increases, the 28-day concrete compressive strength decreases. When cured at an initial curing temperature of 100 \u2070F, a maximum reduction of 23% in the 28-day compressive strength occurred. It is critical to maintain initial curing temperatures ranging from 60 to 80 \u2070F because then the change in 28-day strength remains within the acceptable ranges. When the initial curing temperature ranges from 60 to 80 \u2070F, then increasing the initial curing duration from 48 hour to 72 hour does not significantly affect the 28-day concrete compressive strength. The maximum initial curing duration can thus be increased from 48 to 72 hours, which will permit cylinders made on Fridays to be transported to their final curing location on Mondays

Integration of Machine Learning and Mechanistic Models Accurately Predicts Variation in Cell Density of Glioblastoma Using Multiparametric MRI

Glioblastoma (GBM) is a heterogeneous and lethal brain cancer. These tumors are followed using magnetic resonance imaging (MRI), which is unable to precisely identify tumor cell invasion, impairing effective surgery and radiation planning. We present a novel hybrid model, based on multiparametric intensities, which combines machine learning (ML) with a mechanistic model of tumor growth to provide spatially resolved tumor cell density predictions. The ML component is an imaging data-driven graph-based semi-supervised learning model and we use the Proliferation-Invasion (PI) mechanistic tumor growth model. We thus refer to the hybrid model as the ML-PI model. The hybrid model was trained using 82 image-localized biopsies from 18 primary GBM patients with pre-operative MRI using a leave-one-patient-out cross validation framework. A Relief algorithm was developed to quantify relative contributions from the data sources. The ML-PI model statistically significantly outperformed (p \u3c 0.001) both individual models, ML and PI, achieving a mean absolute predicted error (MAPE) of 0.106 ± 0.125 versus 0.199 ± 0.186 (ML) and 0.227 ± 0.215 (PI), respectively. Associated Pearson correlation coefficients for ML-PI, ML, and PI were 0.838, 0.518, and 0.437, respectively. The Relief algorithm showed the PI model had the greatest contribution to the result, emphasizing the importance of the hybrid model in achieving the high accuracy

A Student\u27s Guide to giant Viruses Infecting Small Eukaryotes: From Acanthamoeba to Zooxanthellae

The discovery of infectious particles that challenge conventional thoughts concerning “what is a virus” has led to the evolution a new field of study in the past decade. Here, we review knowledge and information concerning “giant viruses”, with a focus not only on some of the best studied systems, but also provide an effort to illuminate systems yet to be better resolved. We conclude by demonstrating that there is an abundance of new host–virus systems that fall into this “giant” category, demonstrating that this field of inquiry presents great opportunities for future research

Targeted proteomic quantitation of NRF2 signaling and predictive biomarkers in HNSCC

The NFE2L2 (NRF2) oncogene and transcription factor drives a gene expression program that promotes cancer progression, metabolic reprogramming, immune evasion, and chemoradiation resistance. Patient stratification by NRF2 activity may guide treatment decisions to improve outcome. Here, we developed a mass spectrometry-based targeted proteomics assay based on internal standard-triggered parallel reaction monitoring to quantify 69 NRF2 pathway components and targets, as well as 21 proteins of broad clinical significance in head and neck squamous cell carcinoma (HNSCC). We improved an existing internal standard-triggered parallel reaction monitoring acquisition algorithm, called SureQuant, to increase throughput, sensitivity, and precision. Testing the optimized platform on 27 lung and upper aerodigestive cancer cell models revealed 35 NRF2 responsive proteins. In formalin-fixed paraffin-embedded HNSCCs, NRF2 signaling intensity positively correlated with NRF2-activating mutations and with SOX2 protein expression. Protein markers of T-cell infiltration correlated positively with one another and with human papilloma virus infection status. CDKN2A (p16) protein expression positively correlated with the human papilloma virus oncogenic E7 protein and confirmed the presence of translationally active virus. This work establishes a clinically actionable HNSCC protein biomarker assay capable of quantifying over 600 peptides from frozen or formalin-fixed paraffin-embedded archived tissues in under 90 min