Defining the Essential and Endocytic Functions of Pan1 in Saccharomyces cerevisiae

Endocytosis is the process by which cells internalize extracellular and transmembrane cargo from their environment. The process requires dozens of proteins to be recruited in a specific order to the site of endocytosis on the plasma membrane. These proteins bind the cargo to be internalized, form a coat on the membrane, deform the membrane using the force of actin polymerization to create the nascent vesicle, and finally pinch off the vesicle to allow for the cargo to be trafficked within the cell. Clathrin-mediated endocytosis (CME) is the most studied endocytic mechanism; both the order of events and the proteins involved are well conserved in eukaryotic organisms. Due to quick reproduction times and ease of genetic manipulations, Saccharomyces cerevisiae is an ideal model system to gain insight into the precise mechanisms that are required to coordinate CME. The timeline of CME is separated into four steps based on the proteins that are recruited during that stage: early coat, late coat, actin polymerization, and scission/uncoating. Although much is known about what proteins are recruited and when, there are still open questions concerning how each stage transitions to the next. The scaffold protein Intersectin/Pan1 may function as a coordinator between endocytic stages due to its multiple interactions with several proteins in the early, late, and actin polymerization stages. Intersectin and Pan1 are essential for life, making research of their function technically difficult. In this dissertation, a degron allele of Pan1 (Pan1-AID) was constructed to acutely deplete cells of Pan1 protein and observe the resulting phenotypes in vivo. Using Pan1-AID, it was discovered that Pan1 is critical for strengthening interactions during three transitions in CME: early coat to late coat, actin regulators to actin machinery, and coat/actin machinery to the plasma membrane. In addition, the regions and domains that are critical for Pan1’s endocytic and essential functions have been defined. Portions of Pan1 were found that can support viability, but not endocytosis, suggesting that these functions can be separated and Pan1, like Intersectin, may have additional roles in the cell

Registration of hard white winter wheat germplasms KS14U6380R5, KS16U6380R10, and KS16U6380R11 with adult plant resistance to stem rust

Resistance to the Ug99 group of races of the stem rust fungus Puccinia graminis f. sp. tritici is limited in winter wheat (Triticum aestivum L.) germplasm adapted to the Great Plains of the United States. Our objective was to generate regionally adapted hard winter wheat germplasm with combinations of adult plant resistance genes that are expected to provide durable resistance. KS14U6380R5 (Reg. no. GP-1043, PI 689115), KS16U6380R10 (Reg. no. GP-1044, PI 689116), and KS16U6380R11 (Reg. no. GP-1045, PI 689117) were derived from backcrosses of the hard white winter wheat germplasm KS05HW14 to the stem rust-resistant Kenyan spring wheat cultivar ‘Kingbird’. KS14U6380R5, KS16U6380R11, and KS16U6380R10 were developed by pedigree selection and were initially evaluated as U6380-11-2R-0A, U6380-210-2R-0A, and U6380-148-4R-2T, respectively. The germplasms were developed by the USDA-ARS and jointly released with the Kansas State University Agricultural Experiment Station. These germplasms provide parents for development of hard winter wheat cultivars with durable resistance to stem rust

Clinical Faculty in the Legal Academy: Hiring, Promotion, and Retention

The Chair of the Association of American Law Schools (AALS) Section on Clinical Legal Education appointed us in 2005 to the Task Force on the Status of Clinicians and the Legal Academy (Task Force) to examine who is teaching in clinical programs and using clinical methodologies in American law schools and to identify the most appropriate models for clinical appointments within the legal academy. Our charges reflected two ongoing concerns: 1) the need to collect valid, reliable, and helpful data that would inform discussions on the breadth of clinical education in the legal academy and the status of clinical educators within the academy; and 2) the need to have a foundation for complex conversations on how American law schools should view and value their clinical teachers. The first primarily describes the present, while the second carries implications for the future

The Status of Clinical Faculty in the Legal Academy: Report of the Task Force on the Status of Clinicians and the Legal Academy

In the midst of ongoing debates within the legal academy and the American Bar Association on the need for \u27practice-ready law school graduates through enhanced attention to law clinics and externships and on the status of faculty teaching in those courses, this report identifies and evaluates the most appropriate modes for clinical faculty appointments. Drawing on data collected through a survey of clinical program directors and faculty, the report analyzes the five most identifiable clinical faculty models: unitary tenure track; clinical tenure track; long-term contract; short-term contract; and clinical fellowships. It determines that, despite great strides in the growth of clinical legal education in the last 30 years, equality between clinical and non-clinical faculty remains elusive. Clinical faculty still lag behind non-clinical faculty in security of position and governance rights at most law schools. The report then identifies four core principles that should guide decisions about clinical faculty appointments: 1) clinical education is a foundational and essential component of legal education; 2) the legal academy and profession benefit from full inclusion of clinical faculty on all matters affecting the mission, function, and direction of law schools; 3) there is no justification for creating hierarchies between clinical and non-clinical faculty; and 4) the standards for hiring, retention, and promotion of clinical faculty must recognize and value the responsibilities and methodologies of clinical teaching. The report concludes that these core principles are best realized when full-time clinical faculty are appointed to a unitary tenure track. This conclusion does not ignore the imperfections of a tenure system. However, to the extent that tenure remains the strongest measure of the legal academy\u27s investment in its faculty and is the surest guarantee of academic freedom, inclusion in faculty governance and job security, the report recommends that law schools predominantly place their clinical faculty on dedicated tenure lines. In addition, it recommends that schools implement standards for hiring, promotion, and retention that reflect the teaching responsibilities and methodologies, as well as practice and service obligations, unique to their clinical faculty. To facilitate the development of such standards, the report suggests good practices for the appointment of clinical faculty on a unitary tenure track

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Effectiveness of Maternal mRNA COVID-19 Vaccination During Pregnancy Against COVID-19–Associated Hospitalizations in Infants Aged <6 Months During SARS-CoV-2 Omicron Predominance — 20 States, March 9, 2022–May 31, 2023

Infants aged <6 months are not eligible for COVID-19 vaccination. Vaccination during pregnancy has been associated with protection against infant COVID-19–related hospitalization. The Overcoming COVID-19 Network conducted a case-control study during March 9, 2022–May 31, 2023, to evaluate the effectiveness of maternal receipt of a COVID-19 vaccine dose (vaccine effectiveness [VE]) during pregnancy against COVID-19–related hospitalization in infants aged <6 months and a subset of infants aged <3 months. VE was calculated as (1 – adjusted odds ratio) x 100% among all infants aged <6 months and <3 months. Case-patients (infants hospitalized for COVID-19 outside of birth hospitalization and who had a positive SARS-CoV-2 test result) and control patients (infants hospitalized for COVID-19–like illness with a negative SARS-CoV-2 test result) were compared. Odds ratios were determined using multivariable logistic regression, comparing the odds of receipt of a maternal COVID-19 vaccine dose (completion of a 2-dose vaccination series or a third or higher dose) during pregnancy with maternal nonvaccination between case- and control patients. VE of maternal vaccination during pregnancy against COVID-19–related hospitalization was 35% (95% CI = 15%–51%) among infants aged <6 months and 54% (95% CI = 32%–68%) among infants aged <3 months. Intensive care unit admissions occurred in 23% of all case-patients, and invasive mechanical ventilation was more common among infants of unvaccinated (9%) compared with vaccinated mothers (1%) (p = 0.02). Maternal vaccination during pregnancy provides some protection against COVID-19–related hospitalizations among infants, particularly those aged <3 months. Expectant mothers should remain current with COVID-19 vaccination to protect themselves and their infants from hospitalization and severe outcomes associated with COVID-19