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In a pair of artificial language experiments, we investigated the learnability and emergence of different dependency structures: branching, center-embedding, and crossed. In natural languages, branching is the most common dependency structure; center-embedding occurs but is often disfavored, and crossed dependencies are very rare. Experiment 1 addressed learnability, testing comprehension, and production on small artificial languages exemplifying each dependency type in noun phrases. As expected, branching dependency grammars were the easiest to learn, but crossed grammars were not different from center-embedding. Experiment 2 employed iterated learning to examine the emergence and stabilization of consistent grammar using the same type of stimuli as Experiment 1. The initial participant in each chain of transmission was trained on phrases generated by a random grammar, with the language produced by that participant passed to the next participant through an iterated learning process. Branching dependency grammar appeared in most chains within a few generations and remained stable once it appeared, although one chain stabilized on output consistent with a crossed grammar; no chains converged on center-embedding grammars. These findings, along with some previous results, call into question the assumption that crossed dependencies are more cognitively complex than center-embedding, while confirming the role of learnability in the typology of dependency structures.

The nursing faculty shortage challenges nursing educators, administrators, and staff to find innovative ways to understand and address faculty retention.The purpose of this study was to examine nurse educators' perceptions of workplace collegiality and the possible correlation to role satisfaction and role persistence.Participants (n = 177) were recruited nationally from a Commission on Collegiate Nursing Education accredited schools listing. Three survey instruments were utilized: Survey of Collegial Communication, Job Satisfaction Survey, and Michigan Organizational Assessment Questionnaire.The study found a positive relationship between collegiality and job satisfaction in academia. The Pearson correlation results indicated there was a significant negative correlation between the intent to remain and collegiality.The findings suggest nursing educators perceive collegiality as an important component of job satisfaction and intent to remain.

Non-negative matrix factorization (NMF) is an unsupervised learning method well suited to high-throughput biology. Still, inferring biological processes requires additional post hoc statistics and annotation for interpretation of features learned from software packages developed for NMF implementation. Here, we aim to introduce a suite of computational tools that implement NMF and provide methods for accurate, clear biological interpretation and analysis. A generalized discussion of NMF covering its benefits, limitations, and open questions in the field is followed by three vignettes for the Bayesian NMF algorithm CoGAPS (Coordinated Gene Activity across Pattern Subsets). Each vignette will demonstrate NMF analysis to quantify cell state transitions in public domain single-cell RNA-sequencing (scRNA-seq) data of malignant epithelial cells in 25 pancreatic ductal adenocarcinoma (PDAC) tumors and 11 control samples. The first uses PyCoGAPS, our new Python interface for CoGAPS that we developed to enhance runtime of Bayesian NMF for large datasets. The second vignette steps through the same analysis using our R CoGAPS interface, and the third introduces two new cloud-based, plug-and-play options for running CoGAPS using GenePattern Notebook and Docker. By providing Python support, cloud-based computing options, and relevant example workflows, we facilitate user-friendly interpretation and implementation of NMF for single-cell analyses.

This review of the literature was conducted to define avoidant restrictive food intake disorder (ARFID) and provide the current evidence-based treatment modalities and implications for Nurse Practitioners. A specific case is used to illustrate the daily struggles of a pediatric patient with ARFID that include bullying, self-doubt, and anxiety related to eating. There is a need for increased awareness of the disorder to increase identification of the disorder, enhance the research on treatment modalities for the disorder, and most importantly, to increase the quality of life for those with the disorder and their family members.

Introduction: High demand for speech-language pathology means children sometimes wait over 12 months for services, missing out on timely support. Waiting can be a time of stress, concern, and powerlessness for caregivers. Provision of information via a website may support families and encourage active waiting. Objective: The aim of this study was to compare children’s speech, intelligibility, language, and literacy outcomes, and caregivers’ satisfaction and empowerment in active versus passive waiting conditions. Methods: Ninety-seven preschool-aged children referred to a community health speech-language pathology service in Australia were screened for eligibility. Eligible children (n =42) with speech/language difficulties were randomly allocated to: (a) active waiting (provision of a purpose-built website; n = 20), or (b) passive waiting (control group; n = 22). Pre- and post-assessments (after 6 months on a waiting list) were completed with children and caregivers by a speech-language pathologist blinded to group allocations. Results: Intention to treat (n =36) and per-protocol analyses (n =30) were conducted to measure group differences in child and caregiver outcomes at post-assessment using one-way ANCOVA, controlling for baseline scores. There were no statistically significant differences between groups for children’s speech, intelligibility, language, and literacy, or caregivers’ empowerment and satisfaction. Children in both groups made minimal gains over 6 months. Conclusions: Provision of an active waiting website did not lead to statistically significant change in child or caregiver outcomes, and children in both groups made little progress over a 6-month period. Early speech-language pathology intervention delivered with appropriate dosage is needed to optimise children’s outcomes. Until timely and effective speech-language pathology intervention can be provided for all who need it, provision of early assessments may be beneficial. There remains a need for effective ways to support children and families on waiting lists.

Previous work suggests that Dihydroorotate dehydrogenase (DHODH) inhibition via teriflunomide (TERI) may provide protection in multiple disease models. To date, little is known about the effect of TERI on the heart. This study was performed to assess the potential effects of TERI on cardiac ischemia reperfusion injury.Male and female rat hearts were subjected to global ischemia (25 min) and reperfusion (120 min) on a Langendorff apparatus. Hearts were given either DMSO (VEH) or teriflunomide (TERI) for 5 min prior to induction of ischemia and during the reperfusion period. Left ventricular pressure, ECG, coronary flow, and infarct size were determined using established methods. Mitochondrial respiration was assessed via respirometry.Perfusion of hearts with TERI led to no acute effects in any values measured across 500 pM-50 nM doses. However, following ischemia-reperfusion injury, we found that 50 nM TERI-treated hearts had an increase in myocardial infarction (p 0.001). In 50 nM TERI-treated hearts, we also observed a marked increase in the severity of contracture (p 0.001) at an earlier time-point (p = 0.004), as well as reductions in coronary flow (p = 0.037), left ventricular pressure development (p = 0.025), and the rate-pressure product (p = 0.008). No differences in mitochondrial respiration were observed with 50 nM TERI treatment (p = 0.24-0.87).This study suggests that treatment with TERI leads to more negative outcomes following cardiac ischemia reperfusion, and administration of TERI to at-risk populations should receive special considerations.

Electronic medical records have made great advances in the provision of quality health care but have increased physician workload and often limit face-to-face time with patients. These effects are particularly felt in the academic dermatology clinic, a critical time of practice development. Time constraints from implementation of electronic medical records have resulted in low patient volume and reduced educational opportunities. A review of the literature suggests that utilizing scribes as physician aides in the academic dermatology setting may increase patient access, clinic volume, educational experience, and hospital revenue.

Background: Oncogenic mutations in KRAS are expressed in up to 90% of pancreatic ductal adenocarcinomas (PDAC). Vaccination against mutant KRAS (mKRAS) is thus a promising approach as an off-the-shelf immunotherapeutic treatment for PDAC. We developed a mKRAS peptide vaccine targeting 6 common KRAS mutations (G12V, G12A, G12C, G12R, G12D, or G13D (NCT04117087). We evaluated the mKRAS specific T cell response induced by vaccination in combination with immune checkpoint inhibitors (ICIs) in patients with resected PDAC. Materials and Methods: This is an ongoing pilot study of a pooled mKRAS long peptide vaccine in combination with ICIs in patients with resected PDAC and mutations in one of 6 KRAS mutations in our vaccine. Patients with no evidence of disease on imaging within 6 months of completion of adjuvant chemotherapy were vaccinated with the mKRAS vaccine (0.3mg/peptide and 0.5mg poly-ICLC (Hiltonol: Oncovir)) weekly for 4 doses followed by booster vaccines every 8 weeks. Patients also received ipilimumab (1mg/kg, every 6 weeks for 2 doses) and nivolumab (3mg/kg, every 3 weeks in the priming phase) followed by nivolumab (480mg, flat dose in boost phase). To evaluate the expansion of mKRAS-specific T cells in the periphery, pre- and post-vaccination peripheral blood mononuclear cells (PBMCs) were restimulated with control or individual mKRAS peptides and assessed for IFNγ release by ELISPOT. To further phenotype the responding CD4 and CD8 T cell compartments, peptide-restimulated PBMCs were evaluated for T cell activation, proliferation, memory and exhaustion marker expression by CyTOF. Paired single-cell RNA and TCR sequencing are being performed to isolate mKRAS-specific TCRs and their corresponding transcriptional profiles. These TCRs are being functionally validated in vitro using CRISPR-Cas12a-based genome knock-in of human T cells. Results: At the time of data cut off (1/12/2023) 8/11 patients enrolled had a positive mKRAS-specific T cell response in post-vaccine sample timepoints defined by a >5 fold increase in IFNγ producing T cells after peptide restimulation. CyTOF analysis of peptide-restimulated PBMCs demonstrated expansion of polyfunctional (IFNγ+IL2+TNFα+) mKRAS-specific CD4 and CD8 T cells with both central and effector memory phenotypes after vaccination. mKRAS-specific CD4 T cells were induced at a greater proportion. Our single-cell analysis has identified and validated a novel CD4+ TCR that recognizes KRAS G12V in the context of HLA-DRB1*07:01. Conclusions: This study thus far indicates the induction of de novo, high quality mKRAS-specific T cells in the periphery post-vaccine. Ongoing studies will define TCR diversity and clonality of mKRAS-specific T cells to each mKRAS epitope. Overall, our data will be used to identify peripheral T cell-based biomarkers that may be able to predict response to mKRAS-targeted immunotherapy. Citation Format: Amanda L. Huff, Saurav D. Haldar, Emily Davis-Marcisak, Thatcher Heumann, Gabriella Longway, Alexei Hernandez, Maximillian F. Konig, Brian Mog, Ludmila Danilova, Luciane Kagohara, Julie M. Nauroth, Amy M. Thomas, Elana J. Fertig, Won Jin Ho, Elizabeth M. Jaffee, Nilo Azad, Neeha Zaidi. A pooled mutant KRAS peptide vaccine activates polyfunctional T cell responses in patients with resected pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB197.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with a low tumor mutational burden and therefore few neoantigen targets that can be recognized by cytotoxic T cells. Most PDACs are thus insensitive to either single or dual immune checkpoint inhibitor (ICI) therapy. Personalized neoantigen vaccines can expand the number and repertoire of anti-tumor T cells that infiltrate the tumor and mediate cytotoxicity. To model a personalized neoantigen vaccine treatment strategy in PDAC, we previously developed PancVAX, a peptide-based vaccine targeting 12 neoantigens expressed in the murine pancreatic cell line Panc02 (Kinkead et al, JCI Insight 2018). Although we observed increased T cell infiltration present in the tumor post-vaccination, these cells expressed high levels of exhaustion markers. We therefore hypothesized that sequential administration of anti-CTLA-4 and anti-PD-1 would enhance the pool of T cells primed by the neoantigen vaccine and maintain activation of antigen-experienced T cells, respectively, to yield optimal and durable neoantigen-specific anti-tumor immunity in PDAC. To address this, mice bearing subcutaneous Panc02 tumors were vaccinated with two rounds of the PancVAX neoantigen vaccine followed by anti-CTLA-4 and anti-PD-1 3 days later. Anti-PD-1 maintenance was given twice weekly beginning at the first vaccine dose. Twelve days after the last peptide vaccine dose, tumors were harvested and dissociated into single-cell suspensions for paired single-cell RNA-sequencing and TCR-sequencing. Mice that were untreated or given ICIs without PancVAX had the highest proportions of CD8+ T cells expressing exhaustion markers. PancVAX-treated mice had more intratumoral cycling CD8 T cells and effector CD8+ T cells with high cytotoxic gene expression. Among mice treated with PancVAX, tumors from mice treated with PancVAX + anti-PD1 or PancVAX + anti-PD1 + anti-CTLA-4 had the highest proportions of effector CD8+ T cells. Ongoing analyses include differential gene expression and pathway analysis between treatment conditions in the T cell compartment in mice treated with combination ICI and PancVAX. Additionally, we will assess changes in T cell clonality and diversity within the tumors when mice are treated with single or combination therapy. These results will define a transcriptional signature associated with the generation of a productive anti-tumor immune response when neoantigen vaccines and ICI are used in combination. This work demonstrates how the addition of ICIs to personalized neo-epitope vaccines for PDAC can further enhance the quality of vaccine-induced T cell effector function in an otherwise immunologically cold tumor type and supports their inclusion in neoantigen vaccination strategies for patients with PDAC. Citation Format: Jacob T. Mitchell, Amanda Huff, Emily Davis-Marcisak, Fangluo Chen, Todd D. Armstrong, Luciane T. Kagohara, James Leatherman, Rulin Wang, Srinivasan Yegnasubramanian, Elizabeth M. Jaffee, Elana J. Fertig, Neeha Zaidi. Combination PancVAX neo-epitope vaccine with anti-CTLA-4 and anti-PD-1 antibodies enhances infiltration of cytotoxic T cells and mitigates T cell exhaustion in a murine model of pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5076.

Earp, Lewis, and Hart (2021) write about the racism entrenched in policies criminalizing drug use and possession and describe the disparate impact that these policies have on certain racialized com...

Much of our understanding of GH’s action stems from animal models and the generation and characterization of genetically altered or modified mice. Manipulation of genes in the GH/IGF1 family in animals started in 1982 when the first GH transgenic mice were produced. Since then, multiple laboratories have altered mouse DNA to globally disrupt Gh, Ghr, and other genes upstream or downstream of GH or its receptor. The ability to stay current with the various genetically manipulated mouse lines within the realm of GH/IGF1 research has been daunting. As such, this review attempts to consolidate and summarize the literature related to the initial characterization of many of the known gene-manipulated mice relating to the actions of GH, PRL and IGF1. We have organized the mouse lines by modifications made to constituents of the GH/IGF1 family either upstream or downstream of GHR or to the GHR itself. Available data on the effect of altered gene expression on growth, GH/IGF1 levels, body composition, reproduction, diabetes, metabolism, cancer, and aging are summarized. For the ease of finding this information, key words are highlighted in bold throughout the main text for each mouse line and this information is summarized in Tables 1, 2, 3 and 4. Most importantly, the collective data derived from and reported for these mice have enhanced our understanding of GH action.

Objective:Healthcare personnel (HCP) were recruited to provide serum samples, which were tested for antibodies against Ebola or Lassa virus to evaluate for asymptomatic seroconversion.Setting:From 2014 to 2016, 4 patients with Ebola virus disease (EVD) and 1 patient with Lassa fever (LF) were treated in the Serious Communicable Diseases Unit (SCDU) at Emory University Hospital. Strict infection control and clinical biosafety practices were implemented to prevent nosocomial transmission of EVD or LF to HCP.Participants:All personnel who entered the SCDU who were required to measure their temperatures and complete a symptom questionnaire twice daily were eligible.Results:No employee developed symptomatic EVD or LF. EVD and LF antibody studies were performed on sera samples from 42 HCP. The 6 participants who had received investigational vaccination with a chimpanzee adenovirus type 3 vectored Ebola glycoprotein vaccine had high antibody titers to Ebola glycoprotein, but none had a response to Ebola nucleoprotein or VP40, or a response to LF antigens.Conclusions:Patients infected with filoviruses and arenaviruses can be managed successfully without causing occupation-related symptomatic or asymptomatic infections. Meticulous attention to infection control and clinical biosafety practices by highly motivated, trained staff is critical to the safe care of patients with an infection from a special pathogen.

Multiple source apportionment approaches were employed to investigate PAH sources which contribute to small craft harbor (SCH) sediments in Nova Scotia (NS), Canada. A total of 580 sediment samples were analyzed using PAH diagnostic ratios, Unmix Optimum receptor modeling, and by assessment of the composition of the PAH profile. PAH diagnostic ratios suggest PAHs are primarily of pyrogenic (thermal) origin, while UnmixO modeling identifies four individual sources which best describe surficial sediments and suggests contributions from both pyrogenic and petrogenic origins. These include coal combustion, automobile exhaust, and biomass incineration. PAH profile assessment determined an overwhelming contribution of high molecular weight PAHs, which exhibited a strong correlation with total PAH concentrations.

Ecological risk assessment of metals (As, Cd, Cr, Cu, Hg, Ni, Pb and Zn) in surface sediments from 31 small craft harbours (SCHs) in Nova Scotia, Canada was conducted using multiple risk assessment approaches. Approaches used were contamination factor, pollution load index, geoaccumulation index, potential ecological risk factor for individual metals, comprehensive potential ecological risk index, mean probable effect level quotient and mean effects range median quotient. Results indicated most SCHs exhibited low ecological risk from sediment metal concentrations, except for two harbours. Metal contamination was highest in Canso Harbour, followed by Clarks Harbour. SCH sediments were only slightly contaminated with low probability of pollution according to mean probable effect level and mean effects range median quotients. However, pollution load and geoaccumulation indexes indicated Cd and Hg had the highest metal contamination across SCH sediments. Cadmium and Hg had the highest potential ecological risk, respectively compared to other metals.

Pancreatic cancer is responsible for more than 48,000 deaths and 60,000 new cancer cases every year in the United States while the overall 5-year survival rate is only 10%. These numbers point towards an urgent need for new therapeutic approaches wherein therapy resistance poses a tremendous challenge. We and others have identified the role of growth hormone (GH) and its cognate receptor (GHR), overexpressed in pancreatic ductal adenocarcinoma patients (PDAC; >90% of pancreatic cancer cases), in driving therapy resistance by directly upregulating multidrug efflux, phenotype switch via epithelial-to-mesenchymal transition (EMT) and inhibition of apoptosis. Our laboratory had pioneered the discovery of pharmacologic GHR antagonists including the only approved and prescribed GHR antagonist, pegvisomant, and a new antagonist candidate named compound-G. Here, we used in vitro, in vivo and in silico analyses to assess the feasibility and efficacy of a treatment regimen including GHR antagonist and chemotherapy to manage PDAC. Both pegvisomant and compound-G exhibit significant suppression of cancer cellular viability, invasive potential, drug efflux rate and apoptosis in PDAC cell cultures. In male and female Nude mice with human PDAC xenografts, GHR inhibition by either pegvisomant or compound-G markedly re-sensitized the tumors towards both low and high doses of gemcitabine treatment. Compound G plus high doses of gemcitabine lead to almost complete tumor clearance in 40% of the mice. Also, tissue analyses reveal increased production of GH in tumors treated with chemotherapy. In the GHR antagonist treated tumors, significantly lower expression of ABC transporter (Abcb1, Abcg5, Abcc2, Abcg2), EMT mediator (Cdh2, Zeb1, Snai2, Epas1) and apoptosis marker (Bcl2) genes compared to control were observed - accounting for the observed sensitization to gemcitabine. In the human PDAC patient datasets, increased expression of GHR correlates strongly with increased expression of multidrug efflux transporters, anti-apoptotic markers, and EMT transcription factors. Therefore, we provide robust pre-clinical validation for a treatment regimen combining GHR antagonist and chemotherapy leading to highly efficacious tumor clearance. Acknowledgement: This work was supported in part by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, by the AMVETS, and Ohio University’s Student Enhancement Award and Edison Biotechnology Institute. Citation Format: Reetobrata Basu, Prateek Kulkarni, Emily Davis, Silvana Duran, John J. Kopchick. Combination of growth hormone receptor antagonist and gemcitabine leads to highly efficacious tumor clearance in a mouse model of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2620.

Knockdown of the growth hormone receptor (GHR) in melanoma cells downregulates ATP-binding cassette (ABC) transporters and sensitizes them to multiple drug treatments in vitro. The goal for this study is to understand whether a GHR antagonist (GHA) could suppress different types of cancers by sensitizing tumors to drug treatments in vivo through the downregulation of ABC transporters. Sera from GHA transgenic mice inhibited the proliferation of mouse melanoma cells (B16F10) in culture and suppressed expression of multiple ABC transporters. When B16-F10 cells were intradermally inoculated into GHA mice, tumor size was markedly reduced, as was STAT5 activation and ABCG1, ABCG2 levels. We then tested the effect of the GHA on the efficacy of cisplatin in vivo. GHA sensitized melanomas to cisplatin, leading to the smallest tumors among all groups. GHKO mice showed the same effect. We further extended this investigation to hepatocellular carcinoma (HCC). GHA mice were subcutaneously inoculated with mouse HCC (Hepa1 6 cells) and subsequently treated with sorafenib. The HCC tumors in GHA mice were markedly sensitive to sorafenib treatment compared to the same in wild-type mice. RNA analysis showed that when HCC was exposed to the combined treatment, relatively decreased ABC transporters expression was found. Immunohistochemical staining showed that phosphorylation of STAT5 and ABCB1 were downregulated in HCC tissues, suggesting that GHA in vivo downregulates ABC transporters in HCC, and therefore sensitizes them to sorafenib. Clinical data derived from HCC patients using the TCGA database showed that multiple ABC transporters in both types of cancer correlate with GHR levels; that is, when GHR levels are relatively high, patient survival is significantly decreased. Additionally, higher ABCC1 levels also lead to significantly decreased survival rate in HCC patients. Collectively, the results indicate that a GHA is effective in sensitizing both melanoma and HCC to available treatments in vivo and may be used as a therapeutic strategy for higher efficacy of tumor clearance. Citation Format: Yanrong Qian, Reetobrata Basu, Samuel Mathes, Prateek Kulkarni, Emily Davis, Darlene Berryman, Edward List, Silvana Duran, John J. Kopchick. Growth hormone receptor antagonist sensitizes melanoma and hepatocarcinoma to drug treatments via downregulation of ABC transporters in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2621.

Growth hormone (GH) has been reported to drive leukemia cell proliferation as early as 1977, while downstream effectors of the GH signaling pathway (i.e., insulin-like growth factor 1; IGF1) have more recently been widely implicated in the aggressive pathology and robust therapy resistance phenotypes of acute myeloid leukemia (AML). It is also known that patients with acromegaly (high levels of circulating GH and IGF1) develop AML at a significantly higher rate than the general population, while individuals with GH resistance remain completely resistant to all types of cancer. Despite all of the aforementioned evidence pointing to a critical role of GH in AML progression and prognosis, a detailed transcriptomic analysis of human patients is lacking. We aim to address this gap by thorough in silico studies aimed at revealing the nature and extent to which the GH axis can be suitable targeted in AML. Here, we present a summary of our analyses of clinical and transcriptomic data from 200 human patients with AML from The Cancer Genome Atlas database, using multiple bioinformatics software programs in the public domain. Our study revealed that GH receptor (GHR) is expressed more highly in AML than in normal myeloid cells, and a robust correlation exists between GH responsiveness and patient survival. A sex-specific profiling of the patient transcriptomic data identified critical pathways related to therapy resistance, extracellular matrix remodeling, metastasis, and immune evasion to be upregulated differentially in male and female AML patients with relatively elevated GHR expression compared to patients with relatively lower GHR expression. Furthermore, we identified microRNAs which are differentially expressed in AML patients with higher than median GHR expression. We validated these miRNAs to be effective indicators of disease progression and prognosis and can be valuable markers in liquid biopsy approaches. Acknowledgement: This work was supported in part by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, by the AMVETS, and Ohio University’s Edison Biotechnology Institute. Citation Format: Emily Davis, Reetobrata Basu, John J. Kopchick. Transcriptomic profiling of human patients with acute myeloid leukemia reveals critical effects of growth hormone responsiveness on patient survival and mechanisms of tumor therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2695.

Additional file 2 : Table S2. Primers used for breakpoint junction analyses: Primers used to define breakpoint junctions in families 1-4. Table S3. Missense variants identified in ATAD3A: Bioinformatic predictions of missense variants identified in this study. Figure S1. Homozygous variant in Family 8: Visualization of exome sequencing reads showing the homozygous variant c.980G>C, p.(Arg327Pro). Figure S2. Segregation analysis in Family 7: Data showing that the c.150C>G variant is de novo, whereas the c.1703_1705del variant is maternally inherited. Figure S3. Compound heterozygous deletion affecting ATAD3A in Family 1: Visualization of exome sequencing read alignments indicating two overlapping deletions inherited in trans. Figure S4. Breakpoint junction sequencing of paternally inherited ATAD3B/ATAD3A deletion in Family 1: Alignment to ATAD3B and ATAD3A shows that the breakpoint occurred within a region of identity between the paralogs. Figure S5. Read depth analysis of exome sequencing data in Family 2: The compound heterozygous deletion can be appreciated. Figure S6. Breakpoint junction sequencing of first ATAD3B/ATAD3A deletion in Family 2: Alignment to ATAD3B and ATAD3A shows that the breakpoint occurred within a region of identity between the paralogs. Figure S7. Breakpoint junction sequencing of second inherited ATAD3B/ATAD3A deletion in Family 2: Alignment to ATAD3B and ATAD3A shows that the breakpoint occurred within a region of identity between the paralogs. Figure S8. Confirmatory array data from Family 3: The heterozygous deletion can be appreciated in the proband and mother’s samples, but not in the father’s sample. Figure S9. Breakpoint junction sequencing of maternally inherited ATAD3B/ATAD3A deletion in Family 3: Alignment to ATAD3B and ATAD3A shows that the breakpoint occurred within a region of identity between the paralogs. Figure S10. Breakpoint junction sequencing of paternally inherited 2-exon deletion in ATAD3A (Family 4): Delineation of the breakpoint junction by Sanger sequencing spanning the deletion, and evolutionary conservation of the skipped exons. Figure S11. Schematic diagram of all CNVs identified in this study: Diagram of the six CNVs studied; five of six were resolved at the breakpoint junction level. Figure S12. dAtad3a is expressed ubiquitously in embryos: Confocal micrographs of an embryo expressing GFP protein under the control of dAtad3a-T2A-Gal4 showed that dAtad3a is expressed ubiquitously. Figure S13. R176W and L83V did not affect mitochondria content and morphology in larvae muscles: Mitochondria content and morphology of dAtad3a mutant muscles expressing dAtad3aR176W, or dAtad3aL83V are comparable to those in wildtype controls. Figure S14. dAtad3a null, F56L, G242V, and R333P cause increased mitochondrial content in embryos: Mitochondrial content in dAtad3a null mutant embryo and those expressing dAtad3aF56L, dAtad3aG242V, or dAtad3aR333P is higher than those in wild type control embryos. Figure S15. dAtad3a null, F56L, G242V, and R333P cause increased mitochondrial numbers and size in embryos: In embryo VNC, dAtad3a null mutant and those expressing dAtad3aF56L, dAtad3aG242V, or dAtad3aR333P exhibited an increase in the mitochondrial size and numbers compared to those in wild type controls. Figure S16. R176W causes small mitochondria in adult muscles: dAtad3a mutant muscles expressing dAtad3aR176W exhibited smaller size of mitochondria compared to those expressing dAtad3aWT, or dAtad3aL83V. Figure S17. R176W and L83V cause various defects in mitochondria in adult muscles: dAtad3a mutant muscles expressing dAtad3aR176W, or dAtad3aL83V exhibited small, and membrane-defective mitochondria compared to those expressing dAtad3aL83V.

Naturalistic stimuli (e.g., movies) provide the opportunity to study lifelike experiences in the lab. While young adults respond to these stimuli in a highly synchronized manner (as indexed by intersubject correlations [ISC] in their neural activity), older adults respond more idiosyncratically. Here, we examine whether eye movement synchrony (eye-ISC) also declines with age during movie-watching and whether it relates to memory for the movie. Our results show no age-related decline in eye-ISC, suggesting that age differences in neural ISC are not caused by differences in viewing patterns. Both age groups recalled the same number of episodic details from the movie, however, older adults recalled more semantic and false information. In both age groups, more recall of false information related to lower eye-ISC. Finally, older adults showed better cued-recall than younger adults across event boundaries, suggesting that older adults may form broader associations across events when encoding everyday experiences.

The output of the retina is organized into many detector grids, called 'mosaics', that signal different features of visual scenes to the brain1-4. Each mosaic comprises a single type of retinal ganglion cell (RGC), whose receptive fields tile visual space. Many mosaics arise as pairs, signalling increments (ON) and decrements (OFF), respectively, of a particular visual feature5. Here we use a model of efficient coding6 to determine how such mosaic pairs should be arranged to optimize the encoding of natural scenes. We find that information is maximized when these mosaic pairs are anti-aligned, meaning that the distances between the receptive field centres across mosaics are greater than expected by chance. We tested this prediction across multiple receptive field mosaics acquired using large-scale measurements of the light responses of rat and primate RGCs. ON and OFF RGC pairs with similar feature selectivity had anti-aligned receptive field mosaics, consistent with this prediction. ON and OFF RGC types that encode distinct features have independent mosaics. These results extend efficient coding theory beyond individual cells to predict how populations of diverse types of RGC are spatially arranged.

Using an ensemble of atoms in an optical cavity, we engineer a family of nonlocal Heisenberg Hamiltonians with continuously tunable anisotropy of the spin-spin couplings. We thus gain access to a rich phase diagram, including a paramagnetic-to-ferromagnetic Ising phase transition that manifests as a diverging magnetic susceptibility at the critical point. The susceptibility displays a symmetry between Ising interactions and $XY$ (spin-exchange) interactions of the opposite sign, which is indicative of the spatially extended atomic system behaving as a single collective spin. Images of the magnetization dynamics show that spin-exchange interactions protect the coherence of the collective spin, even against inhomogeneous fields that completely dephase the noninteracting and Ising systems. Our results underscore prospects for harnessing spin-exchange interactions to enhance the robustness of spin squeezing protocols.