cssi/SciSciGPT-SciSciNet huggingface dataset:
Inhibition of colorectal cancer genomic copy number alterations and chromosomal fragile site tumor suppressor FHIT and WWOX deletions by DNA mismatch repair

// Sohail Jahid 1, * , Jian Sun 1, * , Ozkan Gelincik 1 , Pedro Blecua 8 , Winfried Edelmann 2 , Raju Kucherlapati 3 , Kathy Zhou 4 , Maria Jasin 5 , Zeynep H. Gumus 6, 7 and Steven M. Lipkin 1 1 Departments of Medicine and Genetic Medicine, Weill Cornell Medicine, 10021, NY, USA 2 Department of Cell Biology and Department of Genetics, Albert Einstein College of Medicine of Yeshiva University, 10461, NY, USA 3 Department of Genetics, Harvard Medical School, 02115, Boston, MA, USA 4 Department of Biostatistics and Epidemiology, Weill Cornell Medical College, 10021, NY, USA 5 Developmental Biology Program, Memorial Sloan Kettering Cancer Center, 10065, NY, USA 6 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 10029, NY, USA 7 Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 10029, NY, USA 8 Division of Clinical Genetics, Memorial Sloan Kettering Cancer Center, 10065, NY, USA * These authors contributed equally to this work Correspondence to: Steven M. Lipkin, email: stl2012@med.cornell.edu Zeynep H. Gumus, email: zeynep.gumus@mssm.edu Keywords: mismatch repair, homologous recombination, homeologous recombination, colorectal cancer Received: January 16, 2017 Accepted: April 24, 2017 Published: May 10, 2017 ABSTRACT Homologous recombination (HR) enables precise DNA repair after DNA double strand breaks (DSBs) using identical sequence templates, whereas homeologous recombination (HeR) uses only partially homologous sequences. Homeologous recombination introduces mutations through gene conversion and genomic deletions through single-strand annealing (SSA). DNA mismatch repair (MMR) inhibits HeR, but the roles of mammalian MMR MutL homologues (MLH1, PMS2 and MLH3) proteins in HeR suppression are poorly characterized. Here, we demonstrate that mouse embryonic fibroblasts (MEFs) carrying Mlh1 , Pms2 , and Mlh3 mutations have higher HeR rates, by using 7,863 uniquely mapping paired direct repeat sequences (DRs) in the mouse genome as endogenous gene conversion and SSA reporters. Additionally, when DSBs are induced by gamma-radiation, Mlh1 , Pms2 and Mlh3 mutant MEFs have higher DR copy number alterations (CNAs), including DR CNA hotspots previously identified in mouse MMR-deficient colorectal cancer (dMMR CRC). Analysis of The Cancer Genome Atlas CRC data revealed that dMMR CRCs have higher genome-wide DR HeR rates than MMR proficient CRCs, and that dMMR CRCs have deletion hotspots in tumor suppressors FHIT/WWOX at chromosomal fragile sites FRA3B and FRA16D (which have elevated DSB rates) flanked by paired homologous DRs and inverted repeats (IR). Overall, these data provide novel insights into the MMR-dependent HeR inhibition mechanism and its role in tumor suppression.
Inflatable antenna for CubeSat: A new spherical design for increased X-band gain

Interplanetary1 CubeSats and small satellites have potential to provide means to explore space and to perform science in a more affordable way. As the goals for these spacecraft become more ambitious in space exploration, the communication systems currently implemented will need to be improved to support those missions. One of the bottlenecks is the antennas' size, due to the close relation between antenna gain and dimensions. Hence, a possible solution is to develop inflatable antennas which can be packaged efficiently, occupying a small amount of space, and they can provide, once deployed, large dish dimension and correspondent gain. A prototype of a 1 m inflatable antenna for X-Band has been developed in a joint effort between JPL and ASU. After initial photogrammetry tests and radiation tests, it was discovered that the design was not able to meet the required gain. As a result, a new design, based on a spherical inflatable membrane, is proposed. This new design will allow reaching a more stable inflatable surface, hence improving the electromagnetic performance. This paper will detail the principle challenges in developing this new antenna focusing on: design, EM analysis, fabrication and tests.
Spiritual Stories: Exploring Ultimate Meaning in Social Work Practice

This chapter presents a narrative exploration of spirituality as a vehicle for making ultimate meaning of human life and experience. The relationship between spiritual and religious narratives is examined, and a narrative approach to the integration of spirituality in clinical social work practice is proposed. The relationship between the spiritual narratives of the client and the social worker is considered. Clinical case illustrations are provided.
Fasting or fear: disentangling the roles of predation risk and food deprivation in the nitrogen metabolism of consumers

Predators can alter nutrient cycles simply by inducing stress in prey. This stress accelerates prey's protein catabolism, nitrogen waste production, and nitrogen cycling. Yet predators also reduce the feeding rates of their prey, inducing food deprivation that is expected to slow protein catabolism and nitrogen cycling. The physiology of prey under predation risk thus balances the influences of predation risk and food deprivation, and this balance is central to understanding the role of predators in nutrient cycles. We explored the separate and combined effects of predation risk and food deprivation on prey physiology and nutrient cycling by exposing guppies (Poecilia reticulata) to predation risk and food deprivation in a 2 × 2 design. We simulated predation risk using chemical cues from a natural predator of guppies, and we created food deprivation by rationing food availability. We measured guppy response as food consumption, growth, tissue energy density, tissue carbon:nitrogen, and nitrogen (N) excretion and assimilation. We found that N-linked physiological processes (N consumption, assimilation, excretion) were strongly affected by predation risk, independent of food consumption. Guppies excreted substantially less under predation risk than they did under food deprivation or control conditions. These results suggest that predation risk, per se, triggers physiological changes in guppies that increase N retention and decrease N excretion. We suggest that slower N metabolism under predation risk is an adaptive response that minimizes protein loss in the face of predictable, predator-induced food restriction. Notably, N metabolism shares common hormonal control with food seeking behavior, and we speculate that increased N retention is a direct and immediate result of reduced food seeking under predation risk. Contrary to predation-stress-based hypotheses for how predators affect nutrient cycling by prey, our result indicates that even short-term exposure to predators may decelerate, rather than accelerate, the speed of N cycling by suppressing N turnover by prey.
Conceptual Perspectives: Bacterial Antimicrobial Peptide Induction as a Novel Strategy for Symbiosis with the Human Host.

Human beta defensins (hBDs) are small cationic peptides, expressed in mucosal epithelia and important agents of innate immunity, act as antimicrobial and chemotactic agents at mucosal barriers. In this perspective, we present evidence supporting a novel strategy by which the oral bacterium Fusobacterium nucleatum induces hBDs and other antimicrobial peptides (AMPs) in normal human oral epithelial cells and thereby protects them from other microbial pathogens. The findings stress (1) the physiological importance of hBDs, (2) that this strategy may be a mechanism that contributes to homeostasis and health in body sites constantly challenged with bacteria and (3) that novel properties identified in commensal bacteria could, one day, be harnessed as new probiotic strategies to combat colonization of opportunistic pathogens. With that in mind, we highlight and review the discovery and characterization of a novel lipo-protein, FAD-I (Fusobacterium Associated Defensin Inducer) associated with the outer membrane of F. nucleatum that may act as a homeostatic agent by activating endogenous AMPs to re-equilibrate a dysregulated microenvironment. FAD-I has the potential to reduce dysbiosis-driven diseases at a time when resistance to antibiotics is increasing. We therefore postulate that FAD-I may offer a new paradigm in immunoregulatory therapeutics to bolster host innate defense of vulnerable mucosae, while maintaining physiologically responsive states of inflammation.
Working Memory and Clinical Developmental Disorders : Theories, Debates and Interventions

List of contributors Chapter 1: Introduction Chapter 2: Working Memory and intellectual disabilities Chapter 3: Memory and language in children with SLI Chapter 4: Working Memory and autism Chapter 5: Working Memory & attention-deficit/hyperactivity disorder Chapter 6: Working Memory & Specific Learning Disorders: Reading Chapter 7: Role of Working Memory in the language learning mechanism by ear, mouth, eye, and hand in individuals with and without Specific Learning Disabilities in written language Chapter 8: Working Memory and Specific Learning Disability: Math Chapter 9: Working Memory and low birth weight Chapter 10: Developmental Coordination Disorder and Working Memory Chapter 11: Working Memory in Down syndrome: Methodological considerations and intervention implications Chapter 12: Working Memory and TBI Chapter 13: Working Memory and youth depression Epilogue: Working Memory and clinical development disorders: Theories, debates and interventions Index
An intelligence-based state of charge prediction for VRLA batteries

A battery management system (BMS) has three main functions, voltage monitoring, current discharge monitoring and remaining life monitoring. This paper primarily focuses on remaining life monitoring through the estimation of battery's state of charge (SOC). An Experimental set-up was prepared to measure the Valve-Regulated Lead-Acid (VRLA) battery's SOC under different operating conditions. Backpropagation (BP) neural network to estimate the battery's SOC using the experimental data. The results showed a satisfactory estimation of battery's SOC with a small (4.25%) root mean square perdition error (RMS).
Diagnostic utility of flexible fiberoptic nasopharyngolaryngoscopy recorded onto a smartphone: A pilot study

Abstract Objectives To evaluate the diagnostic accuracy of flexible fiberoptic examinations of the larynx recorded onto smartphones. Methods Prospective, blinded study of inpatients requiring laryngoscopy. A live exam was performed, then a smartphone was attached to the endoscope using a novel coupling device and the same examination was recorded. The live and recorded exams were evaluated by two laryngologists, each blinded to the findings of the other. Results Eighteen subjects were evaluated. Evaluation of airway patency was identical (Kappa = 1.0 [1, 1]). Evaluation of vocal cord motion was identical for 14 subjects: 9 normal, 3 paretic, 2 paralytic (Kappa = 0.69 [0.38, 1]). Conclusion There is high correlation between laryngeal diagnoses using live flexible fiberoptic laryngoscopy and recordings using a coupling device to transfer the recordings on to smartphones. Critical findings such as airway patency and vocal fold motion showed the highest correlation.
General Existence and Uniqueness Theorems for Incompressible Bipolar and Non-Newtonian Fluid Flow

In Sect. 1.4 we introduced the equations which govern the motion of a nonlinear, incompressible, bipolar fluid. For a bounded domain in \({\mathbb{R}}^{n}\), n = 2, 3 the appropriate boundary conditions were set forth in Sect. 1.4 and, for flows in all of \({\mathbb{R}}^{n}\), the relevant periodic (boundary) conditions were also delineated.
Universal Weights from Dynamical Systems To Mean-Bounded Positive Operators on Lp

Let be a universal weight for all dynamical systems (i.e., converges a.e. for all and all dynamical systems (Ω, a, μ, ϕ) where ϕ is an invertible measure preserving transformation on (Ω, a, μ)). We show that (a n ) is also a universal weight for all mean bounded positive operators on L p i.e., converges a.e. for all positive mean bounded operators T on L p , 1<p<∞ (p is fixed).
Compact, Efficient Laser Systems Required for Laser Inertial Fusion Energy

This paper presents our conceptual design for laser drivers used in Laser Inertial Fusion Energy (LIFE) power plants. Although we have used only modest extensions of existing laser technology to en...
John P. Jackson Jr. and David J. Depew. Darwinism, Democracy, and Race: American Anthropology and Evolutionary Biology in the Twentieth Century. New York: Routledge, 2017. 240 pages. $140.00 hardcover.

John P. Jackson Jr. and David J. Depew’s Darwinism, Democracy, and Race: American Anthropology and Evolutionary Biology in the Twentieth Century is an important, much needed, closely reasoned, and ...
Design of Air Cooling Housing for Image Sensors Using Additive Manufacturing Technology

Machine vision is widely used in industry for monitoring and inspection. In additive manufacturing technology (AM), it is especially important in that it can cover an entire 2-dimensional printed surface area instantly. Additionally, AM technologies can also be used to make a mechanical part for a machine vision system such as mount or illumination devices on a 3D printer. For the industrial 3D printer, the camera mount requires to have temperature control capabilities for the vision system. This research aims to develop a method to build a mount with cooling capability with AM technology. This paper introduces a 3D printed camera cooling housing and proposes a temperature feed-back control method based on the image sensor itself without adding a thermal sensor to increase the user friendliness and simplicity. In the demonstration, a camera cooling housing that was developed enabled a camera module to operate at 200C in an industrial Fortus 400 (Stratasys, MN).
Abstract TP421: Admission Neutrophil-Lymphocyte Ratio Predicts Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage

Introduction: Immune dysregulation has long been implicated in the development of delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH). The neutrophil-lymphocyte rati...
Do Credit Unions have Distinct Objectives? Evidence from Executive Compensation Structures

Credit unions compete directly with commercial banks in markets for consumer financial services yet receive an exemption from federal corporate income tax. Commercial banks claim that credit unions are no different than banks and that the credit union tax exemption represents an unfair competitive advantage. Credit unions counter that while they offer similar products and services, they differ from commercial banks in terms of structure and mission, given their not-for-profit, cooperative status. In this paper, we test for substantive differences in the objective functions of commercial banks and nonprofit credit unions by comparing CEO compensation structures. Drawing on the relevant principal-agent literature, we provide several arguments to support the hypotheses that credit union boards of directors establish lower-powered incentive contracts with their CEOs relative to similarly sized commercial banks, and offer lower total compensation. We find that credit union CEOs receive approximately two-and-a-half times less performance-based compensation relative to CEOs of similarly sized community banks. Bank CEOs also earn approximately 15% to 20% more total compensation on average. The results are generally robust to controlling for CEO- and board-level characteristics, local economic conditions, and institution-level indicators of size, growth, complexity, liquidity and risk. The findings suggest important differences in incentive structures and objectives between banks and credit unions.
REVERSAL OF POST TRANSLATIONAL TYROSYLATION OF TUBULIN

Publisher Summary This chapter describes the reversal of posttranslational tyrosylation of tubulin. A proteolytic enzyme with carboxypeptidase activity has been purified from sheep brain extracts. Enzymatic properties were similar to tubulin carboxypeptidase activity in rat brain extracts. The enzyme reverses the reaction catalyzed by tyrosine tubulin ligase which attaches tyrosine to the c-terminal glutamyl residue of the α subunit of tubulin. After homogenization of sheep brain, the majority of carboxypeptidase activity resided in the soluble fraction. Some activity copolymerized with tubulin with an increase in specific activity during three polymerization cycles. Purification by NH4SO4 fractionation and DEAE cellulose chromatography removed ligase and tubulin. Further chromatography on CM cellulose gave a 500-fold purification with 60% recovery of soluble activity. The purified exoprotease activity was inhibited by EDTA, o-phenanthroline, and 3-phenylpropionate. Dithiothreitol and a carboxypeptidase inhibitor isolated from potato tubers were not inhibitory. Tubulin that was reduced and alkylated could also serve as a substrate. Carbobenzoxy-glu-tyr was inhibitory at mM levels. It is found that colchicine that inhibits tubulin polymerization and GTP that promotes polymerization were inhibitory.
Development and Content Validity of a Respiratory Distress Observation Scale-Infant

Background: Respiratory distress is one of the most commonly reported symptoms in infants in the neonatal intensive care unit and can lead to substantial morbidity and mortality if not assessed and...
Neuronal maturation reduces the type I IFN response to orthobunyavirus infection and leads to increased apoptosis of human neurons

La Crosse virus (LACV) is the leading cause of pediatric arboviral encephalitis in the USA. LACV encephalitis can result in learning and memory deficits, which may be due to infection and apoptosis of neurons in the brain. Despite neurons being the primary cell infected in the brain by LACV, little is known about neuronal responses to infection. Human cerebral organoids (COs), which contain a spectrum of developing neurons, were used to examine neuronal responses to LACV. Plaque assay and quantitative reverse transcription (qRT) PCR were used to determine the susceptibility of COs to LACV infection. Immunohistochemistry, flow cytometry, and single-cell transcriptomics were used to determine specific neuronal subpopulation responses to the virus. Overall, LACV readily infected COs causing reduced cell viability and increased apoptosis. However, it was determined that neurons at different stages of development had distinct responses to LACV. Both neural progenitors and committed neurons were infected with LACV, however, committed neurons underwent apoptosis at a higher rate. Transcriptomic analysis showed that committed neurons expressed fewer interferon (IFN)-stimulated genes (ISGs) and genes involved IFN signaling in response to infection compared to neural progenitors. Furthermore, induction of interferon signaling in LACV-infected COs by application of recombinant IFN enhanced cell viability. These findings indicate that neuronal maturation increases the susceptibility of neurons to LACV-induced apoptosis. This susceptibility is likely due, at least in part, to mature neurons being less responsive to virus-induced IFN as evidenced by their poor ISG response to LACV. Furthermore, exogenous administration of recombinant IFN to LACV COs rescued cellular viability suggesting that increased IFN signaling is overall protective in this complex neural tissue. Together these findings indicate that induction of IFN signaling in developing neurons is an important deciding factor in virus-induced cell death.
Segmentation of Hidden Delaminations with Pitch–Catch Ultrasonic Testing and Agglomerative Clustering

This paper studies the detection of hidden polymer matrix composite delaminations with a pitch–catch ultrasonic testing system and an agglomerative clustering algorithm. Existing ultrasonic testing methods characterize damage through normal-incidence pulse-echo measurements. Yet, these pulse-echo methods are ineffective at detecting delaminations underneath other delaminations. The ultrasonic waves only reflect off the top delamination. As a result, no information about the lower delamination is transmitted to the receiver. To address this problem, we investigate an oblique-angle pitch–catch ultrasonic testing method to transmit ultrasonic waves underneath the delaminations. The ultrasonic waves interact with the lower delaminations and carry that information to the receiver. We describe and discuss our experiments, which use two polytetrafluoro-ethylene (PTFE) inserts to simulate delaminations. We show that applying agglomerative clustering to the experimental data can successfully distinguish three regions: regions with two PTFE inserts, regions with only an upper PTFE insert, and regions with only the lower PTFE insert. Normal-incidence measurements only observe two regions.
Respiratory dysbiosis and population-wide temporal dynamics in canine chronic bronchitis and non-inflammatory respiratory disease

The lungs of people and companion animals are now recognized to harbor diverse, low biomass bacterial communities. While these communities are difficult to characterize using culture-based approaches, targeted molecular methods such as 16S rRNA amplicon sequencing can do so using DNA extracted from samples such as bronchoalveolar lavage fluid (BALF). Previous studies identified a surprisingly uniform composition of the microbiota in the lungs of healthy research dogs living in a controlled environment, however there are no reports of the lung microbiota of client-owned dogs. Moreover, compositional changes in the lung microbiota depending on disease status have been reported in people, suggesting that similar events may occur in dogs, a species subject to several respiratory disease mechanisms analogous to those seen in people. To address these knowledge gaps, BALF samples from client-owned dogs presenting to the University of Missouri Veterinary Health Center for respiratory signs between 2014 and 2017 were processed for and subjected to 16S rRNA sequencing. Based on specific diagnostic criteria, dogs were categorized as Chronic Bronchitis (CB, n = 53) or non-CB (n = 11). Community structure was compared between groups, as well as to historical data from healthy research dogs (n = 16) of a uniform breed and environment. The lung microbiota detected in all client-owned dogs was markedly different in composition from that previously detected in research dogs and contained increased relative abundance of multiple canine fecal and environmental bacteria, likely due to aspiration associated with their clinical signs. While inter-sample diversity differed significantly between samples from CB and non-CB dogs, the variability within both groups made it difficult to discern reproducible bacterial classifiers of disease. During subsequent analyses to identify other sources of variability within the data however, population-wide temporal dynamics in community structure were observed, with substantial changes occurring in late 2015 and again in early 2017. A review of regional climate data indicated that the first change occurred during a historically warm and wet period, suggesting that changes in environmental conditions may be associated with changes in the respiratory microbiota in the context of respiratory disease. As the lung microbiota in humans and other animals is believed to result from repetitive micro-aspirations during health and in certain disease states associated with dyspnea and laryngeal dysfunction, these data support the increased colonization of the lower airways during compromised airway function, and the potential for temporal effects due to putative factors such as climate.
Finite complements trigger reality responses in attitude verb acquisition... but so do non-finite complements

The syntactic bootstrapping hypothesis was developed to explain how children learn verbs whose meanings are opaque, e.g. attitude verbs, which refer to the mental state of the subject of the sentence. Belief verbs (like think ) take finite complements, while desire verbs (like want ) take non-finite complements. Children differentiate these subclasses by three: they are lured by reality when there is a mismatch between the subject’s belief and reality when interpreting think , but not with want . Previous work also shows that when interpreting a less common attitude verb, hope , children are influenced by syntactic frame, supporting view that syntax guides children’s acquisition of attitude verbs. The current study investigates when syntax becomes useful to the learner. Children are presented with sentences including a novel verb with either a finite or a non-finite complement. Children are not influenced by syntax when interpreting a novel attitude verb, suggesting that syntactic complements only become useful for hypothesizing meaning once the learner has some experience with a specific attitude verb.
Classical electron mass and fields. II

Continued here is the development of a model of the electron (HYDRA), which includes rotational and magnetic terms. The atomic electron state is discussed and a comparison is made with a simple harmonic oscillator. Experimental data is reviewed that supports the possibility of a new lepton.
Deep Analytics for Management and Cybersecurity of the National Energy Grid

The United States’s energy grid could fall into victim to numerous cyber attacks resulting in unprecedented damage to national security. The smart concept devices including electric automobiles, smart homes and cities, and the Internet of Things (IoT) promise further integration but as the hardware, software, and network infrastructure becomes more integrated they also become more susceptible to cyber attacks or exploitation. The Defense Information Systems Agency (DISA)’s Big Data Platform (BDP), deep analytics, and unsupervised machine learning (ML) have the potential to address resource management, cybersecurity, and energy network situation awareness. In this paper, we demonstrate their potential using the Pecan Street data. We also show an unsupervised ML such as lexical link analysis (LLA) as a causal learning tool to discover the causes for anomalous behavior related to energy use and cybersecurity.
Deployment of a Clinical Pathway to Improve Postcardiac Arrest Care: A Before-After Study

OBJECTIVES Postcardiac arrest care bundles following adult cardiac arrest are associated with improved survival to discharge. We aimed to evaluate whether a clinical pathway and computerized order entry were associated with improved pediatric postcardiac arrest care and discharge outcomes. DESIGN Single-center retrospective before-after study. SETTING Academic PICU. PATIENTS Patients who suffered an in- or out-of-hospital cardiac arrest from January 2008 to December 2015 cared for in the PICU within 12 hours of sustained return of circulation. INTERVENTION Deployment of a postcardiac arrest clinical pathway and computerized order entry system. MEASUREMENTS AND MAIN RESULTS There were 380 patients included-163 in the pre-pathway period and 217 in the post-pathway period. Primary outcome was percent adherence to pathway clinical goals at 0-6 and 6-24 hours post-return of circulation and to diagnostics (continuous electroencephalogram monitoring, head CT for out-of-hospital cardiac arrests, echocardiogram). Secondary outcomes included survival to hospital discharge and survival with favorable neurologic outcome (Pediatric Cerebral Performance Category of 1-3 or no change from baseline). The pre-pathway and post-pathway groups differed in their baseline Pediatric Cerebral Performance Category scores and the following causes of arrest: airway obstruction, arrhythmias, and electrolyte abnormalities. Pathway adherence was not significantly different between the pre-pathway and post-pathway groups, with the exception of higher rates of continuous electroencephalogram monitoring (45% vs 64%; p < 0.001). There was no difference in survival to hospital discharge between the two groups (56% vs 67%; adjusted odds ratio, 1.68; 95% CI, 0.95-2.84; p = 0.05). Survival to discharge was higher in the post-pathway group for the in-hospital cardiac arrest cohort (55% vs 76%; adjusted odds ratio, 3.06; 95% CI, 1.44-6.51; p < 0.01). There was no difference in favorable neurologic outcome between all patients (adjusted odds ratio, 1.21; 95% CI, 0.72-2.04) or among survivors (adjusted odds ratio, 0.72; 95% CI, 0.27-1.43). CONCLUSIONS After controlling for known potential confounders, the creation and deployment of a postcardiac arrest care pathway and computerized order entry set were not associated with improvement in pathway adherence or overall outcomes, but was associated with increased survival to hospital discharge for children with in-hospital cardiac arrests.
Abstract IA10: Activating innate and adaptive immunity to improve outcome for “cold” tumors

Unlike some adult cancers, most pediatric cancers are considered immunologically cold and generally less responsive to immunotherapy. Anti-GD2 mAb plus cytokine-based immunotherapy has already been incorporated into standard-of-care treatment for pediatric patients with high-risk neuroblastoma achieving remission. However, overall survival remains poor. We are pursuing clinical and preclinical studies to engage innate and adaptive immune responses against immunologically cold tumors. In a recent trial of adjuvant/neoadjuvant anti-GD2 mAb + IL2 (in the form of the hu14.18-IL2 immunocytokine) for advanced resectable melanoma, we evaluated whole-genome transcriptomics (using RNAseq determined immunologic signatures found to be predictive of outcome for patients with neuroblastoma) on resected tumors. The immunologic signatures were highly correlated with overall survival and relapse-free survival for tumors obtained 2 weeks after starting hu14.18-IL2, but not for tumors obtained 2 weeks before starting hu14.18-IL2. In a “functionally cold” mouse melanoma model, we found that radiation and hu14.18-IL2 immunocytokine generate an in situ vaccination-induced adaptive immune response in syngeneic mice bearing large tumors. In contrast, this same approach was not effective in mice bearing a very cold, low-tumor-mutation burden, MYCN driven syngeneic neuroblastoma (9464D-GD2). The addition of checkpoint blockade (IgG2a anti-CTLA-4) was not able to induce tumor eradication. However, the further addition of CpG (as a “danger signal”) and agonist anti-CD40 mAb (as an activator of effector macrophages and of dendritic cells) resulted in tumor-free mice with immune memory. These results suggest that immune activation, with “off the shelf” reagents, may be applicable to the treatment of cold cancers, via innate/adaptive immune engagement. They also suggest that monitoring of intratumoral immune activation could potentially become a useful predictor of which patients will respond to their therapy and which will require additional or alternate therapy. Citation Format: Paul M. Sondel. Activating innate and adaptive immunity to improve outcome for “cold” tumors [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA10.
Lipophilic signals lead to organ-specific gene expression changes in Arabidopsis seedlings.

In plants, N-acylethanolamines (NAEs) are most abundant in desiccated seeds and their levels decline during germination and early seedling establishment. However, endogenous NAE levels rise in seedlings when ABA or environmental stress is applied, and this results in an inhibition of further seedling development. When the most abundant, polyunsaturated NAEs of linoleic acid (18:2) and linolenic acid (18:3) were exogenously applied, seedling development was affected in an organ-specific manner. NAE 18:2 primarily affected primary root elongation and NAE 18:3 primarily affected cotyledon greening and expansion and overall seedling growth. The molecular components and signaling mechanisms involved in this pathway are not well understood. In addition, the bifurcating nature of this pathway provides a unique system in which to study the spatial aspects and interaction of these lipid-specific and organ-targeted signaling pathways. Using whole transcriptome sequencing (RNA-seq) and differential expression analysis, we identified early (1-3 hr) transcriptional changes induced by the exogenous treatment of NAE 18:2 and NAE 18:3 in cotyledons, roots, and seedlings. These two treatments led to a significant enrichment in ABA-response and chitin-response genes in organs where the treatments led to changes in development. In Arabidopsis seedlings, NAE 18:2 treatment led to the repression of genes involved in cell wall biogenesis and organization in roots and seedlings. In addition, cotyledons, roots, and seedlings treated with NAE 18:3 also showed a decrease in transcripts that encode proteins involved in growth processes. NAE 18:3 also led to changes in the abundance of transcripts involved in the modulation of chlorophyll biosynthesis and catabolism in cotyledons. Overall, NAE 18:2 and NAE 18:3 treatment led to lipid-type and organ-specific gene expression changes that include overlapping and non-overlapping gene sets. These data will provide future, rich opportunities to examine the genetic pathways involved in transducing early signals into downstream physiological changes in seedling growth.
Health insurance status and type associated with varying levels of glycemic control in the US: The multi-ethnic study of atherosclerosis (MESA).

Abstract Aims To investigate associations of health insurance with measures of glucose metabolism, and whether associations vary by diabetes status or insurance type. Methods Cross-sectional analysis of baseline data from the Multi-Ethnic Study of Atherosclerosis. Cohort a priori stratified by age Results In participants Conclusions In this large multiethnic cohort, having any insurance was associated with significantly lower fasting glucose for individuals with diabetes. Levels of fasting glucose and insulin resistance varied across different insurance types.
Dynamic Changes in the Nasal Microbiome Associated With Disease Activity in Patients With Granulomatosis With Polyangiitis

OBJECTIVE Little is known about temporal changes in nasal bacteria in granulomatosis with polyangiitis (GPA). This study was undertaken to examine longitudinal changes in the nasal microbiome in association with relapse in GPA patients. METHODS Bacterial 16S ribosomal RNA gene sequencing was performed on nasal swabs from 19 patients with GPA who were followed up longitudinally for a total of 78 visits, including 9 patients who experienced a relapse and 10 patients who remained in remission. Relative abundance of bacteria and ratios between bacteria were examined. Generalized estimating equation models were used to evaluate the association between bacterial composition and 1) disease activity and 2) levels of antineutrophil cytoplasmic antibody (ANCA) with specificity for proteinase 3 (PR3), adjusted for medication. RESULTS Corynebacterium and Staphylococcus were the most abundant bacterial genera across all nasal samples. Patients with quiescent disease maintained a stable ratio of Corynebacterium to Staphylococcus across visits. In contrast, in patients who experienced a relapse, a significantly lower ratio was observed at the visit prior to relapse, followed by a higher ratio at the time of relapse (adjusted P < 0.01). Species-level analysis identified an association between a higher abundance of nasal Corynebacterium tuberculostearicum and 1) relapse (adjusted P = 0.04) and 2) higher PR3-ANCA levels (adjusted P = 0.02). CONCLUSION In GPA, significant changes occur in the nasal microbiome over time and are associated with disease activity. The occurrence of these changes months prior to the onset of relapse supports a pathogenic role of nasal bacteria in GPA. Our results uphold existing hypotheses implicating Staphylococcus as an instigator of disease and have generated a novel finding involving Corynebacterium as a potential mediator of disease in GPA.
An improved 211At-labeled agent for PSMA-targeted alpha therapy.

α-Particle emitters targeting the prostate-specific membrane antigen (PSMA) proved effective in treating patients with prostate cancer who were unresponsive to the corresponding β-particle therapy. Astatine-211 is an α-emitter that may engender less toxicity than other α-emitting agents. We synthesized a new 211At-labeled radiotracer targeting PSMA that resulted from the search for a pharmacokinetically optimized agent. Methods: A small series of 125I-labeled compounds were synthesized from their tin precursors to evaluate the effect of location of radiohalogen within the molecule and the presence of lutetium in the chelate on biodistribution. On that basis, 211At-VK-02-90-Lu was selected and evaluated in cell uptake and internalization studies, biodistribution and PSMA+ PC3 PIP tumor growth control in experimental flank and metastatic (PC3-ML-Luc) models. A long-term (13-month) toxicity study was performed for 211At-VK-02-90-Lu, including tissue chemistries and histopathology. Results: The radiochemical yield of 211At-VK-02-90-Lu was 17.8 ± 8.2%. Lead compound 211At-VK-02-90-Lu demonstrated total uptake within PSMA+ PC3 PIP cells of 13.4 ± 0.5% of the input dose after 4 h of incubation with little uptake in control cells. In SCID mice, 211At-VK-02-90-Lu provided 30.6 ± 4.8 percentage of injected dose per gram (%ID/g) of uptake in PSMA+ PC3 PIP tumor at 1 h post-injection that decreased to 9.46 ± 0.96 %ID/g by 24 h. Tumor-to-salivary gland and tumor-to-kidney ratios were 129 ± 99 at 4 h and 130 ± 113 at 24 h, respectively. De-astatination was not significant (stomach 0.34 ± 0.20%ID/g at 4 h). Dose-dependent survival was demonstrated at higher doses (>1.48 MBq) in both flank and metastatic models. There was little off-target toxicity as demonstrated by hematopoietic stability, unchanged tissue chemistries, weight gain rather than loss throughout treatment, and favorable histopathology. Conclusion: Compound 211At-VK-02-90-Lu or close analogs may provide limited and acceptable toxicity while retaining efficacy in management of prostate cancer.
Hyperparathyroidism subsequent to radioactive iodine therapy for Graves' disease.

Background The development of primary hyperparathyroidism (PHPT) after radioactive iodine (RAI) treatment for thyroid disease is poorly characterized. The current study is the largest reported cohort and assesses the disease characteristics of patients treated for PHPT with a history of RAI exposure. Methods A retrospective analysis comparing patients, with and without a history of RAI treatment, who underwent surgery for PHPT. Results Twenty-eight of the 469 patients had a history of RAI treatment, all for Graves' disease. Patients with a history of RAI exposure had similar disease characteristics compared to control; however, patients with a history of RAI treatment had a higher rate of recurrence (7.4% vs 1.2%, p = 0.012). Conclusion PHPT in patients with a history of RAI treatment can be approached in the same manner as RAI naive PHPT patients; however, the risk of recurrence of PHPT in RAI exposed patients may be higher.
Formalist Textualism and the Cernauskas Problem

In this short piece I respond to a recent article in the Harvard Law Review advocating an approach to interpretation that amounts to semantic literalism. I point out the pitfalls of thereby ignoring what the lawmakers are asserting.
S U ( 5 ) × U ( 1 ) X axion model with observable proton decay

We propose a $SU(5)\ifmmode\times\else\texttimes\fi{}U(1{)}_{X}\ifmmode\times\else\texttimes\fi{}U(1{)}_{\mathrm{PQ}}$ model, where $U(1{)}_{X}$ is the generalization of the $B\ensuremath{-}L$ (baryon minus lepton number) gauge symmetry and $U(1{)}_{\mathrm{PQ}}$ is the global Peccei-Quinn (PQ) symmetry. There are four fermions families in $\overline{\mathbf{5}}+\mathbf{10}$ representations of $SU(5)$, a mirror family in $\mathbf{5}+\overline{\mathbf{10}}$ representations, and three $SU(5)$ singlet Majorana fermions. The $U(1{)}_{X}$ related anomalies all cancel in the presence of the Majorana neutrinos. The $SU(5)$ symmetry is broken at ${M}_{\mathrm{GUT}}\ensuremath{\simeq}(6--9)\ifmmode\times\else\texttimes\fi{}{10}^{15}\text{ }\text{ }\mathrm{GeV}$ and the proton lifetime ${\ensuremath{\tau}}_{p}$ is estimated to be well within the expected sensitivity of the future hyper-Kamiokande experiment, ${\ensuremath{\tau}}_{p}\ensuremath{\lesssim}1.3\ifmmode\times\else\texttimes\fi{}{10}^{35}\text{ }\text{ }\mathrm{years}$. The $SU(5)$ breaking also triggers the breaking of the PQ symmetry, resulting in axion dark matter (DM), with the axion decay constant ${f}_{a}$ of order ${M}_{\mathrm{GUT}}$ or somewhat larger. The CASPEr experiment can search for such an axion DM candidate. The Hubble parameter during inflation must be low, ${H}_{\mathrm{inf}}\ensuremath{\lesssim}{10}^{9}\text{ }\text{ }\mathrm{GeV}$, in order to successfully resolve the axion domain wall, axion DM isocurvature and $SU(5)$ monopole problems. With the identification of the $U(1{)}_{X}$ breaking Higgs field with the inflaton field, we implement inflection-point inflation, which is capable of realizing the desired value for ${H}_{\mathrm{inf}}$. The vectorlike fermions in the model are essential for achieving successful unification of the SM gauge couplings as well as the phenomenological viability of both axion DM and inflation scenario.
Gender differences in freshmen weight gain.

Abstract Objective Predictors of first semester and year weight change by gender were examined. Participants The participants were 304 freshmen recruited over three years (September 2010, 2011, & 2012). Methods Psychosocial and lifestyle variables and weight were assessed at the beginning and end of the Fall semester and end of the Spring semester. Results The average weight gain over the year was 6.38 lbs for males versus 4.38 lbs for females. In the first semester, alcohol use was associated with weight gain among males. For females, higher levels of physical activity and lower BMI were associated with weight gain. At the end of the year, happiness was negatively associated with weight gain among males and physical activity positively associated with weight gain in females. Conclusions Alcohol consumption in males and physical activity in females produced positive associations with weight gain with most of the weight gained during the first semester. This implies that efforts to prevent weight gain in college freshmen need to be tailored by gender and focus on first semester.
Generating Design Decomposition Knowledge for Parametric Design Problems

Design is a very complicated problem-solving activity that uses many types of knowledge. Among them, decomposition knowledge is very important. Designers usually apply a divide-and-conquer approach to solve complicated design problems. That approach is guided by decomposition knowledge. The problem in which we are interested is how to obtain decomposition knowledge. Instead of acquiring it from design experts, is it possible to generate it from the problem specification plus other types of knowledge?
The Problem of Gay Pornography in a Straight Supremacist System

The following is a chapter from my recently released book, The End of Straight Supremacy: Realizing Gay Liberation. This chapter interrogates the legal, political, and social implications of gay (specifically male) pornography for Gay citizenship and equality. Rooted in the politics and theories of early Gay liberation and Radical feminism, Shannon Gilreath’s The End of Straight Supremacy presents a cohesive theory of Gay life under straight domination. Beginning with a critique of formal equality law centered on the “like-straight” demands of liberal equality theory as highlighted in Lawrence v. Texas, Gilreath goes on to criticize the “gay rights” movement itself, challenging the assimilation politics behind the movement’s blithe acceptance of discrimination in the guise of free speech and pornography in the name of sexual liberation, as well as same-sex marriage and transsexuality as tools of straight hegemony. Ultimately, Gilreath rejects both the liberal demand for Gay erasure in exchange for meager legal progress and the gay establishment agenda. In so doing, he provides both the vocabulary and analysis necessary to understand and to resist straight supremacy in all its forms. In The End of Straight Supremacy, Gilreath calls Gays and their allies to the difficult task of rethinking what liberation and equality really mean.The reader will quickly notice my use of irregular capitalization. I used “Gay,” capitalized, to refer to that which is Gay-identified. I use “gay,” lower-case, as in “gay pornography” or “gay establishment,” to distinguish that which is essentially straight supremacist in origin and operation.
Federal and Local Electric Power in the Central Valley: Coordination or Duplication

The purpose of electric power in the Central Valley project was first declared by Congress in the Rivers and Harbors Act of 1937, Section 2 of which reauthorized the project and transferred it from the Secretary of War to the Secretary of the Interior.' "Generation and sale of electric energy" are authorized "as a means of financially aiding and assisting" the water features of the project. Project reservoirs are to be "used, first, for river regulation, improvement of navigation, and flood control; second, for irrigation and domestic uses; and, third, for power." How this power shall be marketed presents a question of vital concern not only to California but to the entire nation. For the alleged purpose of disposing of project power, the Bureau of Reclamation proposes to construct a huge federal power system in northern and central California, consisting of hundreds of miles of transmission lines, substations and a large steam-electric generating plant. The cost of these facilities would exceed $80,000,000. The area which the Bureau proposes to serve is now completely served by the interconnected system of Pacific Gas and Electric Company.
Are Traffic Tickets Countercyclical

There is anecdotal evidence that local governments use traffic tickets to generate revenue. Using panel data for North Carolina counties, we examine whether changes in local government revenue influence the number of traffic tickets issued. We find strong evidence of an asymmetric response by local governments. Specifically, positive changes in revenue have no effect on traffic tickets, but negative revenue changes increase the number of traffic tickets issued. A one percentage point decrease in revenue yields a 0.38 percentage point increase in traffic tickets. We calculate that traffic ticket revenue supplements a low percentage of local revenue losses.
Lichens to Gunnera — with emphasis on Azolla

N2-fixing cyanobacteria occur in symbiotic associations with fungi (ascomycetes) as lichens and with a few green plants. The associated cyanobacterium is always a species of Nostoc or Anabaena. Only a small number of plant genera are involved but there is a remarkable range of host diversity. Associations occur with several bryophytes (e.g. Anthoceros, Blasia, Cavicularia), a pteridophyte (Azolla), cycads (nine genera including Macrozamia and Encephalartos) and an angiosperm (Gunnera). Except for Gunnera, where the cyanobacterium penetrates the plant cells, the cyanobacteria are extracellular with specialized morphological modifications and/or structures of the host plant organs providing an environment which facilitates interaction with the prokaryote.
Direct conversion of light to radio frequency energy

A description is presented of the test results obtained with the latest models of the phototron. The phototron was conceived as a replacement for the high voltage solar cell-high power klystron combination for the solar power satellite concept. Physically, the phototron is a cylindrical evacuated glass tube with a photocathode, two grids, and a reflector electrode in a planar configuration. The phototron can be operated either in a biased mode where a low voltage is used to accelerate the electron beam produced by the photocathode or in an unbiased mode referred to as self-oscillation. The device is easily modulated by light input or voltage to broadcast in AM or FM. The range of operation of the present test model phototrons is from 2 to 200 MHz.