cssi/SciSciGPT-SciSciNet huggingface dataset:
Fractionated radiotherapy combined with PD-1 pathway blockade promotes CD8 T cell-mediated tumor clearance for the treatment of advanced malignancies.

Programmed death-1 (PD-1) is a T cell inhibitory receptor, expressed on recently activated and chronically stimulated CD4 and CD8 T cells (1,2). Through interacting with programmed death ligand-1 (PD-L1), PD-1 limits T cell receptor signaling, and maintains peripheral tolerance (1,2). PD-1 pathway blockade has the potential to restore effector function to exhausted T cells, thus boosting their antiviral and antitumor activity (2). This has prompted the development of PD-1/PD-L1 antibodies for treating cancer. Success in numerous preclinical studies (3-5) led to multicenter clinical trials, and FDA approval of anti- PD-1 agents (nivolumab or Opdivo ® and pembrolizumab or Keytruda ® ) for the treatment of metastatic melanoma and non-small cell lung cancer (6-8). With as many as 31% of patients benefiting from treatment and median response duration lasting 2 years (8), it is not surprising that PD-1 pathway blockade, and interference with other T cell signaling checkpoints such as cytotoxic T lymphocyteassociated antigen 4 (CTLA-4), continues to generate excitement for cancer immunotherapy. Given that PD-1 and CTLA-4 blockade exert distinct effects on tumor control, combined blockade has been successful in mouse models of melanoma and clinical trials with 53% response rate (9). In order to further increase efficacy, it is necessary to understand how immunotherapy could complement already approved treatment modalities, such as chemotherapy and radiation.
Stand(ard) and Deliver: Yet Another Standards-Based Framework and the Ground-Level Work of Preservice Teacher Education

The C3 Framework for Social Studies Standards, InTASC, and edTPA represent recent, influential standards-based initiatives directed toward the reform of preservice teacher education programs. Carried by the same neoliberal reform currents propelling broader educational reform in the United States, all three initiatives share common intellectual underpinnings. What does this apparent uniformity of purpose mean for the ground-level work of teacher education? We employ a self-study conceptual analysis of how we interpret reform-based standards in the context of our work in a social studies teacher education program. Reforms are continuously interpreted and adopted in education programs. Yet little is written about how educators take up these reforms and implement them in their work. This analysis reveals the meanings brought to bear on the comparatively stable discourse evident in this most recent reform movement, and troubles the assumed relationship between reformed standards documents and reformed teacher education.
Material Analysis of Lead Free Solder Deposited by Electrochemical Deposition

Lead-free solders have essentially replaced lead-tin solders for new microelectronic applications. At the same time, many products are continuing to go through miniaturization, so the behavior of the solder material is changing as a function of the connection size. As lead-tin solder has been replaced by lead-free alloys, electrodeposited SnAg has become the standard solder alloy used on wafers. Tin-based solders exhibit a complex material structure in the deposit, as recrystallization occurs in the deposit, and as intermetallic compounds form. Understanding the complex nature of these materials is becoming increasingly important to the performance of our electronic products. We have characterized ECD SnAg solder alloy deposits in terms of composition, grain size, phase, microstructure, and texture using EBSD analysis. We will discuss the effects of modifying the process parameters on the microstructure which could implications on the performance of the solder bump as a chip-level interconnect. We have se...
Adapting Low-Bitrate Skip Mode in a Mobile Environment

A method is introduced to enhance the High Efficiency Video Coding early skip decision process. The proposed method exploits visual acuity and high-velocity motion perception of the human visual system (HVS). The method determines coding units where the HVS is unlikely to notice the changes and hence can be skipped. In this paper, the focus is mobile devices, such as smart phones, where displays are less than 5 in diagonal length and bandwidth availability is low. The proposed method exploits the mismatch between the video resolution, display resolution, and visual acuity of users. This method has very low impact on subjective quality while reducing encoding time for low bitrate environments. The proposed method reduces both encoding time and bitrate; the results show an average of 21.7% decrease in encoding time, 13.4% decrease in average bitrate, and very low impact on subjective quality ratings. The proposed methods can be adapted to decrease encoding time and bitrate in devices with lower resolution displays.
Beta adrenergically mediated cardiac chronotropic and vascular smooth muscle responses during propranolol therapy and withdrawal in young and elderly persons.

Aging is associated with diminished beta-adrenergic responsiveness in a variety of tissues. Desensitization of tissues secondary to the age-associated increase in sympathetic nervous system activity has been proposed as a potential explanation for diminished beta-adrenergic responsiveness. If this hypothesis is correct, then beta-blockade in older people might be expected to reverse the blunted beta-adrenergic responses of tissues having diminished responsiveness. Cardiac chronotropic responses to bolus isoproterenol (ISO) doses and ISO-induced venous smooth muscle dilatation in superficial hand veins were examined in 8 young (26.2 +/- 2.6 yrs) and 9 elderly (68.0 +/- 2.2 yrs) healthy subjects before, during, and 3 and 7 days following 2 weeks of treatment with propranolol. Baseline cardiac chronotropic responsiveness, CD25, was 1.55 +/- 0.77 mcg in the young and 5.97 +/- 2.77 mcg in the elderly subjects (p less than .01), increasing to 84 +/- 56 mcg and 194 +/- 172 mcg during treatment with propranolol. At 3 and 7 days following withdrawal of propranolol, CD25s were respectively 1.24 +/- 0.79 (p = .14) and 1.10 +/- 0.42 (p = .04) in the young and 5.63 +/- 2.34 (p = .31) and 4.85 +/- 2.37 (p = .05) in the elderly subjects. In contrast, there was no decrease in the ED50 or increase in Emax for ISO-induced venodilation of hand veins following propranolol withdrawal. These results demonstrate that both young and elderly subjects have similar increases in cardiac chronotropic responsiveness following discontinuation of beta-blockade and do not support the concept that desensitization is responsible for the diminished beta-adrenergic responsiveness seen with aging.
Multiphysics Model for Chlorine-Ion Related Corrosion in Cu-Al Wirebond Microelectronic Packages

The increasing price of gold has resulted in industry interest in use of copper as alternative wire bonds interconnect material. Copper wire has the advantages of the lower cost, lower thermal resistivity, lower electrical resistivity, higher mechanical strength and higher deformation stability over the gold wire. In spite of the upside above, the Cu-Al wire bond is susceptible to the electrolytic corrosion and the reliability of Cu-Al wire bond is of great concern. Typical electronic molding compounds are hydrophilic and absorb moisture when exposed to humid environmental conditions. EMC contain ionic contaminants including chloride ions as a result of the chemical synthesis of the subcomponents of the resin, etching of metallization and the decomposition of the die-attach glue. The presence of moisture in the operating environment of semiconductor package makes the ion more mobile in the EMC. The migration of chloride ions to the Cu-Al interface may induce electrolytic corrosion inside the package causing degradation of the bond interface resulting in eventual failure. The rate at which the corrosion happens in the microelectronic packages is dependent upon the rate at which the ions transport through the EMC in addition to the reaction rate at the interface. In this effort, a multiphysics model for galvanic corrosion in the presence of chloride has been presented. The contaminant diffusion along with the corrosion kinetics has been modeled. In addition, contaminated samples with known concentration of KCl contaminant have been subjected to the temperature humidity conditions of 130°C/100RH. The resistance of the Cu-Al interconnects in the PARR test have been monitored periodically using resistance spectroscopy. The diffusion coefficients of chloride ion has been measured in the electronic molding compound at various temperatures using two methods including diffusion cell and inductively coupled plasma (ICPMS). Moisture ingress into the EMC has been quantified through measurements of the weight gain in the EMC as a function of time. Tafel parameters including the open circuit potential and the slope of the polarization curve has been measured for both copper, aluminum under different concentrations of the ionic species and pH values in the EMC. The measurements have been incorporated into the COMSOL model to predict the corrosion current at the Cu-Al bond pad. The model predictions have been correlated with experimental data.Copyright © 2015 by ASME
Analysis on 2006～2010 epidemics of national key monitoring STDs in Beitang District,Wuxi

Analysis was made on the epidemics of national key monitoring STDs between 2006 and 2010 in Beitang district,Wuxi.The results indicated that the overall STD occurrences tended to decrease during the period with a significant drop since 2008.However,there wasn't much improvement in syphilis occurrence,and syphilis has become the most important type of STDs.
Dynamic chromatin modifications control GnRH gene expression during neuronal differentiation and protein kinase C signal transduction.

GnRH, a neuropeptide produced by rare, specialized hypothalamic secretory neurons, is critical for reproduction. During development, GnRH gene expression increases as neurons migrate from the olfactory placode to the hypothalamus, with highest levels in the mature, postmitotic state. While neuronal differentiation is known to be controlled by chromatin modulations, the role of chromatin dynamics in GnRH gene regulation has not been studied. Here, we use mature and immature GnRH neuronal cell models to show that both neuron-specific and protein kinase C regulation of GnRH expression are mediated by chromatin structure and histone modifications. Only in GT1-7 mature GnRH neuronal cells did GnRH regulatory elements display high sensitivity to DNase and enrichment of active histone markers histone-H3 acetylation and H3 lysine 4 trimethylation (H3K4-Me3), as well as RNA polymerase II (RNAPII) binding and enhancer RNA transcription. In contrast, H3K9-Me2, a marker of inactive chromatin, was highest in nonneuronal cells, low in GT1-7 cells, and intermediate in immature GnRH neuronal cells. The chromatin of the GnRH gene was therefore active in mature GnRH neuronal cells, inactive in nonneuronal cells, but not fully inactive in immature GnRH neuronal cells. Activation of protein kinase C (PKC) potently represses GnRH expression. PKC activation caused closing of the chromatin and decreased RNAPII occupancy at the GnRH minimal promoter (−278/−97). At GnRH-Enhancer-1 (−2404/−2100), PKC activation decreased phosphorylated-RNAPII binding, enhancer RNA transcription, and H3 acetylation, and reciprocally increased H3K9-Me2. Chromatin modifications therefore participate in the dynamic regulation and specification of GnRH expression to differentiated hypothalamic neurons.
A variance component method for integrated pathway analysis of gene expression data.

The application of pathway and gene-set based analyses to high-throughput data is increasingly common and represents an effort to understand underlying biology where single-gene or single-marker analyses have failed. Many such analyses rely on the a priori identification of genes associated with the trait of interest. In contrast, this variance-component–based approach creates a similarity matrix of individuals based on the expression of genes in each pathway. We compared 16 methods of calculating similarity for positive control matrices based on probes for the genes used to model the simulated Genetic Analysis Workshop phenotypes. A simple correlation matrix outperforms the other methods by identifying pathways associated with the simulated phenotypes at nearly twice the rate expected based on the associations of the component transcripts and an approximate false-positive rate of 0.05. This method has a number of additional advantages compared to single-transcript and pathway overrepresentation analyses, including the ability to estimate the proportion of variation explained by each pathway and the logistical advantage of only calculating the distance matrices once for each messenger RNA data set regardless of the number of phenotypes. Additionally, it offers a significant reduction in the multiple testing burden over individual consideration of each probe.
Outcomes of HCV-Positive Patients with Lymphoma Treated with Rituximab-Containing Therapies

Introduction: The impact that hepatitis C virus (HCV) infection has on the clinical outcome of patients with lymphoma treated with rituximab-containing therapies is uncertain. Rituximab has improved outcomes in patients with aggressive lymphomas however the prognostic value of rituximab in HCV infected patients has not been well established. It has been shown that reactivation is a common complication in patients with hepatitis B treated with rituximab. It is possible that patients with hepatitis C also develop reactivation with rituximab resulting in worsening liver function and a poor clinical outcome. A prior Japanese study showed that HCV-positive patients with diffuse large B-cell lymphoma have a high incidence of severe hepatic toxicity (Ennishi, D., Maeda, Y., et al. 2010). In this study we wanted to further analyze this idea and see if it is applicable to American population with hepatitis C and lymphoma receiving rituximab-containing therapies. Methods: We collected data from patients who were HCV-positive with lymphoma treated with rituximab between 2003 and 2014 at Montefiore Medical Center. Patients were included who were over 18 years old with a positive HCV test prior to treatment. Data was analyzed using statistical software Stata (version 12.0, StataCorp LP, College Station, TX, USA). Results: A total of 33 HCV-positive patients with lymphoma were included. Most of these patients (82%) had diffuse large B-cell lymphoma (DLBCL). Of the 33 patients, 24 (73%) showed worsening liver function after starting Rituximab containing therapy. Hepatitis C viral load before and after the treatment was documented for 8 patients. 5 of these 8 patients had clear reactivation of hepatitis C with rising hepatitis C viral load. All of these 5 patients noted with worsening of liver function tests. These patients received an average of 2 doses of Rituximab before having the rise in liver function tests (LFTs). Also, the median duration to see a rise in liver transaminases was at 2.5 months with the peak level in liver enzymes observed at 4 months after starting rituximab. Conclusion: These results show that patients with HCV infection have a high incidence of hepatic toxicity with rituximab. Some of these patients also showed evidence of reactivation with increased hepatitis C viral load. Further studies need to be done to determine if addition of new oral hepatitis C treatments like Sofosbuvir to the chemotherapy would change the course of viral reactivation and hepatic toxicity. These patients may need closer hepatic monitoring during and after treatment with rituximab. References: Ennishi, D., Maeda, Y., et al. (2010). “Hepatic toxicity and prognosis in hepatitis C virus-infected patients with diffuse large B-cell lymphoma treated with rituximab-containing chemotherapy regimens: a Japanese multicenter analysis.” Blood 116(24): 5119-25 Disclosures No relevant conflicts of interest to declare.
Opioid analgesic use among patients presenting with acute abdominal pain and factors associated with surgical diagnoses.

Background The prevalence of chronic opioid use among non-cancer patients presenting with acute abdominal pain (AAP) is unknown. The aim was to characterize opioid use, constipation, diagnoses, and risk factors for surgical diagnoses among non-cancer patients presenting with AAP to an emergency department (ED). Methods We performed a retrospective, observational cohort study of all (n=16,121) adult patients (88% from MN, IA and WI) presenting during 2014 with AAP. We used electronic medical records, and focused on 2352 adults with AAP who underwent abdominal CT scan within 24 hours of presentation. We determined odds ratios of association with constipation and features predicting conditions that may require surgery (surgical diagnosis). Key Results There were 2352 eligible patients; 18.8% were opioid users. Constipation was more frequent in opioid (35.1%) compared to non-opioid users [OR 2.88 (95% CI 2.28, 3.62)]. Prevalence of surgical diagnosis in the opioid and non-opioid users was 35.3% and 41.7% respectively (P=.019). By univariate analysis, age and neutrophil count independently predicted increased risk, and chronic opioid use decreased risk of surgical diagnosis. Internal validation of logistic models using a randomly selected validation subset (25% of entire cohort, 587/2352) showed receiver operating characteristic (ROC) curves for the validation and full cohorts were similar. Conclusions and Inferences Approximately 19% of adults presenting with AAP were opioid users; constipation is almost three times as likely in opioid users compared to non-opioid users presenting with AAP. Factors significantly associated with altered risk of surgical diagnoses were age, opioid use, and neutrophil count.
Range-wide conservation of Pinus aristata: a genetic collection with ecological context for proactive management today and resources for tomorrow

Tree species are highly vulnerable to anthropogenic environmental change, and are increasingly being challenged by non-native pests and climate change. Rocky Mountain bristlecone pines are long-lived, exhibit delayed maturation, have low genetic diversity, and inhabit cold, high-elevation environments. They are threatened by the non-native disease white pine blister rust, warming temperatures, changing precipitation patterns, and altered disturbance regimes. The goal of this work was to (1) sample the range-wide genetic diversity of bristlecone pine for ex situ seed and tissue collections and research before the populations are impacted, (2) assess the health and ecological conditions of the species across its geographic range (61 stands) to provide a baseline by which to evaluate future changes, and (3) assess relationships between stand and regeneration characteristics and topographic, geographic, and climatic factors to identify vulnerabilities and proactive management interventions to increase population resilience. Local variation in topoclimate was strongly related to stand structure, composition, health, and regeneration. Bristlecone pine currently showed only minor impacts from insects and pathogens, but relationships between cone production and regeneration with climate variables suggest vulnerabilities to projected climate change. Both cone production and seedling regeneration were also linked to stand structure and ground cover that provide opportunities for proactive in situ management to increase population size to mitigate potential future climate- and pathogen-driven declines. These efforts represent the first proactive coordinated range-wide genetic collection design and forest health assessment for a threatened, but not yet impacted, tree species and offers a model for other species at risk.
Ownership structure and earnings management in emerging markets—An institutionalized agency perspective

Abstract Previous earnings management research has largely focused on firm-level governance mechanisms in single countries or on macro-level variables in multiple countries. Building on this research, we incorporate firm ownership predictors along with national institutional dimensions to explore why firm decision makers in emerging markets vary in their earnings management behavior. Our theoretical framework integrates agency and institutional theories proposing that firm-level ownership mechanisms do not function in isolation, but are reinforced or attenuated by elements of the institutional governance environment. The multilevel empirical analysis of 1200 firms in 24 emerging markets indicates that controlling ownership is positively related to earnings management. We find that the level of minority shareholder protection in a country weakens this positive relationship. We also find that regulatory quality strengthens the negative relationship between institutional ownership and earnings management activity. It is hoped that awareness of how firm ownership structures interact with national-level institutions in affecting firm-level behavior will help managers and investors develop skills and practices to better cope with business norms in emerging economies.
Play it Again: Evolved Audio Effects and Synthesizer Programming

Automatic programming of sound synthesizers and audio devices to match a given, desired sound is examined and a Genetic Algorithm (GA) that functions independent of specific synthesis techniques is proposed. Most work in this area has focused on one synthesis model or synthesizer, designing the GA and tuning the operator parameters to obtain optimal results. The scope of such inquiries has been limited by available computing power, however current software (Ableton Live, herein) and commercially available hardware is shown to quickly find accurate solutions, promising a practical application for music creators. Both software synthesizers and audio effects processors are examined, showing a wide range of performance times (from seconds to hours) and solution accuracy, based on particularities of the target devices. Random oscillators, phase synchronizing, and filters over empty frequency ranges are identified as primary challenges for GA based optimization.
Understanding User Behavior Through Log Data and Analysis

HCI researchers are increasingly collecting rich behavioral traces of user interactions with online systems in situ at a scale not previously possible. These logs can be used to characterize user interactions with existing systems and compare different designs. Large-scale log studies give rise to new challenges in experimental design, data collection and interpretation, and ethics. The chapter discusses how to address these challenges using search engine logs, but the methods are applicable to other types of log data.
5.8-GHz ISM band intermodulation radar for high-sensitivity motion-sensing applications

Many electronic components such as diodes and transistors exhibit certain degree of nonlinearity. In this paper, this nonlinearity is used for a radar target to generate intermodulation tones from incident waves with two fundamental frequencies, so that the radar detects only the target and rejects clutter reflections. In this paper, the intermodulation radar at 5.8 GHz ISM band and the passive tag were designed, fabricated and characterized. The motion and the intermodulation generated by the tag were measured, as compared with undesired fundamental reflections. This intermodulation-based nonlinear radar approach can overcome some drawbacks of harmonic radars. It has wide potential applications in clutter noise rejection and detection of unauthorized electronic devices.
Considering the vascular hypothesis of Alzheimer's disease: effect of copper associated amyloid on red blood cells.

The vascular hypothesis of Alzheimer’s disease (AD) considers cerebral hypoperfusion as a primary trigger for neuronal dysfunction. We have previously reported that red blood cells (RBCs) bind amyloid, which are the characteristic deposits found in AD brains, and interact with amyloid on the vasculature [1–3]. Oxidative stress triggered by these RBC/amyloid interactions could impair oxygen delivery. Recent literature has implicated copper bound amyloid-β peptide (CuAβ) and the associated production of reactive oxygen species (ROS) as one of the primary factors contributing to AD pathology. In this work, we have investigated CuAβ generated RBC oxidative stress. Aβ1–40 peptide with a stoichiometric amount of copper bound was produced and compared to the metal-free form of the peptide. Different aggregation states of the peptides were isolated and incubated with RBCs for 15 h. Interestingly, CuAβ stimulated a pronounced increase in red cell oxidative stress as indicated by increased hemoglobin (Hb) oxidation, increased formation of fluorescent heme degradation products, and a decrease in RBC deformability. These findings demonstrate a potential role for CuAβ in promoting vascular oxidative stress leading to impaired cerebral oxygen delivery, which may contribute to neurodegeneration associated with AD.
PERIPHERAL BLOOD NATURAL CELL-MEDIATED CYTOTOXICITY IN PATIENTS WITH ATOPIC DERMATITIS

Publisher Summary This chapter examines the peripheral blood natural cell-mediated cytotoxicity in patients with atopic dermatitis. Natural cell-mediated cytotoxic activity of the peripheral blood lymphocytes was studied in 10 patients with atopic dermatitis, and simultaneously in a healthy control matching each patient for sex, skin, color, and age ± 6 years. Eight patients gave a family history of allergic disease (as atopic dermatitis, asthma, hives or allergic rhinitis), and four patients had a personal history of asthma. None of the patients had systemic corticosteroids for at least a year prior to the investigation, and none had anti-histamines for at least 48 h before blood samples were obtained. Mononuclear leucocytes were separated using LSM solution. K562 target cells were maintained in RPMI containing 20% inactivated FCS, were radio-labeled by incubation with 51Cr as sodium chromate at 37°C for one hour, centrifuged, washed, and adjusted to a count of 0.2 × 106 viable cells/ml. The results showed that there was a marked reduction in the natural cytotoxicity of most of the atopic dermatitis patients studied. The patients with the least or no reduction in natural cytotoxicity were the three with only moderate or mild degrees of atopic dermatitis.
IGFs in Pregnancy: Developmental Expression in Uterus and Mammary Gland and Paracrine Actions during Embryonic and Neonatal Growth

The insulin-like growth factors (IGF-I, IGF-II) are structural homologs of insulin that are mitogenic in vivo and in vitro 1. These peptides are also characterized by other actions which include the ability to alter the differentiation state of target cells by affecting specific aspects of messenger RNA (mRNA) production, protein synthesis and protein secretion. The IGF peptides are synthesized in multiple organ systems by a process that is subject to hormonal, developmental and tissue-specific regulation. The molecular mechanisms underlying the complex regulation of IGF biosynthesis remain for the most part obscure.
Initiation of targeted therapy based on ctDNA only in metastatic NSCLC.

e20687Background: Next generation sequencing (NGS) of circulating tumor DNA (ctDNA) can identify sensitizing and resistance mutations in Non-Small Cell Lung Cancer (NSCLC). ctDNA is helpful when ti...
Directional kinetics analysis of the progression of geographic atrophy

To investigate the influence of baseline geographic atrophy (GA) size on the rate of GA progression by using both distance and area measurements. Thirty-five eyes from 24 patients with GA due to age-related macular degeneration were obtained from anonymized datasets available at the Doheny Image Reading Center. Baseline and month 12 fundus autofluorescence (FAF) images were used for this analysis. Borders of GA lesions were semiautomatically segmented by certified reading center graders to create masks of the GA lesion. The masks from the two visits were registered and overlaid to allow the differences in area as well as the differences in the position of GA border between the visits to be computed. Distance measurements were performed using a Euclidean distance map. Sectoral (clock hour)/directional GA progression rates with respect to the foveal center were also calculated. GA progressed 1.6 ± 0.9 mm2 in area and 92.9 ± 64.9 μm in distance over the 12 months. Smaller GA lesions were associated with more rapid progression when measured using distance (P = 0.0004, R = − 0.554). In contrast, there was no significant correlation in this cohort between baseline GA area and the progression measured in area (P = 0.406). In the sectoral/directional GA progression analysis, progression speed differed among clockwise directions, when progression was evaluated by using area measurements. However, this difference was not found, when evaluated by using distance measurements. Use of linear distance-based measurements enables evaluation of GA progression which is not confounded by baseline lesion size.
The synthesis of 1,2,3,3a,4,5,6,11‐octahydro‐6,11a‐methano‐11aH‐benzo[4,5]cycloocta[1,2‐c]pyrroles. As new heterocyclic ring system

The synthesis of the novel 1,2,3,3a,4,5,6,11-octahydro-6,11a-methano-11aH-benzo[4,5]cycloocta[1,2-c]-pyrrole system by acid-catalyzed cyclization of cis-3a-benzyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-diones is described.
Abstract 2639: Insulin receptor alternative splicing during development and cancer

It has been shown that alternative splicing of some genes changes during development from embryogenesis to adulthood. Intriguingly, transformation of cells is also often accompanied by a reversion to the embryonic spliced isoforms. Insulin receptor (IN-R) undergoes alternative splicing to produce two isoforms: the full-length IN-RB isoform and the exon 11-skipped IN-RA isoform. The IN-RB isoform encodes a receptor with high affinity for insulin, while the IN-RA isoform has high affinity for both insulin & IGF2 growth hormones. IN-RAexploits the IGF pathway to accelerate growth, proliferation and angiogenesis. It is known that during embryogenesis the IN-R gets spliced to primarily express the INR-A form. Recently, the A isoform has has also been shown to be expressed in certain cancer types. Because the insulin receptor signaling converges on the mTOR/AKTpathway that is one of the most critical pathways for organismal development as well in cancer, it is important to understand the expression of these isoforms and their role in signaling and cellular fate. However, a tissue and a temporal description of the expression of these two isoforms is lacking. Towards this end we have shown that the mouse insulin receptor gene is spliced similarly to the human gene and have used the mouse model to study IR splicing during development. We harvested tissues from mice at different developmental stages (E10, E18, P1, P7, 3 months and 6 months) and performed RT-PCR for the insulin receptor gene. Our data confirmed that the whole embryos at embryonic day 10 (E10) express mostly IN-RA (90%). However, as the embryo develops and we can obtain discrete tissues we are able to detect tissue-specific profiles of IN-Rsplicing. For example, in bone at E18 as well as postnatal day P1 and 7, IN-RBis highly expressed (65%) and decreases to (40%) as the mouse reaches 6 months of age. Likewise, the liver and pancreas, which are primarily involved with metabolic functions, express mostly IN-RB(90%) from postnatal day P1 and into adult hood (6 months). In contrast, when we analyzed IR-splicing in human cancers, we find that in both liver cancer and cancers of the bone (osteosarcoma and Ewing’s sarcoma) there is a shift toward increased levels of the pro-proliferative isoform, IN-RA. We believe that understanding the molecular underpinnings of the splicing regulation during development will provide us with knowledge that will help us better understand the transformation process and how to control it, possibly through splicing corrective therapy. Citation Format: Safiya Khurshid. Insulin receptor alternative splicing during development and cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2639.
Low-dose ladostigil for mild cognitive impairment: A phase 2 placebo-controlled clinical trial

Objective Ladostigil reduces oxidative stress and microglial activation in aging rats. We assessed its safety and potential efficacy in a 3-year, randomized, double-blind, placebo-controlled phase 2 clinical trial in patients with mild cognitive impairment (MCI) and medial temporal lobe atrophy. Methods Patients 55 to 85 years of age with MCI, Clinical Dementia Rating (CDR) score of 0.5, Mini-Mental State Examination (MMSE) score >24, Wechsler Memory Scale–Revised Verbal Paired Associates I score ≤18, and Medial Temporal Lobe Atrophy Scale score >1 were stratified by APOE e4 genotype and randomly assigned (1:1) to ladostigil 10 mg/d or placebo. Primary outcomes were safety and onset of Alzheimer disease dementia. Secondary endpoints were Neuropsychological Test Battery (NTB) composite, Disability Assessment in Dementia (DAD), and Geriatric Depression Scale (GDS) scores. Exploratory outcomes were NTB component, CDR, and MMSE scores. Biomarkers included MRI-derived whole-brain, hippocampus, and entorhinal cortex volumes. Results Two hundred ten patients from 15 sites in Austria, Germany, and Israel were randomly allocated to placebo (107 patients) or ladostigil (103 patients). After 36 months, 21 of 103 patients on placebo and 14 of 99 patients receiving ladostigil progressed to Alzheimer disease (log-rank test p = 0.162). There were no significant effects on the NTB composite, DAD, or GDS score. Whole-brain and hippocampus volumes decreased more in the placebo than in the ladostigil group (whole brain, p = 0.025, Cohen d = 0.43; hippocampus, p = 0.043, d = 0.43). Serious adverse events were reported by 28 of 107 patients treated with placebo and 26 of 103 with ladostigil. Conclusion Ladostigil was safe and well tolerated but did not delay progression to dementia. Its association with reduced brain and hippocampus volume loss suggests a potential effect on atrophy. ClinicalTrials.gov identifier NCT 01429623. Classification of evidence This study provides Class II evidence that for patients with MCI and medial temporal lobe atrophy, ladostigil did not significantly decrease the risk of the development of Alzheimer disease.
Transgenerational shame in postcolonial Italy: Igiaba Scego’s Adua

This article reads Igiaba Scego’s 2015 novel Adua as an expression of shame within the parameters of transgenerational emotion. The passage of shame is traced from a Somali subject of 1930s Italian...
Glass 3D Printing of Microfluidic Pressure Sensor Interrogated by Fiber-Optic Refractometry

This letter reports a novel fused silica microfluidic device with pressure sensing capability that is fabricated by integrated additive and subtractive manufacturing (IASM) method. The sensor consists of a capillary and a 3D printed glass reservoir, where the reservoir volume change under pressure manifests liquid level deviation inside the capillary, thus realizing the conversion between small pressure change into large liquid level variation. Thanks to the design flexibility of this unique IASM method, the proposed microfluidic device is fabricated with liquid-in-glass thermometer configuration, where the reservoir is sealed following a novel 3D printing assisted glass bonding process. And liquid level is interrogated by a fiber-optic sensor based on multimode interference (MMI) effect. This proposed microfluidic device is attractive for chemical and biomedical sensing because it is flexible in design, and maintains good chemical and mechanical stability, and adjustable sensitivity and range.
A Digital Twin Approach to a Quantitative Microstructure-Property Study of Carbon Fibers through HRTEM Characterization and Multiscale FEA

Microstructures of typical carbon fibers (CFs) from polyacrylonitrile (PAN) and pitch-based precursors were studied using a novel digital twin approach with individual carbon fibers for a local crystal scale model. The transmission electron microscopy (TEM) samples were prepared using a focused-ion beam (FIB) for both longitudinal and transverse directions of carbon fibers. Measurements of the crystal size and orientation were estimated from X-ray scattering. TEM imaging of graphitic packing facilitated further comprehension of associations between processing and final material properties, which could enable customization of microstructures for property targets. Then the detailed microstructural information and their X-ray scattering properties were incorporated into the simulation model of an individual carbon fiber. Assuming that graphene properties are the same among different forms of carbon fiber, a reasonable physics-based explanation for such a drastic decrease in strength is the dislocations between the graphitic units. The model reveals critical defects and uncertainty of carbon fiber microstructures, including skin/core alignment differences and propagating fracture before ultimate failure. The models are the first to quantify microstructures at the crystal scale with micromechanics and to estimate tensile and compressive mechanical properties of carbon fiber materials, as well as potentially develop new fundamental understandings for tailoring carbon fiber and composites properties.
Global change adaptation reduces plasticity and limits future resilience

Abstract Species may persist through the unprecedented changes in global conditions using genetic adaptation or physiological plasticity. However, few empirical studies have revealed the relationship between adaptation and plasticity or addressed the long-standing debate on whether plasticity impedes or facilitates adaptive evolution. Here, we used experimental evolution and reciprocal transplantation of the marine coastal copepod, Acartia tonsa, to present-day and future greenhouse conditions (high temperature, high CO2). Despite the presence of plasticity in ambient conditions, twenty generations of selection resulted in highly parallel genetic adaptation to greenhouse conditions where genes related to stress response, actin regulation, developmental processes, and energy production diverged between conditions. Genetic adaptation, however, reduced fecundity and population growth when greenhouse animals were returned to ambient conditions or reared in low food conditions. Concurrently, adaptation reduced gene expression plasticity by 12.7 fold. Despite the loss of plasticity, across three successive transplant generations, greenhouse-adapted animals were able to match the ambient-adaptive transcriptional profile through genetic adaptation, which in turn eroded nucleotide diversity in greenhouse-adaptive genes. These results demonstrate the power of experimental evolution from natural populations to reveal the mechanisms, timescales of responses, consequences, and reversibility of complex, physiological adaptation. While plasticity facilitated initial survival in global change conditions, it eroded after 20 generations as populations genetically adapted, limiting resilience to new stressors and previously benign environments.
Oxytocin and ‘social hyperthermia’: Interaction with β3-adrenergic receptor-mediated thermogenesis and significance for the expression of social behavior in male and female mice

Abstract Oxytocin (OT) is a critical regulator of multiple facets of energy homeostasis, including brown adipose tissue (BAT) thermogenesis. Nevertheless, it is unclear what, if any, consequence the thermoregulatory and metabolic effects of OT have for the display of social behavior in adult rodents. Here, we examine the contribution of the OT receptor (OTR) and β3 adrenergic receptor (β3AR) to the increase in body temperature that typically accompanies social interaction (i.e., social hyperthermia; SH) and whether SH relates to the expression of social behavior in adult mice. Specifically, we examined how OTR antagonism via peripheral injection of L-368,899 (10 mg/kg) affects the expression of social behavior in C57BL/6J mice, in the presence of active/agonized versus antagonized β3AR, the receptor known to mediate stress-induced BAT thermogenesis. After drug treatment and a 30 min delay, mice were provided a 10 min social interaction test with an unfamiliar, same-sex conspecific. We hypothesized that OTR and β3AR/BAT interact to influence behavior during social interaction, with at least some effects of OT on social behavior dependent upon OT's thermal effects via β3AR/BAT. We found that OTR-mediated temperature elevation is largely responsible for SH during social interaction in mice—albeit not substantially via β3AR-dependent BAT thermogenesis. Further, our results reveal a complex relationship between OTR, β3AR, social hyperthermia and the display of specific social behaviors, with SH most closely associated with anxiety and/or vigilance-related behaviors—that is, behaviors that antagonize or interfere with the initiation of close, non-agonistic social behavior.
Efficacy and benefits of mock residency interviews.

Abstract Introduction Obtaining a residency has become more competitive as more pharmacy students seek postgraduate training. This is likely due to pharmacist positions increasing in clinical settings. To be fully prepared, students seeking residency positions should be trained for the interview process by their pharmacy school. Methods Mock residency interviews (MRI) were conducted at the Texas Tech University Health Sciences Center School of Pharmacy which included components of typical residency interviews. The primary outcome compared residency match rates for MRI participants vs. non-participants. Secondary outcomes evaluated student preparedness, student and faculty feedback, and satisfaction/benefit of the event along with comparison of school vs. national match rate and assessment of those matching compared to grade point average (GPA). Results Match rates were similar between MRI participants vs. non-participants (75% vs. 73%) with significant difference in Phase I match rates between MRI participants vs. non-participants (75% vs. 51%, P = .007). MRI was significantly associated with Phase I matching in the multivariable analysis (odds ratio (OR) = 2.81, 95% CI 1.27–6.22). The overall school's match rate exceeded the national two out of three years in the quality improvement project period. GPA was the only other factor independently associated with Phase I matching (OR = 1.15, 95% CI 1.01–1.32). Students and faculty consistently reported positive feedback following participation. Conclusions MRI are valuable and are making a difference as indicated by improved Phase I match rates for those that participated. Students and faculty reported an increase in preparedness and overall satisfaction after attending MRI.
Using Artificial Intelligence to Estimate Nonlinear Resilient Modulus Parameters from Common Index Properties

The Mechanistic–Empirical Pavement Design Guide (MEPDG) considers a hierarchical approach to determine the input values necessary for most design parameters. Level 1 requires site-specific measurem...
Irony: The Capacity for Cultivating a Sense of Irony

Becoming mature involves, in part, adopting the ironic attitude of perpetually acknowledging our not-knowing, while pursuing self-and-relational knowledge; our own moral ugliness, while reaching out for a life of moral beauty; our own destructiveness, while attempting to live a good life; our own self-deception, while trying our best to be truthful; and our own hatefulness, while struggling to purify our lovingness. The ironizing self is capable of playing with opposites; of balancing the serious with the light-hearted; of being amused by the twists of fate, the unexpected turn of events, and the topsy-turvy nature of life’s unfolding drama; and of modulating the polar meanings of existence. The ironic orientation recognizes the comical in the tragic and the tragic in the comical.
Brief Introduction to Primary Headaches and Overview of the Book

Headache is a widely prevalent, burdensome disorder. Because most individuals with headache believe that there are one or more triggers, or causes, of their headaches, the study of triggers is important in understanding these associations and their effects on individuals. Before beginning to study triggers, it is helpful to understand different headache diagnoses and how they relate to trigger assessment. In this chapter, primary headache disorders are described, important definitions are delineated, and an overview of the book is detailed.
Smad2 inhibition of MET transcription potentiates human vascular smooth muscle cell apoptosis

Abstract Background Vascular smooth muscle cell (SMC) apoptosis is involved in major cardiovascular diseases. Smad2 is a transcription factor implicated in aortic aneurysm. The molecular mediators of Smad2-driven SMC apoptosis are not well defined. Here we have identified a Smad2-directed mechanism involving MET and FAS, both encoding cell membrane signaling receptors. Methods and results Guided by microarray analysis in human primary aortic SMCs, loss/gain-of-function (siRNA/overexpression) indicated that Smad2 negatively and positively regulated, respectively, the gene expression of Met which was identified herein as anti-apoptotic and that of Fas, a known pro-apoptotic factor. While co-immunoprecipitation suggested a physical association of Smad2 with p53, chromatin immunoprecipitation followed by quantitative PCR revealed their co-occupancy in the same region of the MET promoter. Activating p53 with nutlin3a further potentiated the suppression of MET promoter-dependent luciferase activity and the exacerbation of SMC apoptosis that were caused by Smad2 overexpression. These results indicated that Smad2 in SMCs repressed the transcription of MET by cooperating with p53, and that Smad2 also activated FAS, a target gene of its transcription factor activity. Conclusions Our study suggests a pro-apoptotic mechanism in human SMCs, whereby Smad2 negatively and positively regulates MET and FAS, genes encoding anti-apoptotic and pro-apoptotic factors, respectively.
Chapel graph library (CGL)

In this talk, I summarize prior work on the Chapel HyperGraph Library (CHGL), the Chapel Aggregation Library (CAL), and introduce the more general Chapel Graph Library (CGL). CGL is being designed to enable global-view programming, such that locality is abstracted from the user. CGL is also being designed in a way that is similar to Chapel's multiresolution design philosophy, where graphs are implemented in terms of hyper graphs, and where both the underlying hypergraph and overlying graphs are available for use. Some of the kinds of graphs being designed are bipartite graphs, directed and undirected graphs, and even trees.