cssi/SciSciGPT-SciSciNet huggingface dataset:
Reconstructing the Past: Parsimony, Evolution, and Inference

Reconstructing the Past seeks to clarify and help resolve the vexing methodological issues that arise when biologists try to answer such questions as whether human beings are more closely related to chimps than they are to gorillas. It explores the case for considering the philosophical idea of simplicity/parsimony as a useful principle for evaluating taxonomic theories of evolutionary relationships.For the past two decades, evolutionists have been vigorously debating the appropriate methods that should be used in systematics, the field that aims at reconstructing phylogenetic relationships among species. This debate over phylogenetic inference, Elliott Sober observes, raises broader questions of hypothesis testing and theory evaluation that run head on into long standing issues concerning simplicity/parsimony in the philosophy of science.Sober treats the problem of phylogenetic inference as a detailed case study in which the philosophical idea of simplicity/parsimony can be tested as a principle of theory evaluation. Bringing together philosophy and biology, as well as statistics, Sober builds a general framework for understanding the circumstances in which parsimony makes sense as a tool of phylogenetic inference. Along the way he provides a detailed critique of parsimony in the biological literature, exploring the strengths and limitations of both statistical and nonstatistical cladistic arguments.
Measurement of thermal conductivity of PbTe nanocrystal coated glass fibers by the 3ω method

Fiber-based thermoelectric materials can conform to curved surfaces to form energy harvesting devices for waste heat recovery. Here we investigate the thermal conductivity in the axial direction of glass fibers coated with lead telluride (PbTe) nanocrystals using the self-heated 3ω method particularly at low frequency. While prior 3ω measurements on wire-like structures have only been demonstrated for high thermal conductivity materials, the present work demonstrates the suitability of the 3ω method for PbTe nanocrystal coated glass fibers where the low thermal conductivity and high aspect ratio result in a significant thermal radiation effect. We simulate the experiment using a finite-difference method that corrects the thermal radiation effect and extract the thermal conductivity of glass fibers coated by PbTe nanocrystals. The simulation method for radiation correction is shown to be generally much more accurate than analytical methods. We explore the effect of nanocrystal volume fraction on thermal conductivity and obtain results in the range of 0.50-0.93 W/mK near room temperature.
Interventions for Parents of People with Intellectual Disabilities

Parents of children with intellectual disabilities (ID) consistently report higher levels of parenting stress than parents of typically developing children, which has psychological and physical consequences for both the parent and child. Further, high levels of parenting stress are often associated with poor outcomes in behavioral interventions for children with ID. Thus, parental stress and mental health concerns in general are critical targets for intervention. Nevertheless, there are few evidence-based treatments aimed at reducing stress in parents of children with ID. Parent-led support groups are the most common type of intervention for these parents; however, little empirical evidence is available to support the efficacy of these interventions. Other evidence-based interventions include mindfulness, cognitive-behavior therapy, respite, and behavioral parent training interventions. We argue for a combined intervention model that addresses both parental stress and child behavior problems directly in order to optimize outcomes for children with ID and their families.
Abstract C115: Targeting glutamine metabolism in colorectal cancers with PIK3CA mutations

Glutamine addiction is a major metabolic reprogramming event that occurs in cancer cells. Many tumors exhibit oncogene-dependent addiction to glutamine. PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase α, is the most frequently mutated oncogene in human cancers. However, whether PIK3CA mutations reprogram cancer metabolism is an important unaddressed question. Here we show that oncogenic PIK3CA mutations render colorectal cancers (CRCs) more dependent on glutamine to growth. As a metabolite, glutamine is first converted glutamate by glutaminase (GLS) and then to α-ketoglutarate (α-KG) by either a transaminase or a glutamate dehydrogenase. Calithera Biosciences recently developed a potent GLS inhibitor called CB-839, which is currently in phase I clinical trials in cancer patients. Using isogenic colorectal cancer cell lines with either WT or mutant PIK3CA allele knockout, we demonstrated that CRCs with PIK3CA mutations are more sensitive to growth inhibition by CB-839. Remarkably, combination of CB-839 with 5-FU induces regression xenograft tumors from a CRC with a PIK3CA mutation, suggesting that this combinational therapy may be effective approach to treat CRC patients whose tumors harbor PIK3CA mutations. Mechanistically, mutant p110α up-regulates gene expression of glutamate pyruvate transaminase 2 (GPT2) in CRC cells, thereby facilitate conversion of glutamate to α-KG. Using [13C5-]glutamine isotope-tracing technology, we showed that PIK3CA mutant CRCs produce more α-KG from glutamine to α-KG to replenish the tricarboxylic acid (TCA) cycle to generate ATP. Moreover, aminooxyacetate, which inhibits enzymatic activity of transaminases including GPT2, suppresses xenograft tumor growth of CRCs with PIK3CA mutations, but not CRCs with WT PIK3CA. Mutant p110α up-regulates the transcription of GPT2 through an AKT-independent PDK1-RSK2-ATF4 signaling axis. We showed that ATF4 is a transcription factor that activates GPT2 gene expression. We further demonstrated that mutant p110α activates RSK2 kinase through PDK1. Activated RSK2 then phosphorylates ATF4 at the serine residue 245, which in turn recruits deubiquitinase USP8 and protects ATF4 from ubiquitin-mediated degradation. Together, our data establish oncogenic PIK3CA mutations as a cause of glutamine addiction in CRCs and that targeting glutamine metabolism may be effective approach to treat CRCs with PIK3CA mutations. Citation Format: Zhenghe John Wang, Yujun Hao. Targeting glutamine metabolism in colorectal cancers with PIK3CA mutations. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C115.
Beyond standard anti-dementia therapies: diet, exercise, socialization, and supplements.

Several lines of evidence point to lifestyle choices that may improve brain health. Genetic factors are important to the process of aging, especially as it relates to vulnerability to Alzheimer’s disease (AD), but non-genetic factors clearly have a role as well. This paper highlights studies suggesting that diet, exercise, socialization, and supplements may protect the brain from age-related decline.Observational evidence has indicated that several dietary practices can help maintain the health of one’s brain. The first such practice is to moderate one’s caloric intake. Illnesses related to obesity, such as diabetes, hypertension, and high cholesterol, are associated with poorer brain health. The second is to increase one’s intake of antioxidant foods, such as fresh fruits, and vegetables. The third is to increase intake of foods rich in omega-3 fatty acids, such as fish and olive oil. These fats in the diet may be associated with lower risk of dementia. Finally, consuming low glycemic-index carbohydrates instead of high glycemic-index carbohydrates, which spike blood sugar levels and are associated with higher risk of type 2 diabetes, may benefit the brain.Many studies have been conducted on the connection between a lower risk for AD and healthy diet. While there are not much data from randomized-controlled trials, epidemiologic studies support the theory that diet can have an impact on vulnerability to AD.
Effect of Project Management Practices on Project Success in Make-to-Order Manufacturing Organizations

Background/Objectives: Engineering organizations operating on Make-to-Order projects have a specific work environment where an integration of manufacturing practices with the project management practices is needed for project success. The aim of this research is to analyse the Project Management Practices. Methods/Statistical Analysis: Engineering organizations operating on Make-to-Order projects have a specific work environment where an integration of manufacturing practices with the project management practices is needed for project success. The Project Management practices evaluated are Project Scope Management, Project HR Management, Project Communications Management, Project Stakeholder Management and Project Planning. The effect of these Project Management Practices is analysed on Project Success. Various statistical tools were employed to validate the hypotheses. Findings: The aim of this research is to analyse the Project Management Practices adopted by engineering organizations operating on Make-to-Order projects both for public sector and private sector manufacturing organizations of Pakistan. The proposed results provide realistic analysis and are quite different from previous research works. Using the suggested techniques, the performance of the organization can be improved. The analyses and results point out that Project Success is directly correlated with Project Management Practices in Make-to-Order manufacturing organizations. The Private sector and Public sector organizations primarily implement the Project Management Practices to the same extent and there is no significant difference in the practices being put into practice by them. Application/Improvements: The suggested work is more suitable in small and large scale organization.
Protein Kinase C Signaling in Adenoviral Infection

Activation of protein kinase C (PKC), a serine/threonine protein kinase, ubiquitously influences cellular signal transduction and has been shown to play a role in viral entry. In this study, we explored a role for PKC in human adenovirus type 37 infection of primary human corneal fibroblasts, a major target cell for infection. We sought evidence for an interaction between PKC activation and two potential downstream targets: cSrc kinase, shown previously to play a critical role in adenovirus signaling in these cells, and caveolin-1, reported earlier to be important to entry of adenovirus type 37. Infection of fibroblasts increased PKCα phosphorylation and translocation of PKCα from the cytosol to caveolin-1 containing vesicles. Virus-induced phosphorylation of both cSrc and AKT was abolished in cell lysates pretreated with calphostin C, a chemical inhibitor of PKC. Inhibition of PKC also reduced virus associated phosphorylation of caveolin-1, while inhibition of cSrc by the chemical inhibitor PP2 reduced only caveolin-1 phosphorylation, but not PKCα phosphorylation, in lipid rafts. These results suggest a role for PKCα upstream to both cSrc and caveolin-1. Phosphorylated PKCα was found in the same endosomal fractions as phosphorylated cSrc, and PKCα was present to a greater degree in caveolin-1 pull downs from virus infected than mock infected cell lysates. Calphostin C also reduced early viral gene expression, indicating that PKCα activity may be required for viral entry. PKCα plays a central role in adenovirus infection of corneal fibroblasts and regulation of downstream molecules, including the important lipid raft component caveolin-1.
Follow YOUR Heart: development of an evidence-based campaign empowering older women with HIV to participate in a large-scale cardiovascular disease prevention trial.

Background: Women’s under-representation in HIV and cardiovascular disease (CVD) research suggests a need for novel strategies to ensure robust representation of women in HIV-associated CVD research.Objective: To elicit perspectives on CVD research participation among a community-sample of women with or at risk for HIV, and to apply acquired insights toward the development of an evidence-based campaign empowering older women with HIV to participate in a large-scale CVD prevention trial.Methods: In a community-based setting, we surveyed 40 women with or at risk for HIV about factors which might facilitate or impede engagement in CVD research. We applied insights derived from these surveys into the development of the Follow YOUR Heart campaign, educating women about HIV-associated CVD and empowering them to learn more about a multi-site HIV-associated CVD prevention trial: REPRIEVE.Results: Endorsed best methods for learning about a CVD research study included peer-to-peer communication (54%), provider comm...
"Madness Is Contagious": Language and Violence in the Goodman Theatre's 2666

A marathon adaptation of Roberto Bolano's epic novel 2666 at Chicago's Goodman Theatre revealed how the act of artistic creation has become implicated in the global machinery of political violence. Repeated throughout the five-hour play, the refrain "madness is contagious" seems to permeate 2666 like the stench of a body left to decompose on the side of a road.
The Mathematics of Optimization

In “Introduction to Optimization Models” (UVA-QA-0682), we explored the basics of using optimization models, or mathematical programming. In this technical note, we turn our attention to the mathematics underlying optimization. While not essential, a deeper understanding of the math can help you become a significantly more effective and efficient user of optimization models. It is well worth the investment if you anticipate using optimization on a regular basis. Among other things, a deeper understanding of the math enables you to use the more advanced options that are generally available in most optimization software packages. (These options enable you, for example, to solve large models more quickly than you otherwise might.) Excerpt UVA-QA-0683 March 29, 2010 The Mathematics of Optimization In “Introduction to Optimization Models” (UVA-QA-0682), we explored the basics of using optimization models, or mathematical programming. In this technical note, we turn our attention to the mathematics underlying optimization. While not essential, adeeper understanding of the math can help you become a significantly more effective and efficient user of optimization models. It is well worth the investment if you anticipate using optimization on a regular basis. Among other things, a deeper understanding of the math enables you to use the more advanced options that are generally available in most optimization software packages. (These options enable you, for example, to solve large models more quickly than you otherwise might.) In “Introduction to Optimization Models,” we used the language of the spreadsheet to describe, build, and solve optimization models. This was useful because the spreadsheet is clearly the preferred medium for implementing quantitative business analysis of all kinds, including math programming. In this note, however, we will draw heavily on the language of algebra, particularly graphs. This was the original language of optimization models and will help us deal with some of the more technical issues. We begin by considering the algebraic statement of optimization models. Using algebra, it is easy to distinguish between the three different categories of optimization models explored in “Introduction to Optimization Models”—nonlinear, linear, and integer. We then devote a section apiece to the most commonly encountered solution techniques for each category of the program. (Remember: “Solving” an optimization model means finding an optimal solution.) Most advanced options in optimization software packages are levers that allow you to direct and control the solution procedures for the various categories of problems. Understanding the solution techniques enables you to control the levers. . . .
Theories of Toileting

Few other developmental concerns trigger as much stress in parents as toileting difficulties. Many questions have been raised and even more opinions have been given regarding how children can be better assisted in the process of toilet training. Numerous treatments and interventions emerged targeting different hypothesized underlying mechanisms of toileting. Upon reviewing the existing literature, proposed theories regarding the etiology of eliminative disturbances can be divided into three categories. Behavioral theories focus on the learning process of appropriate toileting behaviors and are mainly composed of classical and operant conditioning. The second category provides physiological and biochemical explanations through the discussion of the functions of relevant muscle, nervous, and endocrine systems; damages or abnormalities in these systems may contribute to elimination difficulties. Third, hypotheses were also made regarding the associations between psychological disturbances and incontinence due to the high comorbid rates. However, it is not clear at this time whether or not a causal relationship exists. This chapter will cover these three theoretical models along with corresponding empirical evidence.
Prevention and Treatment of Thrombotic and Hemorrhagic Complications in Patients Supported by Continuous-Flow Left Ventricular Assist Devices

The purpose of this review is to describe the current knowledge in prevention and treatment of thrombotic (pump thrombosis and ischemic stroke) and bleeding (gastrointestinal and hemorrhagic stroke) complications in patients supported by continuous-flow left ventricular assist devices (CF-LVAD). Left ventricular assist devices (LVADs) are now widely used for the management of end-stage heart failure. Unfortunately, in spite of the indisputable positive impact LVADs have on patients, the frequency and severity of complications are limitations of this therapy. Stroke, pump thrombosis, and gastrointestinal bleeding are among the most serious and frequent complications in these patients. The balance between hemorrhagic and thrombotic complications in patients supported with CF-LVAD is difficult as most patients do not necessarily fit a “bleeder” or a “clotter” profile but rather move from one side to the other of the thrombotic/bleeding spectrum. Further research is necessary to better understand the risk factors and mechanisms involved in the development of these complications.
Looks Like Me, Sounds Like Me! Race, Culture, and Language in the Creation of Digital Media

The technology education movement includes the introduction and application of digital books into science classrooms. These digital books are attractive alternatives to traditional texts because th...
Signatures of a quantum diffusion limited hydrogen atom tunneling reaction

We are studying the details of hydrogen atom (H atom) quantum diffusion in highly enriched parahydrogen (pH2) quantum solids doped with chemical species in an effort to better understand H atom transport and reactivity under these conditions. In this work we present kinetic studies of the 193 nm photo-induced chemistry of methanol (CH3OH) isolated in solid pH2. Short-term irradiation of CH3OH at 1.8 K readily produces CH2O and CO which we detect using FTIR spectroscopy. The in situ photochemistry also produces CH3O and H atoms which we can infer from the post-photolysis reaction kinetics that display significant CH2OH growth. The CH2OH growth kinetics indicate at least three separate tunneling reactions contribute; (i) reactions of photoproduced CH3O with the pH2 host, (ii) H atom reactions with the CH2O photofragment, and (iii) long-range migration of H atoms and reaction with CH3OH. We assign the rapid CH2OH growth to the following CH3O + H2 → CH3OH + H → CH2OH + H2 two-step sequential tunneling mechanism by conducting analogous kinetic measurements using deuterated methanol (CD3OD). By performing photolysis experiments at 1.8 and 4.3 K, we show the post-photolysis reaction kinetics change qualitatively over this small temperature range. We use this qualitative change in the reaction kinetics with temperature to identify reactions that are quantum diffusion limited. While these results are specific to the conditions that exist in pH2 quantum solids, they have direct implications on the analogous low temperature H atom tunneling reactions that occur on metal surfaces and on interstellar grains.
The Influence of Ibsen and Hauptmann

So much has been made of claims of foreign influences on Heijermans, that it seems desirable to accumulate all the evidence in one chapter, where it can be examined in detail and put aside once and for all. Most of these claims of influence turn out to have no solid foundation in fact, but there does remain some evidence that Heijermans at times drew inspiration from his two most influential contemporaries. Thus, aside from the effect of Tolstoi through The Power of Darkness,the only playwrights who may be said to have exerted any direct influence on him are Ibsen and Hauptmann.
Co-Occurrence Cluster Features for Lexical Substitutions in Context

This paper examines the influence of features based on clusters of co-occurrences for supervised Word Sense Disambiguation and Lexical Substitution. Co-occurrence cluster features are derived from clustering the local neighborhood of a target word in a co-occurrence graph based on a corpus in a completely unsupervised fashion. Clusters can be assigned in context and are used as features in a supervised WSD system. Experiments fitting a strong baseline system with these additional features are conducted on two datasets, showing improvements. Co-occurrence features are a simple way to mimic Topic Signatures (Martinez et al., 2008) without needing to construct resources manually. Further, a system is described that produces lexical substitutions in context with very high precision.
Effect of Plastic Anisotropy on Drawing Characteristics of Aluminum Alloy Sheet

The production of annealed tempers of commercial aluminum alloy sheet for deep drawing applications has been aimed at providing three characteristics: good drawability, a fine grain size, and minimum earing tendencies. The latter property is one manifestation of anisotropy for which control is attempted by means of fabricating practices designed to balance annealing and rolling crystallographic textures.
Folk-economic beliefs as moral intuitions.

Although Boyer & Petersen's (B&P's) cataloguing of and evolutionary explanations for folk-economic beliefs is important and valuable, the authors fail to connect their theories to existing explanations for why people do not think like economists. For instance, people often have moral intuitions akin to principles of fairness and justice that conflict with utilitarian approaches to resource allocation.
Postcolonial perspectives on weapons control

Several months ago, I received an invitation from the editorial board of the Asian Journal of Political Science to serve as a guest editor for a special issue of this journal. This unexpected invit...
The complexity of bank regulation: audit requirements in the USA

We use requirements governing external audits in the US banking industry as a case study to illustrate the complexity of regulatory structure. Complexity reflects a flexibility that has been used to “tailor” regulations for particular categories of banks. But it appears to conflict with recent proposals to “rationalize” a system that is said to lack coherence.
A Noise-resilient Detection Method against Advanced Cache Timing Channel Attack

Recent researches show that computers which are physically shared by multiple users are vulnerable to microarchitecture-based information leakage. Among all microarchitecture components, cache provides the largest attack surface. Cache timing channels manipulate the cache access latency to leak information leaving no physical trace. To mitigate cache timing channels, various detection methods are proposed. However, with the knowledge of existing detection methods, an advanced adversary can intentionally inject noise to evade detection. For example, the detection based on correlation method which extracts the repetitive behavior of cache timing channels can be evaded by randomizing the gap between information transmitting and receiving activity. The classification based detection would be obfuscated if adversary imitate the behavior of benign applications. We propose a novel noise-resilient detection method which focuses on the dependency between behavior of two processes. For each process, we define a group of events and track the conditional probability of every event given the appearance of the events from another process. With this method, we are able to detect the existence of cache timing channels. Our detection method is hard to evade because the dependency of cache behavior is necessary for any communication through cache timing channels.
Novel parent-of-origin-specific differentially methylated loci on chromosome 16

Congenital malformations associated with maternal uniparental disomy of chromosome 16, upd(16)mat, resemble those observed in newborns with the lethal developmental lung disease, alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Interestingly, ACDMPV-causative deletions, involving FOXF1 or its lung-specific upstream enhancer at 16q24.1, arise almost exclusively on the maternally inherited chromosome 16. Given the phenotypic similarities between upd(16)mat and ACDMPV, together with parental allelic bias in ACDMPV, we hypothesized that there may be unknown imprinted loci mapping to chromosome 16 that become functionally unmasked by chromosomal structural variants. To identify parent-of-origin biased DNA methylation, we performed high-resolution bisulfite sequencing of chromosome 16 on peripheral blood and cultured skin fibroblasts from individuals with maternal or paternal upd(16) as well as lung tissue from patients with ACDMPV-causative 16q24.1 deletions and a normal control. We identified 22 differentially methylated regions (DMRs) with ≥ 5 consecutive CpG methylation sites and varying tissue-specificity, including the known DMRs associated with the established imprinted gene ZNF597 and DMRs supporting maternal methylation of PRR25, thought to be paternally expressed in lymphoblastoid cells. Lastly, we found evidence of paternal methylation on 16q24.1 near LINC01082 mapping to the FOXF1 enhancer. Using high-resolution bisulfite sequencing to evaluate DNA methylation across chromosome 16, we found evidence for novel candidate imprinted loci on chromosome 16 that would not be evident in array-based assays and could contribute to the birth defects observed in patients with upd(16)mat or in ACDMPV.
Pain, Opioid Use, and Palliative Care of Older Adults in the Emergency Department

An 82-year-old female with history of advanced breast cancer was brought to the emergency department with uncontrolled back pain secondary to metastatic disease. She was recently admitted for evaluation and management of her back pain but since discharge has been struggling to improve her strength and functional status at a subacute nursing facility. This case highlights how malignant pain can be rapidly and effectively controlled as well as how the emergency medicine clinicians can help support patient’s palliative care needs including exploring of goals of care.
Vincristine and bortezomib use distinct upstream mechanisms to activate a common SARM1-dependent axon degeneration program

Chemotherapy-induced peripheral neuropathy is one of the most prevalent dose-limiting toxicities of anticancer therapy. Development of effective therapies to prevent chemotherapy-induced neuropathies could be enabled by a mechanistic understanding of axonal breakdown following exposure to neuropathy-causing agents. Here, we reveal the molecular mechanisms underlying axon degeneration induced by 2 widely used chemotherapeutic agents with distinct mechanisms of action: vincristine and bortezomib. We showed previously that genetic deletion of SARM1 blocks vincristine-induced neuropathy and demonstrate here that it also prevents axon destruction following administration of bortezomib in vitro and in vivo. Using cultured neurons, we found that vincristine and bortezomib converge on a core axon degeneration program consisting of nicotinamide mononucleotide NMNAT2, SARM1, and loss of NAD+ but engage different upstream mechanisms that closely resemble Wallerian degeneration after vincristine and apoptosis after bortezomib. We could inhibit the final common axon destruction pathway by preserving axonal NAD+ levels or expressing a candidate gene therapeutic that inhibits SARM1 in vitro. We suggest that these approaches may lead to therapies for vincristine- and bortezomib-induced neuropathies and possibly other forms of peripheral neuropathy.
Predictors of benefits from frontline chemoimmunotherapy in stage IV non-small-cell lung cancer: a meta-analysis

Background: Immune checkpoint inhibitors (ICIs) have dramatically expanded the therapeutic landscape of non-small-cell lung cancer (NSCLC). In a previous study, gender, smoking history, and PD-L1 status were found to influence the efficacy of single-agent ICI in NSCLC. This meta-analysis evaluated the clinical and molecular factors that could predict a benefit from adding ICIs to first-line chemotherapy in metastatic NSCLC. Patients and Methods: The pooled hazard ratio (HR) of progression-free survival (PFS) and overall survival (OS) among the selected subgroups were analyzed using the random effects model. The correlation between PD-L1 expression and outcome was analyzed by meta-regression. Results: Seven phase III randomized controlled trials comparing chemo-immunotherapy (CIT) with chemotherapy in untreated stage 4 NSCLC were included. CIT evenly improved PFS irrespective of age, gender, histology, smoking history, and performance status. Among patients with baseline hepatic metastasis treated with Atezolizumab-containing CIT, PFS improvement was only detected with the addition of Bevacizumab. Whereas patients with EGFR/ALK-driven cancer exhibited greater PFS with the addition of ICI to a Bevacizumab (BEV)-based regimen, the derived benefit was no longer statistically significant among those treated with non-BEV-based regimens. Although the superior PFS conferred by CIT was noticeable across all PD-L1 expression subgroups, this benefit correlated with PD-L1 level and was more pronounced in the "PD-L1 high" cohort. Except for patients harboring EGFR/ALK aberrations or squamous histology, CIT consistently improved OS across the other selected subgroups. Conclusions: The survival advantage associated with first-line CIT in metastatic NSCLC was observed in different patient populations, including those for which single-agent ICI has marginal therapeutic benefit. Our findings support the role of chemotherapy with or without VEGF blockade as enhancers of ICI activity in NSCLC.
Abstract WP437: Where Are We Located Now With Artificial Neural Network? Application of Deep Learning for the Development of Culturally Sensitive Social Support Interventions for Dementia Caregivers

Introduction: Little is known about culturally sensitive interventions for Hispanic and African American family caregivers for persons living with vascular dementia. Applications of deep-learning n...
Recent Advances in the Treatment of Sickle Cell Disease

Sickle cell anemia (SCA) was first described in the Western literature more than 100 years ago. Elucidation of its molecular basis prompted numerous biochemical and genetic studies that have contributed to a better understanding of its pathophysiology. Unfortunately, the translation of such knowledge into developing treatments has been disproportionately slow and elusive. In the last 10 years, discovery of BCL11A, a major γ-globin gene repressor, has led to a better understanding of the switch from fetal to adult hemoglobin and a resurgence of efforts on exploring pharmacological and genetic/genomic approaches for reactivating fetal hemoglobin as possible therapeutic options. Alongside therapeutic reactivation of fetal hemoglobin, further understanding of stem cell transplantation and mixed chimerism as well as gene editing, and genomics have yielded very encouraging outcomes. Other advances have contributed to the FDA approval of three new medications in 2017 and 2019 for management of sickle cell disease, with several other drugs currently under development. In this review, we will focus on the most important advances in the last decade.
Assessing the Advanced Placement Program in American Politics

The Advanced Placement (AP) program has been growing rapidly in the last decade. In 1987, a new AP program was begun in American Government and Politics and its impact is beginning to be felt in high schools and colleges across the country. However, there has been no objective assessment of the program communicated and discussed throughout the political science community.To begin—what is the AP program? The Advanced Placement program offers the equivalent of introductory college courses which may lead to college credit upon satisfactory performance on an AP exam. The AP program is administered by the College Board which contracts with the Educational Testing Service (ETS) to operate the AP examinations. “About 31 percent of American secondary schools currently participate, serving approximately 17 percent of their college-bound students in this way. This use, by both schools and students, has been growing steadily in recent years” (Guide to the AP Program, 1986, p. 4).The College Board highlights the positive aspects of the AP program for learning, education, and all concerned—students, teachers, and administrators. AP programs are considered part of society's effort to revitalize the educational system in the United States, especially in high schools and higher education. The quality and implications of the AP program are all positively portrayed. Yet, the implementation of the AP program has not been closely examined and publicly discussed.
Shocks and the spatial distribution of economic activity: The role of institutions

Abstract Why do some historical shocks permanently impact local development, while others do not? This paper examines how institutions influence local recovery to population shocks, using a model with multiple regions and increasing returns to economic activity within regions. Extractive institutions crowd out productive activity, making its spatial coordination more difficult in the aftermath of large, negative shocks. Hence, when one region experiences such a shock, extractive institutions can hinder recovery, ensuring a redistribution of productive activity away from that region over the long-run. Using a dataset of major earthquakes and 1860 world cities from 1973 to 2018, I find sustained negative effects of earthquakes on city population growth, with effects being driven by cities located outside of stable democracies, consistent with the theory.
Oligophrenin-1 moderates behavioral responses to stress by regulating parvalbumin interneuron activity in the medial prefrontal cortex

Ample evidence indicates that individuals with intellectual disability (ID) are at increased risk of developing stress-related behavioral problems and mood disorders, yet a mechanistic explanation for such a link remains largely elusive. Here, we focused on characterizing the syndromic ID gene oligophrenin-1 (OPHN1). We find that Ophn1 deficiency in mice markedly enhances helpless/depressive-like behavior in the face of repeated/uncontrollable stress. Strikingly, Ophn1 deletion exclusively in parvalbumin (PV) interneurons in the prelimbic medial prefrontal cortex (PL-mPFC) is sufficient to induce helplessness. This behavioral phenotype is mediated by a diminished excitatory drive onto Ophn1-deficient PL-mPFC PV interneurons, leading to hyperactivity in this region. Importantly, suppressing neuronal activity or RhoA/Rho-kinase signaling in the PL-mPFC reverses helpless behavior. Our results identify OPHN1 as a critical regulator of adaptive behavioral responses to stress and shed light onto the mechanistic links among OPHN1 genetic deficits, mPFC circuit dysfunction, and abnormalities in stress-related behaviors.
Multiorgan failure in a fatal case of autoimmune hemolytic anemia.

Background Autoimmune hemolytic anemia (AIHA) results in red blood cell destruction by auto-antibodies directed against surface antigens and is rarely fatal. Here we describe a case of AIHA, refractory to both standard and experimental therapies, complicated by multiorgan failure, and rapidly leading to death. Case report and results A 65 year-old man who presented with progressive dyspnea and jaundice was found to have hemolytic anemia. Diagnostic work-up revealed a positive direct antiglobulin test and a strong pan-reactive antibody in the plasma reacting to a titer of 1:1024 with strongest reactivity at 37 °C Coombs' phase with reagent anti-IgG. The red cell eluate contained a pan-agglutinin. The patient received multiple lines of treatment including glucocorticoids, intravenous immunoglobulin, rituximab, eculizumab, splenectomy and etoposide. Despite these interventions, he continued to experience brisk hemolysis and remained transfusion dependent. Repeat testing on day 16 demonstrated persistent high titer IgG auto-antibodies, suggesting minimal suppressive effect of therapy. His course was complicated by acute renal and liver failure, venous thrombosis, and worsening coagulopathy, and he ultimately died from multiorgan failure on day 18. Conclusion Severe cases of AIHA can result in multiorgan failure and a fatal outcome. The rapid development of liver failure in this setting has been described in only few case reports to date, and represents an important complication for clinicians to be aware of when treating patients with AIHA.
Health Information Beyond Pandemic Emergencies: Privacy for Social Justice

Moving beyond notice and choice is necessary if data are to be used responsibly for public health. But what directions might this movement take? Transparency and enactment of statutory limits on data uses are the two most prominent possibilities. Transparency could require entities collecting, possessing and using information drawn from more than a specified number of individuals to make public disclosures of their information collection, possession, and use. There are models for developing such transparency requirements. The California CPPA could provide a model for delineating the size of entities required to make such disclosures. The requirements to disclose the results of federally funded research could provide a model for the form disclosures could take. The Native American Graves Protection and Repatriation Act (NAGPRA) could provide a model for how making information available could enable watchdog groups or groups with particular interest to call attention to particular forms of data protection and use. Prohibition of certain forms of data collection and use is both more drastic and more problematic. The observation that over-regulation may lead to under-regulation is common. Although there are models of prohibition, in particular GINA and the ADA, these models are limited in scope and of limited efficacy because they can be avoided in so many ways. At present, moreover, our knowledge of the universe of data use and the impacts of these uses is woefully incomplete. Required transparency about data collection, possession, and use may be a needed initial step to increase public discussion about the benefits and burdens of data use, including its use in pandemic emergencies. Notice and choice is a move in the wrong direction for the evolution of data use in pandemics.
Effects of rTMS on Behavioral and Electrocortical Measures of Error Monitoring and Correction Function in Children with Autism Spectrum Disorder

Error monitoring and correction is one of the executive functions and is important for effective goal-directed behavior. Deficient executive functioning, including reduced error monitoring ability, is one of the typical features of such neurodevelopmental disorders as autism spectrum disorder (ASD), probably related to perseverative responding, stereotyped repetitive behaviors, and an inability to accurately monitor ongoing behavior. Our prior studies of behavioral and event-related potential (ERP) measures during performance on visual oddball tasks in high-functioning autistic children showed that despite only minor differences in reaction times (RT) children with autism committed significantly more errors. The chapter reviews behavioral (reaction time, accuracy, rate of omission and commission errors, post-error reaction time slowing) error monitoring in children with ASD and response-locked event-related potentials (ERP), in particular, the error-related negativity (ERN) and error-related positivity (Pe) recorded at the fronto-central EEG sites. The ERN reflects early error detection processes, whereas the Pe has been associated with later conscious error evaluation and attention reallocation. Our prior studies showed significant differences of behavioral and ERN indices between children with ASD and with ADHD as well as with typical developing peers. The goal of our chapter is to review effects of slow frequency repetitive TMS (rTMS) over dorsolateral prefrontal cortex (DLPFC) in high-functioning children with ASD on behavioral and electrocortical measures found in a series of studies conducted by our group. Our results show significant post-TMS differences in the response-locked ERPs such as ERN, as well as behavioral response-monitoring measures indicative of improved error monitoring and correction function. Our review suggests that TMS has the potential to become a viable therapeutic tool in ASD treatment and may play an important role in improving the quality of life of many children with the disorder. The chapter provides rationale to use ERN and Pe, along with behavioral performance measures as functional outcome measures, to assess the effectiveness of neuromodulation (e.g., rTMS and rTMS combined with neurofeedback) in children with autism, and thus, may have important practical implications.
Metalloproteases in gonad formation and ovulation

Changes in expression or activation of various metalloproteases including matrix metalloproteases (Mmp), a disintegrin and metalloprotease (Adam) and a disintegrin and metalloprotease with thrombospondin motif (Adamts), and their endogenous inhibitors (tissue inhibitors of metalloproteases, Timp), have been shown to be critical for ovulation in various species from studies in past decades. Some of these metalloproteases such as Adamts1, Adamts9, Mmp2, and Mmp9 have also been shown to be regulated by luteinizing hormone (LH) and/or progestin, which are essential triggers for ovulation in all vertebrate species. Most of these metalloproteases also express broadly in various tissues and cells including germ cells and somatic gonad cells. Thus, metalloproteases likely play roles in gonad formation processes comprising primordial germ cell (PGC) migration, development of germ and somatic cells, and sex determination. However, our knowledge on the functions and mechanisms of metalloproteases in these processes in vertebrates is still lacking. This review will summarize our current knowledge on the metalloproteases in ovulation and gonad formation with emphasis on PGC migration and germ cell development.
Fluorescence Imaging of Mitochondrial DNA Base Excision Repair Reveals Dynamics of Oxidative Stress Responses.

Mitochondrial function in cells declines with aging and with neurodegeneration, due in large part to accumulated mutations in mitochondrial DNA (mtDNA) that arise from deficient DNA repair. However, measuring this repair activity is challenging. Here we employ a molecular approach for visualizing mitochondrial base excision repair (BER) activity in situ by use of a fluorescent probe ( UBER ) that reacts rapidly with AP sites resulting from BER activity. Administering the probe to cultured cells revealed signals that were localized to mitochondria, enabling selective observation of mtDNA BER intermediates. The probe showed elevated DNA repair activity under oxidative stress, and responded to suppression of glycosylase activity. Furthermore, the probe illuminated the time lag between the initiation of oxidative stress and the initial step of BER. Absence of MTH1 in cells resulted in elevated demand for BER activity upon extended oxidative stress, while the absence of OGG1 activity limited glycosylation capacity.
Enhancement of the Lethal Effects of Endotoxins by Interferon Inducers

Abstract Prior treatment of mice with poly I:C or NDV enhanced the lethal effect of E. coli or B. dermatitidis endotoxins.
Lesbian, Gay, Bisexual, and Transgender (LGBT) Content Representation on the Psychiatry Resident In-Training Examination, 2009–2013

This article explores the extent to which lesbian, gay, bisexual, or transgender (LGBT) content is included in the Psychiatry Residency in Training Exam (PRITE®) questions and how these rates compare with other specialized topics. Five PRITE in-training examinations from 2009–2013 were reviewed for questions relating to LGBT issues, trauma and abuse, pregnancy and postpartum, and religion and culture. Totals for each category were tabulated and compared with each other and to the total number of questions (300 questions for each year analyzed). The LGBT category had the fewest number of questions of the categories examined. Out of a total of 1,500 questions over five years, three question stems or answer choices had LGBT content. This is an average of less than one item per year (out of 300 questions). Given the increased national attention devoted to improving health care disparities for sexual minorities, increased coverage of this topic in the residency education examination in psychiatry appears to be...
2D-affine invariants that distribute uniformly and can be tuned to any convex feature domain

We derive and discuss a set of parametric equations which, when given a convex 2D feature domain, K, will generate affine invariants with the property that the invariants' values are uniformly distributed in the region [0,1]/spl times/[0,1]. Definition of the shape of the convex domain K allows computation of the parameters' values and thus the proposed scheme can be tuned to a specific feature domain. The features of all recognizable objects (models) are assumed to be two-dimensional points and uniformly distributed over K. The scheme leads to improved discrimination power, improved computational-load and storage-load balancing and can also be used to determine and identify biases in the database of recognizable models (over-represented constructs of object points). Obvious enhancements produce rigid-transformation and similarity-transformation invariants with the same good distribution properties, making this approach generally applicable. An extension to the case of affine invariants for feature points in three-dimensional space, with the invariants now being uniformly distributed in the region [0,1]/spl times/[0,1]/spl times/[0,1], has also been carried out and is discussed briefly. We present results for several 2D convex domains using both synthetic data and real databases.
Programmable Energy Ignition System For Engine Optimization

This new ignition system uses inductive-discharge to strike the arc and, together with transformer action, sustains the arc from a single coil for any duration. Its principal features are: (1) programable arc duration, (2) high arc current for full arc period, (3) fast voltage rise, (4) low average battery current drain, (5) no intermediate power supply, and (6) since it uses inductive storage, it can be integrated into present electronic systems if the need is proven. Limited test results are presented to show the effect of arc duration on engine operation. /GMRL/