cssi/SciSciGPT-SciSciNet huggingface dataset:
The Orion Nebula and Its Associated Population

▪ Abstract The Orion Nebula (M 42) is one of the best studied objects in the sky. The advent of multi-wavelength investigations and quantitative high resolution imaging has produced a rapid improvement in our knowledge of what is widely considered the prototype H II region and young galactic cluster. Perhaps uniquely among this class of object, we have a good three dimensional picture of the nebula, which is a thin blister of ionized gas on the front of a giant molecular cloud, and the extremely dense associated cluster. The same processes that produce the nebula also render visible the circumstellar material surrounding many of the pre–main sequence low mass stars, while other circumstellar clouds are seen in silhouette against the nebula. The process of photoevaporation of ionized gas not only determines the structure of the nebula that we see, but is also destroying the circumstellar clouds, presenting a fundamental conundrum about why these clouds still exist.
Progress toward novel treatments for chronic kidney disease.

Chronic kidney failure remains a major health problem worldwide. Although current treatment is focused on the renin–angiotensin system, it is essential that new treatments targeted toward novel pathophysiological mechanisms are developed if we are to make significant progress in this area. In this review, we have outlined several promising new areas while emphasizing that large, randomized, well-controlled clinical trials are essential to reach a meaningful conclusion about the efficacy and safety of novel treatment.
Fault-tolerant clock synchronization in large multicomputer systems

The cost of synchronizing a multicomputer increases with system size. For large multicomputers, the time and resources spent to enable each node to estimate the clock value of every other node in the system can be prohibitive. We show how to reduce the cost of synchronization by assigning each node to one or more groups, then having each node estimate the clock values of only those nodes with which it shares a group. Since each node estimates the clock value of only a subset of the nodes, the cost of synchronization can be significantly reduced. We also provide a method for computing the maximum skew between any two nodes in the multicomputer, and a method for computing the maximum time between synchronizations. We also show how the fault tolerance of the synchronization algorithm may be determined. >
Comparison of Experimental and Real-Time Data in Amateur Boxers

The sport of boxing dates back to the time of the ancient Greeks and Romans. While boxing has come a long way from its origin in fist fighting, head injury is of great concern in the sport of boxing. A study found that over 70% of acute injuries occur in the head region, with almost half of the injuries to this region being concussions [1]. Various techniques have been implemented to discern the risk of head injury in boxing. Although some surrogate data have been collected to assess the mechanism that causes the injuries [2], real-time head acceleration data from the ring has yet to be obtained.Copyright © 2009 by ASME
Multimedia communication over OFDM mobile wireless networks: a cross-layer diversity approach

Diversity can be used to combat multipath fading and improve the performance of mobile wireless multimedia communication systems. In this work, by considering transmission of an embedded bitstream over a slow varying Rayleigh faded environment, we develop a cross-layer diversity technique which takes advantage of both multiple description source coding and frequency diversity techniques. More specifically, assuming a frequency-selective channel, we study the packet loss behavior of an OFDM system and construct multiple independent descriptions using an FEC-based strategy. We demonstrate the superior performance of this approach using the set partitioning in hierarchical trees (SPIHT) coder.
hablamos juntos (together we speak): a brief patient-reported measure of the quality of interpretation

Purpose: This study evaluates the psychometric properties of three newly developed items assessing the quality of interpretation from the patient’s perspective among Spanish-speaking limited English proficient Latino patients. Patients and methods: The authors examined the psychometric properties of a patientreported measure of quality of interpretation using a cross-sectional survey study of 1,590 adult Spanish-speaking limited English proficient Latinos in the United States. Quality of interpreta tion, doctor communication, and satisfaction with care were assessed using a three survey-item, an independent multiple-item measure, and a single-item measure, respectively. Results: Sixty-nine percent (1,104) of patients surveyed used interpreters. Cronbach’s alpha for the three items assessing interpreter quality was 0.31, while dropping item three resulted in an alpha of 0.56. Items one and two were moderately correlated with doctor communication (r=0.39) and satisfaction with care scores (r=0.21) supporting construct validity. Conclusion: Two out of three survey items can be scaled to measure quality of interpretation from the patient’s perspective. Quality of interpretation reported by patients is moderately associated with doctor communication and satisfaction with care.
Hepcidin induces HIV-1 transcription inhibited by ferroportin

Physiological regulation of cellular iron involves iron export by the membrane protein, ferroportin, the expression of which is induced by iron and negatively modulated by hepcidin. We previously showed that iron chelation is associated with decreased HIV-1 transcription. We hypothesized that increased iron export by ferroportin might be associated with decreased HIV-1 transcription, and degradation of ferroportin by hepcidin might in turn induce HIV-1 transcription and replication. Here, we analyzed the effect of ferroportin and hepcidin on HIV-1 transcription. Expression of ferroportin was associated with reduced HIV-1 transcription in 293T cells and addition of hepcidin to ferroportin-expressing cells counteracted this effect. Furthermore, exposure of promonocytic THP-1 cells to hepcidin was associated with decreased ferroportin expression, increased intracellular iron and induction of reporter luciferase gene expression. Finally, exposure of human primary macrophages and CD4+ T cells to hepcidin and iron was also associated with induction of viral production. Our results suggest that the interplay between ferroportin-mediated iron export and hepcidin-mediated degradation of ferroportin might play a role in the regulation of HIV-1 transcription and may be important for understanding of HIV-1 pathogenesis.
Engineering as a political activity

Because the practice of engineering authoritatively reshapes the world, it deserves to be seen as a public and political activity. If technology is a form of legislation, are engineers the legislators or do they occupy some other political role? Because engineering in the 20th century has served some social interests much better than others, might those who have been disadvantaged reasonably construe engineers as their political opponents? What constraints face engineers individually and collectively in attempting to reconsider and retarget beliefs and actions bearing on their work as technological decision makers?.
Ancient default activators of terminal photoreceptor differentiation in the pancrustacean compound eye: the homeodomain transcription factors Otd and Pph13

The origin of the Drosophila compound eye predates the ancestor of Pancrustacea, the arthropod clade that includes insects and Crustaceans. Recent studies in emerging model systems for pancrustacean development-the red flour beetle Tribolium castaneum and water flea Daphnia pulex-have begun to shed light on the evolutionary conservation of transcriptional mechanisms found for the Drosophila compound eye. Here, we discuss the conserved roles of the transcription factors Otd and Pph13, which complement each other in two terminal events of photoreceptor differentiation: rhabdomere morphogenesis and transcriptional default activation of opsin gene expression. The synthesis of these data allows us to frame an evolutionary developmental model of the earliest events that generated the wavelength-specific photoreceptor subtypes of pancrustacean compound eyes.
Medium Effects in Biologically Related Catalysis

Abstract Enzymes catalyze chemical reaction in aqueous media, but their active sites significantly differ in properties from water. In this chapter, the work on selected chemical reactions with important biological roles is reviewed to assess our current understanding of the effect of the environment that surrounds the reactive species. In particular, simple medium effects such as the ones provided by organic solvents, ionic liquids, and simple micelles are focused on. The findings that led to the computational design of enzymes that catalyze the Kemp elimination, a prototypical proton transfer reaction that has fascinated researchers for more than a century, are discussed.
Cancer Patients and Skin Disease

Cancer patients are in the unique position for immune diseases. Their malignancy tends to be immunosuppressive and the therapies used to treat their cancer further compromises their immune systems. Newer therapies complicate the immunity further by acting to accentuate the immune response. The skin is not left out of these immunologic crises, and this chapter will review how the skin responds in a crucial way to lead the doctor to suspect underlying cancer.
Education of Health Professionals

Interest in aging is probably as old as human self-reflection, but the body of published work on geriatrics education for physicians and other health care professionals in training is quite young. When geriatric medicine emerged as a distinct focus of medical study and practice in the twentieth century, it became necessary to define the body of knowledge and the education needed to prepare both clinicians and faculty for practice and research. In the mid-1970s, the American Geriatrics Society (AGS) led this effort through two national conferences that represented “the first major attempt at clarifying alternative models and strategies in relation to geriatric education” (1). The conference chose “not to recommend a new Board-certified specialty” but to suggest fellowship-level geriatrics-specific training in appropriate specialties, along with the infusion of geriatrics into undergraduate medical education, faculty development, and continuing medical education. These recommendations were supported by the Institute on Medicine and multiple specialty societies (2) and continue to shape geriatrics education.
Competence- and Integrity-Based Trust in Interorganizational Relationships: Which Matters More?:

Trust is an important factor for managing transaction costs within interorganizational relationships (IORs). Research on trust indicates that separate dimensions of trust arise from a partner’s competence (i.e., technical skills, experience, and reliability) and integrity (i.e., motives, honesty, and character), and that these dimensions have potentially unique effects. Because scholars rarely apply this distinction within IOR research, past studies may have masked important relationships involving competence- and integrity-based trust. In response, we build and test theory that explains how competence- and integrity-based trust have asymmetric effects on different kinds of transaction costs. In particular, we build on theory that describes how parties process positive and negative information about others’ behavior to predict that integrity-based trust in IORs is more potent for reducing transaction costs than is competence-based trust. We also theorize that building strong IORs requires more up-front in...
Barriers to cardiovascular disease risk reduction: Does physicians’ perspective matter?

Abstract Background Cardiovascular disease (CVD) is emerging as a major epidemic and the leading cause of death and disability in India. This study is an attempt to understand the barriers and challenges faced by physicians in CVD risk reduction in a rural setting. Methods The study was conducted among 34 physicians across six randomly selected villages of Bangalore Rural District. Convergent parallel design was used to combine the strengths of qualitative and quantitative approaches to develop a stronger understanding of the experiences and challenges of practicing physicians in reducing the risk of CVD in this region. After concurrently collecting the data, rigorous procedures for both quantitative and qualitative methods were used independently and then merged to provide an enhanced understanding of the research question. Results Lack of knowledge and understanding of the disease, myths and beliefs, attitude of the patients, non-adherence to lifestyle changes and medications, the chronic nature of the disease, financial constraints, and lack of national guidelines were identified as the major barriers. Conclusion This study highlights the challenges faced by physicians in dealing with the increasing number of patients presenting with CVD risk factors in rural areas. It also suggests options that could minimize these barriers, enabling them to manage their patients with CVD risk in the best way possible. It is critical to institute guidelines and algorithms to manage these risk factors in the rural Indian context.
The Mythological Geography of California: Origins, Development, Confirmation and Disappearance

Heir to Greek and Roman culture, the revelations of Holy Scripture and the great commentaries upon it written by Saint Augustine, Saint Thomas Aquinas, John Duns Scotus, and lesser theologians and philosophers of the Middle Ages, the cultured European of the fifteenth century was content that the corpus of his knowledge was complete, and that within it was all that was necessary for a full understanding of the universe. Nevertheless, this satisfaction was greatly upset by the explorations of Christopher Columbus and his followers during the final decade of the century. The European discovery of extensive lands populated with theretofore unknown peoples, with a flora and fauna totally distinct from that of Europe, was, in all senses, a New World. In that this New World had not been incorporated into the extensive and well-defined knowledge of Western civilization, it was, therefore, open to any and all concepts conceivable to the imagination; everything was possible, even the very improbable.
Regional Ulnar Nerve Strain Following Decompression and Anterior Subcutaneous Transposition in Patients With Cubital Tunnel Syndrome.

Purpose Simple decompression and anterior subcutaneous transposition are effective surgical interventions for cubital tunnel syndrome and yield similarly favorable outcomes. However, a substantial proportion of patients demonstrate unsatisfactory outcomes for reasons that remain unclear. We compared effects of decompression and transposition on regional ulnar nerve strain to better understand the biomechanical impacts of each strategy. Methods Patients diagnosed with cubital tunnel syndrome and scheduled for anterior subcutaneous transposition surgery were enrolled. Simple decompression, circumferential decompression, and anterior transposition of the ulnar nerve were performed during the course of the transposition procedure. Regional ulnar nerve strain around the elbow was measured for each surgical intervention based on 4 wrist and elbow joint configurations. Results With elbow extension at 180°, both circumferential decompression and anterior transposition resulted in approximately 68% higher nerve strains than simple decompression. Conversely, with elbow flexion, simple decompression resulted in higher average strains than anterior transposition. Limited regional differences in strain were observed for any surgical intervention with elbow extension. However, with elbow flexion, strains were higher in distal and central regions compared with the proximal region within all surgical groups, and proximal region strain was higher after simple decompression compared with anterior transposition. Conclusions As predicted by the altered anatomic course, anterior transposition results in lower ulnar nerve strains than simple decompression during elbow flexion and higher nerve strains during elbow extension. Irrespective of anatomic course, circumferential release of paraneurial tissues may also influence nerve strain. Nerve strain varies regionally and is influenced by surgery and joint configuration. Clinical relevance Our data provide insight into how surgery resolves and redistributes traction on the ulnar nerve. These findings may help inform which surgical procedure to perform for a specific patient, guide rehabilitation protocols, and suggest regions of anatomic concern during index and revision surgery.
Socioeconomic status is associated with urinary diversion utilization after radical cystectomy for bladder cancer.

Purpose To assess socioeconomic disparities in urinary diversion utilization in a contemporary American cohort.
Catalytic, Enantioselective, Intramolecular Sulfenoamination of Alkenes with Anilines

A method for the catalytic, enantioselective, intramolecular sulfenoamination of alkenes with aniline nucleophiles has been developed. The method employs a chiral, Lewis basic selenophosphoramide catalyst and a Bronsted acid co-catalyst to promote stereocontrolled C–N and C–S bond formation by activation of an achiral sulfenylating agent. Benzoannulated nitrogen-containing heterocycles such as indolines, tetrahydroquinolines, and tetrahydrobenzazepines were prepared with high to excellent enantioselectivities. The impact of tether length and electron density of both the nucleophile and olefin on the reactivity, site selectivity, and enantioselectivity were investigated and interpreted in terms of substrate-dependent stereodetermining thiiranium ion formation or capture.
Probing of the Nasolacrimal Duct

Congenital nasolacrimal duct obstructions may present with mucoid discharge, epiphora, or lacrimal swelling, and is most commonly located at the distal end of the nasolacrimal duct. Nasolacrimal duct probing may be performed to treat an obstruction after conservative measures have failed. Patients should be educated about the risks and benefits of the procedure, including alternatives.
Reconfigurable Dual-Band Bidirectional Reflection Amplifier With Applications in Van Atta Array

We designed a reconfigurable dual-band reflection amplifier with operation frequency bands over 1.8 GHz and/or 2.4 GHz. This one-port amplifier boosts the reflected signal over either of these two frequency bands or both as a dual-band reflection amplifier. The amplifier circuit consists of an FET transistor and two p-i-n diodes, which act as switches to form a reconfigurable system. The measured reflection gains at single 1.8 GHz and 2.4 GHz frequency bands are 17.6 dB and 16.75 dB, respectively. The dual-band operation frequency shows 11.2 dB and 15 dB gain at 1.8 GHz and 2.4 GHz, respectively. Then, we realized a bidirectional amplifier using a dual-band −3 dB 90° branch line coupler integrated with two of the proposed reconfigurable reflection amplifiers. This bidirectional amplifier is a two-port bilateral amplifier. The measured reflection gains show at least 10 dB transmission gains ( ${S} _{21}$ and ${S} _{12}$ ) at operation frequency bands. The proposed reconfigurable bidirectional amplifier is then used in a dual-band Van Atta array. The proposed active retrodirective system outperformed passive Van Atta array by 5 dB gain with only half the number of antenna elements. Each component is investigated analytically and analyzed by advanced design system. Fabricated circuits are measured and show good agreement with simulations.
Current status and future challenges for molecular imaging

Molecular imaging (MI), used in its wider sense of biology at the molecular level, is a field that lies at the intersection of molecular biology and traditional medical imaging. As advances in medicine have exponentially expanded over the last few decades, so has our need to better understand the fundamental behaviour of living organisms in a non-invasive and timely manner. This commentary draws from topics the authors addressed in their presentations at the 2017 Royal Society Meeting 'Challenges for chemistry in molecular imaging', as well as a discussion of where MI is today and where it is heading in the future.This article is part of the themed issue 'Challenges for chemistry in molecular imaging'.
Cross-National Variation in Occupational Prestige

This article investigates cross-national differences in occupational prestige amongst French, American and Canadian privacy officers. Privacy officers design and implement programs to protect private information in organizations. As a consequence, members of the privacy occupation serves as key interfaces between organizations and their information environments. The current study seeks to extend structuralist theories of occupational prestige- which suggest that all complex societies engender similar hierarchies of occupations. In contrast, in my chosen empirical case of privacy officers, I find that national contexts accord varying degrees of prestige to the privacy occupation. On the one hand, American privacy officers are upwardly mobile and endowed with the potentiality of being strategic organizational actors. On the other, French privacy officers are low-status actors- largely relegated to documentation and compliance tasks. Using a comparative case study method and a multimodal data corpus (intervi...
Velocity-Dependent Changes in Electrical Efficiency of the Leg Extensors during Eccentric Isokinetic Muscle Actions.

The mechanisms underlying velocity-specific decreases in torque production during eccentric muscle actions remain unclear. Therefore, the purpose of the present study was to examine electrical efficiency at 60 and 180°·s −1 during fatiguing, maximal eccentric isokinetic muscle actions of the leg extensors. Thirteen men visited the lab on two occasions and randomly performed 30 repeated maximal eccentric isokinetic muscle actions of the leg extensors at 60 and 180°·s − ¹ through a 90° range of motion. Polynomial regression analyses and separate repeated measures ANOVAs were used to examine the composite patterns of responses for electromyographic amplitude, eccentric torque, and electrical efficiency across the 60 and 180°·s − ¹ protocols. Eccentric torque remained unchanged across the 30 maximal eccentric muscle actions performed at 60 and 180°·s −1. Electromyographic amplitude and electrical efficiency, however, increased linearly across the 180°·s −1 protocol, but there were no changes for either electromyographic amplitude or electrical efficiency during the 60°·s −1 fatiguing protocol. These findings indicated that performing eccentric muscle actions at a fast velocity (i. e., 180°·s −1) was characterized by greater efficiency (i. e., decreased electrical efficiency) compared to eccentric muscle actions performed at a slow velocity (i. e., 60°·s −1). Thus, it is possible that eccentric muscle actions performed at fast velocities are more robust to fatigue due, in part, to greater efficiency compared to slow-velocity eccentric muscle actions.
Conjugation of Haptens

Many naturally occurring proteins, peptides, carbohydrates, nucleic acids, and lipids, as well as synthetic peptides, are successful immunogens. To elicit an immune response, a compound must contain an antigenic determinant or epitope and must be of sufficient size to initiate lymphocyte activation necessary for an antibody response. In practice, small chemical compounds (haptens) are generally not good immunogens. However, when attached to macromolecules (carriers), they can become immunogenic. An immunogen must have epitopes that can be recognized by antigen-presenting cells and a T-cell receptor, and it must be degradable. Haptens and corresponding hapten-carrier conjugates have been essential to the development of sensitive quantitative and qualitative immunoassays. In the design of hapten conjugates, consideration must be given to the hapten, the carrier, the coupling strategy, and the hapten density because the amount of hapten attached to the carrier influences the strength of the immune response directed toward the newly created antigenic determinant. Hence the haptenic density of the conjugate is also important in the development of immunoassays. The optimal epitope density of a conjugate to elicit either a strong immune response or provide the best immunoassay is dependent on the structure of the epitope and the nature of the immunoassay. The aim of this chapter is to describe the diverse techniques used to couple haptens to carriers and provide guidance in the selection of the most appropriate procedure for a particular hapten.
Experiments on Genomics Ad Hoc Retrieval.

This paper represents te results of the State University of New York at Buffalo (School of Informatics) in the TREC 2005 Conference. We participated in the Genomics ad hoc retrieval task. Our approach used the SMART system for indexing the large collection of MEDLINE documents. For this purpose we used a distributed retrieval approach and divided the large collection into 5 non overlapping sub collections. We tried several approaches on the training topics to select the best run possible. Our results perform slightly above the median system in the conference. We also paired with the NLM team to contribute a run for their fusion approach.
Implementing a Finite Difference-Based Real-time Sound Synthesizer using GPUs

this paper, we describe an implementation of a real-time sound synthesizer using Finite Difference-based simulation of a two-dimensional membrane. Finite Difference (FD) methods can be the basis for physics-based music instrument models that generate realistic audio output. However, such methods are compute-intensive; large simulations cannot run in real time on current CPUs. Many current systems now include powerful Graphics Processing Units (GPUs), which are a good fit for FD methods. We demonstrate that it is possible to use this method to create a usable real-time audio synthesizer. KeywordsDifference, GPU, CUDA, Synthesis
Horse alpha-1-antitrypsin, beta-lactoglobulins 1 and 2, and transferrin map to positions 24q15-q16, 28q18-qter, 28q18-qter and 16q23, respectively.

An equine genomic library in Lambda FIX II (Stratagene) was screened with DNA and PCR probes for alpha-1-anti-trypsin (AAT), beta-lactoglobulins 1 and 2 (BLG1 and BLG2), and transferrin (TF) using random-primed 32P-labeled DNA, and clones isolated. AAT is a member of the protease inhibitor superfamily and a highly polymorphic glycoprotein. In the proposed classification system for the equine AATs, the lambda clone used in fluorescence in situ hybridisation (FISH) experiments is Spi 2. BLG1 and BLG2 are polymorphic milk proteins. BLG clone identities were confirmed by comparison with cDNA sequences. TF is a glycoprotein that carries iron to the cells of the body. The identity of the TF clone was confirmed by direct sequencing of upstream sequence and exons 13, 15 and 16 and comparison with published cDNA horse sequence.© 1999 Kluwer Academic Publishers.
Overloading is NP-Complete

We show that overloading is NP-complete. This solves exercise 6.25 in the 1986 version of the Dragon book.
Divine Text, National Language, and Their Publics: Arguing an Indonesian Qur'an

The entry of a universal revelation into the mundane world of language threatens to be paradoxical: it must take a specific and local form. As such, it becomes implicated in nationalist, ethnic, linguistic, and other sources of community. This article centers on a small melodrama in late twentieth-century Indonesia, home to the largest number of Muslims of any country. After undergoing a mid-life spiritual awakening, H. B. Jassin, a modernist literary critic, editor, and ardent defender of freedom of expression, undertook two projects intended to convey the aesthetic power of the Qur'an to a non-Arabic speaking public. But if Qur'anic Arabic summons a transnational community of the faithful, standardized Indonesian was developed to address a nation of citizens. If scripture speaks in a divine, uncreated idiom, the national language is shaped by human efforts. Jassin's career had served a vision of literature and its public whose values and semiotic ideologies were dramatically at odds with Qur'anic traditions. Although this may appear at first glance to be a familiar story of progress and its opponents, this article asks whether Jassin's critics grasped something about signs and communities that his defenders did not. Examining the furor that resulted from his Qur'ans, it explores an array of conflicting assumptions about language, freedom, truth, and people's lives together in the late twentieth century.
Differences between Men and Women in Mortality and the Health Dimensions of the Morbidity Process.

BACKGROUND: Do men have worse health than women? This question is addressed by examining sex differences in mortality and the health dimensions of the morbidity process that characterize health change with age. We also discuss health differences across historical time and between countries. CONTENT: Results from national-level surveys and data systems are used to identify male/female differences in mortality rates, prevalence of diseases, physical functioning, and indicators of physiological status. Male/female differences in health outcomes depend on epidemiological and social circumstances and behaviors, and many are not consistent across historical time and between countries. In all countries, male life expectancy is now lower than female life expectancy, but this was not true in the past. In most countries, women have more problems performing instrumental activities of daily living, and men do better in measured performance of functioning. Men tend to have more cardiovascular diseases; women, more inflammatory-related diseases. Sex differences in major cardiovascular risk factors vary between countries—men tend to have more hypertension; women, more raised lipids. Indicators of physiological dysregulation indicate greater inflammatory activity for women and generally higher cardiovascular risk for men, although women have higher or similar cardiovascular risk in some markers depending on the historical time and country. SUMMARY: In some aspects of health, men do worse; in others, women do worse. The lack of consistency across historical times and between countries in sex differences in health points to the complexity and the substantial challenges in extrapolating future trends in sex differences.
Signed, Sealed, Delivered: Conjugate and Prodrug Strategies as Targeted Delivery Vectors for Antibiotics

Innate and developed resistance mechanisms of bacteria to antibiotics are obstacles in the design of novel drugs. However, antibacterial prodrugs and conjugates have shown promise in circumventing resistance and tolerance mechanisms via directed delivery of antibiotics to the site of infection or to specific species or strains of bacteria. The selective targeting and increased permeability and accumulation of these prodrugs not only improves efficacy over unmodified drugs but also reduces off-target effects, toxicity, and development of resistance. Herein, we discuss some of these methods, including sideromycins, antibody-directed prodrugs, cell penetrating peptide conjugates, and codrugs.
Abstract 4260: Novel insights into immunotherapy by deep mining of big cancer genomic data

Immunotherapy has revolutionized patient care and cancer research. To gain novel insights into immunotherapy, we performed the pan-cancer analyses of >11,000 tumor samples of 33 cancer types from The Cancer Genome Atlas and CPTAC as well as large amounts of in-house immunotherapy related data. Through the mining on these large-scale cancer genomics and proteomics data, I will discuss three novel ideas that would challenge the current paradigm for developing effective immunotherapy. (I) Checkpoint inhibition: antibody is NOT the only approach. I will discuss the role of enhancers in regulating immune checkpoint. (II) Neoantigen: Somatic mutations are NOT the only source. I will discuss the contribution of RNA editing to proteomics diversity and neoantigen in cancer. (III) Predictive markers: gene-based markers is NOT the only option. I will discuss the utility of a global energy index for predicting the response to anti-PD1 treatment. Collectively, these results suggest novel directions for future immunotherapy development. Citation Format: Han Liang. Novel insights into immunotherapy by deep mining of big cancer genomic data [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 4260.
New Directions for Understanding the Codon Redefinition Required for Selenocysteine Incorporation

The fact that selenocysteine (Sec) is delivered to the elongating ribosome by a tRNA that recognizes a UGA stop codon makes it unique and a thorn in the side of what was originally thought to be a universal genetic code. The mechanism by which this redefinition occurs has been slowly coming to light over the past 30 years, but key questions remain. This review seeks to highlight the prominent mechanistic questions that will guide the direction of work in the near future. These questions arise from two major aspects of Sec incorporation: (1) novel functions for the Sec insertion sequence (SECIS) that resides in all selenoprotein mRNAs and (2) the myriad of RNA-binding proteins, both known and yet to be discovered, that act in concert to modify the translation elongation process to allow Sec incorporation.
Analytic gradients for the single-reference driven similarity renormalization group second-order perturbation theory.

We derive and implement analytic energy gradients for the single-reference driven similarity renormalization group second-order perturbation theory (DSRG-PT2). The resulting equations possess an asymptotic scaling that is identical to that of the second-order Moller-Plesset perturbation theory (MP2), indicating that the exponential regularizer in the DSRG equations does not introduce formal difficulties in the gradient theory. We apply the DSRG-PT2 method to optimizing the geometries of 15 small molecules. The equilibrium bond lengths computed with DSRG-PT2 are found similar to those of MP2, yielding a mean absolute error of 0.0033 A and a standard deviation of 0.0045 A when compared with coupled cluster with singles, doubles, and perturbative triples.
Importance of operating room case scheduling on analyses of observed reductions in surgical site infections from the purchase and installation of capital equipment in operating rooms.

Background We review the impact of the consequences of operating room (OR) management decision making on power analyses for observational studies of surgical site infections (SSIs) among patients receiving care in ORs with interventions versus without interventions involving physical changes to ORs. Examples include ventilation systems, bactericidal lighting, and physical alterations to ORs. Methods We performed a narrative review of operating room management and surgical site infection articles. We used 10-years of operating room data to estimate parameters for use in statistical power analyses. Results Creating pivot tables or monthly control charts of SSI per case by OR and comparing among ORs with or without intervention is not recommended. This approach has low power to detect a difference in SSI rates among the ORs with or without the intervention. The reason is that appropriate OR case scheduling decision making causes risk factors for SSI to differ among ORs, even when stratifying by surgical specialty. Such risk factors include case duration, urgency, and American Society of Anesthesiologists’ Physical Status. Instead, analyze SSI controlling for the OR, where the patient had surgery, and matching patients using these variables is preferable. With α = 0.05, 600 cases per OR, 5 intervention ORs, and 5 or 1 control patients for each intervention patient, reasonable power (≅94% or 78%, respectively) can be achieved to detect reductions (3.6% to 2.4%) in the incidence of SSI between ORs with or without the intervention. Conclusions By using this matched cohort design, the effect of the purchase and installation of capital equipment in ORs on SSI can be evaluated meaningfully.
The Roles of Nurses in Hematopoietic Cell Transplantation for the Treatment of Leukemia in Older Adults.

ABSTRACT Objective To review and summarize nurses’ roles in the care of the older adult undergoing an allogeneic hematopoietic cell transplant (HCT) for the treatment of leukemia. Data Sources Published literature indexed in PubMed, CINAHL, textbooks, and clinical expertise. Conclusion Nurses are a vital component of the highly specialized care delivered before, during, and after an allogeneic HCT. Implications for Nursing Practice Nurses who are prepared for the complex HCT care trajectory will be able to optimally meet the complex needs of the older adult patient and their caregiver(s).
Variance estimation in inverse probability weighted Cox models.

Inverse probability weighted Cox models can be used to estimate marginal hazard ratios under different point treatments in observational studies. To obtain variance estimates, the robust sandwich variance estimator is often recommended to account for the induced correlation among weighted observations. However, this estimator does not incorporate the uncertainty in estimating the weights and tends to overestimate the variance, leading to inefficient inference. Here we propose a new variance estimator that combines the estimation procedures for the hazard ratio and weights using stacked estimating equations, with additional adjustments for the sum of terms that are not independently and identically distributed in a Cox partial likelihood score equation. We prove analytically that the robust sandwich variance estimator is conservative and establish the asymptotic equivalence between the proposed variance estimator and one obtained through linearization by Hajage et al. in 2018. In addition, we extend our proposed variance estimator to accommodate clustered data. We compare the finite sample performance of the proposed method with alternative methods through simulation studies. We illustrate these different variance methods in both independent and clustered data settings, using a bariatric surgery dataset and a multiple readmission dataset, respectively. To facilitate implementation of the proposed method, we have developed an R package ipwCoxCSV.
Affect Dynamics as Predictors of Symptom Severity and Treatment Response in Mood and Anxiety Disorders: Evidence for Specificity.

Studies of affect dynamics in psychopathology often focus on the prediction of broad constructs like subjective well-being and psychological health. Less is known about how fluctuation in affect over time relates to specific symptom measures (e.g., anxiety or depression), or how these domains change in treatment. A clinical sample of 32 adults with mood and anxiety disorders (13 generalized anxiety, 5 major depression, 14 comorbid) completed four daily assessments of positive (PA) and negative affect (NA) for 30 days prior to receiving cognitive behavioral treatment. Anxiety and depression symptom severity were assessed pre- and post-treatment. We calculated three metrics of affect dynamics for each person’s PA and NA time series: (1) variability (experiencing emotional extremes, the standard deviation of a person’s PA or NA vector); (2) instability (magnitude of point-to-point change in emotion, the vector’s mean squared successive difference); and (3) inertia (the extent to which emotions self-perpetuate over time, the lag-1 auto-correlation of the vector). Multiple regression models were run to test dynamics of positive and negative affect as between-subjects predictors of symptom severity and pre-to-posttreatment change in symptoms. Findings suggest NA dynamics are unrelated to depression symptom severity or treatment response, but we observed a specific effect of NA instability (MSSD) on both severity and response of anxiety symptoms. All PA dynamics were unrelated to anxiety or depression symptom severity. However, variability, instability, and inertia of PA were all found to relate to treatment response for both anxiety and depression symptoms. Taken together, our results suggest that affect dynamics have some specificity in their relationship to clinically relevant phenomena such as symptom severity and treatment outcomes at the between-subjects level of analysis.
Repeat Revascularization for Severe Recurrent Coronary Artery Disease in a Young Woman With Takayasu Arteritis.

Abstract A young woman with Takayasu arteritis presented with an acute coronary syndrome with ostial left main coronary artery stenosis. She underwent urgent coronary artery bypass surgery but deve...
Unilateral atlantoaxial pseudoarticulation: A case report, literature review, and proposed mechanism.

Background Atlantoaxial pseudoarticulation rarely involves the cervical spine, and its etiology is unclear. In theory, pseudoarticulation is comparable to Bertolotti's syndrome in the lumbar spine or may be attributed to an aberrant focal fusion between C0-C1-C2 that occurs during the gastrulation of embryologic development. Case description A 39-year-old female presented with neck pain and upper extremity weakness. Magnetic resonance/computed tomography studies documented a left-sided unilateral pseudoarticulation between the lamina of C1 and C2 causing compression of the dorsal spinal cord. Following resection of the accessory C1/C2 joint utilizing a C1 hemilaminectomy and partial C2 laminectomy, the patient's neck pain and weakness resolved. Histologically, the tissue showed benign osteocartilaginous tissue with no synovial capsule. Conclusion Here, the authors present a case of occiput-C1-C2 pseudojoint formation, leading to clinical and radiographic findings of cord compression due to boney outgrowth.
Exploring the Impact of ACA on Rural-Urban Disparity in Oral Health Services Among US Noninstitutionalized Adults.

Purpose To explore the effect of the Affordable Care Act (ACA) on rural disparities in oral health services utilization based on disability status. Methods Comparing the 2011-2013 with the 2014-2016 Medical Expenditure Panel Survey, the study estimated the impacts of ACA on the likelihood of having preventive checkup and utilization of dental treatments in adults older than 18. Findings The sample consists of 216,184 noninstitutionalized adults with 14.5% living in rural areas. There was a slight improvement in the receipt of oral health services after ACA, but the improvement was not statistically significant. Disability remains a barrier to receiving preventive oral health checkups, and living in rural areas is a barrier for both utilization of preventive checkups and dental treatments. Conclusions Unmet needs for preventive checkups may result in unnecessary, costly dental treatments. More strategies are needed to reduce the disparities in oral health services.
Early Life Exposure to Environmentally Relevant Levels of Endocrine Disruptors Drive Multigenerational and Transgenerational Epigenetic Changes in a Fish Model

The inland silverside, Menidia beryllina, is a euryhaline fish and a model organism in ecotoxicology. We previously showend that exposure to picomolar (ng/L) levels of endocrine disrupting chemicals (EDCs) can cause a variety of effects in M. beryllina, from changes in gene expression to phenotypic alterations. Here we explore the potential for early life exposure to EDCs to modify the epigenome in silversides, with a focus on multi- and transgenerational effects. EDCs included contaminants of emerging concern (the pyrethroid insecticide bifenthrin and the synthetic progestin levonorgestrel), as well as a commonly detected synthetic estrogen (ethinylestradiol), and a synthetic androgen (trenbolone) at exposure levels ranging from 3 to 10 ng/L. In a multigenerational experiment, we exposed parental silversides to EDCs from fertilization until 21 days post hatch (dph). Then we assessed DNA methylation patterns for three generations (F0, F1, and F2) in whole body larval fish using reduced representation bisulfite sequencing (RRBS). We found significant ( = 0.05) differences in promoter and/or gene body methylation in treatment fish relative to controls for all EDCs and all generations indicating that both multigenerational (F1) and transgenerational (F2) effects that were caused by strict inheritance of DNA methylation alterations and the dysregulation of epigenetic control mechanisms. Using gene ontology and pathway analyses, we found enrichment in biological processes and pathways representative of growth and development, immune function, reproduction, pigmentation, epigenetic regulation, stress response and repair (including pathways important in carcinogenesis). Further, we found that a subset of potentially EDC responsive genes (EDCRGs) were differentially methylated across all treatments and generations and included hormone receptors, genes involved in steroidogenesis, prostaglandin synthesis, sexual development, DNA methylation, protein metabolism and synthesis, cell signaling, and neurodevelopment. The analysis of EDCRGs provided additional evidence that differential methylation is inherited by the offspring of EDC-treated animals, sometimes in the F2 generation that was never exposed. These findings show that low, environmentally relevant levels of EDCs can cause altered methylation in genes that are functionally relevant to impaired phenotypes documented in EDC-exposed animals and EDC exposure has the potential to affect epigenetic regulation in future generations of fish.
Increased hepatic and circulating chemokine and osteopontin expression occurs early in human NAFLD development.

Background & aims Non-alcoholic steatohepatitis (NASH), a subtype of non-alcoholic fatty liver disease (NAFLD) that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma, is characterized by hepatic inflammation. Despite evolving therapies aimed to ameliorate inflammation in NASH, the transcriptional changes that lead to inflammation progression in NAFLD remain poorly understood. The aim of this pilot study was to define transcriptional changes in early, non-fibrotic NAFLD using two independent biopsy-proven NAFLD cohorts. Methods We extracted RNA from liver tissue of 40 patients with biopsy-proven NAFLD based on NAFLD Activity Score (NAS) (23 patients with NAS ≤3, 17 with NAS ≥5) and 21 healthy controls, and we compared changes in expression of 594 genes involved in innate immune function. Using plasma from an independent cohort of 67 patients with NAFLD and 15 healthy controls, we validated the gene changes observed using a multiplex protein assay. Results Compared to healthy controls, NAFLD patients with NAS ≥5 had differential expression of 211 genes, while those with NAS ≤3 had differential expression of only 14 genes. Notably, osteopontin (SPP1) (3.74-fold in NAS ≤3, 8.28-fold in NAS ≥5) and CXCL10 (2.27-fold in NAS ≤3, 8.28-fold in NAS ≥5) gene expression were significantly upregulated with histologic progression of NAFLD. Plasma osteopontin (SPP1) and CXCL10 are significantly increased in the presence of NAFLD, regardless of histologic grade. In addition, the plasma levels of these two proteins distinguish clearly between the presence or absence of NAFLD (AUC>0.90). Conclusions Osteopontin (SPP1) and CXCL10 are upregulated early in non-fibrotic NAFLD and may serve as valuable non-invasive biomarkers.