cssi/SciSciGPT-SciSciNet huggingface dataset:
Oxytetracycline Marking Efficacy for Yellow Perch Fingerlings and Temporal Assays of Tissue Residues

Differentiating between hatchery and naturally reproduced fishes is difficult because of the lack of appropriate marking techniques. Chemical immersion techniques can be a practical method for mass marking juvenile fishes. The objectives of this study were to determine the concentration of oxytetracycli ne (OTC) hydrochloride needed to effectively mark age-0 yellow perch Perca flavescens. to observe the retention lime of the mark, and to measure the persistence of OTC in body tissues. Fish were immersed in 309, 534, and 748 mg OTC/L for 12 h. Initial fish collections were made weekly, and monthly collections began 1 month postmarking for tissue and mark analyses. High-pressure liquid chromatography was used to quantitate OTC residues in tissues; OTC concentrations were undetectable (<0.05 jxg/g) in the edible tissue (muscle) at 110 d postimmersion. Aided by a Nikon Labophot fluorescence microscope, we discerned otolith marks 56 d postimmersion on 100% of the fish treated at 534 and 748 mg/L. Marks were still visible on 100% of the fish treated with 534 and 748 mg/L at 8 months postimmersion.
Validating therapeutic targets through human genetics

More than 90% of the compounds that enter clinical trials fail to demonstrate sufficient safety and efficacy to gain regulatory approval. Most of this failure is due to the limited predictive value of preclinical models of disease, and our continued ignorance regarding the consequences of perturbing specific targets over long periods of time in humans. 'Experiments of nature' - naturally occurring mutations in humans that affect the activity of a particular protein target or targets - can be used to estimate the probable efficacy and toxicity of a drug targeting such proteins, as well as to establish causal rather than reactive relationships between targets and outcomes. Here, we describe the concept of dose-response curves derived from experiments of nature, with an emphasis on human genetics as a valuable tool to prioritize molecular targets in drug development. We discuss empirical examples of drug-gene pairs that support the role of human genetics in testing therapeutic hypotheses at the stage of target validation, provide objective criteria to prioritize genetic findings for future drug discovery efforts and highlight the limitations of a target validation approach that is anchored in human genetics.
Epidermal growth factor receptor signaling in tissues

A peptide purified from the salivary gland of a mouse was shown few years ago to accelerate incisor eruption and eyelid opening in newborn mice, and was named epidermal growth factor (EGF). The members of this family of peptide growth factors had been identified in numerous physiological and pathological contexts. EGF binds to a cell surface EGF receptor, which induces a biochemical modification (phosphorylation) of the receptor's cytoplasmic tail. There is a growing consensus in the research community that, in addition to cellular and molecular studies, the dynamics of the EGFR network and its operation must be examined in tissues. A key challenge is to integrate the existing molecular and cellular information into a system-level description of the EGFR network at the tissue and organism level. In this paper, the two examples of EGFR signaling in tissues are described, and the recent efforts to model EGFR autocrine loops, which is a predominant mode of EGFR activation in vivo, are summarized.
Investigations of human platelet-type 12-lipoxygenase: role of lipoxygenase products in platelet activation

Human platelet-type 12-lipoxygenase (12-LOX) has recently been shown to play an important role in regulation of human platelet function by reacting with arachidonic acid (AA). However, a number of other fatty acids are present on the platelet surface that, when cleaved from the phospholipid, can be oxidized by 12-LOX. We sought to characterize the substrate specificity of 12-LOX against six essential fatty acids: AA, dihomo-γ-linolenic acid (DGLA), eicosapentaenoic acid (EPA), α-linolenic acid (ALA), eicosadienoic acid (EDA), and linoleic acid (LA). Three fatty acids were comparable substrates (AA, DGLA, and EPA), one was 5-fold slower (ALA), and two showed no reactivity with 12-LOX (EDA and LA). The bioactive lipid products resulting from 12-LOX oxidation of DGLA, 12-(S)-hydroperoxy-8Z,10E,14Z-eicosatrienoic acid [12(S)-HPETrE], and its reduced product, 12(S)-HETrE, resulted in significant attenuation of agonist-mediated platelet aggregation, granule secretion, αIIbβ3 activation, Rap1 activation, and clot retraction. Treatment with DGLA similarly inhibited PAR1-mediated platelet activation as well as platelet clot retraction. These observations are in surprising contrast to our recent work showing 12(S)-HETE is a prothrombotic bioactive lipid and support our hypothesis that the overall effect of 12-LOX oxidation of fatty acids in the platelet is dependent on the fatty acid substrates available at the platelet membrane.
Young Adolescents’ Perceptions of Parental Management of Peer Relationships

In two short-term longitudinal studies, the relation of direct parental management of peer relationships with young adolescents’ and their best friends’ antisocial behavior and academic achievement were examined. Ninth-graders reported perceptions of parental monitoring and parental prohibiting of peer relationships. Ninth-graders and best friends reported drug use, delinquent behavior, grade point average (GPA), and educational expectations. At Time 1, adolescents who reported higher levels of parental monitoring reported lower levels of drug use, lower levels of delinquent behavior, higher GPAs, and higher educational expectations. At Time 1, perceptions of moderate levels of prohibiting were associated with lower levels of drug use and delinquent behavior for adolescents and their peers. Adolescents who reported moderate levels of prohibiting reported higher levels of Time 3 academic achievement.
The Role of Firm Status in Appointments of Financial Experts to Audit Committees

Since 1999 regulators have attempted to improve the monitoring of financial reporting by exerting significant pressure on firms to appoint accounting financial experts (AFEs) to their audit committees. Yet, many firms have been reluctant to do so, which has made these firms more prone to financial reporting problems. We examine appointments of AFEs to the audit committees of S&P 1500 firms during the period 1999-2008 to explore whether concerns about the status of these experts discouraged firms from appointing them. We find that typical AFEs (CFOs and retired audit partners) have lower director status (board seats, trusteeships, social club memberships, and elite education) than other types of directors, and that this status gap is greater for higher status firms (larger, better connected, and more admired firms). Moreover, we find that higher status firms are less likely to appoint AFEs, suggesting that status-related concerns reduce the demand for accounting financial expertise on audit committees.
Effects of Age and Estrogen on Skeletal Gene Expression in Humans as Assessed by RNA Sequencing

Precise delineation of the specific genes and pathways altered with aging and estrogen (E) therapy may lead to new skeletal biomarkers and the development of novel bone therapeutics. Previous human bone studies, however, have been limited by only examining pre-specified genes and pathways. High-throughput RNA sequencing (RNAseq), on the other hand, offers an unbiased approach to examine the entire transcriptome. Here we present an RNAseq analysis of human bone samples, obtained from iliac crest needle biopsies, to yield the first in vivo interrogation of all genes and pathways that may be altered in bone with aging and E therapy in humans. 58 healthy women were studied, including 19 young women (mean age ± SD, 30.3 ± 5.4 years), 19 old women (73.1 ± 6.6 years), and 20 old women treated with 3 weeks of E therapy (70.5 ± 5.2 years). Using generally accepted criteria (false discovery rate [q] < 0.10), aging altered a total of 678 genes and 12 pathways, including a subset known to regulate bone metabolism (e.g., Notch). Interestingly, the LEF1 transcription factor, which is a classical downstream target of the Wnt/β-catenin signaling pathway, was significantly downregulated in the bones from the old versus young women; consistent with this, LEF1 binding sites were significantly enriched in the promoter regions of the differentially expressed genes in the old versus young women, suggesting that aging was associated with alterations in Wnt signaling in bone. Further, of the 21 unique genes altered in bone by E therapy, the expression of INHBB (encoding for the inhibin, beta B polypeptide), which decreased with aging (by 0.6-fold), was restored to young adult levels in response to E therapy. In conclusion, our data demonstrate that aging alters a substantial portion of the skeletal transcriptome, whereas E therapy appears to have significant, albeit less wide-ranging effects. These data provide a valuable resource for the potential identification of novel biomarkers associated with age-related bone loss and also highlight potential pathways that could be targeted to treat osteoporosis. Trial Registration ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02349113","term_id":"NCT02349113"}}NCT02349113
Production and Photodissociation of the Methyl Perthiyl Radical

The photodissociation dynamics of the methyl perthiyl (CH3SS) radical are investigated via molecular beam photofragment translational spectroscopy, using “soft” electron ionization to detect the radicals and their photofragments. With this new capability, we have shown that CH3SS can be generated from flash pyrolysis of dimethyl trisulfide. Utilizing this source of radicals and the advantages afforded by soft electron ionization, we have reinvestigated the photodissociation dynamics of CH3SS at 248 nm, finding CH3S + S to be the dominant dissociation channel with CH3 + SS as a minor process. These results differ from previous work reported in our laboratory in which we found CH3 + SS and CH2S + SH as the main dissociation channels. The difference in results is discussed in light of our new capabilities for characterization of radical production.
The whole system is broke and in desperate need of fixing: Notes on the Second Industrial Revolution

Today there is virtually no problem, from technological to economic, whose various aspects can be considered in isolation one from another. The world in which we live is a complex highly–interconnected system, yet most people are still trying to solve problems with the mentality and tools appropriate only for a simpler, mechanistic, view of the world. The result is occasional catastrophic failure. The authors describe the challenge to managers of adapting a holistic or systems view.
Intracerebroventricular administration of leukocytic endogenous mediators (LEM) in the rat.

SummaryLEM obtained from glycogen-induced peritoneal exudates in rabbits were injected into the lateral cerebral ventricle of rats to determine if LEM had a primary site of action in the central nervous system. LEM injected icv in the dose of 10, 20, or 50 μl was observed to produce a rapid hy-perthermia. Injection of heated LEM failed to cause a hyperthermic response. Endo-toxin and heated endotoxin (20 ng/20 μl/ rat) administered icv each produced a delayed hyperthermia as compared to LEM. The various doses of LEM were also observed to significantly decrease plasma iron and zinc, increase plasma copper, increase the synthesis of plasma α2 acute-phase protein (α2-MFP), and cause a flux of a nonme-tabolizable amino acid ([14C]AIB) to the liver. These observations suggest that LEM in doses which are inactive systemically can mediate certain effects on or through the central nervous system following icv administration.The authors wish to acknowledge the invaluable technical assistance of Ms. Beverly A. Cart...
Reference Value Changes and Improvement of Test Performance

Any test that shows different probabilities of positive results for distinct subgroups of the disease population will have a sensitivity dependent on prevalences of the disease subgroups. A change in a reference value (cutoff point) of such a test with prevalence-dependent sensitivity may not improve the test performance for detecting the entire disease spectrum.
Heterojunction PbS nanocrystal solar cells with oxide charge-transport layers.

Oxides are commonly employed as electron-transport layers in optoelectronic devices based on semiconductor nanocrystals, but are relatively rare as hole-transport layers. We report studies of NiO hole-transport layers in PbS nanocrystal photovoltaic structures. Transient fluorescence experiments are used to verify the relevant energy levels for hole transfer. On the basis of these results, planar heterojunction devices with ZnO as the photoanode and NiO as the photocathode were fabricated and characterized. Solution-processed devices were used to systematically study the dependence on nanocrystal size and achieve conversion efficiency as high as 2.5%. Optical modeling indicates that optimum performance should be obtained with thinner oxide layers than can be produced reliably by solution casting. Room-temperature sputtering allows deposition of oxide layers as thin as 10 nm, which enables optimization of device performance with respect to the thickness of the charge-transport layers. The best devices achi...
Effect of a dengue clinical case management course on physician practices in Puerto Rico

BACKGROUND Prior to 2010, the clinical management of dengue in Puerto Rico was inconsistent with World Health Organization guidelines. A 4-hour classroom-style course on dengue clinical management was developed in 2009 and mandated for Puerto Rico medical licensure in 2010. Fifty physicians were trained as "master trainers" and gave this course to 7638 physicians. This study evaluated the effect of the course on the clinical management of hospitalized dengue patients. METHODS Pre- and post-course test responses were compared. Changes in physician practices were assessed by reviewing medical records of 430 adult and 1075 pediatric dengue patients at the 12 hospitals in Puerto Rico that reported the most cases during 2008-2009 (pre-intervention) and 2011 (post-intervention). Mixed-effects logistic regression was used to compare key indicators of dengue management. RESULTS Physician test scores increased from 48% to 72% correct. Chart reviews showed that the percentage of adult patients who did not receive corticosteroids increased from 30% to 68% (odds ratio [OR], 5.9; 95% confidence interval [CI], 3.7-9.5) and from 91% to 96% in pediatric patients (OR, 2.7; 95% CI, 1.5-4.9). Usage of isotonic intravenous saline during the critical period increased from 57% to 90% in adult patients (OR, 6.2; 95% CI, 1.9-20.4) and from 25% to 44% in pediatric patients (OR, 3.4; 95% CI, 2.2-5.3). CONCLUSIONS Management of dengue inpatients significantly improved following implementation of a classroom-style course taught by master trainers. An online version of the course was launched in 2014 to expand its reach and sustainability.
Metabolism and Residues of 2,4-Dichlorophenoxyacetic Acid in DAS-40278-9 Maize (Zea mays) Transformed with Aryloxyalkanoate Dioxygenase-1 Gene

DAS-40278-9 maize, which is developed by Dow AgroSciences, has been genetically modified to express the aryloxyalkanoate dioxygenase-1 (AAD-1) protein and is tolerant to phenoxy auxin herbicides, such as 2,4-dichlorophenoxyacetic acid (2,4-D). To understand the metabolic route and residue distribution of 2,4-D in DAS-40278-9 maize, a metabolism study was conducted with 14C-radiolabeled 2,4-D applied at the maximum seasonal rate. Plants were grown in boxes outdoors. Forage and mature grain, cobs, and stover were collected for analysis. The metabolism study showed that 2,4-D was metabolized to 2,4-dichlorophenol (2,4-DCP), which was then rapidly conjugated with glucose. Field-scale residue studies with 2,4-D applied at the maximum seasonal rate were conducted at 25 sites in the U.S. and Canada to measure the residues of 2,4-D and free and conjugated 2,4-DCP in mature forage, grain, and stover. Residues of 2,4-D were not detectable in the majority of the grain samples and averaged <1.0 and <1.5 μg/g in forag...
Case Study 10. Reading the Bones (2): Sizing Up the Ancestors

To identify a fossil mammal or to describe a new species, paleontologists like to have good specimens of the skull, especially the jaws and teeth. However, when they want to know what an animal looks like, they need to have more of the skeleton. Unfortunately, it is rare to have both skull and limb bones of the same individual, and it may be some time before scientists can reconstruct the body with some confidence. Paleontologists can apply the tools used commonly by forensic anthropologists to reconstruct stature and body proportions from individual bones to give a better picture of the size and proportions of the australopithecines and early Homo. The bodies of early hominins did not evolve as quickly as had been believed.
Do planets remember how they formed

One of the most directly observable features of a transiting multi-planet system is their size-ordering when ranked in orbital separation. Kepler has revealed a rich diversity of outcomes, from perfectly ordered systems, like Kepler-80, to ostensibly disordered systems, like Kepler-20. Under the hypothesis that systems are born via preferred formation pathways, one might reasonably expect non-random size-orderings reflecting these processes. However, subsequent dynamical evolution, often chaotic and turbulent in nature, may erode this information and so here we ask - do systems remember how they formed? To address this, we devise a model to define the entropy of a planetary system's size-ordering, by first comparing differences between neighboring planets and then extending to accommodate differences across the chain. We derive closed-form solutions for many of the micro state occupancies and provide public code with look-up tables to compute entropy for up to ten-planet systems. All three proposed entropy definitions exhibit the expected property that their credible interval increases with respect to a proxy for time. We find that the observed Kepler multis display a highly significant deficit in entropy compared to a randomly generated population. Incorporating a filter for systems deemed likely to be dynamically packed, we show that this result is robust against the possibility of missing planets too. Put together, our work establishes that Kepler systems do indeed remember something of their younger years and highlights the value of information theory for exoplanetary science.
Measuring Heightened Attention to Alcohol in a Naturalistic Setting: A Validation Study

Attentional bias to alcohol-related stimuli is believed to be an important contributor to the development and maintenance of drug abuse. There is a considerable body of research examining attentional bias, much of which has typically utilized image-display tasks as a means to assess the phenomenon. Little, however, is known about the nature of this bias in an individual's natural environment. The current study sought to implement a novel approach to assessing attentional bias in vivo. Participants wore portable eye-tracking glasses that recorded video from their point of view and measured fixation time to objects they observed. They entered a room that was designed to represent a recreational setting in which both alcohol- and nonalcoholic-neutral beverages were placed along with other stimuli. In two different testing sessions, participants were free to visually explore the room. Participants showed similar fixation times to alcohol and neutral beverages during Session 1. Attentional bias to alcoholic beverages was observed in Session 2 because fixation time decreased to neutral but not to alcoholic beverages. The magnitude of attentional bias was positively associated with drinking habits, with heavier drinkers demonstrating a higher degree of bias to alcohol. These findings provide an ecological model of how attentional bias can develop as the net result of attention being sustained to alcoholic stimuli while diminishing to other stimuli over time. (PsycINFO Database Record
Predictors of Successful Vocational Rehabilitation Closure among Individuals with Substance and Alcohol Use Disorders: An Analysis of Rehabilitation Services Administration Data 2010–2014

ABSTRACTEmployment has consistently proven to increase treatment retention and lead to sustained recovery among individuals with substance and alcohol use disorders; however, rates of employment remain low for this group and the utilization of employment services by treatment professionals continues to be quite limited. Employment is listed as a primary goal in treatment plans; therefore, employment specialist (i.e., Vocational Rehabilitation Counselors) and treatment professionals should work in tandem to assist in the realization of this goal. Vocational rehabilitation provides a number of specialized services, which serve to increase the likelihood of obtaining gainful employment. Addiction professionals generally identify these services as ancillary, but should recognize the importance of offering them throughout the entire treatment and recovery process. This study utilized employment data obtained from the Rehabilitation Services Administration for 2010–2014 and sought to identify trends associated ...
Direct-acting antiviral regimens are safe and effective in the treatment of hepatitis C in simultaneous liver-kidney transplant recipients.

Hepatitis C (HCV) remains the single most common etiology of end-stage liver disease leading to simultaneous liver/kidney transplant (SLKT) and has worse post-transplant survival compared to non-HCV patients. We aim to assess the effectiveness and tolerance of the all-oral direct-acting antiviral (DAA) agents with or without ribavirin (RBV) in the treatment of HCV recurrence post-SLKT. Thirty-four patients were studied retrospectively, composed predominantly of treatment-naive (73.5%) non-Caucasian (61.8%) males (82.4%) infected with genotype 1a (64.7%). 94.1% reached a sustained virologic response (SVR) after 24 weeks (32/34 patients), without difference between 12 and 24 weeks of therapy. 64.7% had no clinical side effects. Three deaths occurred, all unrelated to treatment. One patient had liver rejection; tacrolimus was increased and prednisone was initiated while HCV treatment was continued and the patient ultimately achieved SVR. No liver graft losses. No kidney rejection or losses. We demonstrated that DAA combinations with or without RBV result in a remarkable SVR rate and tolerated in the majority of the studied SLKT patients. It is safe to wait to treat until post-kidney transplant and therefore increase the donor pool for these patients. Our cohort is ethnically diverse, making our results generalizable.
Modeling the effects of lipid contamination in poly(styrene-isobutylene-styrene) (SIBS)

Lipid uptake and subsequent degradation was characterized as a function of molecular weight and styrene content in four different formulations of poly(styrene-block-Isobutylene-block-styrene) (SIBS). Mechanical testing in uniaxial tension at varying lipid concentrations showed a consistent decrease in tensile strength for all specimens due to lipid contamination. Higher styrene content was associated with an improved resistance to lipid intrusion. A decrease in elongation at break was observed for low molecular weight formulations only; an expected result of the stiffer network and local chain motion restriction due to increased entanglements in high molecular weight SIBS. A new, coupled diffusion/finite element method was used to recover the swelling coefficient of the four different SIBS formulations. The Ogden strain-density energy function recovered from unidirectional tensile testing and diffusion properties from gravimetric analysis were used to construct the finite element model. The predicted swelling behavior matched experimental data and the swelling coefficients were recovered for all formulations tested. Results indicate that the higher lipid affinity of the isobutylene phase contributed to increased swelling, as expected. This novel method to calculate swelling coefficient effectively circumvents the inability of commonly-used thermal deswelling methods to characterize lipid and oil-induced swelling behavior; enabling better prediction of long-term in vivo performance of polymer-based biomedical devices and more accurate evaluation of lipid-induced degradation and swelling.
Charge Control Strategy for Aircraft-Triggered Lightning Strike Risk Reduction

We propose a charge control strategy to reduce the risk of an aircraft-triggered lightning strike that exploits the asymmetry between the positive and negative ends of the bidirectional leader deve...
Acquiring wanna: Beyond Universal Grammar

The wanna facts are a classic Poverty of Stimulus (PoS) problem: Wanna is grammatical in certain contexts (Who do you want PRO to play with?) but not others (Who do you want who to play with you?)....
Immune regulation by ubiquitin conjugation.

It becomes increasingly evident that protein ubiquitination is closely linked to many aspects of the immune system and the E3 ubiquitin ligases play an important role in those processes via specific targeting of protein substrates. Gene database searching has indicated that there are several hundred E3 ubiquitin ligases, with the majority being RING finger-containing E3 ligases. It is conceivable that there will be very complicated interplay among the E3 ligases. Several E3 ligases may target the same substrate, or otherwise, one E3 ligase may target different substrates under diverse physiological conditions. In addition, the list of de-ubiquiting enzymes involved in immune regulation will increase in the near future. It has to be mentioned that biochemical and molecular approaches are still the main tools for identification of a substrate for a particular E3 ubiquitin ligase. The physiological relevance of such findings has to be correlated with genetic investigations. In any case, the field of research on protein ubiquitination in immune modulation will continue to be a hot topic in the years to come.
Assessing Current Local Capacity for Agrifood Production To Meet Household Demand: Analyzing Select Food Commodities across 377 U.S. Metropolitan Areas

Increasing food production in local urban and peri-urban areas is articulated as a potential way for local governments to achieve multiple sustainability outcomes (environmental, social, and human health). However, scientific judgements on localization are difficult to make because the degree of current food localization has not been systematically measured or defined across large numbers of cities. We develop new methods to quantify current local capacity for food production to meet total household agrifood demand, harmonizing bottom-up and top-down approaches to assess direct-plus-embodied agrifood demand of both fresh and processed foods. We find unique patterns of localization for different agrifoods, with 21% of U.S. metropolitan statistical areas (MSAs) currently capable of local self-sufficiency for eggs and milk equivalents embodied in diet, versus 12% and 16% of MSAs self-sufficient in fruits and vegetables, respectively. Focusing only on the direct fresh food demand, increased current local capa...
Startle evokes nearly identical movements in multi-jointed, two-dimensional reaching tasks

StartReact is the ability of the startle reflex to involuntarily release a planned movement in the presence of a loud acoustic stimulus resulting in muscle activity patterns and kinematics that are tightly regulated and scaled with the intended action. Previous studies demonstrated startReact’s robustness during simple single-joint reaching tasks and found no difference between startReact and voluntary movements for movement kinematics and muscle activation patterns. However, startReact has not been evaluated during multi-joint reaching movements with multiple degrees of freedom. It is unclear if startReact would evoke accurate and precise multi-joint reaching movements in an unrestricted workspace. Furthermore, if tested more rigorously, multi-joint startReact movement kinematics and muscle activation patterns might not be truly equivalent despite showing no difference through traditional ANOVAs. A previous study found multi-joint startReact was possible during unrestricted elbow and shoulder movement when reaching to a forward target. Therefore, we hypothesized that startReact would evoke similar multi-joint reaching movements for movement accuracy and muscle activation patterns when compared to voluntary movements in a multi-directional workspace. Expanding upon the previous study, our study uses a larger workspace and fully evaluates movement kinematics and muscle activations patterns. Results confirmed our hypothesis and found startReact movements were readily evoked in all directions. StartReact responses presented stereotypically earlier muscle activation, but the relative timing of agonist/antagonist firing pairs between startReact and voluntary movements remained similar. Results demonstrate that startReact is robustly present and equivalent in multi-joint reaching tasks and has potential clinical use for evaluating healthy and impaired movement.
Antimicrobial Chrysophaentin Analogs Identified from Laboratory Cultures of the Marine Microalga Chrysophaeum taylorii.

A laboratory culture of the colonial marine alga Chrysophaeum taylorii NIES-1699 yielded a set of new bioactive chrysophaentin analogs, and their structures were determined by HRESIMS and NMR spect...
Abstract ES3-1: Brain metastases of breast cancer

Brain metastases are devastating consequences of breast cancer. Both the lesions and their treatments cause physical and neurocognitive complications. Translational investigations have provided several new insights into the brain metastatic process which are hoped to lead to new preventive and therapeutic approaches. First, DNA sequencing of matched primary tumors and brain metastases revealed that nearly half of the brain lesions harbor potentially actionable mutations not present in the primary tumor. Second, model systems reveal that brain metastatic colonization arises through a complex interplay between the tumor cells and their microenvironment. Astrocytes are found in the normal blood-brain barrier and activate and surround a developing metastasis. They have been reported to modulate metastatic growth via several pathways. Additional investigations have uncovered other mechanistic contributions from activated microglia and other cells. The blood-brain barrier is also a contributor to heterogeneous and insufficient uptake of drugs to brain metastases. When a metastasis forms, the blood-brain barrier is termed a blood-tumor barrier (BTB). Multiple facets of the BBB are altered in the BTB. Alterations to the sphingosine-1 phosphate receptor 3 (S1P3) pathway in neuroinflammatory astrocytes of the BTB functionally altered BTB permeability. These data indicate that the BTB is a tractable structure to improve drug uptake and efficacy. Finally, investigators have identified brain permeable drugs and hormonal therapies that prevent the development of brain metastases in models, and which stand as support for new trials. Citation Format: Steeg P. Brain metastases of breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES3-1.
Temperature Control of psaA Expression by PsaE and PsaF in Yersinia pestis.

ABSTRACT PsaA, the subunit of the fimbria originally referred to as the “pH 6 antigen,” is required for full virulence of Yersinia pestis during bubonic plague. The expression of psaA is dependent upon specific environmental signals, and while the signals (high temperature and acidic pH) are defined, the mechanisms underlying this regulation remain unclear. In the closely related species Yersinia pseudotuberculosis, psaA transcription requires two regulatory genes, psaE and psaF, and it is speculated that posttranscriptional regulation of PsaE and/or PsaF contributes to the regulation of psaA transcription. Few studies have examined the regulation of psaA expression in Y. pestis, and prior to this work, the roles of psaE and psaF in Y. pestis had not been defined. The data presented here show that both psaE and psaF are required for psaA transcription in Y. pestis and that the impact of temperature and pH is mediated through discrete posttranscriptional effects on PsaE and PsaF. By generating antibodies that recognize endogenous PsaE and PsaF, we determined that the levels of both proteins are impacted by temperature and pH. High temperature is required for psaE and psaF translation via discrete mechanisms mediated by the mRNA 5′ untranslated region (UTR) upstream of each gene. Additionally, levels of PsaE and PsaF are impacted by pH. We show that PsaF enhances the stability of PsaE, and thus, both PsaE and PsaF are required for psaA transcription. Our data indicate that the environmental signals (temperature and pH) impact the expression of psaA by affecting the translation of psaE and psaF and the stability of PsaE and PsaF. IMPORTANCEY. pestis is a Gram-negative bacterial pathogen that causes bubonic plague. As a vector-borne pathogen, Y. pestis fluctuates between an arthropod vector (flea) and mammalian host. As such, Y. pestis must recognize environmental signals encountered within each host environment and respond by appropriately regulating gene expression. PsaA is a key Y. pestis mammalian virulence determinant that forms fimbriae. Our work provides evidence that Y. pestis utilizes multiple posttranscriptional mechanisms to regulate the levels of two PsaA regulatory proteins in response to both temperature and pH. This study offers insight into mechanisms that bacteria utilize to sense environmental cues and regulate the expression of determinants required for mammalian disease.
Design, synthesis and biological evaluation of spiropyrazolopyridone derivatives as potent dengue virus inhibitors.

The effective treatment for dengue virus infection continues to be a challenge. We herein reported our continued SAR exploration on the spiropyrazolopyridone scaffold. Introducing different substituents at the 3- or 5-site of the pyrazolopyridone core or moving the benzyl chain to the adjacent nitrogen led to a significant loss of potency on DENV-2. While a narrow range of substitutions were tolerated at the para-position of the phenyl ring, di-substitution on the phenyl ring is beneficial for DENV-2 potency and has variable influences on DENV-3 potency depending on the exact compound. Among these molecules, compounds 22 (JMX0376) with 4-chloro-3-fluorobenzyl and 24 (JMX0395) with 2,4-bis(trifluoromethyl)benzyl showed the most potent and broadest inhibitory activities against DENV-1 to -3 with nanomolar to low micromolar EC50 values.
Aquaculture applications of the Family Blenniidae

Marine ornamental fish production is still in its infancy compared with its freshwater ornamental counterpart. With ~1,800 wild caught fish species imported into the US each year, there is clear need for the expansion of marine ornamental production to include new species and families of fish. Distinct behavior and a wide range of colors makes blennies a popular choice in the aquarium hobby. These hardy fish are small and rarely aggressive to other reef species making them great for beginning aquarists, or fishes that can be added to an established reef community. The Blenniidae family is particularly common in the reef keeping community not only for their active nature, but also for their substrate cleaning and algae eating abilities. According to a 2012 report on marine ornamental fish, the family Blenniidae is 11th most imported group into the United States by volume with over 75 distinct species being traded (Rhyne et al. 2012). Due to this popularity many species of blennies are currently cultured and sold worldwide, with additional research underway to bring new species to market. A summary document highlighting culture protocols for members of the Blenniidae family is lacking and would provide valuable information to potential producers as well as the general public. This publication briefly covers: description and taxonomy, natural history, culture techniques, as well as diseases and marketing ornamental Blennids.
Impact of feed form, liquid application method, and feed augering on feed quality, nutrient segregation, and subsequent broiler performance

Summary Replicated research has not identified the impact of augering feed on the pellet quality, feed segregation, and resulting bird performance; therefore, 2 experiments were conducted. Experiment 1 was conducted to determine the effects of pellet-to-fine ratios (P:F; 55:45 or 75:25) and liquid application method (LAM; mixer liquid application method [MLAM] or postpellet liquid application method [PPLAM] addition of fat and phytase) on feed segregation, after augering, throughout a commercial feed line. Samples for each augered diet were obtained at 0, 15, 30, 32, 44, and 58 m on the feed line. After augering, each diet was retained by a feed pan location (FPL) from 0 to 30 and 32 to 58 m for experiment 2, to determine the effects of P:F, segregation, and FPL on day 28 to 56 performance and day 57 processing. Augering PPLAM diets increased percent pellets vs. MLAM diets. An FPL × P:F interaction found decreased percent pellets when augering from 0 to 15 and 44 to 58 m; 55:45 P:F diets had no change from 15 to 44 m; 75:25 P:F diets fluctuated. An LAM × P:F × FPL interaction showed decreased day 28 to 42 BW gain (BWG) for the MLAM and 75:25 P:F diets across FPL vs. PPLAM and 75:25 P:F diets. In addition, an LAM × P:F × FPL interaction demonstrated that the PPLAM affected day 56 BW uniformity by the FPL. The 75:25 P:F diet improved the BWG, as well as carcass and total breast weight. These data verify physical and nutrient (phytase) segregation occurs during augering and subsequently affects performance; future research should examine the specific nutrient segregation due to augering and the resulting impact on bird performance.
Size effects in plain-weave Astroquartz® deployable thin shells

The general scaling trend for brittle materials, in which the strength increases when the sample size decreases, is reversed in plain-weave laminates of Astroquartz® and cyanate ester resin. Specif...
Application of a convolutional neural network to improve automated early warning of harmful algal blooms

Continuous monitoring and early warning together represent an important mitigation strategy for harmful algal blooms (HAB). The coast of Texas experiences periodic blooms of three HAB dinoflagellates: Karenia brevis, Dinophysis ovum, and Prorocentrum texanum. A plankton image data set acquired by an Imaging FlowCytobot over a decade of operation was used to train and evaluate two new automated image classifiers. A 112 class, random forest classifier (RF_112) and a 112 class, convolutional neural network classifier (CNN_112) were developed and compared with an existing, 54 class, random forest classifier (RF_54) already in use as an early warning notification system. Both 112 class classifiers exhibited improved performance over the RF_54 classifier when tested on three different HAB species with the CNN_112 classifier producing fewer false positives and false negatives in most of the cases tested. For K. brevis and P. texanum, the current threshold of 2 cells.mL-1 was identified as the best threshold to minimize the number of false positives and false negatives. For D. ovum, a threshold of 1 cell.mL-1 was found to produce the best results with regard to the number of false positives/negatives. A lower threshold will result in earlier notification of an increase in cell concentration and will provide state health managers with increased lead time to prepare for an impending HAB.
Glial fibrillary acidic protein (GFAP) autoimmunity in the setting of seropositive rheumatoid arthritis treated with etanercept (P5.419)

Objective: We describe a case of GFAP IgG-associated autoimmune meningo-encephalo-myelo-neuritis in a patient with rheumatoid arthritis on etanercept. Background: GFAP-IgG is a recently discovered biomarker of an autoimmune central nervous system disorder characterized commonly by a steroid-responsive meningo-encephalo-myelitis. Underlying neoplasms are present in some patients, including ovarian teratomas and adenocarcinomas. Design/Methods: Case Report Results: A 63 year-old man with seropositive rheumatoid arthritis on etanercept developed steroid-responsive headaches and foot drop. MRI head showed multifocal white matter disease and leptomeningeal enhancement along the cervical cord. CSF showed 6 nucleated cells (normal, 0–5), elevated oligoclonal bands and protein (55 mg/dL; normal, 0–35) but negative infectious and paraneoplastic studies. Etanercept was discontinued, and steroids were held for a brain biopsy which showed a T-cell perivascular infiltrate. Ataxia, dysarthria, and dysphagia then developed and responded to restarting steroids with a prolonged taper. At prednisone 20 mg daily, vomiting, headache, and antalgic gait returned. EMG showed a subacute neurogenic process affecting bilateral lower extremities, and MRI demonstrated enhancement of the left tibial and common peroneal nerves. Sural nerve biopsy showed collections of endoneurial perivascular T-cells. Repeat brain MRI demonstrated progression of the intracranial leukoencephalopathy, and repeat CSF showed elevation in protein and oligoclonal bands with 2 nucleated cells. FDG-PET and bone marrow biopsy were negative for malignancy. Rapidly progressive encephalopathy occurred on prednisone 5 mg daily leading to hospitalization and initiation of high dose steroids. During this hospitalization, the repeat paraneoplastic panel demonstrated a GFAP antibody on mouse tissue immunofluorescence confirmed by cell-based assay. Cyclophosphamide and a prednisone taper were started with near complete resolution of symptoms. Conclusions: This case describes GFAP-IgG autoimmunity leading to a T-cell perivascular inflammatory central and peripheral nervous system disorder highly responsive to immunotherapy. The onset of the clinical syndrome was while on a TNF-alpha inhibitor, which also have been associated with inflammatory demyelinating disorders. Disclosure: Dr. Smith has nothing to disclose. Dr. Amin has nothing to disclose. Dr. Jones has nothing to disclose. Dr. Lachance has nothing to disclose. Dr Flanagan has nothing to disclose. Dr. Jentoft has nothing to disclose. Dr. Kantarci has nothing to disclose.
Abstract 023: Angiotensin-(1-7) Reduces Doxorubicin-Induced Cardiac Fibrosis

Doxorubicin (Dox) is a commonly used and effective chemotherapeutic agent for childhood leukemias and sarcomas. However, Dox administration often results in cumulative dose-dependent cardiotoxicity...
Non-collagenous ECM Matrix Components Growth Factors and Cytokines Involved in Matrix Mineralization

Biomineralization is a widespread process in living organisms to form minerals to harden tissues via hierarchically structured organic−inorganic composites. These processes are very diverse and complex. However, the site-specific location, size, and morphology of the crystals formed are specifically controlled by various cellular activities that vary between organisms. In vertebrates, bone, cartilage, and teeth are calcified tissues that are essential for the functional and structural integrity of the organism. The composition, crystal morphology, and materials properties of these structural elements are intriguing to multidisciplinary scientists. Further, the simplicity of biomineralization process with low energy costs, high quality, and formation under ambient conditions are impossible to reproduce in a bio-free system. Studies have implicated that the organic component of the mineralized tissues which include collagen and non-collagenous proteins (NCPs) play a critical role in mineral nucleation and growth. In this review, we highlight recent developments in dentin biomineralization process with respect to matrix proteins and growth factors.
A Cyber-Physical System for Freeway Ramp Meter Signal Control Using Deep Reinforcement Learning in a Connected Environment

Freeway bottlenecks such as on-ramp merging areas account for about 40% of recurring freeway congestion. It is generally agreed that building more roads and adding more lanes to existing infrastructure does not solve the congestion problem, and so dynamic traffic control measures offer a more cost-effective alternative. Ramp meters, traffic signal devices that regulate traffic flow entering freeways, are among the most effective measures to mitigate congestion at on-ramp merging areas on freeways. The confluence of deep reinforcement learning (RL) and connectivity provides a possible solution to advance ramp meter signal control. Deep RL is a group of machine-learning methods that enables an agent learning from the environment to improve its performance. In this study, three deep RL methods-proximal policy optimization (PPO), Ape-X deep Q-network (DQN), and asynchronous advantage actor-critic agents (A3C)-are explored for ramp meter signal control to maximize vehicle speed and traffic throughput, as well as to minimize energy consumption and emissions at freeway on-ramp merging areas in a connected environment. The low computational requirement and scalability of deep RL for deployment make it a powerful optimization tool for time-sensitive applications such as ramp meter signal control. The results of this study show that deep RL methods yield superior performance to both a fixed-time controller and ALINE A, a state-of-the-art feedback controller.
9 Using the QI essentials toolkit to assess risk, drive and sustain improvement in medication safety

Background Barcode-assisted medication administration (BCMA) is an evidence based practice to reduce medication administration errors; however, compliance rates with the use of this technology sometimes vary between different healthcare workers. Improving BCMA compliance benefits healthcare organizations in their efforts towards Zero Harm. Objectives Achieve less than 2% BCMA overrides at a pediatric hospital, within a 12 months’ timeframe. Methods To improve BCMA adherence across all disciplines, the IHI’s QI Essentials Toolkit was used to guide an interprofessional team of nurses, physicians, pharmacists, respiratory therapists, imaging techs and quality professionals. The team came together to conduct a Failure Mode and Effects Analysis (FMEA) and identify units with overrides rates above 2% to build a task force (figure 3). A nurse manager was identified as the task force leader and every unit was represented by a leader and a worker at the point of care. The task force prioritized addressing knowledge, attitudes and behaviors towards BCMA and applied change concepts to engage the workforce in using the technology. This priority was backed up by availability of weekly data that allowed drilling down to individual measurement of medications administered and BCMA use. Continuous improvement was tracked through run charts that displayed organizational and unit-level results starting with pre-interventions baseline data. Results A sustained BCMA overrides rate below 2% was achieved, with a mean of 1.26 (figures 1 and 2). Conclusions When introducing an interprofessional team to proactive risk assessment and continuous improvement, the IHI’s QI Essentials Toolkit proved effective in providing the team with tools to prioritize efforts, test change, achieve results and sustain improvement over time, all while supporting organizational learning.