cssi/SciSciGPT-SciSciNet huggingface dataset:
Learning from the Steersman: A Natural History of Cybernetic Models

Cybernetic models rely on optimal control heuristics to predict the effects of metabolic regulation on the dynamics of biochemical reaction networks. Over the past 30+ years, this fertile paradigm has brought forth scores of research publications and has witnessed diverse applications ranging from bioprocess optimization and control to the redesign of cellular hosts through rational metabolic engineering. This review traces the historical development of the cybernetic modeling framework, beginning with its philosophical presuppositions and then following its progress from first-generation “lumped” cybernetic models to biochemically detailed second-generation models to recent “hybrid” cybernetic models that combine aspects of both first- and second-generation models. The broad and lasting influence of the cybernetic modeling approach is due in large part to the fact that it has remained true to its foundational principles while adapting over time to meet the changing demands of biotechnology research.
A Resident-Led Institutional Patient Safety and Quality Improvement Process:

The authors used a multipronged approach to gain resident involvement in institutional quality improvement over a 3-year period; the initiative included a survey, a retreat, workgroups, a resurvey, and another retreat. Survey results (from 2007 compared with those of 2010) demonstrated significant improvement in almost all the top issues concerning patient safety for residents-emergency department boarding and crowding, adequacy of patient flow through the institution, adequacy of nursing and technical support staffing, and laboratory specimen handling (initial overall mean concern level was 2.87, and final concern level was 2.19; P < .01). This perceived improvement in patient safety concerns for residents was associated with observable improvements in areas of high concern for hospital leaders. By surveying residents and students, prioritizing concerns, convening a hospital-wide retreat with key leaders, and implementing accountable plans, the authors have demonstrated that resident perceptions of quality and safety can help drive quality improvement and engage residents in improvement efforts at an institutional level.
Response of post-mortem human head under primary blast loading conditions- effect of blast overpressures

Blast induced neurotrauma (BINT), and posttraumatic stress disorder (PTSD) are identified as the “signature injuries” of recent conflicts in Iraq and Afghanistan. The occurrence of mild to moderate traumatic brain injury (TBI) in blasts is controversial in the medical and scientific communities because the manifesting symptoms occur without visible injuries. Whether the primary blast waves alone can cause TBI is still an open question, and this work is aimed to address this issue. We hypothesize that if a significant level of intracranial pressure (ICP) pulse occurs within the brain parenchyma when the head is subjected to pure primary blast, then blast induced TBI is likely to occur.In order to test this hypothesis, three post mortem human heads are subjected to simulated primary blast loading conditions of varying intensities (70 kPa, 140 kPa and 200 kPa) at the Trauma Mechanics Research Facility (TMRF), University of Nebraska-Lincoln. The specimens are placed inside the 711 mm × 711 mm square shock tube at a section where known profiles of incident primary blast (Friedlander waveform in this case) are obtained. These profiles correspond to specific field conditions (explosive strength and stand-off distance). The specimen is filled with a brain simulant prior to experiments. ICPs, surface pressures, and surface strains are measured at 11 different locations on each post mortem human head. A total of 27 experiments are included in the analysis.Experimental results show that significant levels of ICP occur throughout the brain simulant. The maximum peak ICP is measured at the coup site (nearest to the blast) and gradually decreases towards the countercoup site. When the incident blast intensity is increased, there is a statistically significant increase in the peak ICP and total impulse (p 235 kPa for blunt impacts. Based on these criteria, no injury will occur at incident blast overpressure level of 70 kPa, moderate to severe injuries will occur at 140 kPa and severe head injury will occur at the incident blast overpressure intensity of 200 kPa. However, more work is needed to confirm this finding since peak ICP alone may not be sufficient to predict the injury outcome.© 2013 ASME
Can Western science provide a foundation for acupuncture

Acupuncture and other complementary medical modalities that involve holistic principles challenge the dominant biomedical paradigm of mechanical reductionism and therefore are considered unconventional or alternative. This keynote presentation will review three different hypotheses of acupuncture, two of which lie within the dominant scientific paradigm, and a third that is built upon frontier ideas at the edge of the new science of bioelectromagnetics. The Zhang-Popp hypothesis, based on endogenous electromagnetic fields of the body, is capable of accommodating many puzzling features of acupuncture. In order to embody the latter, it appears that a new paradigm for the life sciences is needed to address the wholeness and integrity of the organism. Nonetheless, I believe that there are serious limitations in attempting to embrace the indigenous knowledge system of the East, one of the oldest systems of empirical knowledge, by a 300-year-old science of the West, because of their vast differences in biophilosophies and cultural orientations. All knowledge systems, East or West, are context-dependent; none can represent true objectivity. Despite this pluralistic view, working toward a unity of Eastern and Western thought may lead to a more universal understanding of acupuncture in the future.
Basics of Biomolecule Mass Spectrometry

The chapter examines the general application of mass spectrometry to biomolecules. As compounds are being developed in the hope of creating new treatments for cancer, AIDS, and other diseases, mass analysis offers a routine and relatively easy means of characterization. For such routine mass analysis to be successful, a few simple conditions must be met. The chapter familiarizes the reader with these general conditions as well as sample preparation. Biomolecule mass analysis is typically accomplished by adding protecting groups to make molecules more volatile and stable. A stable molecule can then be thermally vaporized into the mass spectrometer's ionization source that utilizes either electron or chemical ionization. The amount of a sample is critical. Too little or even too much of a sample can dramatically affect the mass spectrum, and mean the difference between a successful and an unsuccessful analysis. If too little of a sample is used, the instrument is unable to detect. Analyzing too much of a sample can even cause signal suppression. Therefore, more samples are not always better; it is important to be in the right range.
Interaction of decreased arterial Po2 and exercise on carbohydrate metabolism in the dog

To determine the mechanism by which low arterial PO2 (PaO2) affects muscle carbohydrate (CHO) metabolism during exercise, dogs inhaled gas consisting of 0.21 (NO; n = 6) or 0.11 (LO; n = 6) inspire...
Phenyhexyl Isothiocyanate, a Novel Inhibitor of Histone Deacetylation and Methylation, Induce Growth Arrest and Apoptosis of Myeloma Cells.

Abstract Histone deacetylase (HDAC) inhibitors are emerging as a promising family of new agents in the therapy of hematologic malignancies. We have shown that phenyhexyl isothiocyanate(PHI) is a novel histone deacetylase inhibitor and can also modulate histone methylation in leukemia cells. In this study we investigated the effect of PHI on human myeloma cell line RPMI8226 in vitro. We have observed that cell proliferation was inhibited by PHI in a dose and time dependent manner. Cell cycle analysis indicated an arrest in G0/G1 phase, and significant apoptosis was detected in PHI treated RPMI8226 cells. The accumulation of P21 and reduced Levels of PCNA were detected. We also examined the effect of PHI on vascular endothelial growth factor (VEGF) production by the myeloma cells. Treatment with 20μM PHI for 24hrs led to a decrease of VEGF concentration by 50% of that secreted by the control cells. VEGF production further decreased to 25% when the cells were exposed to PHI for 48hrs. These data suggest that myeloma cells are sensitive to the novel HDAC inhibitor, and PHI may become a novel agent in multiple myeloma therapy. Download : Download high-res image (93KB) Download : Download full-size image
Management of Skin Disorders of the Newborn

Skin disorders of the newborn are unique in that some are only seen during the newborn period, whilst others have inherently more risk to the child within this period. Some of these disorders are self-limiting but may warrant additional monitoring or have therapeutic interventions to expedite resolution. Other disorders require prompt diagnosis and intervention to decrease potential morbidity to the neonate. Furthermore, many of these entities clinically mimic one another. This chapter highlights the most important diagnostic and management strategies of skin disorders seen in the first month of life.
New wine in old wineskins: A critical appraisal of diaspora missiology:

In the past decade, there has been an explosion of research that uses insights from migration studies as a way of understanding various shifts in global Christianity. As a result, missiology has bo...
Three-dimensional Monte Carlo simulations of materials on the physical deposition process

The sputtering technique is largely used for the deposition of thin layers. In this study, the Monte Carlo (MC) method combined with the binary collision theory of hard spheres is used to simulate the energy, direction and topology of the film deposit. The effects of several parameters such as the substrate, target, pressure and the distance between substrate and target were analyzed. Our results showed that for large pressures or distances, energy and angular distributions are uniform and consequently the obtained film will be uniform. The obtained results are in agreement with other works, which validates our calculations.
Lead-induced permeability changes in immature vessels of the developing cerebellar microcirculation.

The ultrastructure and microcirculatory permeability changes of lead encephalopathy were studied in an animal model using horseradish peroxidase as an intravascular tracer. The fine structure of capillary sprouts in the developing cerebellar microcirculation of lead-poisoned rats were described. Immature vessels, characterized by the presence of endothelial sprouts, were found to have focal areas of endothelial injury with degenerating endothelial cells. These disruptions of the microcirculatory endothelium had tracer extending from the vessel lumen to the surrounding neuropil. The degenerating endothelial cells were found as early as 24–28 h after the first administration of lead acetate by gastric lavage (2–3-day-old rats). The early injury to endothelial cells of immature vessels in the developing microcirculation is suggested as an important component of the vascular permeability changes which characterize lead encephalopathy. Older animals (5–10 days old) had microaneurysmal vascular dilatations which had a complex internal structure formed by endothelial cells. These microaneurysmally dilated vessels may represent an endothelial response to preceding endothelial injury of immature vessels.
Microstructural evolution and deformation behavior of Al-Cu alloys: A Transmission X-ray Microscopy (TXM) and micropillar compression study

Abstract A unique approach to correlating an evolving 3D microstructure in an Al-Cu alloy and its micro-scale mechanical properties has been introduced. Using these nanoscale three-dimensional microstructures derived from Transmission X-ray Microscopy (TXM), individual contributions from different strengthening mechanisms were quantified. The spatial distribution and morphology of the individual θ′ and θ phases were seen to play an important role in influencing dislocation storage. Uniaxial micro-compression experiments were used to quantify the stress-strain response of the alloy at different aging times. Transmission electron microscopy (TEM) aided in discerning dislocation activity at these precipitates. A model is proposed to accurately predict the variation in yield stress by using appropriate morphological parameters from the 3D microstructure and its validity has been corroborated using experimental measurements. Distributions of 2D and 3D inter-precipitate spacing were seen to provide crucial insights on influencing deformation in such precipitation-strengthened alloys. Finally, the transition in deformation behavior and origin of numerous strain bursts were investigated using in situ micropillar compression testing.
Obscure Dichotomy of Early Childhood Trauma in PTSD Versus Attachment Disorders

There are two competing schools of thoughts involving children who have experienced early childhood trauma. One posture's nosology focuses on the post-traumatic stress responses; the other focuses on the deviant behaviors that ensue from pathogenic care in early childhood. This author sought to review the literature from a holistic perspective, embracing both diagnostic positions. Seventy-three articles addressing childhood trauma and the ensuing emotional or behavioral disturbances were evaluated, mostly empirical-including 16 that specified posttraumatic stress disorder (PTSD), 21 that specified attachment disorders, and 37 that included potential overlaps between both trauma derivatives. An additional 138 studies were reviewed but not included herein because those focused on broader issues. Statistical data, financial and emotional impacts, and the effects of disrupted attachments were addressed-including both children with secure attachments and those with compromised attachments. The critical effect of both positive and negative parental responses was evaluated, as well as correlations or overlaps in the diagnostic criteria and symptom manifestations of the children and any apparent gaps in the current research. The literature details that the prognosis and course of treatment vary significantly between the two etiologies-apparently at least in part due to possible clinician bias in conceptualizations of the two populations. There are clear overlaps in the diagnostic criteria that strongly suggest comorbidity between the disorders, however, which is especially critical to analyze in the future, since there are solid, empirical, evidence-based treatment protocols for PTSD, but not for attachment disorders resulting from pathogenic caregiver maltreatment.
Reasoning About the Scope of Religious Norms: Evidence From Hindu and Muslim Children in India.

Conflicts arise when members of one religion apply their norms to members of another religion. Two studies explored how one hundred 9- to 15-year-old Hindu and Muslim children from India reason about the scope of religious norms. Both Hindus and Muslims from a diverse Hindu-Muslim school (Study 1) and Hindus from a homogeneous Hindu school (Study 2) more often judged it wrong for Hindus to violate Hindu norms, compared to Muslim norms, and said the opposite for Muslims. In contrast, children judged it wrong for both Hindus and Muslims to harm others. Thus, even in a setting marred by religious conflict, children can restrict the scope of a religion's norms to members of that religion, providing a basis for peaceful coexistence. [ABSTRACT FROM AUTHOR]
Examining Predictors of Bullying and Sexual Violence Perpetration Among Middle School Female Students

This chapter includes the first systematic attempt to examine the association between bullying perpetration and sexual violence perpetration among a middle school sample and the most comprehensive longitudinal study to examine whether risk (e.g., anger, family violence exposure) and protective factors (e.g., caring, school support) predict these two behaviors among female middle school students (N = 576). Using longitudinal data, two separate regression analyses were performed to predict future bullying and sexual violence perpetration by middle school girls. The strongest predictors of bullying perpetration over a 2-year period were sibling aggression, depression, and delinquency, after controlling for baseline levels of bully perpetration. Additionally, greater perceived family social support was associated with less bullying perpetration over time. For sexual harassment perpetration, significant predictors included attitudes that were dismissive of sexual harassment and earlier sexual harassment perpetration. The lack of overlap between predictors for these two behaviors suggests that sexual harassment perpetration among girls in middle school could not be explained by predictors that are well documented in the bullying literature. Much more scholarship needs to focus on identifying what predicts sexual harassment perpetration among girls. Finally, the assumption that addressing risk and protective factors associated with bullying perpetration might reduce sexual violence perpetration over time was not supported. Additional results and implications are presented.
[18] Proton transfer in carbonic anhydrase measured by equilibrium isotope exchange

Publisher Summary Kinetic and structural studies demonstrate the pathways of inter- and intramolecular proton transfer in the hydration of CO 2 catalyzed by carbonic anhydrase. A histidine residue at position 64 is the most efficient of the carbonic anhydrases, carbonic anhydrase II, and acts as a transfer group shuttling protons between the buffer in solution and the zinc-bound water at the active site. This conclusion is confirmed by mutations to replace His-64 that results in the inactivation of catalysis. Mutations to introduce His-64 in the less efficient carbonic anhydrase III results in activation, with the mutant showing proton transfer properties, similar to the efficient form of the enzyme. In a series of site-specific mutants of isozyme III, the rate constants for proton transfer obeys a Bronsted correlation and show sharp curvature characteristic of facile proton transfers. Application of Marcus rate theory shows that this proton transfer has the small intrinsic energy barrier (near 1.5 kcal/mol) characteristic of rapid bimolecular proton transfer between nitrogen and oxygen acids and bases in solution. The observed overall energy barrier (near 10 kcal/mol) for proton transfer in the catalysis indicates the involvement of accompanying energy-requiring processes, such as solvent reorganization or conformational change. Some of this barrier is likely to involve the formation of hydrogen-bonded water in the active-site cavity through the intramolecular proton transfer that occurs.
Solidly Mounted Anti-Symmetric Lamb-Wave Delay Lines as an Alternate to SAW Devices

This letter reports the first results on a new generation of anti-symmetric lamb-wave devices using a simple solidly mounted platform of AlN/Mo/Si and operating at very-high-to-super-high frequency range. AlN/Mo/Si-based solidly mounted resonators (SMRs) with sub-micrometer interdigitated transducers were fabricated using the electron beam lithography and liftoff process. Plasma etching was used to etch vias in ground pads to get access to the bottom electrode for grounding. By comparing the floating, grounded, and no bottom electrode device performances, it has been observed that the presented SMR design with grounded bottom electrode results in enhancement of the coupling efficiency by 500% compared with conventional SAW devices. In addition, these devices are more mechanically robust and can be monolithically integrated with a CMOS platform without requiring complex packaging processes compared with conventional released lamb-wave resonators.
Pathologic Nodal Involvement in Patients With Penile Cancer With Cavernosal Versus Spongiosal Involvement.

Abstract Background The American Joint Committee on Cancer recently proposed new TNM staging for penile cancer, with proposed T2 as spongiosal invasion and T3 as cavernosal invasion. We sought to validate the proposed staging system for predicting pathologic nodal involvement using the National Cancer Data Base. Patients and Methods Invasive penile cancer cases from 2010 to 2012 were identified. Differences in demographic and pathologic factors between T2 and T3 tumors were compared using χ2 and t tests. Logistic regression was performed to determine the odds of pathologically involved lymph nodes (pN+) by T classification. Results There were 378 T2 and 524 T3 patients with penile cancer. Compared with T2 tumors, T3 tumors were larger (mean size, 5.8 cm vs. 4.3 cm), had higher positive surgical margin rates (12% vs. 9%), and were more likely to have lymphovascular invasion (42% vs. 31%) (all P Conclusion The proposed new American Joint Committee on Cancer staging system for the penile cancer distinguishes spongiosal (T2) from cavernosal (T3) involvement. There does not appear to be a difference in positive lymph node status between the 2 grades when other clinical and pathologic variables are considered.
Scaling tree-based automated machine learning to biomedical big data with a dataset selector

Abstract Automated machine learning (AutoML) systems are helpful data science assistants designed to scan data for novel features, select appropriate supervised learning models and optimize their parameters. For this purpose, Tree-based Pipeline Optimization Tool (TPOT) was developed using strongly typed genetic programming to recommend an optimized analysis pipeline for the data scientist’s prediction problem. However, TPOT may reach computational resource limits when working on big data such as whole-genome expression data. We introduce two new features implemented in TPOT that helps increase the system’s scalability: Dataset selector and Template. Dataset selector (DS) provides the option to specify subsets of the features as separate datasets, assuming the signals come from one or more of these specific data subsets. Built in at the beginning of each pipeline structure, DS reduces the computational expense of TPOT to only evaluate on a smaller subset of data rather than the entire dataset. Consequently, DS increases TPOT’s efficiency in application on big data by slicing the dataset into smaller sets of features and allowing genetic programming to select the best subset in the final pipeline. Template enforces type constraints with strongly typed genetic programming and enables the incorporation of DS at the beginning of each pipeline. We show that DS and Template help reduce TPOT computation time and may provide more interpretable results. Our simulations show TPOT-DS significantly outperforms a tuned XGBoost model and standard TPOT implementation. We apply TPOT-DS to real RNA-Seq data from a study of major depressive disorder. Independent of the previous study that identified significant association with depression severity of the enrichment scores of two modules, in an automated fashion, TPOT-DS corroborates that one of the modules is largely predictive of the clinical diagnosis of each individual. Author Summary Big data have recently become prevalent in many fields including meteorology, complex physics simulations, large scale imaging, genomics, biomedical research, environmental research and more. TPOT is a Python Automated Machine Learning (AutoML) tool that uses genetic programming to optimize machine learning pipelines for analyzing biomedical data. However, like other AutoML tools, when analyzing big data, the early implementations of TPOT face the challenges of long runtime, high computational expense as well complex pipeline with low interpretability. Here, we develop two novel features for TPOT, Dataset Selector and Template, that leverage domain knowledge, greatly reduce the computational expense and flexibly extend TPOT’s application to biomedical big data analysis.
Economic Outcomes for Harvesters under the West Coast Groundfish Trawl Catch Share Program: Have Goals and Objectives Been Met?

AbstractThe West Coast Groundfish Trawl Catch Share Program was designed to achieve multiple economic goals and objectives, including increasing net benefits, profitability, flexibility, and utilization of harvest allocations. In this article, we leverage seven years of comprehensive cost and earnings data to evaluate progress towards these goals with a focus on harvesters. Our assessment shows that five years post-implementation, net benefits to the nation have doubled, and indicators of productivity and profitability have increased. The fleet that targets Pacific whiting has seen the largest gains, due in part to increases in total allowable catch and the elimination of the race-to-fish. However, increased revenues have not been realized to the degree that was expected for harvesters targeting non-whiting groundfish, partly due to lower than predicted consolidation and relatively low quota utilization. Economic outcomes indicate that tradeoffs exist between certain objectives of the program, specificall...
Remembering the Presidents

Here we report research on how important historical figures—presidents of the United States—are remembered and forgotten. When students are given 5 min to recall presidents (in order, if possible),...
Black Cat Bias: Prevalence and Predictors:

There is anecdotal and empirical evidence for black cat bias, the phenomenon where cats (Felis silvestris catus) with black coats are viewed more negatively, adopted less often, and euthanized more often than lighter colored cats. Despite the anecdotal claims, there is scarce empirical evidence for black cat bias. Using evaluations of cat photos, the researchers examined differences in people's attitudes toward black and non-black cats of various colorations on measures of perceived aggression, perceived friendliness, and willingness to adopt. The researchers also explored whether participants' levels of religiosity, superstitious beliefs, and prejudicial racial attitudes were related to black cat bias. Finally, the researchers explored whether black cat bias was related to difficulties people had in reading the emotions of black cats compared to non-black cats. This study provided evidence of black cat bias in the sample. People exhibiting higher degrees of black cat bias had higher levels of superstition, but not religiosity or racial prejudice. Additionally, people who had difficulty reading the emotions of black cats tended to exhibit a stronger bias against adopting black cats.
Psychophysical test results in the determination of an appropriate gamma for transmissive color displays

Following research reported by the authors to SID in 2017 and SPIE in 2018, this paper presents an expanded set of research results for psychophysical research conducted to determine of 255 Just Noticeable Color Differences (JNCDs). Given transmissive displays shall continue to create their color palette via color sub-pixel gray levels; given the number of such gray levels shall continue to be 255 (plus black) for most avionic, vetronic and shipboard applications, the authors propose to identify a set of gamma values unique to a transmissive display’s three color channels and which conform to the intensity difference thresholds of the tritanoptic visual system. Method of research, to include procedure, equipment, stimuli and test subjects shall be identified. Results shall include raw data regarding psychophysically determined intensity difference thresholds and a range of gammas for the red, green, and blue color channels of an hypothetic, JND adapted, 256 gray level transmissive display.
Towards spike-based machine intelligence with neuromorphic computing.

Guided by brain-like ‘spiking’ computational frameworks, neuromorphic computing—brain-inspired computing for machine intelligence—promises to realize artificial intelligence while reducing the energy requirements of computing platforms. This interdisciplinary field began with the implementation of silicon circuits for biological neural routines, but has evolved to encompass the hardware implementation of algorithms with spike-based encoding and event-driven representations. Here we provide an overview of the developments in neuromorphic computing for both algorithms and hardware and highlight the fundamentals of learning and hardware frameworks. We discuss the main challenges and the future prospects of neuromorphic computing, with emphasis on algorithm–hardware codesign. The authors review the advantages and future prospects of neuromorphic computing, a multidisciplinary engineering concept for energy-efficient artificial intelligence with brain-inspired functionality.
Mutant P53 induces MELK expression by release of wild-type P53-dependent suppression of FOXM1

Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer, and is associated with a poor prognosis due to frequent distant metastasis and lack of effective targeted therapies. Previously, we identified maternal embryonic leucine zipper kinase (MELK) to be highly expressed in TNBCs as compared with ER-positive breast cancers. Here we determined the molecular mechanism by which MELK is overexpressed in TNBCs. Analysis of publicly available data sets revealed that MELK mRNA is elevated in p53-mutant breast cancers. Consistent with this observation, MELK protein levels are higher in p53-mutant vs. p53 wild-type breast cancer cells. Furthermore, inactivation of wild-type p53, by loss or mutation of the p53 gene, increases MELK expression, whereas overexpression of wild-type p53 in p53-null cells reduces MELK promoter activity and MELK expression. We further analyzed MELK expression in breast cancer data sets and compared that with known wild-type p53 target genes. This analysis revealed that MELK expression strongly correlates with genes known to be suppressed by wild-type p53. Promoter deletion studies identified a p53-responsive region within the MELK promoter that did not map to the p53 consensus response elements, but to a region containing a FOXM1-binding site. Consistent with this result, knockdown of FOXM1 reduced MELK expression in p53-mutant TNBC cells and expression of wild-type p53 reduced FOXM1 expression. ChIP assays demonstrated that expression of wild-type p53 reduces binding of E2F1 (a critical transcription factor controlling FOXM1 expression) to the FOXM1 promoter, thereby, reducing FOXM1 expression. These results show that wild-type p53 suppresses FOXM1 expression, and thus MELK expression, through indirect mechanisms. Overall, these studies demonstrate that wild-type p53 represses MELK expression by inhibiting E2F1A-dependent transcription of FOXM1 and that mutation-driven loss of wild-type p53, which frequently occurs in TNBCs, induces MELK expression by suppressing FOXM1 expression and activity in p53-mutant breast cancers.
Abstract P5-05-11: Novel small molecule STAT3 inhibitors induce apoptosis and suppress cell migration and tumor growth in triple-negative breast cancer cells

Persistent STAT3 signaling is frequently detected in many cancer types and thus could potentially serve as a viable therapeutic target. In this study, we tested two novel small STAT3 inhibitors, LLY17 and LLL12B in triple-negative breast cancer cells, which frequently express persistent STAT3 phosphorylation. LLY17 and LLL12B selectively inhibited IL-6-mediated induction of STAT3 phosphorylation but no effect on IFN-γ mediated induction of STAT1 phosphorylation. LLY17 and LLL12B induced apoptosis in triple-negative breast cancer cells but exhibited minimal toxicity toward normal mammary epithelial cells. RNAi attenuation experiments confirmed the requirement of STAT3 for LLY17 and LLL12B-mediated inhibition of cell viability in triple-negative breast cancer cells. LLY17 and LLL12B inhibited STAT3 phosphorylation in human and murine triple-negative breast cancer cells. In addition, LLY17 and LLL12B inhibited cell migration of human and murine triple-negative breast cancer cells. Furthermore, LLY17 and LLL12B suppressed tumor growth and STAT3 phosphorylation of triple-negative breast cancer cells in vivo in a mammary fat pad murine syngeneic mouse model. Together, our findings suggest that targeting persistent STAT3 signaling pathway by novel oral bioavailable small molecules LLY17 and LLL12B may be a potential approach for the therapy of triple-negative breast cancer. Citation Format: Li Pan, Xiang Chen, Shengling Fu, Chenglong Li, Hui-Wen Lo, Jiayuh Lin. Novel small molecule STAT3 inhibitors induce apoptosis and suppress cell migration and tumor growth in triple-negative breast cancer cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-05-11.
Fine-scale habitat heterogeneity and vole runways influence seed dispersal in Plagiobothrys nothofulvus.

PREMISE Seed dispersal allows plants to colonize new sites and contributes to gene flow among populations. Despite its fundamental importance to ecological and evolutionary processes, our understanding of seed dispersal is limited due to the difficulty of directly observing dispersal events. This is particularly true for the majority of plant species that are considered to have gravity as their primary dispersal mechanism. The potential for long-distance movement of gravity-dispersed seeds by secondary dispersal vectors is rarely evaluated. METHODS We employ whole-genome assays of maternally inherited cpDNA in Plagiobothrys nothofulvus to resolve patterns of genetic variation due to effective (realized) seed dispersal within a 16 hectare prairie that is characterized by a mosaic of habitat types. We evaluate the effects of microgeographic landscape features extracted from micro-UAV aerial surveys on patterns of seed dispersal using landscape genetics methods. RESULTS We found evidence of high resistance to seed-mediated gene flow (effective dispersal) within patches of Plagiobothrys nothofulvus, and strong genetic structure over distances of less than 20 m. Geographic distance was a poor predictor of dispersal distance, while landscape features had stronger influences on patterns of dispersal (distance and direction of seed movement). Patterns of dispersal were best predicted by the combined distribution of flower patches, habitat type, and the network of vole runways, with the latter explaining the largest proportion of variation in the model. CONCLUSIONS Our results suggest that primary dispersal occurs mostly within microhabitats and infrequent secondary dispersal may occur over longer distances due to the activity of small mammals and other vertebrates.
Prevention of the progression of atherosclerosis and aging through nitric oxide (NO)

The EDRF discovered in 1986 by Furchgott was later identified as NO by Ignarro. NO was a widely noted gas with diverse functions, having arginine (L-Arg) as a substrate for the NO synthase (NOS). L-Arg and L-citrulline (L-Cit) have long been associated with the urea cycle. L-Cit was produced with NO by the reaction of L-Arg and oxygen. It was shown that administration of L-Arg in animals and humans caused vasodilation and anti-arteriosclerosis effects. Despite the arginine paradox ratio of intracellular arginine concentration to the Km value of NOS gaining widespread attention, advanced arteriosclerosis is known to reduce vascular reactivity towards L-Arg. In recent years, the anti-arteriosclerosis and anti-cell aging effects of the reactive substance citrulline (L-Cit) have been studied. L-Cit and L-Arg combination therapy are starting to be considered in various clinical applications as well.
Immunodeficiency-Associated Lymphoproliferative Disorders Other Than PTLD (in Primary Immune Deficiency, HIV, and Iatrogenic Conditions)

This chapter discusses the three categories of lymphoproliferative disorders arising from immune deficiencies: primary immune deficiency, human immunodeficiency virus (HIV) infection, and iatrogenic medication. Posttransplant lymphoproliferative disorder is discussed in a separate chapter. In all three categories, various forms of immune suppression result in increased risks of developing lymphoproliferative disorders. In primary immune deficiency, compromised humoral immunity, cellular immunity, or both are associated with inherited or congenital disorders that result in increased incidence of lymphoid neoplasms. These lymphomas most commonly arise in children and young adults. In HIV infection, cellular immunities are compromised by direct viral infection of helper/inducer T cells. In conditions associated with iatrogenic medication, lymphomas arise after prolonged immune suppression by cytotoxic chemotherapy or immune modulatory therapy. These drugs suppress and modulate cellular and humoral immunities resulting in immunologic dysregulation and lymphoid hyperactivation. Although the etiologies of the immune deficiencies vary in these disorders, they result in similar consequences with dysregulation and suppression of immune system and increased risk of lymphomas most commonly EBV-driven large cell and aggressive lymphomas.
Mentoring pathways program for first-year education doctor of education students: perspectives of a program redesigned for sustainability

Education doctoral (EdD) students face unique challenges to complete a doctorate as scholar-practitioners. An EdD mentoring pathways program for first year EdD students to receive support and advic...
Genome editing with CRISPR–Cas nucleases, base editors, transposases and prime editors

The development of new CRISPR-Cas genome editing tools continues to drive major advances in the life sciences. Four classes of CRISPR-Cas-derived genome editing agents-nucleases, base editors, transposases/recombinases and prime editors-are currently available for modifying genomes in experimental systems. Some of these agents have also moved rapidly into the clinic. Each tool comes with its own capabilities and limitations, and major efforts have broadened their editing capabilities, expanded their targeting scope and improved editing specificity. We analyze key considerations when choosing genome editing agents and identify opportunities for future improvements and applications in basic research and therapeutics.
Sex, Age, and Race Effects on Immunogenicity of MenB-FHbp, A Bivalent Meningococcal B Vaccine: Pooled Evaluation of Clinical Trial Data

An extensive clinical development program showed that the meningococcal serogroup B-factor H binding protein (MenB-FHbp) vaccine affords protection against MenB disease for adolescents and adults. Data were pooled from multiple studies within the program to examine whether MenB-FHbp immunogenicity was influenced by sex, age, or race. Immunogenicity was assessed in subjects from seven studies who received 120 µg MenB-FHbp (at 0, 2, 6 months) and had evaluated immune responses against four representative test strains via serum bactericidal assays using human complement (hSBAs). Immune responses were presented by sex (male, female), age group (10–14, 15–18, 19–25, 10–25 years), and race (white, black, Asian, other). Among 8026 subjects aged 10–25 years included in this analysis, MenB-FHbp elicited robust immune responses in a high percentage of subjects regardless of demographic characteristics. Across all test strains and demographic subsets, a ≥ 4-fold rise in titer from baseline was achieved in 76.7–95.0% of subjects, with no major differences by sex, age groups assessed, or races evaluated. Corresponding percentages achieving titers ≥ the lower limit of quantification (LLOQ) against all four strains combined were 79.7–87.3% (sex), 81.6–85.5% (age), and 80.0–88.1% (race). Minor differences were observed for geometric mean titers and percentages of subjects achieving titers ≥ LLOQ against each strain based on demographics. These data suggested no clinically meaningful differences in MenB-FHbp immunogenicity when administered as a three-dose schedule based on sex, ages assessed, or races evaluated. This analysis supports the continued recommended use of MenB-FHbp to prevent MenB disease in adolescents and young adults. ClinicalTrials.gov identifiers, NCT00808028, NCT01830855, NCT01323270, NCT01461993, NCT01461980, NCT01352845, and NCT01299480.
Identifying as a Good Parent: Considering the Communication Theory of Identity for Parents of Children Receiving Palliative Care.

Background: Parents of seriously ill children are at risk of psychosocial morbidity, which may be mitigated by competent family-centered communication and role-affirming conversations. Parent caregivers describe a guiding desire to do a good job in their parenting role but also depict struggling under the intense weight of parental duty. Objectives and Design: Through this case study, the Communication Theory of Identity (CTI) provides a framework for conceptualizing how palliative care teams can help parents cope with this reality. CTI views communication with care teams as formative in the development and enablement of parental perceptions of their "good parenting" role. Results: Palliative care teams may consider the four frames of identity (personal, enacted, relational, and communal) as meaningful dimensions of the parental pursuit to care well for an ill child. Conclusion: Palliative care teams may consider compassionate communication about parental roles to support the directional virtues of multilayered dynamic parental identity.
A systematic review of the quality of cardiovascular surgery studies that extracted data from the MAUDE database

Abstract Objective To investigate opportunities and limitations of using the Manufacturer and User Facility Device Experience (MAUDE) database for cardiovascular surgery research, we analyzed the quality of studies having ever used MAUDE, in the field of cardiovascular surgery. Methods We systematically searched the Cochrane Library, PubMed, EMBASE, and Google Scholar for randomized and nonrandomized studies, from inception to July 2019. Two authors evaluated the quality of the retrieved observational studies, according to the National Institutes of Health quality assessment tool for either case series or cross-sectional studies. These tools quantify the quality of case series and cohorts/cross-sectional studies, respectively, with nine and 14 queries. Results Fifty-eight studies were included in the final qualitative review. Of 58 identified studies, 32 were case series, 8 were abstracts of case series, and 13 were reviews or case discussion with an included series from MAUDE. Also, five articles were cross-sectional studies. Of the 32 formal case series, 26 (81%) were found to have poor quality. The most common reasons for a poor quality designation included a lack of consecutive participants, undetermined comparability of participants, and undetermined follow-up adequacy. Only one out of five cross-sectional studies had fair quality; four others were evaluated as poor quality studies. Conclusions Cardiovascular surgery studies using the MAUDE database, whether case series or cross-sectional design, are mostly of poor quality. Their low quality is partly caused by poor study design, but mainly by intrinsic limitations to the MAUDE database: cases recruited are not consecutive; patient characteristics are not detailed enough to allow a meaningful comparison of patient characteristics between different patient entries; outcome measures are unclear; there is a limited follow-up; and time-to-event data are lacking. We conclude that the quality of cardiovascular surgery publications that rely on data from MAUDE could be improved if investigators were to extract all relevant data points from MAUDE entries, then apply standard quality assessment tools in compiling and reporting the data. MAUDE might be improved if it used medical case report standards during the process of reporting and indexing adverse events. To calculate the incidence rate of any adverse event, all event-free cases, as well as all adverse events in patients using a device, are required. Neither of these two variables is available in the MAUDE at the time of writing.
Transit and capture in the planar three-body problem leveraging low-thrust invariant manifolds

Path planning in the circular restricted 3-body problem (CR3BP) is frequently guided by the forbidden regions and manifold arcs. However, when low thrust is employed to modify the spacecraft trajectory, these dynamical structures pulsate with the varying Hamiltonian value. In a combined CR3BP, low-thrust (CR3BP + LT) model, an additional low-thrust Hamiltonian is available that remains constant along low-thrust arcs given suitable assumptions. Accordingly, the analogous low-thrust forbidden regions and manifolds remain static and are useful guides for low-thrust trajectory design. Strategies leveraging these structures and other insights from the CR3BP + LT are explored to construct transit and capture itineraries.
Caveolin-1 Expression in the Dorsal Striatum Drives Methamphetamine Addiction-Like Behavior

Dopamine D1 receptor (D1R) function is regulated by membrane/lipid raft-resident protein caveolin-1 (Cav1). We examined whether altered expression of Cav1 in the dorsal striatum would affect self-administration of methamphetamine, an indirect agonist at the D1Rs. A lentiviral construct expressing Cav1 (LV-Cav1) or containing a short hairpin RNA against Cav1 (LV-shCav1) was used to overexpress or knock down Cav1 expression respectively, in the dorsal striatum. Under a fixed-ratio schedule, LV-Cav1 enhanced and LV-shCav1 reduced responding for methamphetamine in an extended access paradigm compared to LV-GFP controls. LV-Cav1 and LV-shCav1 also produced an upward and downward shift in a dose-response paradigm, generating a drug vulnerable/resistant phenotype. LV-Cav1 and LV-shCav1 did not alter responding for sucrose. Under a progressive-ratio schedule, LV-shCav1 generally reduced positive-reinforcing effects of methamphetamine and sucrose as seen by reduced breakpoints. Western blotting confirmed enhanced Cav1 expression in LV-Cav1 rats and reduced Cav1 expression in LV-shCav1 rats. Electrophysiological findings in LV-GFP rats demonstrated an absence of high-frequency stimulation (HFS)-induced long-term potentiation (LTP) in the dorsal striatum after extended access methamphetamine self-administration, indicating methamphetamine-induced occlusion of plasticity. LV-Cav1 prevented methamphetamine-induced plasticity via increasing phosphorylation of calcium calmodulin kinase II, suggesting a mechanism for addiction vulnerability. LV-shCav1 produced a marked deficit in the ability of HFS to produce LTP and, therefore, extended access methamphetamine was unable to alter striatal plasticity, indicating a mechanism for resistance to addiction-like behavior. Our results demonstrate that Cav1 expression and knockdown driven striatal plasticity assist with modulating addiction to drug and nondrug rewards, and inspire new strategies to reduce psychostimulant addiction.