cssi/SciSciGPT-SciSciNet huggingface dataset:
Abstract 14918: A Non-Conservative Mutation (R611C) in Low-Density Lipoprotein Receptor Related Protein (LRP6) Causes Hyperlipidemia by Impaired LDL Clearance and Increased De Novo Hepatic Lipogenesis

Hyperlipidemia is a major risk factor for coronary artery disease (CAD), the leading cause of morbidity and mortality worldwide. Very little is known about the genetic causes of familial combined hyperlipidemia, which is the most common dyslipidemia in the general population and is characterized by elevated serum low-density lipoprotein (LDL) and triglyceride (TG). We recently identified a rare non-conservative mutation (R611C) in the low-density lipoprotein related protein 6 ( LRP6 ) gene, which is the cause of early onset of atherosclerosis, diabetes, and elevated serum LDL and TG in a large outlier kindred. Since discovery of this mutation, the role of LRP6 protein and its genetic variation in lipoprotein homeostasis and atherosclerosis of the general population has been emerging. We have created a humanoid mouse model of R611C mutation (LRP6R611C) by homologous recombination. LRP6R611C mice exhibit elevated serum LDL and TG concentration compared to wildtype littermates (all P < 0.05). Dramatic increase of TG levels after inhibition of lipoprotein lipase and greater uptake and incorporation of [14C]-acetate and [14C]-palmitate in primary hepatocytes of LRP6R611C mice suggested increased triglyceride synthesis compared to wildtype mice. Accordingly, mRNA and protein expressions of enzymes regulating de novo fatty acid synthesis (ACC and FASN), long chain fatty acid modification (ELOVL6 and SCD1), and TG synthesis (DGAT1) were all significantly increased in the liver of LRP6R611C mice compared to wildtype mice. These enzymes are regulated by SREBP-1c, which was expressed at significantly higher levels in LRP6R611C mice liver compared to wildtype mice. Hepatic [125I]-LDL uptake was significantly reduced in LRP6R611C mice compared to wildtype mice. In conclusion, LRP6R611C mutation causes hyperlipidemia by impaired LDL clearance and increased de novo hepatic lipogenesis.
Interpreting Section 107(A)(3) of CERCLA: When Has a Person 'Arranged for Disposal?'

Under Section 107(a)(3) of the Comprehensive Environmental Response Compensation and Liability Act, persons who "arranged for disposal" of hazardous susbstances are included among the group of potentially responsible parties. In general, courts have concluded that sales of products containing hazardous substances do not constitute "arranging for disposal". Given the complexity of business transactions, however, courts have engaged in case-by-case assessments to determine whether a transaction constituted a true sale or was in fact an arrangement involving the disposal of a hazardous substance. These ad hoc assessments undertaken by the courts, however, have left parties with considerable uncertainty as to when a transaction will result in potential liability under CERCLA.This Article assesses the developing case law to determine when a transaction will be considered to be "arranging for disposal." The Article suggests that liability under section 107(a)(3) should be limited to parties who engage in transactions involving solid wastes as defined under the Resource Conservation and Recovery Act (RCRA). Although the scope of materials that are hazardous substances under CERCLA is broader than the class of hazardous wastes under RCRA, this Article suggests that strong reasons exist both in the language and legislative history of CERCLA to limit liability. Given the need for certainty in this area and the fact that the Environmental Protection Agency (EPA) already has struggled with the concept of disposal in its definition of solid waste under RCRA, this Article suggests that it is foolish for courts to "reinvent the wheel" through an ad hoc assessment of liability of persons who may have "arranged for disposal."
Fat Acceptance on Film Reviews of The Fat Body (In)visible [Documentary] and The Size of It [Documentary]

We remain on the lookout for classroom resources that illuminate the pervasiveness of fat oppression and its ill effects, along with efforts to resist weight-based discrimination. This review encom...
Compensatory Actions of Ldb Adaptor Proteins During Corticospinal Motor Neuron Differentiation

Although many genes that specify neocortical projection neuron subtypes have been identified, the downstream effectors that control differentiation of those subtypes remain largely unknown. Here, we demonstrate that the LIM domain-binding proteins Ldb1 and Ldb2 exhibit dynamic and inversely correlated expression patterns during cerebral cortical development. Ldb1-deficient brains display severe defects in proliferation and changes in regionalization, phenotypes resembling those of Lhx mutants. Ldb2-deficient brains, on the other hand, exhibit striking phenotypes affecting layer 5 pyramidal neurons: Immature neurons have an impaired capacity to segregate into mature callosal and subcerebral projection neurons. The analysis of Ldb2 single-mutant mice reveals a compensatory role of Ldb1 for Ldb2 during corticospinal motor neuron (CSMN) differentiation. Animals lacking both Ldb1 and Ldb2 uncover the requirement for Ldb2 during CSMN differentiation, manifested as incomplete CSMN differentiation, and ultimately leading to a failure of the corticospinal tract.
Studies on regeneration of heterotopic splenic autotransplants.

Fragments of spleen autotransplanted to subcutaneous tissue of the abdomen in the rat undergo almost complete necrosis and then regenerate into splenic tissue with a microscopic structure indistinguishable from the structure of the original organ. The regenerative process reminiscent of the spleen’s embryogenesis, originates from a shell of surviving splenic tissue at the surface of the implant. The regenerative zone first consists of almost monotonous connective tissue cells interspersed with red blood cells; it develops into splenic red pulp consisting of sinuses and intersinal cords. As capillaries develop, the structure of small arteries and peri-arterial lymphatic sheaths appear, and soon the structure of splenic white pulp becomes evident. Some 5 wk after autotransplantation, the splenic reconstruction is complete. The weight of the recovered tissue is a linear function of the weight of the implanted tissue; yet the linearity is lost when the weight of the implanted tissue exceeds 100 mg.
Uptake of norepinephrine as a determinant of the magnitude of the inotropic response.

SummaryThe magnitude of the inotropic and chronotropic responses to norepinephrine and uptake of its tritiated isomer (NE-3H) were studied in isolated perfused rat hearts. A statistically significant inverse correlation between the uptake of (NE-3H) and the magnitude of the inotropic response was demonstrated. This correlation disappeared when the hearts were pretreated with cocaine or when uptake of and response to tritiated isoproterenol rather than NE-3H were examined. The variability of the inotropic responses to norepinephrine after cocaine or to isoproterenol were significantly less than responses to norepinephrine in the absence of any pretreatment. These results support the hypothesis which envisions the neuronal uptake of norepinephrine as an important mechanism in the determination of the magnitude of the adrenergic response to exogenous norepinephrine.
An Approach for Estimating System-Wide Environmental Benefits of Future Air Traffic Management Concepts

Environmental implications of aviation activity are increasingly an area of global concern. Performance goals related to reduction in aviation-related fuel consumption, emissions, and noise are prominently featured in proposed modernization plans for air transportation systems in addition to goals related to capacity, efficiency, safety, and security. An in-depth understanding of tradeoffs and synergies among these various performance objectives will aid stakeholders in making investment decisions about future technologies and procedures. This paper presents an approach for conducting integrated assessments with air traffic simulation tools and environmental models to evaluate changes in system-wide operational and environmental performance resulting from proposed improvements. The methods described are illustrated through a notional analysis of projected future airport capacity improvements in the U.S.
A simple method for preparing suspensions of luteal cells.

SummaryA simple and highly reproducible method was developed for the dissociation of ovine luteal tissue into isolated cell suspensions using a crude collagenase preparation in Medium 199. The procedure required less than 3 hr. The mean yield of cells was 81.8 ± 9.1 × 106 cells/g tissue. The resulting cell preparation synthesized progesterone and responded to the addition of LH or HCG, but not prolactin, with increased progesterone production. The quantity of progesterone produced was related to the level of LH added. The cells were still steroidogenically capable and responsive to LH after storage for 48 hr at 4°.The PMSG, LH, HCG, and prolactin used were supplied by the National Institutes of Health. The sheep were synchronized with the aid of Sil Estrus implants, a gift of Abbott Laboratories, North Chicago, Illinois. Ovulation was induced with Gonamone, a gift of Fort Dodge Laboratories, Fort Dodge, Iowa.The authors acknowledge the technical assistance of Bobbie Livingston, Wayne Hopper, and Vaughn Cook.
Burning Rates of Nano-Aluminum/ FC-2175/ Nickel Oxide Composites as a function of Doping, Pressure and Magnetic Field

This paper is focused on how the doping of the oxidizer affects the burning rate. The oxidizer used for this purpose is nickel oxide (NiO). It is doped with lithium (p-doping) and chromium (n-doping). The reducing agent used is nano-aluminum (nAl). Also, experiments are conducted to see the variation in burning rate with pressure for undoped and doped NiO. Lastly, the effect of magnetic field on burning rate is explored. Experiments show that doping has an effect on the burning rate. However, the variation in burning rate is also influenced by other factors like surface area and particle size. The burning rate is found to increase with pressure, and the pressure exponents for each case have also been measured. The burning rate is also found to increase in the presence of a magnetic field. This has been studied for the magnet being placed at two different locations of the pellet that is burned.
Adoptive transfer of aminobisphonate-expanded Vγ9Vδ2+ T cells does not control HIV replication in a humanized mouse model.

Aim: Vγ9Vδ2 γδ T cells have effector potential against several cancers and infectious agents. Whether these cells control HIV replication was tested in humanized mouse model. Methods: NOD SCID gamma mice engrafted with human peripheral blood mononuclear cells (PBMCs) and infected with HIVBAL were treated with zoledronate-expanded Vγ9Vδ2 T cells either alone or in combination with an anti-HIV envelope antibody b12. Results: Severe depletion of CD4+CCR5+ T cells was observed in PBMCs of all infected mice. HIV plasma p24 levels were comparable in all infected groups with no decrease in plasma viremia achieved by adoptive transfer of cells. Conclusion: Autologous transfer of ex vivo expanded Vγ9Vδ2 T cells may not be a successful treatment choice for controlling HIV replication in vivo.
Analyzing Double Delays at Newark Liberty International Airport

When weather or congestion impacts the National Airspace System, multiple different Traffic Management Initiatives can be implemented, sometimes with unintended consequences. One particular perceived inequity that is commonly identified is in the interaction between Ground Delay Programs (GDPs) and time based scheduling of internal departures by the Traffic Management Advisor (TMA) (now operationally superseded by the FAA's the Time-Based Flow Management system). Internal departures under TMA scheduling can take large GDP delays, followed by large TMA scheduling delays, because they cannot easily fit into the arrival flow at the runway. In this paper we examine the causes of these double delays through an analysis of arrival operations at Newark Liberty International Airport (EWR) from June to August 2010. TMA scheduling delays are found to be generally higher than TMA airborne metering delays, regardless of prior GDP delays. Depending on how the double delay is defined, between 42 and 62 of all internal departures in GDP and TMA scheduling experienced double delays in this period. A deep dive into the data reveals that contributors to double delays include upstream flights departing before their Expect Departure Clearance Times (EDCTs); differences in the rates used for setting EDCTs and TMA Scheduled Times of Arrival; differences in the arrival demand expected based on EDCTs and the arrival demand entering TMA; and shorter en route times between takeoff and entry into TMA than assumed in the calculation of flight EDCTs, all of which undermine the sequencing and spacing underlying flight EDCTs. Double delays are also found to coincide with periods in which the virtual runway arrival queue being served by a TMA is large, there are periods of high demand relative to capacity, and there are high airborne metering delays. Data mining techniques are used to confirm that each of these factors contribute to the occurrence of double delay andor high internal departure scheduling delay across three months of data from June to August 2010. Predictors of the occurrence of double delay and high TMA scheduling delay are built using logistic regression, providing prediction accuracies of 69 and 73, respectively.
Management of Seizure Disorders with Anticonvulsant Drugs: Current Concepts

The pharmacology and metabolism of phenobarbital, primidone, diphenylhydantoin, ethosuximide, carbamazepine, diazepam, and clonazepam are reviewed. Much has been learned about the rates of absorption, distribution, metabolism, and excretion of these major anticonvulsant drugs in recent years, and the application of this knowledge has enhanced their rational use in clinical practice.
Voltage-induced frequency drift correction in fourier transform electrostatic linear ion trap mass spectrometry using mirror-switching

Abstract Ion capture from an external nano-electrospray ionization source in a Fourier transform electrostatic linear ion trap has been effected by mirror-switching. This capture method can suffer from time-dependent frequency shifts in the measured ion motion, which compromises mass resolution when using Fourier transform techniques for mass determination. This phenomenon was determined to be a result of the transient voltage recovery of the power supplies used for mirror-switching in response to a pulsed capacitive load, for which several examples are shown. A circuit, based on the AD210AN isolation amplifier, was fabricated to compensate for the voltage perturbation induced by mirror-switching by superimposing the inverted perturbation to the electric field of the opposing reflectron. In doing so, the dependence of the ions path length and frequency on the power supply output was greatly reduced throughout data acquisition. With this circuit enabled, no frequency shifts were observed in the mass spectrum when using mirror-switching, and thus pressure-limited theoretical resolutions were achieved. For example, an absorption mode resolving power of greater than 50,000 M/ΔM FWHM was observed for iodide (m/z 126.9) at a transient length of 300 milliseconds. The use of mirror-switching led to a much greater m/z range than in-trap potential lift for a single ion injection which is demonstrated via simulation and experimental results. This correction method is simple to implement and does not require user intervention once properly tuned.
Green Devices and Hardware

Electronic devices have become ubiquitous and are an intrinsic part of many aspects of our lives. While these devices provide the convenience of faster and better access to people, information and services, there is also a flip side. They have a negative impact on available resources and our environment. With the threat of global warming looming large, prudent use of these devices becomes urgent. Awareness of the impact of usage patterns and ways to minimize the impact is the first step towards a more sustainable practice. In this chapter we explore the impact of these devices on the environment at every stage of its existence. The chapter focuses primarily on hardware devices. We examine the process of manufacturing in an attempt to identify best practices. Further, we explore the resource usage pattern in bringing the product to market. We also look at the usage patterns and adoption of environmentally friendly practices. We are not attempting to answer all questions in this regard, but rather suggest possibilities and more importantly, make the reader sensitive to the issues.
Bowling Online: Mobile Social Games for Korean Teen Girls

Due to their arduous schedules, South Korean high school girls are gradually socializing in online environments such as mobile games. This study explores how Korean high school girls’ mobile social gaming is related to their social networks and social capital. The findings from focus group interviews with 23 high school girls indicate that playing mobile social games helps the interviewees develop their strong-tie relations rather than weak ties. A couple of social functions such as ‘presenting’ or ‘boasting’ induce the interviewees to cooperate or compete with their strong ties constantly, which results in an increase in bonding social capital. Other social functions such as ‘invitation’ entice the interviewees into interacting with their weak ties. However, they interact with their weak ties not for socializing but for earning rewards provided in proportion to the number of interactions. Thus, those behaviors rarely increased their bridging social capital.
HO-2 Pockets Myristoylated Gag.

Membrane binding of viral and cellular N-myristoylated proteins can be regulated by selectively sequestering myristate. In this issue of Cell Host & Microbe, Zhu et al. (2017) report on a myristate binding site within the cellular protein heme oxygenase-2 that acts as a trap to inhibit N-myristoylated protein function.
Faculty Perceptions about Teaching Online: Exploring the Literature Using the Technology Acceptance Model as an Organizing Framework

Academic leaders can better implement institutional strategic plans to promote online programs if they understand faculty perceptions about teaching online. An extended version of a model for technology acceptance, or TAM2 (Venkatesh & Davis, 2000), provided a framework for surveying and organizing the research literature about factors that have influenced faculty’s adoption of online delivery methods for courses and their willingness to continue to teach online. This paper presents the results of a synthesis of 67 empirical studies about faculty teaching online published between 1995 and 2015, using TAM2 constructs as an organizing framework. This validated model provided a lens for understanding research about faculty perceptions of the user-friendliness and ease of use of technology for online course delivery, as well as the overall experience of teaching online. Studies in this review revealed concerns among faculty regarding their perceived barriers to student success in online classes, uncertainty about their image as online instructors, technical support needs, and their desire for reasonable workload and manageable class enrollments in online classes.
Asymptotic h -Expansiveness

This Chapter is devoted to the investigation of the weak expansion properties of expanding Thurston maps and the proof of Theorem 6.1 that asserts that an expanding Thurston map is asymptotically h-expansive if and only if f has no periodic critical points, and moreover, it is never h-expansive.
Nested Gamma-Theta Rhythms

In many brain structures, in particular in the hippocampus, gamma oscillations appear near the crests of much slower, 4–11 ​Hz oscillations, called theta oscillations or theta rhythms. For an example, see Fig. 34.1.
Abyssal near-bottom dispersal stages of benthic invertebrates in the Clarion-Clipperton polymetallic nodule province

Abstract Growing interest in polymetallic nodule mining has intensified the need to characterize the abundance, community structure and vertical flux of meroplankton in the Clarion-Clipperton Zone (CCZ) to facilitate the estimation of larval supply and potential connectivity of benthic populations. These ecological parameters are essential to predict recolonization processes following the expected large-scale, high intensity disturbances associated with nodule extraction. Here, we present the first description of the composition, abundance, temporal variability, and mesoscale distribution of dispersing stages of the benthos in two study areas in the eastern CCZ. Samples from free-vehicle plankton pumps showed little variation in meroplankton diversity and abundance over scales of 30–100 km for time scales of days to weeks. However, sediment-trap samples revealed high temporal variability in vertical flux over weeks to months. Larval abundances and fluxes measured in the abyssal CCZ are ~ 1–2 orders of magnitude lower than observed at deep-sea ridge and hydrothermal-vent habitats. We found significantly higher downward larval fluxes at 11 m above the bottom (mab) than at 146 mab, indicating accumulation or retention of meroplankton within the Benthic Boundary Layer (BBL). The high abundance of meroplankton in the BBL emphasizes its importance to dispersing stages and suggests that the creation of large sediment plumes in the BBL during nodule mining could compromise the dispersal and recruitment abilities of the abyssal benthos, potentially slowing rates and altering patterns of benthic community recovery following mining disturbance.
SybilSCAR: Sybil detection in online social networks via local rule based propagation

Detecting Sybils in online social networks (OSNs) is a fundamental security research problem as adversaries can leverage Sybils to perform various malicious activities. Structure-based methods have been shown to be promising at detecting Sybils. Existing structure-based methods can be classified into two categories: Random Walk (RW)-based methods and Loop Belief Propagation (LBP)-based methods. RW-based methods cannot leverage labeled Sybils and labeled benign users simultaneously, which limits their detection accuracy, and they are not robust to noisy labels. LBP-based methods are not scalable, and they cannot guarantee convergence. In this work, we propose SybilSCAR, a new structure-based method to perform Sybil detection in OSNs. SybilSCAR maintains the advantages of existing methods while overcoming their limitations. Specifically, SybilSCAR is Scalable, Convergent, Accurate, and Robust to label noises. We first propose a framework to unify RW-based and LBP-based methods. Under our framework, these methods can be viewed as iteratively applying a (different) local rule to every user, which propagates label information among a social graph. Second, we design a new local rule, which SybilSCAR iteratively applies to every user to detect Sybils. We compare SybilSCAR with a state-of-the-art RW-based method and a state-of-the-art LBP-based method, using both synthetic Sybils and large-scale social network datasets with real Sybils. Our results demonstrate that SybilSCAR is more accurate and more robust to label noise than the compared state-of-the-art RW-based method, and that SybilSCAR is orders of magnitude more scalable than the state-of-the-art LBP-based method and is guaranteed to converge. To facilitate research on Sybil detection, we have made our implementation of SybilSCAR publicly available on our webpages.
Landing Kinematics and Kinetics at the Knee During Different Landing Tasks

Context: Several tasks have been used to examine landing biomechanics for evaluation and rehabilitation, especially as related to anterior cruciate ligament injuries. However, comparing results among studies in which different tasks were used can be difficult, and it is unclear which task may be most appropriate. Objective: To compare lower extremity biomechanics across 5 commonly used landing tasks. Design: Descriptive laboratory study. Setting: University-operated US Air Force Special Operations Forces human performance research laboratory. Patients or Other Participants: A total of 65 US Air Force Special Tactics Operators (age = 27.7 ± 5.0 years, height = 176.5 ± 5.7 cm, mass = 83.1 ± 9.1 kg). Intervention(s): Kinematic and kinetic analysis of double- and single-legged drop landing, double- and single-legged stop jump, and forward jump to single-legged landing. Main Outcome Measure(s): Hip-, knee-, and ankle-joint kinematics; knee-joint forces and moments; and ground reaction forces (GRFs) were...
Depressive Symptoms Predict Current E-Cigarette Use Among College Students in Texas.

Introduction No studies have examined the longitudinal relationship between e-cigarette use and elevated depressive symptoms among young adults. The main objective of the current study was to establish a potential bi-directional relationship between e-cigarette use and elevated depressive symptoms among college students in Texas, across a 1 year period of time. Methods A survey of 5445 college students in Texas was conducted with 6-month and 1-year follow-ups. A longitudinal cross-lagged model was used to simultaneously examine the bi-directional relationships between current, or past 30-day, e-cigarette use and elevated depressive symptoms across the three study waves. Depressive symptoms were measured using a 10-item Center for Epidemiologic Studies Depression Scale (CES-D) with a cutpoint of ≥ 10 to measure elevated depressive symptoms. Covariates included baseline age, gender, college type (2- or 4-year), and other alternative tobacco products used. Results E-cigarette use did not predict elevated depressive symptoms at 6-month and 1-year follow-ups. However, depressive symptoms predicted e-cigarette use at both 6-month and 1-year follow-ups. Conclusions The current study indicates that depressive symptoms predict subsequent e-cigarette use and not vice versa. Future studies are needed to replicate current findings and also further establish the mechanisms for causality, which could inform Food and Drug Administration regulatory planning. Implications There has been recent evidence for cross-sectional associations between e-cigarette use and elevated depressive symptoms and mental health problems. There have been no studies examining these associations using longitudinal designs. This study established a temporal relationship, such that elevated depressive symptoms predicted e-cigarette use 6 months later among college students. Future research is needed to establish the mechanisms of association as well as causality.
Organs on a chip: a fast-track for engineered human tissues in drug development

Organs-on-a-chip (OOCs) are miniature tissues and organs grown in vitro that enable modeling of human physiology and disease. The technology has emerged from converging advances in tissue engineering, semiconductor fabrication, and human cell sourcing. Encompassing innovations in human stem cell technology, OOCs offer a promising approach to emulate human patho/physiology in vitro, and address limitations of current cell and animal models. Here, we review the design considerations for single and multi-organ OOCs, discuss remaining challenges, and highlight the potential impact of OOCs as a fast-track opportunity for tissue engineering to advance drug development and precision medicine.
Surgeon utilization of minimally invasive techniques for inguinal hernia repair: a population-based study.

MIS utilization for inguinal hernia repair is low compared to in other procedures. The impact of low adoption in surgeons is unclear, but may affect regional access to minimally invasive surgery (MIS). We explored the impact of surgeon MIS utilization in inguinal hernia repair across a statewide population. We analyzed 6723 patients undergoing elective inguinal hernia repair from 2012 to 2016 in the Michigan Surgical Quality Collaborative. The primary outcome was surgeon MIS utilization. The geographic distribution of high MIS-utilizing surgeons was compared across Hospital Referral Regions using Pearson’s Chi-squared test. Hierarchical logistic regression was used to identify patient and hospital factors associated with MIS utilization. Surgeon MIS utilization varied, with 58% of 540 surgeons performing no MIS repair. For the remaining surgeons, MIS utilization was bimodally distributed. High-utilization surgeons were unevenly distributed across region, with corresponding differences in regional MIS rate ranging from 10 to 48% (p 3 (OR 0.79 p < 0.001). MIS utilization varies between surgeons, likely driving differences in regional MIS rates and leading to guideline-discordant care for patients with bilateral or recurrent hernia. Interventions to reduce this practice gap could include training programs in MIS repair, or regionalization of care to improve MIS access.
Region, Geography and Political Party Affiliation in Ghana: An Analysis of the National Democratic Congress (NDC) and the New Patriotic Party (NPP)

This paper attempts to examine how region of origin or dwelling influences an individual’s political affiliation in Ghana. Political Scientist, in advance democracies like the U.S through empirical evidence that spans decades, have identified that region or geography does influence a person’s political attitude hence party affiliation (Elazar 1966; Sharkansky 1970). These finds have nurtured my quest for an analysis on Ghana, on the above subject. The study employs a sample of 1,200 in this analysis from the African led series of the national public attitudes survey on democracy and governance (Afro barometer, Round 4, 2008). This work seeks to observe the two major political parties in Ghana-NDC and NPP. Furthermore, the study controls for the following variables: gender; urban/rural; education and religion of participants. These control variables in the study would help the major political parties to strategize their campaigns on issues and the regions where they can maximize their electoral outcomes.
Chapter 10 – Cognitive Interventions

Publisher Summary Research findings in recent years from both animal models and on human learners converge clearly on the conclusion that there is plasticity in brain and behavior throughout the adult life span. This chapter considers the different types of interventions that vary in the extent to which they involve direct exercise of target outcomes, from retest effects that are highly specific to target outcomes, to ability-specific training of different sorts, to lifestyle interventions that may only be tangentially related to measured outcomes. It also describes challenges for developing evidence-based principles of cognitive optimization that can be authentically translated into programs and social structures with potential to instantiate successful aging as a cultural norm. Thus, it serves both the practical function of informing the creation of evidence-based programs with potential to promote independence, social engagement, and continued participation in work and in civic institutions, as well as the scientific function of testing theories of cognitive aging.
Simplest Optimal Control Problem

The simplest optimal control problem is one that does not involve any states. Such a problem arises when it is possible to eliminate the states between the state differential equations, the performance index, and the prescribed boundary conditions. An example is the aircraft navigation problem discussed in Section 1.4.3.
Relation of Brain Serotonin to the Inhibition and Enhancement of Morphine Tolerance and Physical Dependence

Studies in our laboratory on the mechanisms of morphine tolerance and physical dependence suggest that cerebral macromolecules may play an important role. The protein synthesis inhibitor, cycloheximide, was found to prevent the development of tolerance to and physical dependence on morphine (Way, Loh and Shen, 1968; Loh, Shen and Way, 1969). A logical extension of this work was to consider those reactions or enzymes associated with the putative neurotransmitters. We suggested that one of the proteins involved may be associated with serotonin (5-HT) synthesis on the basis that brain turnover of 5-HT during the morphine tolerant-dependent state was greater than under normal conditions and that tolerance and dependence could be reduced by p-chlorophenylalanine (PCPA) (Shen, Loh and Way, 1970), a relatively specific inhibitor of 5-HT synthesis (Koe and Weissman, 1966). Unfortunately, various laboratories have not been able to confirm certain aspects of our work. We propose to analyze these discrepancies and present additional data which support our original findings.
Application Performance on the Newest Processors and GPUs

This paper discusses the capabilities of the newest processors and GPUs to run a mixture of the most common chemistry applications. The baseline system for these comparisons is the 32-core Intel Broadwell processor which has been around for two years. Comparisons are made to the newer Intel Skylake and the AMD EPYC processors. The EPYC architecture has typically twice as many cores so one point of comparison is whether each code can effectively make use of the higher core count. These codes can be accelerated using GPUs with some taking advantage of 32-bit acceleration while others need good 64-bit performance. The consumer grade NVIDIA GeForce GTX 1080Ti cards are used as the baseline for the GPU comparisons. Higher level NVIDIA Quadro GP100 and Titan V cards are evaluated using each code. All applications use CUDA to enable GPU acceleration. AMD provides tools in its HIP package that allow translation of C and C++ CUDA code into source code that can be compiled with either NVIDIA's NVCC or AMD's HCC compilers. This project also involves investigating the performance and ease of converting CUDA code to run on the AMD Radeon Vega Frontier Edition GPU card.
SOME PROBLEMS IN ELECTROMAGNETICS

This contribution surveys some of Joe Keller’s work in wave propagation and inverse problems, gives a snapshot of the current state of the field, and discusses some open problems in the area.
The concept of Maximal Unschedulable Deadline Assignment for optimization in fixed-priority scheduled real-time systems

This paper considers the problem of design optimization for real-time systems scheduled with fixed priority, where task priority assignment is part of the decision variables, and the timing constraints and/or objective function linearly depend on the exact value of task response times (such as end-to-end deadline constraints). The complexity of response time analysis techniques makes it difficult to leverage existing optimization frameworks and scale to large designs. Instead, we propose an efficient optimization framework that is three orders of magnitude (1000 times) faster than Integer Linear Programming (ILP) while providing solutions with the same quality. The framework centers around three novel ideas: (1) an efficient algorithm that finds a schedulable task priority assignment for minimizing the average worst-case response time; (2) the concept of Maximal Unschedulable Deadline Assignment (MUDA) that abstracts the schedulability conditions, i.e., a set of maximal virtual deadline assignments such that the system is unschedulable; and (3) a new optimization procedure that leverages the concept of MUDA and the efficient algorithm to compute it.
Focused Ultrasound Enhanced Intranasal Delivery of Neurotrophic Factors Exhibit Neurorestorative Effects in Parkinson's Disease Mouse Model

Focused ultrasound enhanced intranasal (IN+FUS) delivery is a unique, noninvasive approach that utilizes the olfactory pathway to administer drugs directly to the brain. Our group has shown that IN+FUS delivery of model drugs provide a more homogenous distribution of delivery when compared to IN delivery alone, and similar delivery efficiency to intravenous delivery after FUS induced BBB opening. The aim of this study was to investigate the delivery efficacy and therapeutic effects that IN+FUS administered brain-derived neurotrophic factor (BDNF) has on an early-stage Parkinsonian mouse model in order to provide an alternate and more direct administration route to the brain. Wild-type mice were given a sub-acute dose of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxin daily for 5 days, causing bilateral degeneration of the nigrostriatal dopaminergic pathway. After a stabilizing period, the mice were split into a treated group and a control group (N=7 /group). The treated group was dosed with IN+FUS of BDNF weekly for 3 weeks. Each week, 0.4 mg of BDNF was intranasally delivered followed by BBB opening in the left substantia nigra (SN) and caudate putamen (CP) using FUS and sized isolated microbubbles. The mice were then survived for 2 months to allow for any neurorestorative effects to occur. Behavioral testing through amphetamine-induced rotations was then conducted. Staining of tyrosine hydroxylase positive (TH+) neurons in the SN and terminals in the CP were used to assess the nigrostriatal dopaminergic pathway integrity. TH+ staining in the SN and CP indicated moderate neuronal survival in the ipsilateral side in treated mice while staining in untreated mice was similar bilaterally. Significant ipsilateral rotation in treated mice corroborated the immunohistochemistry findings, further validating improved ipsilateral nigrostriatal dopaminergic pathway. These findings indicate a modest neurorestorative effect of IN+FUS BDNF on MPTP mice, demonstrating the potential of an alternative and efficient drug delivery route for brain treatment with FUS. Additional immunohistochemistry assays and quantification in the SN and CP are ongoing to confirm these initial findings.
The Kansas University DHA Outcomes Study (KUDOS) clinical trial: long-term behavioral follow-up of the effects of prenatal DHA supplementation.

BACKGROUND Docosahexaenoic acid (DHA) is a long-chain polyunsaturated fatty acid that has been linked to improved vision and cognition in postnatal feeding studies and has been consistently associated with reduction of early preterm birth in prenatal supplementation trials. This is a report of the first long-term follow-up of infants from mothers receiving prenatal DHA supplementation in a US cohort. OBJECTIVE Our objective was to evaluate the efficacy of the prenatal supplementation on both global and granular longitudinal assessments of cognitive and behavioral development. METHODS In a randomized double-blind clinical trial, mothers received either 600 mg/d of DHA or a placebo beginning at 14.5 weeks of gestation and capsules were provided until delivery. Children from those pregnancies were followed by cognitive and behavioral assessments administered from 10 mo through 6 y of age. From 301 mothers in the initial study, ∼200 infants completed the longitudinal schedule. RESULTS Although this intervention had been shown to reduce high-risk pregnancies and improve visual attention in infants during the first year, only a few positive long-term effects of prenatal DHA supplementation emerged from analyses of this follow-up. Increases in maternal blood DHA during pregnancy were related to verbal and full scale intelligence quotient (IQ) scores at 5 and 6 y, but these effects disappeared after controlling for SES. Maternal blood DHA concentrations at delivery were unrelated to outcomes, although maternal DHA at enrollment was related to productive vocabulary at 18 mo. CONCLUSIONS Although prenatal DHA supplementation substantially reduced early preterm birth and improved visual attention in infancy in this sample, no consistent long-term benefits were observed into childhood. Increases in maternal blood DHA concentration in pregnancy were related to higher IQs but this effect was confounded with SES and disappeared when SES was statistically controlled. This trial was registered at http://www.clinicaltrials.gov as NCT00266825 and NCT02487771.
Brain-Dedicated Emission Tomography Systems: A Perspective on Requirements for Clinical Research and Clinical Needs in Brain Imaging

Research applications of human brain positron emission tomography (PET) imaging have been in place for over 40 years. The unique combination of quantitative PET instrumentation and reconstruction, novel radiotracers, and kinetic modeling has led to the development and application of a huge number of imaging paradigms. These have been applied to the understanding of normal function and pathophysiology, the development of drugs for neuropsychiatric disorders, and the study of drug interactions with the brain. I have had been fortunate to be part of this great endeavor throughout my research career, using brain-dedicated PET scanners, such as the HRRT [item [1] in the Appendix]. Over time, these systems have offered important advantages over whole-body systems. However, due to the limited clinical market for brain PET imaging, scanner manufacturers have focused exclusively on large field-of-view systems for the past two decades [item [2] in the Appendix]. The goal of this perspective is to share a viewpoint on the utility of brain-dedicated PET systems for human research, particularly in the context of novel radiotracers with dynamic studies using kinetic modeling.
Density functional theory calculations of generalized stacking fault energy surfaces for eight face-centered cubic transition metals

In this work, we use density functional theory to calculate the entire generalized stacking fault energy (GSFE) surface for eight transition metals with a face-centered cubic structure: Ag, Au, Cu, Ir, Ni, Pd, Pt, and Rh. Analysis of the ⟨ 112 ⟩ GSFE curves finds that the displacements corresponding to the unstable stacking fault energy are larger than the ideal value for all eight metals except Ag and Cu. Over the entire surface, Pt is found to not possess well-defined local maxima or minima, suggesting spreading in favor of dissociation of the dislocation core, unlike the other seven metals. Our calculations also reveal that at a large ⟨ 112 ⟩ displacement, where atoms on two {111} adjacent planes are aligned, an anomalous local minimum occurs for Ir and Rh. The oddity is explained by relatively large, localized atomic displacements that take place in the two metals to accommodate the alignment that do not occur in the other six metals. In addition to the fully calculated surfaces, we characterize a continuous 11-term Fourier-series function, which provides a particularly excellent representation of the GSFE surfaces for Ag, Au, Cu, Ni, and Pd.
Disturbed Regulation and Activity of PI 3-Kinase Activity Due to Enhanced Lyn Kinase but Decreased Ship-1 and Gab2 Levels in Patients with Myelodysplastic Syndrome.

Myelodysplastic Syndrome (MDS) results from ineffective hematopoiesis characterized by peripheral cytopenia(s) and hypercellular bone marrow. Both enhanced proliferation and accelerated apoptosis are hallmarks of the early phases of MDS, while the latter phases are characterized by diminished apoptosis and the accumulation of blasts. The genetic and biochemical basis of this clonal disorder is poorly understood; cell lines and mouse models are few and incomplete. We propose that patients with Severe Congenital Neutropenia who have a ten thousand-fold risk of developing MDS/AML provide a well-defined entity to study the signaling dysfunction in MDS. Almost all of these patients have a truncated G-CSF Receptor. We then compared Ba/F3 cells expressing either the full-length or the truncated G-CSF Receptor. Stimulation with G-CSF led to sustained Lyn tyrosine kinase activity. Altered PI 3-kinase signaling was evidenced by enhanced and sustained Akt serine kinase activity with diminished tyrosine phosphorylation of the adaptor molecule Gab2 and the inositol phosphatase SHIP-1. Furthermore, an in vitro lipid phosphatase assay showed decreased SHIP activity in cells expressing truncated G-CSF Receptor following G-CSF stimulation. Both Gab2 and SHIP-1 critically regulate PI 3-kinase activity in hematopoietic cells. We next sought to corroborate these findings in primary hematopoietic cells from adult patients with MDS. Biochemical analysis of CD3/CD19 depleted bone marrow mononuclear cells from patients with mid- to late-stage MDS revealed similar findings: increased tyrosine phosphorylation of the activated form of Lyn (of 13 specimens, 10 demonstrated 2 to 30-fold increase by western blotting when compared to CD34+ cells from umbilical cord blood), increased serine and threonine phosphorylation of Akt (8/10 specimens), and decreased tyrosine phosphorylation of Gab2 (6/6) and SHIP-1 (9/9). Importantly, decreased total protein levels of Gab2 and SHIP-1 accounted for their decreased tyrosine phosphorylation. Real-time PCR studies confirmed expression of Gab2 and SHIP-1 in MDS patients, but the level of SHIP-1 transcripts was ~40% less than that in CD34+ cells. Short-SHIP (SIP110), a 104 kDa form of SHIP-1 that lacks the SH2 domain and is expressed only in embryonic stem cells and hematopoietic stem cells, was not identified by RT-PCR in MDS mononuclear cells, and hence, it could not substitute for SHIP-1 deficiency. Ongoing studies are examining hypermethylation state of these genes and their sensitivity to azacytidine. Altogether, these findings suggest that enhanced proliferation and diminished apoptosis may be due to changes in PI 3-kinase regulation and activity in some patients with MDS, which is consistent with both cell lines expressing the truncated G-CSF Receptor and the SHIP−/ −, PTEN+/− mouse model for MDS (Blood103:4503, 2004).
Female-Specific Effects of CGRP Suggest Limited Efficacy of New Migraine Treatments in Males

Skepticism of preclinical analgesic development has existed since the failed and discontinued clinical trials of substance P receptor [neurokinin 1 (NK1)] antagonists ([Hill, 2000][1]) and TRPV1 antagonists, respectively ([Gavva et al., 2008][2]). Scrutiny of preclinical pain research has also
DNA structural polymorphism in the proximal promoter of the vascular endothelial growth factor gene

3189 Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis. A polyguanine/polycytosine (polyG/polyC) tract in the proximal promoter of the VEGF gene is essential for its promoter activity. Because this polyG/polyC tract is very dynamic in nature, it is able to unwind into single-stranded DNA and adopt non-B-DNA conformations, which potentially play a role in VEGF transcriptional regulation. In this study, we characterized the secondary structures that are formed in the guanine-rich (G-rich) and cytosine-rich (C-rich) strands of this tract using various biochemical and biophysical techniques. It was revealed that, in the presence of 100 mM KCl, the G-rich strand is able to adopt two parallel G-quadruplex loop isomers containing three G-tetrads with three double-chain-reversal loops of either 1:4:1 or 1:2:3. Our CD melting experiment and polymerase stop assay suggested that the G-quadruplex containing 1:4:1 double-chain-reversal loops is the more thermodynamically stable conformation that the G-rich strand readily adopts. This provides strong evidence that the sequences and sizes of the loops are critical for the formation and stability of G-quadruplexes. Our molecular model showed that the guanines at the 5’-end and the 3’-end of the G-quadruplex provide a stable capping structure. The complementary C-rich strand is able to form an intramolecular i-motif structure at slightly acidic pH, which involves six C-C+ base pairs and three loops of 2:3:2. One guanine and cytosine in one of the loops stabilize the i-motif by stacking interactions. Taken together, our results demonstrate that the G-quadruplex and i-motif structures are able to form in the G-rich and C-rich strands respectively of the polyG/polyC tract in the VEGF proximal promoter under conditions that favor the transition of B-DNA to non-B-DNA conformations. These unique secondary structures may be novel targets for anti-angiogenesis therapy in cancer.
National culture and R&D investments

By using time-collapsed data for 12,362 firms from 40 countries, I document that national culture is significantly associated with R&D investments, controlling for other determinants including a co...