cssi/SciSciGPT-SciSciNet huggingface dataset:
Rapid Ca2+ extrusion via the Na+/Ca2+ exchanger of the human platelet.

This communication reports the kinetics of the Na+/ Ca2+ exchanger and of the plasma membrane (PM) Ca2+ pump of the intact human platelet. The kinetic properties of these two systems were deduced by studying the rate of Ca2+ extrusion and its Na+ dependence for concentrations of cytoplasmic free Ca2+ ([Ca2+]cyt) in the 1–10-μm range. The PM Ca2+ATPase was previously characterized (Johansson, J.S. Haynes, D.H. 1988. J. Membrane Biol.104:147–163) for [Ca2+]cyt] ≤ 1.5 μm with the fluorescent Ca2+ indicator quin2 (Kd= 115 nm). That study determined that the PM Ca2+ pump in the basal state has a Vmax = 0.098 mm/min, a Km= 80 nm and a Hill coefficient = 1.7. The present study extends the measurable range of [Ca2+]cyt with the intracellular Ca2+ probe, rhod2 (Kd= 500 nm), which has almost a fivefold lower affinity for Ca2+. An Appendix also describes the Mg2+ and pH dependence of the Kdand fluorescence characteristics of the commercially available dye, which is a mixture of two molecules. Rates of active Ca2+ extrusion were determined by two independent methods which gave good agreement: (i) by measuring Ca2+ extrusion into a Ca2+-free medium (above citation) or (ii) by the newly developed “ionomycin short-circuit” method, which determines the ionomycin concentration necessary to short circuit the PM Ca2+ extrusion systems. Absolute rates of extrusion were determined by knowledge of how many Ca2+ ions are moved by ionomycin per minute. The major findings are as follows: (i) The exchanger is saturable with respect to Ca2+ with a Km= 0.97 ± 0.31 μm and Vmax = 1.0 ± 0.6 mm/ min. (ii) At high [Ca2+]cyt, the exchanger works at a rate 10 times as large as the basal Vmax of the PM Ca2+ extrusion pump. (iii) The exchanger can work in reverse after Na+ loading of the cytoplasm by monensin. (iv) The PM Ca2+ extrusion pump is activated by exposure to [Ca2+]cyt ≥ 1.5 μm for 20–50 sec. Activation raises the pump Vmax to 1.6 ± 0.6 mm/min and the Kmto 0.55 ± 0.24 μm. (v) The Ca2+ buffering capacity of the cytoplasm is 3.6 mm in the 0.1 to 3 μm range of [Ca2+]cyt. In summary, the results show that the human platelet can extrude Ca2+ very rapidly at high [Ca2+]cyt. Both the Na+/Ca2+ exchanger and Ca2+ pump activation may prevent inappropriate platelet activation by marginal stimuli.
Pregnancy exposure registries: US FDA guidance and case studies

Objective Drug safety for women during pregnancy is an important issue in public health. Method Because little is known about the teratogenic potential of a drug in humans before new drug approval,the drug post-marketing surveillance for women during pregnancy is a critical consideration to detect drug-induced fetal effects.Result The existing passive mechanism of spontaneous reporting of adverse drug effects is inadequate to detect or measure drug-induced fetal risks and effects.Therefore,post-marketing pregnancy exposure registries have been increasingly used to proactively monitor for major fetal effects and to measure margins of safety associated with drug exposure during pregnancy.It is only through the use of rigorous methodology and procedures that data from pregnancy exposure registries will withstand scientific scrutiny.Conclusion In this article we reviewed the US FDA published guidance on Establishing Pregnancy Exposure Registries and suggested Chinese pharmaceutical industry could improve its research in monitoring drug exposures during pregnancy.
Quaternary phase diagrams of spinel Li y □ 1 − y Mn x Ni 2 − x O 4 and composite cathode voltages for concentration gradient materials

Core-shell coating structures and concentration gradient materials may enhance Li-ion battery performance by integrating advantages of core and shell components without introducing unfavorable problems associated with general coatings. The fundamental thermodynamic properties of concentration gradient composite materials are complex due to the multicomponent nature of the problem. We systematically study the thermodynamics of ordering and phase separation in the quaternary spinel ${\mathrm{Li}}_{y}{\ensuremath{\square}}_{1\ensuremath{-}y}{\mathrm{Mn}}_{x}{\mathrm{Ni}}_{2\ensuremath{-}x}{\mathrm{O}}_{4}$ ($\ensuremath{\square}$ means vacancy) system by density functional theory calculations, together with the coupled cluster expansion method with interactions within and between (Li/$\ensuremath{\square}$) and (Mn/Ni) sublattices. On the basis of coupled cluster expansion interactions and Monte Carlo simulations, we calculate quaternary phase diagrams as a function of temperature as well as voltage profiles of single ordered phases and multiphase composite structures. The phase diagram and voltage results are in good agreement with available experimental observations. We also predict a stable high-voltage ordered compound ${\mathrm{LiMnNiO}}_{4}$, with a very high delithiation voltage of 4.76 V. For the composite (Mn-$\text{rich}+\text{Ni}$-rich) cathode materials, the voltage profiles show combinations of plateaus from each component compound. The computational strategy of combining quaternary phase diagrams with voltage calculations provides a pathway to understand and design concentration gradient materials.
Diseases of the Heart and Blood-vessels correlated to the Oral Tissues

This chapter discusses diseases of the heart and blood-vessels correlated to the oral tissues. In rheumatic fever, the heart is affected by a systemic disease of the connective tissue. Rheumatic fever is a disease of children and young adults due indirectly to a poststreptococcal sensitization from group A haemolytic streptococcus. The disease is generally preceded by an upper respiratory infection, tonsillitis, or streptococcal infection. Symptoms of acute rheumatic fever include anaemia, leucocytosis, pancarditis, polyarteritis, subcutaneous nodules of fibrinoid degeneration, inflammation of serous membranes, and pneumonitis. The initial rheumatic valvular damage predisposes the heart to future secondary bacterial endocarditis. This latter finding is the prime reason why the dental practitioner must have a fundamental knowledge of rheumatic endocarditis. Correlation of rheumatic endocarditis to dental practice is therefore of prime importance to all dentists. Rheumatic fever is one of a list of systemic diseases which are aggravated by oral foci of infection.
Monitoring of paces and gaits using binary PIR Sensors with rehabilitation treadmill

Recently, rehabilitation treadmills are designed for helping injured persons such as stroke patients and injury athletes in the process of physical therapy. By monitoring the changes of paces and gaits, one can estimate the progress of rehabilitation. At present, most devices that can estimate paces and gaits are wearable and/or expensive. This paper presents an inexpensive, non-intrusive wireless binary sensor system for pace estimation and lower-extreme gait recognition with low data throughput and high energy efficiency. The asymmetric but periodic movement of injured person allows the study of pace and gait. The pace estimation is achieved by using autocorrelation function. The gait information is represented by three features (1) temporal correlation, (2) marginal density (intersection probability), and (3) spatial correlation from binary data steam. Experimental results shows that our system can estimate the pace of walking or running with the accuracy of 97.7%. By using only three features, abnormal gaits can also be recognized.
Numerical prediction of tropospheric scintillation

Fading depth due to tropospheric scintillation in satellite to ground-station link is obtained from combined electromagnetic and large eddy simulations for low elevation angles. The numerically obtained fading depth is compared to previously established models and variability of fading depth with range and height is shown.
Vanadium-Zirconium Alloy System

The equilibria in the V-Zr alloy system were investigated by solidus temperature determinations, thermal analysis, dilatometry, electrical resistance measurements, microscopic examination, and X-ray diffraction analysis. There is a eutectic reaction at 1230°C between a compound, V2Zr, and a solid solution containing 10 pet V in β zirconium. V2Zr decomposes at 1300°C into liquid and a solid solution containing about 10 pet Zr in vanadium. The eutectic composition is probably about 30 pet V. A eutectoid reaction between V2Zr and α zirconium takes place at 777°C at a very high rate. The eutectoid composition is 5 wt pet V. The limit of solubility of zirconium in vanadium was estimated to be 5 pet at 600°C. No attempt was made to determine the liquidus for the system.
Are Generation Y Nurses Satisfied on the Job? Understanding Their Lived Experiences.

OBJECTIVEThe purpose of this study was to explore the lived experiences of job satisfaction among Generation Y nurses in the workplace.BACKGROUNDJob satisfaction in nursing is at an all-time low. With an increasing shortage of nurses, there is a need for more awareness and understanding of job satis
Uncovering the Values and Constraints of Real-time Ridesharing for Low-resource Populations

Real-time ridesharing services (e.g., Uber and Lyft) are often touted as sharing-economy leaders and dramatically lower the cost of transportation. However, how to make these services work better among low-income and transportation-scarce households, how these individuals experience these services, and whether they encounter barriers in enlisting these services is unknown. To address these questions, we onboarded 13 low-income individuals living in transportation-scarce environments to Uber as passengers. Our participants found these services to be reliable and benefited from rich social interactions with drivers; however, barriers such as cost, limited payment methods, and low digital literacy can make such services infeasible. We contribute platform designs that could lead to increased digital literacy and application transparency. To be more inclusive and to reach critical mass, we suggest that these companies foster belief in commons and community trust by coordinating with local businesses in low-resource areas with lower digital literacy.
Selection of core animals in the Algorithm for Proven and Young using a simulation model.

Summary The Algorithm for Proven and Young (APY) enables the implementation of single-step genomic BLUP (ssGBLUP) in large, genotyped populations by separating genotyped animals into core and non-core subsets and creating a computationally efficient inverse for the genomic relationship matrix (G). As APY became the choice for large-scale genomic evaluations in BLUP-based methods, a common question is how to choose the animals in the core subset. We compared several core definitions to answer this question. Simulations comprised a moderately heritable trait for 95,010 animals and 50,000 genotypes for animals across five generations. Genotypes consisted of 25,500 SNP distributed across 15 chromosomes. Genotyping errors and missing pedigree were also mimicked. Core animals were defined based on individual generations, equal representation across generations, and at random. For a sufficiently large core size, core definitions had the same accuracies and biases, even if the core animals had imperfect genotypes. When genotyped animals had unknown parents, accuracy and bias were significantly better (p ≤ .05) for random and across generation core definitions.
Establishing Automated Vehicle Navigation as a Reality for Production Agriculture

Abstract The navigation of agricultural machines by automated methods has been the dream of numerous researchers for over 80 years. However, automatic and autonomous navigation has been an elusive goal due to the sophisticated structure required to achieve a socially acceptable result. Many of the technological barriers of automation have been recently eliminated by the advancements in sensors, computers, and vehicle systems. Still a number of advancements are required in the enhancement of safety, simplicity of operation, and affordable cost. So what does it take to make autonomous agriculture a reality? Researchers have been motivated by noble concepts supporting automation including a declining and aging work force and a need to achieve production goals with fewer workers. But most of us have avoided a truly close connection to the farmer and his needs. In reaction to the concept of automation, some agriculturists have argued that tractor driving is the most enjoyable task a farmer has to do in his job and that researchers are wasting time if they believe he will give it up. Industry is focused on many of the farmer’s near-term problems and will only offer automation technology if their customer demands it. These conditions make the implementation of navigation technologies very difficult. A natural progression is needed to advance agriculture into the automation and information age using navigation technologies to enhance productivity, the quality of life, or other factors of societal benefit. Researchers must work closely with the farmer and industry to provide significant examples of how this technology can be utilized today and, additionally, build a natural progression to an age of automation that is accepted by the producer. Drawing on examples from recent experiences in vehicle navigation, this lecture will review the status of automation technology and propose a course of action to implement navigation into production agriculture.
Caffeine Toxicity: A Brief Review and Update

Abstract Caffeine is one of the most widely consumed psychoactive compounds and is often marketed for its physical and cognitive performance benefits. The ingestion of potentially toxic amounts of caffeine in the forms of energy drinks, over-the-counter supplements, or anhydrous caffeine products places vulnerable pediatric and adolescent individuals at risk for accidental overdose, resulting in neurologic and cardiac toxicity.
KISS the Tax Blueprint Goodbye: Meet the 25-25-25 Plan

Seeking definitive legislative success after the stall-out on healthcare, Congressional Republicans may want to keep it simple on tax reform. This paper examines the merits and demerits of a particular minimalist tax plan: lower the corporate tax rate to 25%; tax legacy foreign earnings at 25%; move to a “territorial” tax system for foreign earnings with a minimum tax patch at 25%. The paper uses analysis of this specific plan as a vehicle for clarifying some general considerations surrounding business tax reform.
Antitumor immunity is defective in T cell-specific microRNA-155-deficient mice and is rescued by immune checkpoint blockade.

MicroRNA-155 (miR-155) regulates antitumor immune responses. However, its specific functions within distinct immune cell types have not been delineated in conditional KO mouse models. In this study, we investigated the role of miR-155 specifically within T cells during the immune response to syngeneic tumors. We found that miR-155 expression within T cells is required to limit syngeneic tumor growth and promote IFNγ production by T cells within the tumor microenvironment. Consequently, we found that miR-155 expression by T cells is necessary for proper tumor-associated macrophage expression of IFNγ-inducible genes. We also found that immune checkpoint–blocking (ICB) antibodies against programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) and cytotoxic T lymphocyte–associated protein 4 (CTLA-4) restored antitumor immunity in miR-155 T cell–conditional KO mice. We noted that these ICB antibodies rescued the levels of IFNγ-expressing T cells, expression of multiple activation and effector genes expressed by tumor-infiltrating CD8+ and CD4+ T cells, and tumor-associated macrophage activation. Moreover, the ICB approach partially restored expression of several derepressed miR-155 targets in tumor-infiltrating, miR-155–deficient CD8+ T cells, suggesting that miR-155 and ICB regulate overlapping pathways to promote antitumor immunity. Taken together, our findings highlight the multifaceted role of miR-155 in T cells, in which it promotes antitumor immunity. These results suggest that the augmentation of miR-155 expression could be used to improve anticancer immunotherapies.
Folding-Degradation Relationship of a Membrane Protein Mediated by the Universally Conserved ATP-Dependent Protease FtsH

ATP-dependent protein degradation mediated by AAA+ proteases is one of the major cellular pathways for protein quality control and regulation of functional networks. While a majority of studies of protein degradation have focused on water-soluble proteins, it is not well understood how membrane proteins with abnormal conformation are selectively degraded. The knowledge gap stems from the lack of an in vitro system in which detailed molecular mechanisms can be studied as well as difficulties in studying membrane protein folding in lipid bilayers. To quantitatively define the folding-degradation relationship of membrane proteins, we reconstituted the degradation using the conserved membrane-integrated AAA+ protease FtsH as a model degradation machine and the stable helical-bundle membrane protein GlpG as a model substrate in the lipid bilayer environment. We demonstrate that FtsH possesses a substantial ability to actively unfold GlpG, and the degradation significantly depends on the stability and hydrophobicity near the degradation marker. We find that FtsH hydrolyzes 380-550 ATP molecules to degrade one copy of GlpG. Remarkably, FtsH overcomes the dual-energetic burden of substrate unfolding and membrane dislocation with the ATP cost comparable to that for water-soluble substrates by robust ClpAP/XP proteases. The physical principles elucidated in this study provide general insights into membrane protein degradation mediated by ATP-dependent proteolytic systems.
The flyover effect on IPO returns

Election politics highlighted the flyover label—those states between the two coastal regions of the US. The implication is that the interior part of the country may be viewed as behaviorally different from the coastal regions. This research considers whether this perception passes through to the financial markets. In particular, after accounting for risk and lead underwriter prestige and incorporating the fixed effects of year and industry, is underpricing of IPOs affected by company address—coastal versus non-coastal? The results of this research suggest yes—there is less underpricing for non-coastal companies. Flyover IPOs experience about 5.5% less first-day underpricing. Also, IPOs originating from the flyover states appear to outperform coastal IPOs for both one year and three years post IPO, when comparing compounded wealth relatives (assuming investment at the closing price of the first day of trading).
The effect of laser focus and process parameters on microstructure and mechanical properties of SLM Inconel 718

Research on the selective laser melting (SLM) method of laser powder bed fusion additive manufacturing (AM) has shown that surface and internal quality of AM parts is directly related to machine settings such as laser energy density, scanning strategies, and atmosphere. To optimize laser parameters for improved component quality, the energy density is typically controlled via laser power, scanning rate, and scanning strategy, but can also be controlled by changing the spot size via laser focal plane shift. Present work being conducted by The Aerospace Corporation was initiated after observing inconsistent build quality of parts printed using OEM-installed settings. Initial builds of Inconel 718 witness geometries using OEM laser parameters were evaluated for surface roughness, density, and porosity while varying energy density via laser focus shift. Based on these results, hardware and laser parameter adjustments were conducted in order to improve build quality and consistency. Tensile testing was also conducted to investigate the effect of build plate location and laser settings on SLM 718. This work has provided insight into the limitations of OEM parameters compared with optimized parameters towards the goal of manufacturing aerospace-grade parts, and has led to the development of a methodology for laser parameter tuning that can be applied to other alloy systems. Additionally, evidence was found that for 718, which derives its strength from post-manufacturing heat treatment, there is a possibility that tensile testing may not be perceptive to defects which would reduce component performance. Ongoing research is being conducted towards identifying appropriate testing and analysis methods for screening and quality assurance.
Chapter 12 – Magnetic properties

Publisher Summary One of the most important characteristics of a superconductor is its magnetic behavior, which arises from its vortex structure. This chapter examines the configurations and interactions of vortices and discusses the macroscopic magnetic properties that result from them. The role that the vortices play in influencing electric current flow and their dependence on the sample shape are examined in the chapter. The magnetization often exhibits hysteresis, which means that it depends on the previous history of how the external field was applied. A simplified phase diagram of the magnetic states of a Type II superconductor consists of a Meissner phase of perfect diamagnetism (absence of vortices) at the lowest temperatures, and a mixed (vortex lattice) phase at higher temperatures. This shows, in addition to the Meissner phase, a flux solid phase with vortices pinned or otherwise held in place, and flux liquid phase where many vortices are unpinned or free to move, but with dissipation. These two phases are separated by a melting line that is also called the irreversibility line. Flux creep can occur to its left and flux flow to its fight. In the narrow region called the plasma phase, thermal fluctuations create short-lived positively and negatively oriented vortices that are called intrinsic.
A Perceptual-Behavioral Perspective of Decision-Making under Uncertainty

The focus of attention on methods of handling uncertainty in decision-making leaves unanswered the questions as to what are the nature and causes of uncertainty. It is also unclear as to the extent to which uncertainty and what type is actually reduced by the application of methods independent of a framework that provides an understanding of uncertainty. This paper is a post-seminar attempt to provide a framework for the application of methods in managing uncertainty in decision-making.
Perspectives on Advances in Bone Imaging for Osteoporosis

Noninvasive and/or nondestructive techniques can provide structural information about bone, beyond simple bone densitometry. While the latter provides important information about osteoporotic fracture risk, many studies indicate that BMD only partly explains bone strength. Quantitative assessment of macro-structural characteristics, such as geometry, and microstructural features, such as relative trabecular volume, trabecular spacing, and connectivity, may improve our ability to estimate bone strength. Methods for quantitatively assessing macrostructure include (besides conventional radiographs) dual X-ray absorptiometry (DXA) and computed tomography (CT), particularly volumetric quantitative computed tomography (vQCT). Methods for assessing microstructure of trabecular bone noninvasively and/or nondestructively include high-resolution computed tomography (hrCT), micro-computed tomography (µCT), high-resolution magnetic resonance (hrMR), and micromagnetic resonance µmR. Volumetric QCT, hrCT, and hrMR are generally applicable in vivo; µCT and µmR are principally applicable in vitro. Despite progress remain. The important balances between spatial resolution and sampling size, or between signal-to-noise ratio and radiation dose or acquisition time, need further consideration, as do the complexity and expense of the methods vs their availability and accessibility. Clinically, the challenges for bone imaging include balancing the advantages of simple bone densitometry vs the more complex architectural features of bone, or the deeper research requirements vs the broader clinical needs. The biological differences between the peripheral appendicular skeleton and the central axial skeleton must be addressed further. Finally, the relative merits of these sophisticated imaging techniques must be weighed with respect to their applications as diagnostic procedures, requiring high accuracy or reliability, vs their monitoring applications, requiring high precision or reproducibility.
Development of Peptide-Based Inhibitors of Amylin Aggregation Employing Aromatic and Electrostatic Repulsion

Human islet amyloid polypeptide (hIAPP) is a 37-residue hormone that is co-stored and co-secreted with insulin. In type 2 diabetes, the polypeptide misfolds to form amyloid plaques in the pancreas. The self-assembly of hIAPP has been linked to the loss of insulin production and β-cell death. Recent investigations have revealed that soluble oligomers of hIAPP are the cytotoxic species responsible for β-cell death and not insoluble amyloid fibrils. Compounds that prevent the self-assembly of hIAPP or drive self-assembly to the state of innocuous insoluble amyloid may be of potential therapeutic value. In this report we summarize key methods employed in our efforts to identify peptide-based modulators of amylin self-assembly that utilize π-electronic effects or electrostatic charge repulsion. These peptide-based modulators may serve as lead compounds for the development of more drug-like molecules and demonstrate that tuning π-electron density and employing charged amyloid disrupting elements are viable approaches toward the design of potential amyloid inhibitors.
A Locational Demand Model for Bike-Sharing

In operating modern bike-sharing systems, understanding rider demand and behaviors is of significant importance. A key challenge in estimating demand is to account for the choice substitution effect, where a rider may substitute a trip for stations nearby when the first-choice location for picking up or returning a bike is not available. In this paper, we study and analyze a locational demand model to account for substitution behaviors that are determined by proximity. The model assumes that riders originate from a region in space, and each has a heterogeneous consideration radius to find stations with available bikes in the order of closeness to their locations. We study a natural parameterization of this model with distance rankings, each corresponding to a distance ordering of stations within the consideration radius of a rider from a particular origin. We characterize the conditions under which the model is identifiable and its parameters can be consistently estimated. By exploiting the locational structure and sparsity in stock-out patterns, which are inherent to bike-sharing systems, we find sparse representations of the model parameters and develop efficient first-order methods for estimating the parameters. Our approach is tractable on a city scale and has good empirical performance, which we demonstrate on a bike-sharing system in the Boston metropolitan area.
Adult-Onset Still’s Disease Presenting as an Atypical Cutaneous Eruption

Adult-onset Still’s disease classically presents with high fevers, arthralgias, leukocytosis, and an evanescent eruption. There are, however, a known subset of patients who develop an atypical eruption with persistent erythematous to violaceous papules and plaques. Here, we present the case of a white female in her 40s who presented with 2 years of spiking fevers, arthralgias, and a fixed pruritic eruption with erythematous plaques with overlying scale and linear accentuation. She was initially treated with oral prednisone, anakinra, and methotrexate. Due to persistent symptoms, she was switched to adalimumab with significant relief of symptoms. Prompt recognition of adult-onset Still’s disease with this atypical eruption may help prevent delayed or missed diagnosis and allow for early, appropriate intervention.
Prevalence of and factors associated with violations of a campus smoke-free policy: a cross-sectional survey of undergraduate students on a university campus in the USA.

Objective The aim of this study is to estimate the prevalence of smoking behaviour on campus and to identify the key factors that influence adherence to a campus smoke-free policy. Design & participants This study employed a cross-sectional, self-administered survey of undergraduate students at the University of Mississippi. A random sample of all available undergraduate classes was recruited for data collection. Students were provided a survey that included questions on demographics, alcohol use, smoking status, policy awareness, policy attitudes, smoking attitudes, policy support, barriers to policy success and policy violations. Results The prevalence of past 30-day smoking was 23%. More than 63% of current smokers report ever smoking on campus, but less than 10% ever received a warning or a ticket for their violation. Nearly all respondents (92.5%) reported witnessing someone smoking on campus, and 22% reported witnessing someone receiving a ticket. Barriers to policy success include lack of reminders about the policy, lack of support from students and University administrators, and insufficient fines. Smoking behaviour (OR: 7.96; 95% CI: 5.13 to 12.36), beliefs about policy adherence (OR: 0.52; 95% CI: 0.40 to 0.69), support for the policy (OR: 0.71; 95% CI: 0.55 to 0.91) and attitudes against smoking behaviour (OR: 0.35; 95% CI: 0.25 to 0.49) were all significantly associated with self-reported policy violations. Conclusions This study found that violations of the campus smoke-free policy were fairly frequent and the policy has been largely ineffective, indicating a need for other interventions. Approaches to improve adherence to the policy should address barriers such as reminders about the policy, better policy enforcement and support from the administration.
Acute and chronic alcohol effects in zebrafish

Abstract Zebrafish have become a popular animal model for behavioral genetics and to study the effects of alcohol on the brain. The reported effects acute (short-term) and chronic (long-term) alcohol exposure on zebrafish brain and behavior have provided significant insights into this drug’s mechanism of action. In this chapter, I will focus on the behavioral genetics of alcohol exposure by discussing the effects of acute and chronic alcohol exposure on zebrafish behavior, neurochemistry, and gene expression. Furthermore, I will discuss the advantages of using forward and reverse genetic techniques with zebrafish to dissect the mechanisms underlying alcohol’s effect on the central nervous system.
Revealing heritability missed by single locus analyses by examining epistasis in mouse chromosome substitution strains

The genetic contribution of additive versus non-additive (epistasis) effects in the regulation of hematologic and other complex traits is unclear. While genome-wide association studies typically ignore gene-gene interactions, in part because of the lack of statistical power for detecting them, mouse chromosome substitution strains (CSSs) represent an alternate and powerful model for detecting epistasis given their limited allelic variation. Therefore, we utilized CSSs to identify and map both additive and epistatic loci that regulate a range of hematologic- and metabolism-related traits, as well as hepatic gene expression. Quantitative trait loci (QTLs) were identified using a modified backcross strategy involving the segregation of variants on the A/J-derived substituted chromosomes 4 and 6 on an otherwise C57BL/6J genetic background. By analyzing the transcriptomes of offspring from this cross, we identified and mapped additive QTLs regulating the expression of 768 genes, and epistatic QTL pairs for 519 genes. Similarly, we identified additive QTLs for fat pad weight, platelets, and the percentage of granulocytes in blood, as well as epistatic QTL pairs controlling the percentage of lymphocytes in blood and red cell distribution width. The variance attributed to the epistatic QTLs was approximately equal to that of the additive QTLs, demonstrating the importance of identifying genetic interactions to understand the genetic architecture of complex traits. Of particular note, even the epistatic QTLs that accounted for the largest variances were undetected in our single loci GWAS-like association analyses, highlighting the need to account for epistasis in association studies.
Rapid Decay of the Native Intermediate in the Metallooxidase Fet3p Enables Controlled FeII Oxidation for Efficient Metabolism

The multicopper oxidases (MCOs) couple four 1e- oxidations of substrate to the 4e- reduction of O2 to H2O. These divide into two groups: those that oxidize organic substrates with high turnover frequencies (TOFs) up to 560 s-1 and those that oxidize metal ions with low TOFs, ∼1 s-1 or less. The catalytic mechanism of the organic oxidases has been elucidated, and the high TOF is achieved through rapid intramolecular electron transfer (IET) to the native intermediate (NI), which only slowly decays to the resting form. Here, we uncover the factors that govern the low TOF in Fet3p, a prototypical metallooxidase, in the context of the MCO mechanism. We determine that the NI decays rapidly under optimal turnover conditions, and the mechanism thereby becomes rate-limited by slow IET to the resting enzyme. Development of a catalytic model leads to the important conclusions that proton delivery to the NI controls the mechanism and enables the slow turnover in Fet3p that is functionally significant in Fe metabolism enabling efficient ferroxidase activity while avoiding ROS generation.
When Social Media Get Political: How Perceptions of Open-Mindedness Influence Political Expression on Facebook:

The use of social media for developing and maintaining relationships can offer a gateway for users to open up and express their political views. Building on previous literature on the “spillover ef...
The Theory and Applications of Measuring Broad-Range and Chromosome-Wide Recombination Rate from Allele Frequency Decay around a Selected Locus.

Recombination is the exchange of genetic material between homologous chromosomes via physical crossovers. High throughput sequencing approaches detect crossovers genome-wide to produce recombination rate maps but are difficult to scale as they require large numbers of recombinants individually sequenced. We present a simple and scalable pooled-sequencing approach to experimentally infer near chromosome-wide recombination rates by taking advantage of non-Mendelian allele frequency generated from a fitness differential at a locus under selection. As more crossovers decouple the selected locus from distal loci, the distorted allele frequency attenuates distally towards Mendelian and can be used to estimate the genetic distance. Here, we use marker selection to generate distorted allele frequency and theoretically derive the mathematical relationships between allele frequency attenuation, genetic distance, and recombination rate in marker selected pools. We implemented nonlinear curve fitting methods that robustly estimate the allele frequency decay from batch sequencing of pooled individuals, and derive chromosome-wide genetic distance and recombination rates. Empirically, we show that marker selected pools closely recapitulate genetic distances inferred from scoring recombinants. Using this method, we generated novel recombination rate maps of three wild derived strains of Drosophila melanogaster, which strongly correlate with previous measurements. Moreover, we show that this approach can be extended to estimate chromosome-wide crossover interference with reciprocal marker selection and discuss how it can be applied in the absence of visible markers. Altogether, we find that our method is a simple and cost-effective approach to generate chromosome-wide recombination rate maps requiring only one or two libraries.
QTc Prolongation in Pediatric Patients with Diabetic Ketoacidosis.

Objective To investigate the association between diabetic ketoacidosis (DKA) and prolonged QTc interval and to assess for correlation between DKA severity and QTc prolongation. Study design Retrospective observational study in a pediatric hospital. Patients admitted with DKA diagnosed by laboratory criteria and an electrocardiogram (ECG) performed during a period of acidosis were identified using Looking Glass Clinical Analytics. Data including age, sex, pH, electrolytes, anion gap, and ECG variables were collected. Patients were excluded if they had a prior diagnosis of prolonged QTc or were taking QTc prolonging medications. Severity of DKA was classified as mild (pH 7.24-7.3), moderate (pH 7-7.24), or severe (pH Results Ninety-six patients were included (mean age 15.2 ± 4.2 years, pH 7.12 ± 0.12, bicarbonate 8.6 ± 3.7 mmol/L, potassium 5.3 ± 1.1 mEq/L). Mean QTc interval for all patients in DKA was 454 ± 32 msec. Mean QTc in the mild group was 441 ± 22 msec, moderate group 460 ± 36 msec, and severe group 461 ± 34 msec. There was a significant difference in QTc interval across DKA severity groups (P = .05). There was a significant association between higher anion gaps and greater QTc intervals (r = 0.21, P = .04). Conclusions Thirty-one percent of pediatric patients with DKA demonstrated QTc prolongation on ECG. Severity of DKA and worsening acidosis were associated with increased prolongation of the QTc. Further study is required to evaluate the clinical impact of these findings.
Temporal and Spatial Analyses of TB Granulomas to Predict Long-Term Outcomes

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), kills more individuals worldwide per year than any other infectious agent. As the hallmark of TB, lung granulomas are complex structures composed of immune cells that interact with and surround bacteria, infected cells, and a necrotic core. This interaction leads to diverse granuloma outcomes across time, ranging from bacterial sterilization to uncontrolled bacterial growth, as well as diverse spatial structures. At this time, there are no systematic quantitative methods to classify the formation, function, and spatial characteristics of granulomas. This type of analysis would enable better understanding and prediction of granuloma behaviors that have known associations with poor clinical outcomes for TB patients. Herein, we develop a temporal and spatial analysis framework for TB granulomas using a systems biology approach combining in silico granuloma modeling, geographic information systems, topological data analysis, and machine learning. We apply this framework to simulated granulomas to understand temporal granuloma dynamics, quantify granuloma spatial structure, and predict the relationship between granuloma structure and bacterial growth. As a proof-of-concept, we apply our in silico predictions to in vivo derived data to test our framework for future applications and as a personalized medicine intervention.
Troubleshooting problems with antegrade continent enema flushes: The Indiana university algorithm.

Summary Introduction Antegrade continence enemas have transformed treatment and improved the quality of life in children with neuropathic bowel, refractory constipation and fecal incontinence. However, it can often be difficult to manage problems that arise with ACE flushes. Objective We report the use of an online tool designed for nurses to help troubleshoot calls for problems associated with antegrade continence enema (ACE) flushes as well as update our algorithm for managing refractory constipation/fecal incontinence in a large single institution experience. Study design We developed an online tool based on our management protocol for managing refractory constipation/fecal incontinence (Summary Figure). Patient frequency and bother was assessed prior to the intervention and at one month after the intervention using 5- and 4-point Likert scales respectively. Patient demographics, MACE/Chait information, type of difficulty, volume of flush, and use of additives were recorded. Nurses were also interviewed prior to using the tool and 14 months after its development with regards to taking these phone calls and the helpfulness of the tool. Results Over 14 months, the nurses received 22 patients calls via the nursing triage line regarding ACE flush problems and prospectively collected data. Half reported multiple episodes of fecal incontinence. Other complaints included no response to flush (8, 36.4%), occasional episodes of liquid fecal incontinence (2, 9.1%) and time of flush exceeding 60 min (1, 4.5%). While patients did not report decreased frequency of problems as a result of nurse troubleshooting using the ACE algorithm (2.5 vs. 2, p = 0.55), patients did report a significant improvement in their bother scores (4 vs. 2, p = 0.02). All but one patient reported that the recommendation was “some” or “a lot” helpful on follow up interview. The nurses all indicated that the tool helped “some” or “a lot.” Discussion The antegrade continence enema is valuable in managing neurogenic bowel, refractory constipation, and fecal incontinence, however, some patients experience problems with flushes that can often be difficult to manage. Conclusion Patients reported less bother with their bowel issues after using our algorithm for managing refractory constipation/fecal incontinence and nurses reported that the tool was helpful. Download : Download high-res image (613KB) Download : Download full-size image Summary Figure . Institutional algorithm to troubleshoot ACE flush problems.
Characterization of decentralized fixed modes using inverse matrix factorization

This paper deals with issues pertaining to the assignment of closed loop eigenvalues under a decentralized control setting in the following way: 1. Characterization of decentralized fixed modes using inverse matrix factorization. This characterization differs from existing results in that it does not assume an a priori feedback structure and can therefore be used as a constructive test to determine a feasible decentralized structure (i.e. one with no unstable decentralized fixed modes). 2. Determination of a minimal decentralized feedback structure to minimize implementation complexity. 3. Application of the results to the stabilization of lightly damped systems. Furthermore, it is shown that if a plant does not have any co-located open-loop eigenvalues and transmission zeros, then at most min(r,m) feedback elements are required to shift all eigenvalues where r and m are, respectively, the number of outputs and the number of inputs.
ENZYMES OF GLUCOSE AND PYRUVATE CATABOLISM IN CELLS, SPORES, AND GERMINATED SPORES OF CLOSTRIDIUM BOTULINUM

Simmons, R. J. (Michigan State University, East Lansing), and R. N. Costilow. Enzymes of glucose and pyruvate catabolism in cells, spores, and germinated spores of Clostridium botulinum. J. Bacteriol. 84:1274-1281. 1962.-An investigation was made of the enzymes of vegetative cells, spores, and germinated spores of Clostridium botulinum 62-A to elucidate a pathway of glucose metabolism. Manometric studies were conducted with intact cells, and various enzymes and enzyme systems were assayed in cell-free and spore-free extracts by use of spectrophotometric and colorimetric procedures. Glucose fermentation was found to be inducible; glucokinase was the controlling enzyme. All other enzymes of the Embden-Meyerhof-Parnas (EMP) pathway were found in both induced and non-induced cells, but they were in relatively low concentrations in the latter. This, plus the fact that no glucose-6-phosphate dehydrogenase was detected, led to the conclusion that glucose is catabolized primarily by the EMP system. A number of glycolytic enzymes were also found in extracts of spores and germinated spores of this organism, but the activities were extremely low as compared with activities in cell extracts. A phosphoroclastic-type reaction was readily demonstrated in both glucose-adapted and non-adapted cells, but not in spores and germinated spores. However, both acetokinase and phosphotransacetylase, as well as coenzyme A transphorase, were detected in spores and germinated-spore extracts, although at very low activity levels as compared with cell extracts. The specific activity of diaphorase in spore extracts was about one-half that of corresponding cell extracts, and the activity of reduced diphosphopyridine nucleotide (DPNH) oxidase was actually higher in the spore extracts. In addition, the DPNH oxidase in spore extracts was considerably more heat-stable than that in extracts of cells or germinated spores.
Prospective randomized trial of laparoscopic Nissen fundoplication versus maintenance proton pump inhibition in the treatment of gastro-oesophageal reflux disease in patients aged under 65 years: preliminary results

Background: Laparoscopic Nissen fundoplication (LNF) was compared with maintenance proton pump inhibition (PPI) in patients with gastro-oesophageal reflux disease (GORD). Methods: Some 113 patients (60 men; median age 45 (range 25–64) years) presented between June 1997 and June 1998 with a history of GORD of at least 2 years' duration. After giving informed consent they were investigated by endoscopy, 24-h pH and oesophageal manometry. Of 66 patients who completed the investigations, 57 had significant GORD; these were randomized, 29 to PPI and 28 to LNF. Results: Endoscopic findings were equivalent in the two groups: 75 per cent of the PPI group had a hiatus hernia compared with 78 per cent of the LNF group; 54 per cent of the PPI group had oesophagitis compared with 71 per cent in the LNF group. Twenty-four-hour pH monitoring revealed De Meester scores of 21 (range 7–92) in the PPI group compared with 20 (range 10–99) in the LNF group. Manometry revealed a median␣lower oesophageal sphincter pressure (LOSP) of 10 (range 0–30) mmHg in the PPI group compared with 7 (range 1–30) mmHg in the LNF group. At 3 months after start of therapy, 24-h pH monitoring revealed a median De Meester score of 11 for both groups (PPI range 7–24, LNF range 9–39). Median LOSP was 15 mmHg in the PPI group compared with 17 mmHg in the LNF group. Conclusion: Preliminary results suggest that LNF provides the same reduction in acid reflux as maintenance PPI in the short term. Further study of this group of patients will assess not only the physiological benefits of surgery versus maintenance PPI but also its impact on well being and relative costs of the two treatments. © 1999 British Journal of Surgery Society Ltd
First St. John's Wort, Now Sam-E: Is Society as a Whole at Risk without FDA Regulation of Psychiatric Self-Medication?

That is precisely what we are doing when we allow persons who are in need of professional psychiatric help to instead stroll down the aisle of their favorite health food store and select a dietary supplement to alleviate their symptoms. The average consumer is not qualified to judge the efficacy, dosage or drug interaction properties of the herb. Persons afflicted with this disease suffer from mood swings, varying from depression to mania. It can be said with substantial certainty that the FDA lost most if not all control over dietary supplements upon passage of the Dietary Supplement Health and Education Act (DSHEA) in 1994. The FDA responded to consumer concern by formulating a task force to examine the entire dietary supplement arena. A drug may be derived from a plant, as can a dietary supplement or herbal preparation. The FDA can thus challenge a substance which it believes should be regulated as a food additive but is sold as a dietary supplement. DSHEA forbids the FDA from using its food additive jurisdiction to prohibit the marketing of dietary supplement products. As a result of these findings, the FDA proposed labeling regulations in an attempt to clarify whether existing label statements represent a dietary supplement's affect on the structure and function of the body, or whether they constitute a disease claim.