Miracle-dz/UniFAR-FTUs huggingface dataset:
Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo.

Doses of 3H-acetaminophen (300-750 mg/kg) that cause necrosis in mice were shown to result in large amounts of radiolabeled material covalently bound to mouse liver protein in vivo (2 nmol/mg of protein or approximately one molecule bound per two molecules of protein in microsomes and cytoplasm). Both covalent binding and hepatic necrosis were dose dependent, and the peak level of binding preceded the development of recognizable necrosis by at least one to two hours. Pretreatment of mice with phenobarbital, piperonyl butoxide or cobaltous chloride, which changed the rate of metabolism of 3H-acetaminophen and altered the severity of hepatic necrosis, similarly affected the extent of hepatic binding of radiolabeled metabolite. Furthermore, the degree of binding in individual mice was always directly proportional to the severity of hepatic necrosis regardless of the biologic variation among various animals. Accordingly, we propose that acetaminophen-induced hepatic necrosis may be caused by the covalent binding of a chemically reactive metabolite to vital hepatsic macromolecules.
Optimal combined purchasing strategies for a risk-averse manufacturer under price uncertainty

Purpose: The purpose of our paper is to analyze optimal purchasing strategies when a manufacturer can buy raw materials from a long-term contract supplier and a spot market under spot price uncertainty. Design/methodology/approach: This procurement model can be solved by using dynamic programming. First, we maximize the DM’s utility of the second period, obtaining the optimal contract quantity and spot quantity for the second period. Then, maximize the DM’s utility of both periods, obtaining the optimal purchasing strategy for the first period. We use a numerical method to compare the performance level of a pure spot sourcing strategy with that of a mixed strategy. Findings: Our results show that optimal purchasing strategies vary with the trend of contract prices. If the contract price falls, the total quantity purchased in period 1 will decrease in the degree of risk aversion. If the contract price increases, the total quantity purchased in period 1 will increase in the degree of risk aversion. The relationship between the optimal contract quantity and the degree of risk aversion depends on whether the expected spot price or the contract price is larger in period 2. Finally, we compare the performance levels between a combined strategy and a spot sourcing strategy. It shows that a combined strategy is optimal for a risk-averse buyer. Originality/value: It’s challenging to deal with a two-period procurement problem with risk consideration. We have obtained results of a two-period procurement problem with two sourcing options, namely contract procurement and spot purchases. Our model incorporates the buyer’s risk aversion factor and the change of contract prices, which are not addressed in early studies.
Injuries to children involving home exercise equipment.

The past decade has seen a dramatic increase in the popularity of physical fitness. For convenience, products for home exercise have become very popular as well. Each year, new types of exercise equipment are developed and each year a growing number of households are furnished with such equipment. Along with this growth comes the potential for an increasing number of related injuries, particularly those involving young children. In 1982, the US Consumer Product Safety Commission (USCPSC) reported that injuries involving exercise equipment accounted for an estimated 17 686 hospital emergency department visits within a 3-year study period (1979 to 1981), approximately 6000 visits each year.1According to 1991 National Electronic Injury Surveillance System (NEISS) statistics, exercise equipment–related injuries were responsible for an estimated 25 256 emergency department visits, representing an increase of over 400% since 1982.2Children younger than 15 years of age were involved in over
Effects of isolated hyperinsulinaemia on sensory function in healthy adults.

AIMS Gastrointestinal symptoms such as pain, bloating, nausea and vomiting are more frequent in pre-diabetic states as well as established diabetes, compared to healthy individuals. The mechanisms behind these symptoms are multi-factorial and complex. Furthermore, the effect of isolated hyperinsulinaemia on visceral and peripheral sensory function is poorly understood. Thus, the current study aimed to evaluate effects of acute hyperinsulinaemia on sensory function in healthy adults. METHODS The sensitivity to electrical oesophageal and median nerve stimulation was assessed in 15 healthy volunteers together with recording of evoked brain potentials. All subjects were studied both fasting and using a euglycaemic hyperinsulinaemic clamp. RESULTS There was on average a 15% increased sensitivity to oesophageal electrical stimulation during hyperinsulinaemia compared to fasting state (P<0.05), but the sensation after median nerve stimulation remained stable (P=0.58). No significant changes in latencies and amplitudes of evoked brain potentials were observed after oesophageal or median nerve stimulation (all P>0.05). CONCLUSIONS This study suggests that acute isolated hyperinsulinaemia increases visceral sensitivity, but does not influence the somatic sensory function. The lack of changes in the evoked brain potentials may indicate that hyperinsulinaemia affects the visceral sensory system at a peripheral level. Our result suggests distinct functions of insulin in the various parts of the nervous system, and yields further clues to the significance of insulin as a satiety signal.
Intrinsic properties and functional circuitry of the AII amacrine cell

Abstract Amacrine cells represent the most diverse class of retinal neuron, comprising dozens of distinct cell types. Each type exhibits a unique morphology and generates specific visual computations through its synapses with a subset of excitatory interneurons (bipolar cells), other amacrine cells, and output neurons (ganglion cells). Here, we review the intrinsic and network properties that underlie the function of the most common amacrine cell in the mammalian retina, the AII amacrine cell. The AII connects rod and cone photoreceptor pathways, forming an essential link in the circuit for rod-mediated (scotopic) vision. As such, the AII has become known as the rod–amacrine cell. We, however, now understand that AII function extends to cone-mediated (photopic) vision, and AII function in scotopic and photopic conditions utilizes the same underlying circuit: AIIs are electrically coupled to each other and to the terminals of some types of ON cone bipolar cells. The direction of signal flow, however, varies with illumination. Under photopic conditions, the AII network constitutes a crossover inhibition pathway that allows ON signals to inhibit OFF ganglion cells and contributes to motion sensitivity in certain ganglion cell types. We discuss how the AII’s combination of intrinsic and network properties accounts for its unique role in visual processing.
Apoptosis induction and growth suppression by U19/Eaf2 is mediated through its ELL‐binding domain

U19/Eaf2 is an androgen‐response gene and its downregulation is frequently observed in advanced human prostate cancer. U19/Eaf2 interacts with ELL, a fusion partner of MLL in the (11;19) (q23;p13.1) translocation in acute myeloid leukemia. U19/Eaf2 overexpression induces apoptosis and suppresses xenograft tumor growth.
Membrane‐anchored growth factors, the epidermal growth factor family: Beyond receptor ligands

The epidermal growth factor (EGF) family and the EGF receptor (EGFR, ErbB) tyrosine kinase family have been spearheading the studies of signal transduction events that determine cell fate and behavior in vitro and in vivo. The EGFR family and their signaling pathways are giving us tremendous advantages in developing fascinating molecular target strategies for cancer therapy. Currently, two important types of EGFR inhibitors are in clinical use: neutralizing antibodies of EGFR or ErbB2, and synthetic small compounds of tyrosine kinase inhibitors designed for receptors. On the other hand, basic research of the EGF family ligands presents new challenges as membrane‐anchored growth factors. All members of the EGF family have important roles in development and diseases and are shed from the plasma membrane by metalloproteases. The ectodomain shedding of the ligands has emerged as a critical component in the functional transactivation of EGFRs in interreceptor cross‐talk in response to various shedding stimulants such as G‐protein coupled receptor agonists, growth factors, cytokines, and various physicochemical stresses. Among the EGFR‐ligands, heparin‐binding EGF‐like growth factor (HB‐EGF) is a prominent ligand in our understanding of the pathophysiological roles of ectodomain shedding in cancer, wound healing, cardiac diseases, etc. Here we focus on ectodomain shedding of the EGF family ligands, especially HB‐EGF by disintegrin and metalloproteases, which are not only key events of receptor cross talk, but also novel intercellular signaling by their carboxy‐terminal fragments to regulate gene expression directly. (Cancer Sci 2008; 99: 214–220)
Binding of a nonionic detergent to membranes: flip-flop rate and location on the bilayer.

The kinetic aspects of amphiphile interaction with intact membranes (unilamellar and multilamellar liposomes, sarcoplasmic reticulum vesicles) were studied, with the nonionic detergent octa(ethylene glycol) dodecyl monoether (C12E8) as a prototype. C12E8 was bound to these membranes noncooperatively and with a maximum of 0.6-0.8 mol per mole of phospholipid, before the onset of solubilization. Binding was not affected by ultrasonication to expose internal binding sites on the inner leaflet. All detergent could be removed from the membranes by treatment with hydrophobic beads. Furthermore, bound detergent, also from the inside of multilayered liposomes, comprising 10-20 bilayers, was quickly released by dilution of the membranes, followed by gel filtration. The time course of these processes was investigated with a rapid-filtration apparatus, using glass fiber filters to deposit membrane material. Both detergent binding and removal could be described by a monoexponential process with a half-time of approximately 350 ms for all types of membranes. Binding of detergent enhanced the intrinsic fluorescence of sarcoplasmic reticulum vesicles. This occurred in less than 100 ms, probably as the result of direct interaction of C12E8 with Ca2+-ATPase at a few binding sites. The data show that flip-flop of C12E8 across lipid membranes is a rapid process that cannot account for incomplete detergent removal in reconstitution experiments [Ueno, M. , Tanford, C. , & Reynolds, J. A. (1984) Biochemistry 23, 3070-3076]. It is also suggested that other nonionized amphiphiles, including those with an anesthetic action, rapidly gain access to membrane proteins on the inside of the cell, even when used at low, clinical doses.
The Relationship between Cross-Sectional and Time Series Studies

Two classes of observational studies have provided quantitative estimates of the influence of air pollution on mortality. These are cross-sectional and time series studies. Cross-sectional studies examine geographical variations in community mortality rates and air pollution levels and typically involve fitting the parameters of proportional exposure-mortality functions by least squares regression analysis. Control for health-related covariates of pollution, such as socioeconomic status and smoking, is accomplished by inclusion of additional variables in the regression equation. Typically the averaging time for these analyses is one year; and therefore, many assume that these studies reflect chronic effects. Time series studies examine temporal variatons in death rates and air pollution levels in a single community. Using days as the unit of observation and averaging over the community, the parameters of the models are estimated by least squares techniques. Control for covariates is accomplished by reexpressing variables as deviations from trend lines and by including weather variables in the regression equation. Studies using these techniques reflect only the acute effects of air pollution. The similarity in the disease-specific findings of time series studies and cross-sectional studies which were analyzed is discussed. It is possible that the cross-sectional studies which have been conducted to datemore » have reflected the impacts of acute rather than chronic effects of air pollution. « less
Cholesterol metabolism in the brain: importance of 24S‐hydroxylation

During the last three to four decades there has been an increasing interest in the interaction of circulating and brain cholesterol. Recent in vivo and in vitro studies have furthered our knowledge of cholesterol metabolism in the central nervous system (CNS). As the CNS matures and cholesterol pools in the brain become constant, the rate of de novo synthesis of cholesterol in the brain markedly declines. Besides some excretion of apoE‐bound cholesterol via the CSF, another quantitatively more important mechanism has been described – the conversion of cholesterol into 24S‐hydroxycholesterol, that is, in contrast to cholesterol, able to traverse the blood–brain barrier (BBB). The enzyme (CYP46a1) mediating this conversion has been characterized at the molecular level and is mainly located in neurons. Like other oxysterols, 24S‐hydroxycholesterol is efficiently converted into normal bile acids or excreted in bile in its sulfated and glucuronidated form. Within the last 10 years the interest in studying the mechanisms of this and other cholesterol transport systems has increased and the results from these in vivo and in vitro investigations are reviewed.
Habitat Destruction, Fragmentation, and Disturbance Promote Invasion by Habitat Generalists in a Multispecies Metapopulation

Species invasions are extremely common and are vastly outpacing the ability of resource agencies to address each invasion, one species at a time. Management actions that target the whole landscape or ecosystem may provide more cost‐effective protection against the establishment of invasive species than a species‐by‐species approach. To explore what ecosystem‐level actions might effectively reduce invasions, we developed a multispecies, multihabitat metapopulation model. We assume that species that successfully establish themselves outside their native range tend to be habitat generalists and that a tradeoff exists between competitive ability and habitat breadth, such that habitat specialists are competitively superior to habitat generalists. In this model, habitat destruction, fragmentation, and short‐term disturbances all favor invasion by habitat generalists, despite the inferior competitive abilities of generalist species. Our model results illustrate that providing relatively undisturbed habitat and preventing further habitat degradation and fragmentation can provide a highly cost‐effective defense against invasive species.
Brain Homology: Dohrn of a New Era?

swims ‘upside down’, suggested – at least to him – not a vertebrate ancestor but, like the ascidian tadpole, an evolutionary simplified or ‘degenerate’ fish. Anton Dohrn was convinced that annelids were the ancestors of chordates. He suggested that structures could evolve through time leading to a complete change in their structural and functional identity. In his argument for annelid ancestry, Dohrn proposed that a common ancestor to the vertebrates might have had a ringlike brain around the mouth, as does an annelid, whose dorsal brain is connected to the ventral nerve cord and ganglia by connectives that extend around the stomodeum (the front part of the gut). To achieve transformation from an annelid to a vertebrate nervous system, there must evolve in the latter a brain that was not perforated by the stomodeum. To obtain this condition, the annelid mouth would have closed, and a new mouth opened above the brain. Dohrn suggested that this new mouth would have arisen by functional modification of gill slits that would have been present in the ancestral annelid. As a result of this transformation, the inversion would have been that of the vertebrate, to account for its ventral mouth. Dohrn’s monograph, which has been translated by Michael Ghiselin, with a commentary, enunciates Dohrn’s crucial ideas about ‘Funktionswechsel’ or ‘the principle succession of functions’, meaning the evoluIn 1875, the great embryologist Karl von Baer, then in his 82nd year, received a monograph dedicated to him proposing an annelid ancestry of the vertebrates [Ghiselin, 1994]. The monograph was written by Anton Dohrn, best known as the creator and tireless promoter of the Naples Zoological Station, now known as the ‘Stazione Zoologica Anton Dohrn’. A few years earlier, in 1867 and 1871, one of the greatest Russian biologists of the time, Alexandr Kowalevsky, who had worked in the Zoological Station, concluded that Amphioxus is a chordate, as are tunicates, and that these were the most logical candidates for vertebrate ancestry [Kowalevsky, 1867]. Kowalevsky’s colleague, Philip Owsjannikow, working in St. Petersburg, had determined in 1868 that Amphioxus possessed a dorsal nerve cord and what he interpreted as a small rostral brain [Owsjannikow, 1867]. Kowalevsky and Ilja Metschnikoff, his friend and colleague, had also published their discoveries of commonality of embryonic cell organization (‘germ layers’) shared across the Metazoa, a finding that underpinned Charles Darwin’s hypothesis of a common metazoan ancestor [Kowalevsky, 1871; Levit, 2007]. Whether those discoveries encouraged Anton Dohrn to consider an alternative ancestry of the vertebrates is not known. What is known, however, is that Dohrn’s own studies of the lancelet Amphioxus lanceolatus , which typically Published online: December 22, 2010
EFFECTS OF G 169 R AND P 34 S SUBSTITUTIONS PRODUCED BY MUTATIONS OF CYP 2 D 6 * 14 ON THE FUNCTIONAL PROPERTIES OF CYP 2 D 6 EXPRESSED IN V 79 CELLS

CYP2D6 is a polymorphic enzyme that catalyzes the oxidation of various drugs. At least 40-mutant alleles of CYP2D6 have been reported. CYP2D6*14, which is one of them found in Asian populations, causes deficient activity of CYP2D6. Four amino acid substitutions, P34S, G169R, R296C, and S486T, are present in the protein encoded by CYP2D6*14 (CYP2D6 14). Among them, G169R is thought to be a definitive substitution because it is unique to CYP2D6 14. However, a previous study showed that the activity of G169R-substituted CYP2D6 was about 40% of wild-type CYP2D6, suggesting that a combination of G169R and other substitutions may be required to abolish the activity of CYP2D6. In the present study, we examined the effects of combined substitutions of G169R and P34S on the functional properties of CYP2D6 and compared them with those of a single substitution of G169R or P34S using a cDNA expression system of V79 cells. The results showed that a combined substitution of G169R and P34S reduced the activities of CYP2D6 to less than the detection limit of our analytical method for bufuralol 1 -hydroxylation and dextromethorphan O-demethylation. However, these activities were not completely abolished by a single substitution of P34S or G169R. The findings suggest that simultaneous substitution of G169R and P34S is crucial for almost completely abolishing the activity of CYP2D6 at least in V79 cells, although whether the absence of metabolism is due to the absence of functional protein or catalytic incompetency remains unclear because the levels of CYP2D6 protein expressed in V79 cells were too low to be determined by difference CO-
A low-power, compact size millimeter-wave two-stage current-reused low noise amplifier in 90-nm CMOS technology

This paper presents a millimeter-wave (MMW) two-stage low noise amplifier (LNA) that adopts a current-reused topology to reduce the power consumption. The designed current-reused LNA comprises two stacked common source (CS) amplifiers with the same dc current for each stage to enhance the power gain. The proposed LNA is fabricated in tsmcTM 90-nm RF CMOS technology that achieves a peak S21 gain of 12 dB, a noise figure (NF) of 6.9 dB, an input third-intercept point (IIP3) of -4.1 dBm at 51 GHz under DC power of 7.7 mW from a 1.4 V supply voltage. The proposed LNA with transmission line (TL) inductors yields a compact chip size of only 0.37 mm2 and thus the calculated figure-of-merit (FoM) is up to 5.24 at 51 GHz.
The Electrochromic Process at WO3 Electrodes Prepared by Vacuum Evaporation and Anodic Oxidation of W

The kinetics of the electrochromic process and the stability with different WO3 electrodes (evaporated film, electrodes obtained by anodic oxidation of W, polycrystalline, and single crystal) were studied. Cyclic voltammetry and chronoamperometr y, together with optical absorption measurements in the electrochromic region were carried out. Impedance measurements at different frequencies of the WO3-H2SO4 (aq) interface were also made to compare the evaporated film and anodic oxide electrodes. These measurements showed that the electrochromic reaction at the WO3 anodic film was much faster than that at the evaporated film electrode (by about two to three orders of magnitude). This difference in the reaction rates reflects the difference in the rate of diffusion of H + in the films. Infrared spectroscopic measurements of the films were carried out to obtain information about the water content of the films. The differences in the kinetic behavior of the electrochromic process at the two electrodes were attributed to differences in porosity and water content of these two films. The stability of the WO3 film toward dissolution in aqueous solution was also shown to depend on the quantity of water in the film. In addition electrochemical behavior in the electrochromic region was studied in several other systems, including systems which contain H~SO~ as the electrolyte but with nonaqueous solvents and systems which contain Li +, replacing H +, in nonaqueous solvents. The solvent and the cation both affect the kinetics of the electrochromic process and the stability of the amorphous films. The electrochromic process at single crystal and polycrystalline WO3 was also studied and compared to the behavior of the amorphous film electrodes.
Fcgamma receptor polymorphisms and periodontal status: a prospective follow-up study.

AIMS The aims of this study were to assess: (i) the distribution of Fcgamma receptor polymorphisms among patients with chronic periodontitis ("cases") and control subjects with no/minimal loss of periodontal tissue support in a Caucasian population; (ii) whether these polymorphisms can serve as severity markers for periodontitis; and (iii) whether they have any bearing on the response to periodontal therapy. METHODS The study sample consisted of 132 cases and 73 controls of comparable age and gender. Full-mouth periodontal status was assessed. Subgingival plaque (PL) samples and blood samples were obtained and analysed with respect to 19 bacterial species and homologous serum immunoglobulin G titres. Polymorphisms in the Fcgamma receptor IIa (131R/H) and IIIb (NA1/NA2) were assessed by polymerase chain reaction. Patients underwent periodontal therapy and were followed up at 4 and 30 months. RESULTS Neither polymorphism showed a skewed distribution among cases and controls. At baseline, periodontitis patients with Fcgamma RIIa-H/H131 genotype had more PL and deeper pockets than patients in other genotype groups (p < 0.05). Both bacterial levels and antibody titres were unrelated to genotype. The longitudinal analysis failed to detect an association between genotype and response to periodontal therapy. CONCLUSIONS The present data failed to demonstrate a clinically relevant relationship between the Fcgamma receptor IIa (131R/H) or IIIb (NA1/NA2) polymorphism and periodontal status.