Miracle-dz/UniFAR-FTUs huggingface dataset:
Transfer of enalaprilat across rat liver cell membranes is barrier limited.

The liver cell entry of enalaprilat, the polar, pharmacologically active dicarboxylic acid metabolite arising from esterolysis of enalapril, a new angiotensin-converting enzyme inhibitor, was examined in the perfused rat liver by use of the multiple-indicator dilution technique. [Phenylpropyl-2,3-3H]enalaprilat was injected into the portal vein in a bolus of blood containing 51Cr-labeled red blood cells (a vascular reference) and 125I-labeled albumin and [14C]sucrose (interstitial references that do not enter cells), with observation of the time courses of their outflow into the hepatic venous blood. A quantitative evaluation of the data was carried out by use of the barrier-limited, space-distributed variable transit time model (C.A. Goresky, G.G. Bach, and B. E. Nadeau, J. Clin. Invest. 52:991-1009, 1973). For data up to 60 s after injection, the transfer coefficients for influx, efflux, and sequestration were 0.018 +/- 0.004 (means +/- SD), 0.044 +/- 0.017, and 0.033 +/- 0.007 s-1, respectively. The influx permeability surface area product (influx clearance) per gram was 0.0057 +/- 0.0013 ml.min-1.g-1, and the rapidly accessible cellular equilibrium distribution space for enalaprilat was 0.137 +/- 0.022 ml water/g wet wt. At times beyond 60 s, the fitted data deviated systematically from the experimental data, suggesting the presence of an additional intracellular pool. With this addition, the coefficients for transfer between the intracellular pools were 0.0150 +/- 0.0045 s-1 for the direction cytoplasmic pool (pool 1)----additional pool (pool 2) and 0.0234 +/- 0.0069 s-1 for the opposite direction, and the fitted volumes of pools 1 and 2 became 0.126 +/- 0.021 and 0.082 +/- 0.018 ml/g, the total accessible cellular distribution space became 0.208 +/- 0.036 ml/g wet wt, and the sequestration transfer coefficient became 0.027 +/- 0.007 s-1. The data indicate that, as previously postulated (I. A. M. de Lannoy and K. S. Pang, Drug Metab. Dispos. 14: 513-520, 1986), the enalaprilat flux across liver cell membranes is retarded by a diffusional barrier. The results also indicate that enalaprilat is excluded from part of the volume of hepatocytes, as expected for an anionic compound crossing the membrane in charged rather than protonated form, given the negative electrical potential of the cytosol vs. the extracellular space.
Comparison of Multifidus Muscle Atrophy and Trunk Extension Muscle Strength: Percutaneous Versus Open Pedicle Screw Fixation

Study Design. This study was conducted by retrospective case selection and prospective observation of longitudinal changes of the multifidus muscle cross-sectional area and of trunk extension muscle strength in percutaneous and open pedicle screw fixations. Objectives. To compare postoperative multifidus muscle atrophy and trunk muscle performance of percutaneous pedicle screw fixation against those of open pedicle screw fixation. Summary of Background Data. Recent attempts to combine percutaneous pedicle screw fixation with minimally invasive fusion techniques are based on an anecdotal presupposition that percutaneous pedicle screw fixation is superior to its open counterpart. However, the benefits of percutaneous pedicle screw fixation are currently poorly defined. Methods. Nineteen enrolled patients were divided as follows: 11 in the open pedicle screw fixation group (OPF group) and eight in the percutaneous pedicle screw fixation group (PPF group). The preoperative and postoperative cross-sectional area and T2-weighted signal intensity of multifidus muscle were measured by MRI, and trunk extension muscle strength was measured. In addition, various clinical variables were compared between two groups. Results. There was significant decrease in the cross-sectional area of multifidus muscle in the OPF group. In contrast, the results in the PPF group showed no statistical difference between preoperative results and that of the follow-up MRI. Although percutaneous pedicle screw fixation had positive effects on postoperative trunk muscle performance, clinical outcomes were not significantly different in areas of pain score, JOA score, and patient’s opinion regarding the outcome of the surgery. However, percutaneous pedicle screw fixation caused less blood loss, and the proportion of patients who did not need postoperative oral analgesics was greater in the PPF group. Conclusions. Percutaneous pedicle screw fixation caused less paraspinal muscle damage than open pediclescrew fixation and had positive effects on postoperative trunk muscle performance.
B16 melanoma metastasis to an "artificial organ" implant.

The mouse B16 melanoma metastasizes in two stages, first to the lungs and then from lung metastases to systemic organs. Despite widespread dissemination, visible metastases generally occur only in the brain, adrenals, kidneys, ovaries, pancreas, and mesentery. As a novel approach to investigate the basis of metastatic patterning in this system, the possibility was explored that an implantable "artificial organ" could serve as a site for the occurrence and experimental modulation of secondary-stage metastasis. Each implant consisted of a cellulose disc 4 mm in diameter, with a central 1-mm polymer pellet to effect local sustained release of angiogenic or growth factors in a s.c. environment. During the secondary spread of tumors initiated with the B16 melanoma clone G3.12 and with the more metastatic variant G3.12/BM2, metastatic involvement of implants containing angiogenic factors was mainly as invisible micrometastases demonstrable by bioassay; visible metastases were rare and were located in implant blood vessels. Metastasis occurred in about 30% (G3.12) and 50% (G3.12/BM2) of implants with vasculature induced by ethylene-vinyl acetate copolymer alone. Endothelial cell growth factor and heparin promoted greater vascularization but did not significantly alter metastatic involvement of implants. Release of tumor cell mitogenic activity from pellets containing a crude extract of mouse lungs increased the incidence of G3.12/BM2 metastasis in implants to over 70% and stimulated growth of visible metastases within the cellulose matrix. In contrast, liver extract inhibited metastasis growth. Colonization of implants following intracardiac injection of G3.12/BM2 cells was generally similar to metastasis, but visible colonies formed more readily and were less dependent on the influence of lung extract. These results indicate that metastasis and colonization can occur regularly in implants and that the relative favorability of the implant environment for secondary tumor growth can be altered by incorporation of tumor cell growth modulators.
Multiple eIF4GI-Specific Protease Activities Present in Uninfected and Poliovirus-Infected Cells

ABSTRACT Cleavage of eukaryotic translation initiation factor 4GI (eIF4GI) is required for shutoff of host cell translation during poliovirus (PV) infection of HeLa cells. Reports published by several groups have led to confusion whether this cleavage is mediated by viral 2A protease (2Apro) or a putative cellular enzyme (termed eIF4Gase) which is activated by 2Apro or other aspects of viral infection. Here we have further investigated eIF4Gase activities in PV-infected cells. Column purification of eIF4GI cleavage activity separated two activities which generated N-terminal cleavage products of different lengths. Both activities were detected using either native eIF4G or radiolabeled recombinant eIF4G as the substrate. Analysis of cleavage products formed by each activity on native and mutant substrates suggests that one activity cleaves eIF4G1 at or very near the 2Apro cleavage site and the other activity cleaves approximately 40 residues upstream of the 2Apro cleavage site. When PV infections in HeLa cells were supplemented with 2 mM guanidine, which indirectly limits expression of 2Apro, two distinct C-terminal cleavage fragments of eIF4GI were detected. These C-terminal cleavage fragments of eIF4GI were purified from infected cells, and a new eIF4GI cleavage site was mapped to a unique site 43 amino acids upstream of the known 2Apro cleavage site. Further, eIF4GI cleavage in vivo could be blocked by addition of zVAD to PV-guanidine infections. zVAD is a broad-spectrum caspase inhibitor which had no effect on 2Apro cleavage activity or PV polyprotein processing. Lastly, similar types of eIF4Gase cleavage activities were also detected in uninfected cells under various conditions, including early apoptosis or during cell cycle transit. The data suggest that the same types of eIF4GI cleavage activities which are generated in PV-infected cells can also be generated in the absence of virus. Taken together, the data support a model in which multiple cellular activities process eIF4GI in PV-infected cells, in addition to 2Apro.
Evolution and the Explanation of Meaning*

Signaling games provide basic insights into some fundamental questions concerning the explanation of meaning. They can be analyzed in terms of rational choice theory and in terms of evolutionary game theory. It is argued that an evolutionary approach provides better explanations for the emergence of simple communication systems. To substantiate these arguments, I will look at models similar to those of Skyrms (2000) and Komarova and Niyogi (2004) and study their dynamical properties. My results will lend partial support to the thesis that evolution leads to communication. In general, states of partial communication may evolve with positive probability under standard evolutionary dynamics. However, unlike states of perfect communication, they are unstable relative to neutral drift.
Health care costs of primary care patients with recognized depression.

BACKGROUND While an extensive literature documents the influence of depression on general medical services utilization, estimates of the economic burden of depression have focused on the direct costs of depression treatment. Higher use of general medical services may contribute significantly to the true cost of depressive illness. METHODS Computerized record systems of a large staff-model health maintenance organization (HMO) were used to identify consecutive primary care patients with visit diagnoses of depression (n = 6257) and a comparison sample of primary care patients with no depression diagnosis (n = 6257). The HMO accounting records were used to compare components of health care costs. RESULTS Patients diagnosed as depressed had higher annual health care costs ($4246 vs $2371, P < .001) and higher costs for every category of care (eg, primary care, medical specialty, medical inpatient, pharmacy, laboratory). Similar cost differences were observed for each of the subgroups examined (patients treated with antidepressants, those not treated with antidepressants, and those diagnosed at routine physical examination visits). Pharmacy records indicated greater chronic medical illness in the diagnosed depression group, but large cost differences remained after adjustment ($3971 vs $2644). Twofold cost differences persisted for at least 12 months after initiation of treatment. CONCLUSIONS Diagnosis of depression is associated with a generalized increase in use of health services that is only partially explained by comorbid medical conditions. In the primary care sector, this greater medical utilization exceeds direct treatment costs for depression. The persistence of utilization differences suggests that recognition and initiation of treatment alone are not adequate to reduce utilization differences.
The Past, Present, and Future of Selective Estrogen Receptor Modulation

Abstract: The recognition of selective estrogen receptor modulation in the mid‐1980s provided a unique opportunity to develop multifunctional drugs. Tamoxifen, the first selective estrogen receptor modulator (SERM), is the first antiestrogen to be tested successfully for the prevention of breast cancer in high‐risk women. However, the recognition that SERMs maintain bone density and lower circulating cholesterol suggested that the prevention of osteoporosis and coronary heart disease would be beneficial side effects of tamoxifen treatment. This hypothesis has not been pursued in clinical trial, but an alternate hypothesis, that SERMs could be developed to prevent osteoporosis and potentially reduce the risk of breast cancer, has been pursued with raloxifene. Current molecule modeling of the SERM‐ER complex has identified the reason for the promiscuous estrogen‐like actions of tamoxifen compared with raloxifene. Future studies of the signal transduction pathways of the ER alpha (α)‐ and beta (β)‐SERM complexes hold the promise of new drug discoveries and a menu of preventive medicine in clinical practice.
Optimized delay and power performances in multilayer graphene nanoribbon interconnects

Multi-layer graphene nanoribbon (MLGNR) can be considered as an emerging interconnect material in current deep-submicron and nano scale technology. This research paper presents an equivalent RLC model for MLGNR interconnects that is primarily based on the geometry. Using the RLC model, propagation delay, power dissipation and power-delay product are analyzed for different number of layers in MLGNR. Based on the simulation results, approximate number of layers have been calculated for optimized delay and power performances at global interconnect lengths.
SEPARATION OF ALLOSTIMULATORY AND NATURAL SUPPRESSOR/STEM CELL FUNCTIONS OF MURINE BONE MARROW—IMPLICATIONS FOR BONE MARROW TRANSPLANTATION

Natural suppressor (NS) activity is defined by the ability of a null cell population to inhibit antigenic and mitogenic activation of lymphoid cells. We had previously demonstrated that murine and human bone marrow was a rich source of NS activity and could be enriched in a population of large, low-density cells after counterflow centrifugal elutriation (CCE). In this report we confirm previous findings in the mixed lymphocyte reaction (MLR) that NS activity is an endogenous function of BM and is not present in peripheral immune tissues. Furthermore, suppression by BM NS cells in the MLR is not MHC restricted, which distinguishes NS activity from veto activity also associated with BM. To enrich for NS activity, BM cells were separated into 3 fractions according to size and density by CCE. Fraction (F) 1 contained small, high-density cells; F2 contained cells of intermediate size and density; and F3 comprised large, low-density cells. Addition of CCE-enriched fractions to the MLR revealed potent NS activity associated with F3, consistent with our previous findings in the Ab response. CCE-enriched fractions of BM cells were also used as stimulators in an MLR to determine which fraction, if any, could support alloantigen-induced proliferation. The use of unfractionated C57B1/6 (H-2b) BM cells as stimulators for BALB/c (H-2d) splenic responders resulted in little detectable proliferation as compared with that induced by C57B1/6 splenic stimulators. However, when elutriated fractions were used as stimulators, Fl BM cells induced a significant proliferative response, albeit to a lesser magnitude than spleen cells. In order to determine which fraction contained hematopoietic progenitors, CCE-separated cells were assayed for granulocyte/macrophage colony formation (CFU-GM). F3 BM was enriched five-fold for CFU-GM progenitors as compared with unfractionated BM, while progenitors were virtually absent in Fl and F2 BM. The results suggest that CCE may represent an effective way of removing potential alloantigen-presenting cells (Fl) from BM, while retaining hematopoietic progenitors and NS activity (F3). The implications of the findings as they relate to allogeneic BM transplantation are discussed.
The pH Dependence of Violaxanthin Deepoxidation in Isolated Pea Chloroplasts

The absorbance change at 505 nm was used to monitor the kinetics of violaxanthin deepoxidation in isolated pea (Pisum sativum) chloroplasts under dark conditions at various pH values. In long-term measurements (65 min) a fast and a slow exponential component of the 505-nm absorbance change could be resolved. The fast rate constant was up to 10 times higher than the slow rate constant. The asymptote value of the fast kinetic component was twice that of the slow component. The pH dependency of the parameters of the fast kinetic component was analyzed from pH 5.2 to pH 7.0. It was found that the asymptote value dropped slightly with increasing pH. The rate constant was zero at pH values greater than 6.3 and showed maximum values at pH values less than 5.8. Hill plot analysis revealed a strong positive cooperativity for the pH dependency of the fast rate constant (Hill coefficient nH = 5.3). The results are discussed with respect to published activity curves of violaxanthin deepoxidation.
Power grid vulnerability ranking: A linear programming approach

This paper addresses the vulnerability assessment problem of the smart grid using a linear programming approach. Historically, a large number of cascading failures resulted from overflow of transmission lines, motivated the analysis of power grid vulnerability from the perspective of network flow. In order to quickly assess and protect the power grid from potential threat of system stress during any operating interval, a generalized functional vulnerability assessment framework is developed here. The developed vulnerability analysis framework is based on a network flow based centrality measurement of the power grid. The proposed method presents three advantages in comparison with existing works on network flow based vulnerability assessment model for power grid: elimination of combinatoric solution and computationally efficiency. The effectiveness of the proposed framework is validated through simulation on standard IEEE and European test systems.
Prasugrel versus clopidogrel in Asian patients with acute coronary syndromes: design and rationale of a multi-dose, pharmacodynamic, phase 3 clinical trial

Abstract Background: Prasugrel is a third generation thienopyridine that is more potent, rapid in onset, and consistent in inhibition of platelets than clopidogrel. However, early prasugrel dose-ranging studies and the subsequent phase 3 TRITON-TIMI 38 trial were conducted primarily in Caucasian populations. Objectives: The current clinical study is designed to confirm superior inhibition of platelet aggregation with prasugrel versus clopidogrel in the treatment of Asian subjects with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Research design and methods: This is a phase 3, randomized, double-blind, multi-dose, four-arm parallel, multinational clinical trial. East and Southeast Asian patients (N = 715) with moderate- to high-risk ACS undergoing PCI will be randomized to one of three prasugrel dosing regimens (60 mg LD/10 mg MD; 30 mg LD/7.5 mg MD; 30 mg LD/5 mg MD) or clopidogrel (300 mg LD/75 mg MD) for 90 days. Main outcome measures: The primary endpoint is inhibition of platelet aggregation measured by the point-of-care Accumetrics VerifyNow P2Y12 device, and the primary analysis will be performed in a hierarchical manner for descending doses of prasugrel. Additional key endpoints include major adverse cardiovascular events, non-coronary artery bypass-graft (CABG) surgery-related TIMI bleeding, and genetic analyses of cytochrome P450 polymorphisms. Conclusions: This study is a phase 3, multi-dose, pharmacodynamic comparison of prasugrel versus clopidogrel in Asian patients with ACS undergoing PCI. It is the first study designed to investigate prasugrel therapy specifically in Asian ACS subjects, and will inform which doses of prasugrel are effective and safe for patients of Asian ethnicity. Trial registration: ClinicalTrials.gov identifier: NCT00830960.
The new Dutch and German drug laws: social and political conditions for criminalization and decriminalization.

The "drug wave" of the late 1960s was widely perceived as a threat to the legitimacy of normative expectations in Dutch and German society. Although the overwhelming reaction of public opinion to drug users in both countries was hostile and punitive, the German legislature passed even more repressive laws whereas the Dutch legislature adapted the normative system to the use of both "soft" and "hard" drugs. Although in each instance the initiative for legal change came from the political and moral "progressives," the conservative "moral center" retained a veto power. Why it used this veto power in Germany but actively supported the reform bill in Holland is explained in terms of the macrostructure of each society.
Chemical Scent Constituents in the Urine of the Red Fox (Vulpes vulpes L.) During the Winter Season

Four volatile chemical compounds have been identified as apparently unique constituents in urines of red foxes (both sexes) during the winter season when mating occurs. Quinaldine was found only in male fox urine. Several other compounds identified are found in other species also. Some or all of these compounds may function in olfactory communication in the red fox.
Developing a Launch Package for the PEGASUS Launcher

Rail guns are capable to far exceed the muzzle energies of current naval deck guns. Therefore, one of the most promising scenarios for the future application of rail guns in naval warfare is the long range artillery. Hypervelocity projectiles being propelled to velocities above 2 km/s reach targets at the distances of 200 km or more. At the French–German Research Institute, the PEGASUS launcher is used for investigations with respect to this scenario. The 6-m-long barrel has a square caliber of 40 mm. The power supply unit is able to deliver 10 MJ to the gun. Within this investigation, a complete launch package is being developed and experiments are performed that aim at showing that this package can be accelerated to velocities ranging from 2000 to 2500 m/s. A launch package consists out of an armature, a sabot, and the projectile. The armature ensures the electrical contact during launch and pushes the sabot with its payload through the barrel. The sabot guides and protects the payload during the acceleration. At the same time, the accelerating forces generated at the armature need to be transferred to the projectile. After the launch package has left the barrel, the sabot should open and release its payload, the projectile into free-flight. Here, the current status of the launch package development and results from Experiments with the PEGASUS rail gun is presented.
A Survey on Cloud Computing Security Issues

Cloud computing is changing businesses and governments. It offers flexible computation resources in a model where customers only pay for resources they use. This leads to cost savings when compared to a situation where organizations manage their own server farms. Very often such servers are running at a very low utilization level, which is partly because of old habits that lead to not placing more than one server on a single physical server. The benefits of cloud computing are many, but it also introduces new issues regarding security. Often customers feel like they are giving up the control over their data when they make the move to cloud. For the same reason many organizations are yet to make the move. This paper is a survey to some of the most recognized and feared issues in cloud security and also aims to bring forward current solutions for those security issues, or ways to mitigate the risks of making the move to the cloud.