Miracle-dz/UniFAR-FTUs huggingface dataset:
CYP3A Time-Dependent Inhibition Risk Assessment Validated with 400 Reference Drugs

Although reversible CYP3A inhibition testing is well established for predicting the drug-drug interaction potential of clinical candidates, time-dependent inhibition (TDI) has become the focus of drug designers only recently. Failure of several late-stage clinical candidates has been attributed to TDI, and this mechanism is also suspected to play a role in liver toxicities often observed in preclinical species. Measurement of enzyme inactivation rates (kinact and KI) is technically challenging, and a great deal of variability can be found in the literature. In this article, we have evaluated the TDI potential for 400 registered drugs using a high-throughput assay format based on determination of the inactivation rate (kobs) at a single concentration of test compound (10 μM). The advantages of this new assay format are highlighted by comparison with data generated using the IC50 shift assay, a current standard approach for preliminary assessment of TDI. With use of an empirically defined positive/negative kobs bin of 0.02 min−1, only 4% of registered drugs were found to be positive. This proportion increased to more than 20% when in-house lead optimization molecules were considered, emphasizing the importance of identifying this property in selection of promising drug candidates. Finally, it is suggested that the data and technology described here may be a good basis for building structure-activity relationships and in silico modeling.
Antimicrobial potential of two different Hypericum species available in India

The antimicrobial activity of extracts of the leaves and stems of two different varieties of Hypericum was evaluated by the disc diffusion method. Petroleum ether, acetone, chloroform and methanol extracts of Hypericum mysorense and Hypericum patulum stems and leaves were investigated for their antimicrobial activity against six different strains of bacteria and fungi by the zone of inhibition method (ZIM). The results showed that both the stem and leaf extracts of both species have a very broad spectrum of antibacterial activity. The petroleum ether and acetone extract of the leaves and stems of H. mysorense did not show antifungal effects against any of the six fungal organisms tested but other extracts showed a potential antifungal effect which was comparable to that of griseofulvin, the standard antifungal agent. Thus these results demonstrate that the leaf and stem extracts of both the Hypericum species have a very broad spectrum of activity and suggest that they may be useful in the treatment of various microbial infections. Copyright © 2002 John Wiley & Sons, Ltd.
Dynamic demand risk assessment for toll road projects

To bridge the gap between supply of and increasing demand for roads, public–private partnership (PPP) concession contracts in which the investment cost is recovered via payments from the end users have been established. Although this mechanism has been seen as an efficient way for road projects to be completed on time and within budget, the demand risk faced during the operation stage has considerably limited this efficiency. Demand depends on a range of interrelated and dynamic factors such as the demographic and economic conditions. In addition, uncertainty is an inherent aspect of most demand-underlying factors which always make demand estimation inaccurate. However, this uncertainty is largely ignored by modellers where a single demand estimate is often used when evaluating the facility. The aim is to develop a system dynamics model to assess demand risk in road projects. The model captures the factors affecting demand and their relationships and simulates their change over time. By employing Monte Carlo simulation, the model assesses the likelihood and potential effect of an event on the outcome and provides a full picture of the various effects of potential risk. The model can help public, private, and financial stakeholders of PPP facilities make more informed decisions.
Effects of fixation on routine, special and immunohistochemical stains: introduction to a symposium for the Biological Stain Commission

Although the general mission of the Biological Stain Commission (BSC) is to assure that dyes used to stain biological and biomedical specimens are suitable for those purposes, it has always recognized that factors other than the dyes themselves may have a significant role in the outcome of staining procedures. This is true especially in the field of immunohistochemistry (IHC). As IHC gained a prominent place in medical practice, the myriad problems inherent in the technique became a serious topic of discussion at BSC meetings. Since the late 1980s, the BSC has studied many aspects of the situation. As an observer and participant in these sessions for nearly two decades, I have reached several significant conclusions:
Localized maternal mRNA related to transforming growth factor beta mRNA is concentrated in a cytokeratin-enriched fraction from Xenopus oocytes.

The localized maternal RNA Vg1 resides in the cortical region of the vegetal pole of fully grown Xenopus oocytes and is inherited by only a subset of blastomeres in the early embryo [Weeks, D. L. & Melton, D. A. (1987) Cell 51, 861-867]. Because RNA-cytoskeletal interactions may play a role in RNA localization, we have examined the association of Vg1 RNA with components of the oocyte's cytoskeleton. Gel and immunoblot analysis of a detergent-insoluble fraction revealed a greatly simplified protein pattern composed largely of cytokeratins and vimentin. In sharp contrast to the nonlocalized histone H3 mRNA, Vg1 RNA was concentrated some 35- to 50-fold in this insoluble fraction. Extractions at higher salt concentrations yielded preparations further enriched in cytokeratins and in the Vg1 RNA. Upon ovulation, VG1 RNA is released into the soluble fraction. This change in Vg1 RNA distribution coincides with the observed breakdown of cortical cytokeratin filaments [Klymkowsky, M. W. , Maynell, L. A. & Polson, A. G. (1987) Development 100, 543-557] and the loss of Vg1 RNA from the cortical region. Our findings are consistent with the hypothesis that RNA-cytoskeletal interactions are involved in the localization and segregation of information during development.
Effect of number of layers on performance of fractional-slot concentrated-windings interior permanent magnet machines

Interior PM machines equipped with fractional-slot concentrated-windings are good candidates for high-speed traction applications. This is mainly due to the higher power density and efficiency that can be achieved. The main challenge with this type of machines is the high rotor losses at high speeds/frequencies. This paper will thoroughly investigate the effect of number of winding layers on the performance of this type of machines. It will be shown that by going to higher number of layers, there can be significant improvement in efficiency especially at high speeds mainly due to the reduction of the winding factor/magnitude of the most dominant stator mmf sub-harmonic component. It will also be shown that there is significant improvement in torque density. Even though there is reduction in the winding factor of the stator synchronous torque-producing mmf component, this is more than offset by increase in machine saliency and reluctance torque. The paper will provide general guidelines regarding the optimum spp combinations based on torque density and efficiency. Sample designs of various slot/pole combinations are used to quantify the benefit of going to higher number of layers in terms of torque density, efficiency and torque ripple.
Calcium signal‐mediated expression of the vasoactive intestinal polypeptide gene and its small contribution to activity‐dependent survival of mouse cerebellar granule cells

We have demonstrated previously in primary cultures of mouse cerebellar granule cells (CGCs) that endogenously synthesized pituitary adenylate cyclase‐activating polypeptide (PACAP) contributes at least in part to the activity‐dependent survival of CGCs (Tabuchi et al. [ 2001 ] Neurosci. Res. 39:85–93). In this study, we have demonstrated that expression of vasoactive intestinal polypeptide (VIP), a member of the same VIP/secretin/glucagon family as PACAP, was activated markedly by Ca2+ influx through L‐type voltage‐dependent Ca2+ channels (L‐VDCCs), which could be induced under the depolarizing condition induced by high concentration of potassium (K+) in the medium. The activation of VIP mRNA expression, different from that of PACAP, was dependent partly on de novo protein synthesis. On the other hand, mRNA expression of secretin and PACAP/VIP receptors (PAC1, VPAC1, and VPAC2) was not activated by the Ca2+ influx; rather, PAC1 mRNA expression was reduced. Exogenously added VIP prevented apoptosis of CGCs under nondepolarizing conditions, the effect of which was mediated specifically through the VPAC1 receptor. Furthermore, the survival of CGCs under depolarizing conditions could be mediated partly through VPAC1, the contribution of which was much less than that of PAC1. These findings indicate that PACAP and VIP genes are coordinately activated by the Ca2+ signals in CGCs, but the contribution of VIP to the activity‐dependent survival of CGCs is quite small. © 2004 Wiley‐Liss, Inc.
Temozolomide and Radiation for Aggressive Pediatric Central Nervous System Malignancies

This study describes the outcomes of children treated with combinations of temozolomide and radiation therapy for various aggressive central nervous system malignancies. Their age at diagnosis ranged from 1 to 15 years. Patients with focal disease were treated with concomitant temozolomide (daily 75 mg/m2) and three-dimensional conformal radiotherapy in a dose that ranged from 50 to 54 Gy, followed by temozolomide (200 mg/m2/d × 5 days/month in three patients, 150 mg/m2 × 5 days/ month in one patient). Patients with disseminated disease were treated with craniospinal radiation (39.6 Gy) before conformal boost. One patient received temozolomide (200 mg/m2 × 5 days/month) before craniospinal radiation, and one patient received temozolomide (daily 95 mg/m2) concomitant with craniospinal radiation and a radiosurgical boost, followed by temozolomide (200 mg/m2 × 5 days/month). Three patients achieved a partial response during treatment, with two of these patients dying of progressive disease after treatment. One patient has no evidence of disease. Three patients achieved stable disease, with one of these patients dying of progressive disease after treatment. Toxicities observed included low-grade neutropenia, thrombocytopenia, and lymphopenia. The combination of temozolomide and radiotherapy appears to be well tolerated in a variety of treatment schemas for aggressive pediatric central nervous system malignancies. This information is of particular use in designing future studies, given the recent positive results in a randomized study examining the use of temozolomide concomitant with radiation in the treatment of adult glioblastoma.
Microvesicles: potential markers and mediators of endothelial dysfunction

Purpose of reviewMicrovesicles (also known as microparticles) are small membranous structures that are released from platelets and cells upon activation or during apoptosis. Microvesicles have been found in blood, urine, synovial fluid, extracellular spaces of solid organs, atherosclerotic plaques, tumors, and elsewhere. Here, we focus on new clinical and basic work that implicates microvesicles as markers and mediators of endothelial dysfunction and hence novel contributors to cardiovascular and other diseases. Recent findingsAdvances in the detection of microvesicles and the use of cell type-specific markers to determine their origin have allowed studies that associated plasma concentrations of specific microvesicles with major types of endothelial dysfunction – namely, inappropriate or maladaptive vascular tone, leukocyte recruitment, and thrombosis. Recent investigations have highlighted microvesicular transport of key biologically active molecules besides tissue factor, such as ligands for pattern-recognition receptors, elements of the inflammasome, and morphogens. Microvesicles generated from human cells under different pathologic circumstances, for example, during cholesterol loading or exposure to endotoxin, carry different subsets of these molecules and thereby alter endothelial function through several distinct, well characterized molecular pathways. SummaryClinical and basic studies indicate that microvesicles may be novel markers and mediators of endothelial dysfunction. This work has advanced our understanding of the development of cardiovascular and other diseases. Opportunities and obstacles to clinical applications are discussed.
Pheromone induction of agglutination in Saccharomyces cerevisiae a cells

a-Agglutinin, the cell surface sexual agglutinin of yeast a cells, was assayed by its ability to bind its complementary agglutinin, alpha-agglutinin. The specific binding of 125I-alpha-agglutinin to a cells treated with the sex pheromone alpha-factor was 2 to 2.5 times that of binding to a cells not treated with alpha-factor. Competition with unlabeled alpha-agglutinin revealed that the increased binding was due to increased cell surface expression of a-agglutinin, with no apparent change in the binding constant. The increase in site number was similar to the increase in cellular agglutinability. Increased expression of a-agglutinin followed the same kinetics as the increase in cellular agglutinability, with a 10-min lag followed by a 15- to 20-min response time. Induction kinetics were similar in cells in phases G1 and G2 of the cell cycle. Maximal expression levels were similar in cells treated with excess pheromone and in cells exposed to pheromone after destruction of constitutively expressed a-agglutinin.
TV white space in Nigeria in UHF band: Geo-spatial approach

This research is focused on evaluating the amount of television white space (TVWS) in the UHF band in Nigeria. The work takes a new perspective called the Geo-spatial approach in quantifying the available TVWS. Spectrum sharing model was developed from the protection viewpoint where the secondary users (SUs) are only allowed to reuse the spectrum outside the keep-out distance from the broadcast transmission grade B contour of the primary users. The spatial data used include the administrative map of Nigeria showing the states' boundary delineation and parameters for all the TV transmitters, including their coordinates. The broadcast range of transmission and protection contour of each UHF transmitter in Nigeria was obtained using the developed models. To show the broadcast range, the transmitter position, represented by a point, was subjected to GIS Buffering operation using the Analysis Tools extension within the ArcGIS ArcToolbox. Results obtained show that the proposed method recovers more white spaces when compared with the traditional command-and-control spectrum model. The work also provides the channel occupancy distribution of Nigeria, United Kingdom and the USA for the purpose of comparison.
Shunted-Line Stepped-Impedance Resonator

This article provides an extensive review of dual-band bandpass filter designs and discusses the pros and cons of these design methods. The behavior of an SLSIR proposed by the authors shows that two passbands can be generated without using external dual-band impedance transformers. Furthermore, by using the design curves shown in this article, the k and the Qe, which are used for the synthesis of a dual-band bandpass filter, can be accurately calculated. Two examples of dual-band bandpass filters operated at 1.9/5.7 and 2.45/5.7 GHz with different bandwidths was presented to show details of the design technique. The simulation and measurement results shown are in good agreement. The resulting SLSIR dual-band filters using this technique not only provide controllable responses but also have high frequency selectivity and good impedance matching with considerable size reduction. Finally, a performance comparison comparing the technique in this article with previous design methods is listed in Table 3. The design methodology should be useful in dual-band RF transceiver design.
Japan: Still An Exceptional U.S. Ally

After months of contentious debate, Japan’s parliament, called the Diet, in mid-September 2015 finally passed the Shinzo Abe government’s package of eleven bills on security. This legislation, along with the revised U.S.–Japan Defense Cooperation Guidelines of April 2015, will transform the legal and institutional framework for Japanese defense policy and U.S.–Japan security relations. Japanese proponents of this transformation have argued the changes are necessary to make bilateral security cooperation more seamless to respond effectively to new regional and global security challenges and to contribute more proactively to international security affairs. Opponents, however, have charged that the legislation illegitimately hollows out Article 9 of Japan’s constitution—which outlaws war as a means to settle international disputes—and could embroil Japan in misguided wars launched by the United States. Chinese and Korean critics of the legislation have echoed these criticisms by claiming that Japan is now remilitarizing. From a historical perspective, the bills’ passage is part of an incremental process, beginning in the 1980s, of relaxing the self-imposed constraints on Japanese defense policy. Some have referred to this process as Japan’s normalization as a security actor. To be sure, Japan has a relatively large defense budget, and its defense policy has changed profoundly over the last three decades. But what is often ignored is how Japan’s “normalization” compares with the defense policies of similar states in the U.S. alliance network. After all, understanding “normal” requires a comparison with other states. Although the latest changes are indeed
DETERMINANTS OF EXECUTIVE COMPENSATION

from the vagaries of individual leadership, the control and the goal formation process have moved to the management group. In response the corporation has adapted its style, performance, and reward structure to the dominance of the professional manager. The management group tends to be motivated by identification with the company's expansion. In turn, the organization rewards management with a larger organization and a higher salary structure. There is a strong correlation between sales, management compensation, and employment in the large corporation. Beginning with Berle and Mean's observation that effective control of the largest industrial corporations had passed into hands of management, debate has raged over the implications of the change in control [2]. The result has been a great deal of speculation over the impact of management control on the performance of the corporation. Most recent investigations have been tied to Baumol's revenue maximization hypothesis
Muscle Fiber Orientation in the Development and Regression of Right Ventricular Hypertrophy in Pigs

The development and regression of right ventricular hypertrophy was investigated in 12 pigs with special reference to changes in ventricular function and myocardial fiber orientation. Nine ventricles were pressure ‐loaded by banding the pulmonary artery for 28–81 days, and four of them were then released from the load by removing the band. Right ventricular systolic pressure (RVSP), end‐diastolic pressure (RVEDP) and end systolic volume index (ESVI) increased significantly during banding and decreased after debanding. End diastolic volume index (EDVI) and stroke volume index (SVI) showed no significant change during banding and after debanding. The weight of the right ventricle relative to both ventricles (RV/TV) and the thickness of muscle fibers were increased significantly in the loaded ventricles, and reduced again to the control level in ventricles released from the load. The intramyocardial distribution of angles (θ) of inclination of muscle fibers from the transverse plane of the outflow tract was estimated histometrically. There was a significantly larger proportion of circularly oriented fibers (|θ|≦30) in the pressure loaded ventricles than in the control, whereas these fibers decreased again to the control level after removal of the pressure load. The present findings indicates that 1) the right ventricular hypertrophy induced by pressure loading is characterized not only by an increase in ventricular weight and muscle fiber thickness, but also by a change in intramyocardial fiber orientation, and 2) the hypertrophic right ventricle can regress both functionally and morphologically to a normal state after removal of the pressure load.
The mood spectrum in unipolar and bipolar disorder: arguments for a unitary approach.

OBJECTIVE This study examined the extent to which individuals with a lifetime diagnosis of recurrent unipolar disorder endorse experiencing manic/hypomanic symptoms over their lifetimes and compared their reports with those of patients with bipolar I disorder. METHOD The study group included 117 patients with remitted recurrent unipolar depression and 106 with bipolar I. Subjects had their clinical diagnosis confirmed by the Mini International Neuropsychiatric Interview and were administered the Structured Clinical Interview for the Mood Spectrum, which assesses lifetime symptoms, traits, and lifestyles that characterize threshold and subthreshold mood episodes as well as "temperamental" features related to mood dysregulation. RESULTS The patients with recurrent unipolar depression endorsed experiencing a substantial number of manic/hypomanic symptoms over their lifetimes. In both patients with recurrent unipolar depression and patients with bipolar I disorder, the number of manic/hypomanic items endorsed was related to the number of depressive items endorsed. In the group with recurrent unipolar depression, the number of manic/hypomanic items was related to an increased likelihood of endorsing paranoid and delusional thoughts and suicidal ideation. In the bipolar I group, the number of lifetime manic/hypomanic items was related to suicidal ideation and just one indicator of psychosis. CONCLUSIONS The presence of a significant number of manic/hypomanic items in patients with recurrent unipolar depression seems to challenge the traditional unipolar-bipolar dichotomy and bridge the gap between these two categories of mood disorders. The authors argue that their mood spectrum approach is useful in making a more accurate diagnostic evaluation in patients with mood disorders.
Expression during Host Infection and Localization of Yersinia pestis Autotransporter Proteins

ABSTRACT Yersinia pestis CO92 has 12 open reading frames encoding putative conventional autotransporters (yaps), nine of which appear to produce functional proteins. Here, we demonstrate the ability of the Yap proteins to localize to the cell surface of both Escherichia coli and Yersinia pestis and show that a subset of these proteins undergoes processing by bacterial surface omptins to be released into the supernatant. Numerous autotransporters have been implicated in pathogenesis, suggesting a role for the Yaps as virulence factors in Y. pestis. Using the C57BL/6 mouse models of bubonic and pneumonic plague, we determined that all of these genes are transcribed in the lymph nodes during bubonic infection and in the lungs during pneumonic infection, suggesting a role for the Yaps during mammalian infection. In vitro transcription studies did not identify a particular environmental stimulus responsible for transcriptional induction. The primary sequences of the Yaps reveal little similarity to any characterized autotransporters; however, two of the genes are present in operons, suggesting that the proteins encoded in these operons may function together. Further work aims to elucidate the specific functions of the Yaps and clarify the contributions of these proteins to Y. pestis pathogenesis.