Miracle-dz/UniFAR-FTUs huggingface dataset:
Direct and indirect approaches to identify drug modes of action

Phenotypic assays are becoming increasingly more common among drug discovery practices, expanding drug target diversity as lead compounds identified through such screens are not limited to known targets. While increasing diversity is beneficial to the drug discovery process and the fight against disease, the unknown modes of action of new lead compounds can hamper drug discovery as, in most cases, the process of lead compound optimization is made difficult due to the unknown nature of the target; blindly changing substituents can prove fruitless due to the inexhaustible number of potential combinations, and it is therefore desirable to rapidly identify the targets of lead compounds developed through phenotypic screening. In addition, leads identified through target‐based screening often have off‐target effects that contribute towards drug toxicity, and by identifying those secondary targets, the drugs can be improved. However, the identification of a leads mode of action is far from trivial and now represents a major bottleneck in the drug discovery pipeline. This review looks at some of the recent developments in the identification of drug modes of action, focusing on phenotype‐based methods using metabolomics, proteomics, transcriptomics, and genomics to detect changes in phenotype in response to the presence of the drug, and affinity‐based methods using modified/unmodified drug as bait to capture and identify targets. © 2017 IUBMB Life, 70(1):9–22, 2018
Staurosporine advances interblastomeric flattening of the mouse embryo

Staurosporine, an inhibitor of protein kinase activity, causes premature intercellular flattening of blastomeres but does not induce their premature polarisation. The flattening induced is calcium dependent, is reversed transiently at mitosis and requires the continuing presence of the drug. Staurosporine also blocks the decompacting effect of phorbol ester on 8-cell embryos.
Falls among full-time wheelchair users with spinal cord injury and multiple sclerosis: a comparison of characteristics of fallers and circumstances of falls

Abstract Purpose: The purpose of this study is to (1) explore and (2) compare circumstances of falls among full-time wheelchair users with spinal cord injury (SCI) and multiple sclerosis (MS). Methods: A mixed method approach was used to explore and compare the circumstances of falls of 41 full-time wheelchair users with SCI (n = 23) and MS (n = 18). In addition to collecting participants’ demographic information (age, gender, type of wheelchair used, duration of wheelchair use, and duration of disability), self-reported fall frequency in the past 6 months, self-reported restriction in activity due to fear of falling and the Spinal Cord Injury-Fall Concerns Scale (SCI-FCS) was collected. Qualitative data in the form of participants’ responses to an open-ended question yielding information regarding the circumstances of the most recent fall were also collected. To examine differences in survey outcomes and demographic characteristics between participants with SCI and MS, independent t-tests and Pearson’s Chi-square tests were used. Qualitative data were analyzed with a thematic analysis. Results: Statistical analysis revealed that individuals with MS (mean =3.3) had significantly higher average SCI-FCS than individuals with SCI (mean =2.4). The analysis of the participants’ descriptions of the circumstances of their most recent falls resulted in three main categories: action-related fall contributors (e.g., transfer), (2) location of falls (e.g., bathroom), and (3) fall attributions (e.g., surface condition). Conclusions: The results from this study helped to understand fall circumstances among full-time wheelchair users with MS and SCI. Findings from this study can inform the development of evidenced-based interventions to improve the effectiveness of clinically based treatment protocols. Implications for rehabilitation Falls are a common health concern in full-time wheelchair users living with multiple sclerosis and spinal cord injury. The circumstances surrounding falls reported by full-time wheelchair users living with multiple sclerosis and spinal cord injuries were found to be multifactorial. The complex nature of falls must be taken into consideration in the development of fall prevention programs. Findings from this study can inform the development of comprehensive evidence-based, population-specific interventions to manage falls among full-time wheelchair users living with multiple sclerosis and spinal cord injury.
Certain aspects of working capital in a construction company

Abstract The article analyses the profiles of selected construction companies from the viewpoint of working capital formation and their management strategies applied to working capital. The analysis was performed on the basis of financial ratios. The conclusion is that complex working capital management requires controlling methodology to be developed. A specific character of the construction industry, including operational factors and market requirements, make working capital management a task exceeding the financial sphere, as it embraces the issues of organisation of investment processes, the organisation of production processes and logistics.
Effect of Foreign Exchange Rates on Price per Share

The aim of this research was to examine the interaction between stock prices and exchange rates in Kenya with regards to the period from January 1 st 2012 to December 31 st 2013. The findings have implications for investors, investment managers, regulators, listed companies, financial institutions and other market players. The economic theory points to the relationship between stock price and exchange rates but does not properly define the direction of the relationship. This research used the Pearson product-moment correlation coefficient method to determine the degree of correlation between stock prices and exchange rates. The results indicated that there was a positive relationship between exchange rates and share prices. The analyzed data was presented in the form of statistical charts, graphs, frequency tables and percentages.
The Technological Specialization of Advanced Countries: A Report to the EEC on International Science and Technology Activities

and Summary. - Structural Change and International Strategies in Science and Technology. - An Overview of Scientific and Technological Activities in the Advanced Countries. - Sectoral Strengths and Weaknesses of Advanced Countries in Different Patent Institutions. - Changes over Time and Impact of Patenting Activity: The Sectoral Distribution of Patent Counts and Patent Citations in the US. - National Technological Specialization and Sectoral Growth Rates in Patenting. - Sectoral Strengths and Weaknesses of Advanced Countries in Science. - Degree of Specialization and Size of National Scientific and Technological Activities. - The Inter-Industry Structure of Technological Specialization. - The Patterns and Impact of Technological Specialization. - Conclusions.
Suppressors of Cytokine Signaling 1 and 3 Are Upregulated in Brain Resident Cells in Response to Virus-Induced Inflammation of the Central Nervous System via at Least Two Distinctive Pathways

ABSTRACT Suppressors of cytokine signaling (SOCS) proteins are intracellular proteins that inhibit cytokine signaling in a variety of cell types. A number of viral infections have been associated with SOCS upregulation; however, not much is known about the mechanisms regulating SOCS expression during viral infection. In this study, we used two pathologically distinct intracerebral (i.c.) infection models to characterize temporal and spatial aspects of SOCS expression in the virus-infected central nervous system (CNS), and by employing various knockout mouse models, we sought to identify regulatory mechanisms that may underlie a virus induced upregulation of SOCS in the CNS. We found that i.c. infection with either lymphocytic choriomeningitis virus (LCMV) or yellow fever virus (YF) results in gradual upregulation of SOCS1/3 mRNA expression peaking at day 7 postinfection (p.i.). In the LCMV model, SOCS mRNA was expressed in brain resident cells, including astrocytes and some neurons, and for SOCS1 in particular this upregulation was almost entirely mediated by gamma interferon (IFN-γ) produced by infiltrating T cells. After infection with YF, we also found SOCS expression to be upregulated in brain resident cells with a peak on day 7 p.i. , but in this model, the upregulation was only partially dependent on IFN-γ and T cells, indicating that at least one other mediator was involved in the upregulation of SOCS following YF infection. We conclude that virus-induced inflammation of the CNS is associated with upregulation of SOCS1/3 mRNA expression in brain resident cells and that at least two distinctive pathways can lead to this upregulation. IMPORTANCE In the present report, we have studied the induction of SOCS1 and SOCS3 expression in the context of virus-induced CNS infection. We found that both a noncytolytic and a cytolytic virus induce marked upregulation of SOCS1 and -3 expression. Notably, the kinetics of the observed upregulation follows that of activity within proinflammatory signaling pathways and, interestingly, type II interferon (IFN), which is also a key inducer of inflammatory mediators, seems to be essential in initiating this counterinflammatory response. Another key observation is that not only cells of the immune system but also CNS resident cells are actively involved in both the pro- and the counterinflammatory immune circuits; thus, for example, astrocytes upregulate both C-X-C-motif chemokine 10 (CXCL10) and SOCS when exposed to type II IFN in vivo.
NOD1 and NOD2 Regulate Proinflammatory and Prolabor Mediators in Human Fetal Membranes and Myometrium via Nuclear Factor-Kappa B1

ABSTRACT Preterm birth remains one of the most important issues facing perinatal medicine today, with chronic inflammation and/or infection being the biggest etiological factor. The nucleotide oligomerization domain (NOD) intracellular molecules recognize a wide range of microbial products as well as other intracellular danger signals, thereby initiating inflammation through activation of nuclear factor KB (NFKB), a central regulator of the terminal processes of human labor and delivery. The aims of this study were to determine the effect of 1) human labor, proinflammatory cytokines, and bacterial endotoxin LPS on NOD1 and NOD2 expression and 2) NOD1 and NOD2 activation on the expression of prolabor mediators in human fetal membranes and myometrium. NOD1 and NOD2 expression was significantly higher in fetal membranes and myometrium after spontaneous labor when compared to nonlaboring tissues. Bacterial endotoxin LPS and the proinflammatory cytokines TNF and IL1B significantly increased NOD2, but not NOD1, expression. Furthermore, LPS-induced NOD2 expression was decreased by the NFKB inhibitor BAY 11–7082. In both fetal membranes and myometrium, the NOD1 ligand bacterial iE-DAP and the NOD2 ligand bacterial MDP significantly increased the expression and secretion of proinflammatory cytokines (IL6 and IL8), cyclooxygenase (PTGS2) expression and subsequent release of prostaglandins PGE2 and PGF2alpha, and the expression and activity of MMP9. The effects of these NOD1 and NOD2 ligands were mediated via NFKB, as 1) both iE-DAP and MDP significantly increased NFKB activation and 2) the NFKB inhibitor BAY 11–7082 attenuated iE-DAP- and MDP-induced expression and secretion of prolabor mediators. In conclusion, NOD1 and NOD2 are increased in laboring fetal membranes and myometrium and with bacterial infection. Agonist activation of NOD1 and NOD2 by bacterial products leads to NFKB activation and transcription of NFKB induced prolabor genes. NOD1 and NOD2 may thus represent therapeutic targets for the treatment and/or management of preterm birth.
Normative data and psychometric properties of a farsi translation of the strange stories test

The Strange Stories test is one of the most commonly used tests to evaluate advanced “theory of mind,” i.e. attribution of mental states. Normative data and psychometric properties of a new Farsi translation of this test were evaluated in a large community‐based sample of Iranian school‐aged children. Methods: Through randomized cluster sampling, 398 children aged 9–11 years studying at 20 elementary schools were recruited from 4 central regions of Tehran, Iran. The mean age of the students was 9.96 years (SD = 0.92), and 51% were girls (n = 202). The Child Behavior Checklist (CBCL) was completed by parents. The Strange Stories test was completed by all children and repeated for 20% of them after 2–4 weeks to assess the test‐retest reliability. Findings: Students in upper grades had higher scores (P < .01); age predicted 2% of variance on the mental state score. Girls had significantly higher mentalizing scores than boys (P = .003). The split‐half internal reliability coefficient was good (0.73). The test‐retest reliability was fair to good. Item‐scale score correlations were all significant (P < .01). Conclusion: This new translation of the Strange Stories test is a reliable and valid instrument to evaluate higher level theory of mind abilities in community samples of Farsi speaking children. Autism Res 2017, 10: 1960–1967. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.
Global Macroeconomic Interdependence: A Minimum Spanning Tree Approach

This paper measures the evolution of the interdependence level of the global economic system using a novel approach that combines network analysis and time-varying correlations. A Scalar-BEKK model is employed to determine the dynamic conditional bilateral correlations of 102 economies for the period 1952-2011. A subdominant ultrametric space is then defined for each year by applying a single-link cluster analysis to filter and highlight first-order connections in the network. I find the core of the global economic network to be dominated by advanced economies while the periphery is composed by nearly all of the developing economies and some of the emergent market economies; France occupies the central hub of the network, which coincides with recent findings from studies on European financial markets. I also find that the global macroeconomic interdependence rose over 61 percents between 1952-2011, which is in line with the majority of the empirical research on business cycle synchronization; however, this paper reveals an accelerating convergence process during the phase 1996-2011 that exceeds results from previous studies.
The putatively functional Mkrn1-p1 pseudogene is neither expressed nor imprinted, nor does it regulate its source gene in trans

A recently promoted genome evolution model posits that mammalian pseudogenes can regulate their founding source genes, and it thereby ascribes an important function to “junk DNA. ” This model arose from analysis of a serendipitous mouse mutant in which a transgene insertion/deletion caused severe polycystic kidney disease and osteogenesis imperfecta with ≈80% perinatal lethality, when inherited paternally [Hirotsune, S. , et al. (2003) Nature 423, 91–96]. The authors concluded that the transgene reduced the expression of a nearby transcribed and imprinted pseudogene, Mkrn1-p1. This reduction in chromosome 5-imprinted Mkrn1-p1 transcripts was proposed to destabilize the cognate chromosome 6 Mkrn1 source gene mRNA, with a partial reduction in one Mkrn1 isoform leading to the imprinted phenotype. Here, we show that 5’ Mkrn1-p1 is fully methylated on both alleles, a pattern indicative of silenced chromatin, and that Mkrn1-p1 is not transcribed and therefore cannot stabilize Mkrn1 transcripts in trans. A small, truncated, rodent-specific Mkrn1 transcript explains the product erroneously attributed to Mkrn1-p1. Additionally, Mkrn1 expression is not imprinted, and 5’ Mkrn1 is fully unmethylated. Finally, mice in which Mkrn1 has been directly disrupted show none of the phenotypes attributed to a partial reduction of Mkrn1. These data contradict the previous suggestions that Mkrn1-p1 is imprinted, and that either it or its source Mkrn1 gene relates to the original imprinted transgene phenotype. This study invalidates the data upon which the pseudogene trans-regulation model is based and therefore strongly supports the view that mammalian pseudogenes are evolutionary relics.
The complete mitochondrial genome sequence of Pterophyllum scalare (Cichliformes: Cichlidae)

Abstract Pterophyllum scalare belongs in the family Cichlidae of Cichliformes. This species and its congeners are characterized by a compressed and disc-shaped body with dorsal and anal spiny rays increasing in length from anterior to posterior part of the fin. In this study, we determine and describe the complete mitogenome sequence of Pterophyllum scalare for the first time, which is 16,494 bp in length, and contains 37 genes, including 13 protein-coding genes, 2 rRNAs, 22 tRNAs, 1 origin of replication on the light-strand (OL) and a putative control region. The overall base composition is 27.5% A, 26.8% T, 30.1% C and 15.6% G, with a slight AT bias (54.3%). All protein-coding genes share the start codon ATG, except for COI that begins with GTG. These results are expected to provide useful molecular data for phylogenetic studies of Cichlidae and Cichliformes. Maximum Likelihood (ML) tree and Bayesian analyses based on partitioned nucleotide sequences of 12 mitochondrial protein-coding genes were constructed and both yielded trees with identical topologies.
A Conformational Investigation of Propeptide Binding to the Integral Membrane Protein γ-Glutamyl Carboxylase Using Nanodisc Hydrogen Exchange Mass Spectrometry

Gamma (γ)-glutamyl carboxylase (GGCX) is an integral membrane protein responsible for the post-translational catalytic conversion of select glutamic acid (Glu) residues to γ-carboxy glutamic acid (Gla) in vitamin K-dependent (VKD) proteins. Understanding the mechanism of carboxylation and the role of GGCX in the vitamin K cycle is of biological interest in the development of therapeutics for blood coagulation disorders. Historically, biophysical investigations and structural characterizations of GGCX have been limited due to complexities involving the availability of an appropriate model membrane system. In previous work, a hydrogen exchange mass spectrometry (HX MS) platform was developed to study the structural configuration of GGCX in a near-native nanodisc phospholipid environment. Here we have applied the nanodisc–HX MS approach to characterize specific domains of GGCX that exhibit structural rearrangements upon binding the high-affinity consensus propeptide (pCon; AVFLSREQANQVLQRRRR). pCon binding was shown to be specific for monomeric GGCX-nanodiscs and promoted enhanced structural stability to the nanodisc-integrated complex while maintaining catalytic activity in the presence of carboxylation co-substrates. Noteworthy modifications in HX of GGCX were prominently observed in GGCX peptides 491–507 and 395–401 upon pCon association, consistent with regions previously identified as sites for propeptide and glutamate binding. Several additional protein regions exhibited minor gains in solvent protection upon propeptide incorporation, providing evidence for a structural reorientation of the GGCX complex in association with VKD carboxylation. The results herein demonstrate that nanodisc–HX MS can be utilized to study molecular interactions of membrane-bound enzymes in the absence of a complete three-dimensional structure and to map dynamic rearrangements induced upon ligand binding.
Sucrose and Ethylene Signaling Interact to Modulate the Circadian Clock1[CC-BY]

There are conditional effects of sucrose through ethylene signaling and the F-box protein ZTL that act on GI to provide input from metabolism to adjust the circadian clock in Arabidopsis. Circadian clocks drive rhythmic physiology and metabolism to optimize plant growth and performance under daily environmental fluctuations caused by the rotation of the planet. Photosynthesis is a key metabolic process that must be appropriately timed to the light-dark cycle. The circadian clock contributes to the regulation of photosynthesis, and in turn the daily accumulation of sugars from photosynthesis also feeds back to regulate the circadian oscillator. We have previously shown that GIGANTEA (GI) is required to sustain Suc-dependent circadian rhythms in darkness. The mechanism by which Suc affects the circadian oscillator in a GI-dependent manner was unknown. Here, we identify that Suc sustains rhythms in the dark by stabilizing GI protein, dependent on the F-box protein ZEITLUPE, and implicate CONSTITUTIVE TRIPLE RESPONSE1 (CTR1), a negative regulator of ethylene signaling. Our identification of a role for CTR1 in the response to Suc prompted a reinvestigation of the effects of ethylene on the circadian oscillator. We demonstrate that ethylene shortens the circadian period, conditional on the effects of Suc and requiring GI. These findings reveal that Suc affects the stability of circadian oscillator proteins and can mask the effects of ethylene on the circadian system, identifying novel molecular pathways for input of sugar to the Arabidopsis (Arabidopsis thaliana) circadian network.
Modulation Method of a Full-Bridge Three-Level LLC Resonant Converter for Battery Charger of Electrical Vehicles

This paper proposes a modulation method for a full-bridge three-level LLC resonant converter. The target converter is known to enable fixed frequency operation, small resonant inductance ratio, and zero-current switching operation of rectifier diodes under wide output-voltage variation. Therefore, it is suitable for an application such as in battery chargers. A new parameter named “master duty,” which determines each voltage-level duty, is introduced to this modulation method. It simplifies the modulation method; therefore, a modification of the modulation is easy. It also makes possible seamless handling of two-level, three-level, and mixed modes. The modulation method is represented by the relationship between the master duty and each gate-pulse edge position. This representation can clearly depict a complex modulation such as a combination of pulse-width and phase-shift modulations. The voltage gain of the converter is analyzed using the first-harmonic approximation technique. The result of the analysis is verified by the circuit simulation. The voltage gain is also analyzed using lossy components, which is verified by the experimental result. A 385-V input 225- to 378-V/6.6-kW output prototype converter is fabricated for this verification. It shows 98.14% peak efficiency, and its power density is 1036 W/L.