Miracle-dz/UniFAR-FTUs huggingface dataset:
Mutation analysis of p53, K‐ras, and BRAF genes in colorectal cancer progression

Gene mutations in APC, K‐ras, and p53 are thought to be essential events for colorectal cancer development. Recent data seem to indicate that K‐ras and p53 mutations rarely co‐exist in the same tumor, indicating that these alterations do not represent a synergistic evolutionary pathway. Moreover, an inverse relation between K‐ras gene activation and BRAF mutations has been demonstrated, suggesting alternative pathways for colorectal cancer transformation. To reconstruct the chronological modulation of these gene mutations during cell transformation and colorectal cancer progression, mutations of p53, K‐ras, and BRAF genes were analyzed by Single Strand Conformation Polymorphism (SSCP) or sequencing analysis in 100 colorectal cancer samples, evenly distributed among different Dukes' stages. We found mutations in p53, K‐ras, and BRAF genes in 35%, 30%, and 4% of tumors, respectively, and observed a minimal or no co‐presence of these gene alterations. Moreover, the frequency of molecular p53 mutations increased as tumor stage increased, suggesting an important role for this gene in the progression of colorectal cancer. Conversely, K‐ras or BRAF genes were not related to tumor stage or location. These data seem to indicate the absence of a co‐presence of the genes, highlighting the possibility of multiple pathways for colorectal tumor progression. Moreover, mutations in p53, K‐ras, and BRAF are not present in about one‐third of colorectal cancers and therefore other gene mutations need to be investigated to better understand molecular mechanisms at the basis of cell transformation and the progression of colorectal cancer. © 2005 Wiley‐Liss, Inc.
Thiacremonone Augments Chemotherapeutic Agent–Induced Growth Inhibition in Human Colon Cancer Cells through Inactivation of Nuclear Factor-κB

Chemotherapeutic strategies commonly use multiple agents to overcome drug resistance and to lower drug toxicity. Activation of nuclear factor-κB (NF-κB) is implicated in drug resistance in cancer cells. Previously, we reported that thiacremonone, a novel sulfur compound isolated from garlic, inhibited NF-κB and cancer cell growth with IC50 values about 100 μg/mL in colon cancer cells. In the present study, we tested whether thiacremonone could increase susceptibility of cancer cells to chemotherapeutics through inactivation of NF-κB. Colon cancer cells were cotreated with thiacremonone (50 μg/mL, half dose of IC50) and lower doses of each chemotherapeutic agent (half dose of IC50) for 24 hours. NF-κB activity was completely abrogated in cells treated with a combination of thiacremonone and docetaxel, whereas thiacremonone on its own did not alter NF-κB activity. This combined drug effect was also found with other anticancer drugs in colon cancer and in other cancer cells. In good correlation with inhibition of cell growth and NF-κB activity, the combination treatment also regulated NF-κB target genes. Oral treatment of mice with thiacremonone (1 mg/kg) by administering it in drinking water for 4 weeks significantly augmented docetaxel (1 mg/kg, i.p., four times)–induced decrease of tumor growth accompanied with regulation of NF-κB activity and NF-κB target genes. These results warrant carefully designed clinical studies investigating the combination of thiacremonone and commonly used chemotherapeutic agents for the treatment of human cancers. (Mol Cancer Res 2009;7(6):870–9)
Discovery of a Broad-Spectrum Antiviral Compound That Inhibits Pyrimidine Biosynthesis and Establishes a Type 1 Interferon-Independent Antiviral State

ABSTRACT Viral emergence and reemergence underscore the importance of developing efficacious, broad-spectrum antivirals. Here, we report the discovery of tetrahydrobenzothiazole-based compound 1, a novel, broad-spectrum antiviral lead that was optimized from a hit compound derived from a cytopathic effect (CPE)-based antiviral screen using Venezuelan equine encephalitis virus. Compound 1 showed antiviral activity against a broad range of RNA viruses, including alphaviruses, flaviviruses, influenza virus, and ebolavirus. Mechanism-of-action studies with metabolomics and molecular approaches revealed that the compound inhibits host pyrimidine synthesis and establishes an antiviral state by inducing a variety of interferon-stimulated genes (ISGs). Notably, the induction of the ISGs by compound 1 was independent of the production of type 1 interferons. The antiviral activity of compound 1 was cell type dependent with a robust effect observed in human cell lines and no observed antiviral effect in mouse cell lines. Herein, we disclose tetrahydrobenzothiazole compound 1 as a novel lead for the development of a broad-spectrum, antiviral therapeutic and as a molecular probe to study the mechanism of the induction of ISGs that are independent of type 1 interferons.
Quantity Control of the ErbB3 Receptor Tyrosine Kinase at the Endoplasmic Reticulum

ABSTRACT The ErbB3 receptor tyrosine kinase contributes to a variety of developmental processes, and its overexpression and aberrant activation promote tumor progression and therapeutic resistance. Accumulating evidence suggests that tumor overexpression may be mediated by the loss of posttranscriptional negative regulatory mechanisms, such as protein degradation, that normally keep receptor levels in check. Our previous studies indicate that the RING finger E3 ubiquitin ligase Nrdp1, a protein lost in breast and other tumor types, suppresses ErbB3 levels by mediating ligand-independent receptor ubiquitination and degradation. Here we demonstrate that Nrdp1 preferentially associates with the nascent form of ErbB3 to accelerate its degradation, and we show that the two proteins colocalize at the endoplasmic reticulum (ER). Blocking the exit of ErbB3 from the ER does not affect the ability of Nrdp1 to mediate receptor ubiquitination or degradation, while functional disruption of the conserved ER-associated degradation (ERAD) pathway ATPase VCP/p97 leads to the Nrdp1-dependent accumulation of ubiquitinated ErbB3 but blocks receptor degradation. Further evidence indicates that the ErbB3 targeted by Nrdp1 for degradation is properly folded and fully functional. Collectively, these observations point to a novel mechanism of receptor tyrosine kinase quantity control wherein steady-state levels of signaling-competent receptor are dictated by an ER-localized degradation pathway.
Chromosomal stasis in distinct families of marine Percomorpharia from South Atlantic

Abstract The weakness of physical barriers in the marine environment and the dispersal potential of fish populations have been invoked as explanations of the apparent karyotype stasis of marine Percomorpha, but several taxa remain poorly studied cytogenetically. To increase the chromosomal data in this fish group, we analyzed cytogenetically three widespread Atlantic species from distinct families: Chaetodipterus faber Broussonet, 1782 (Ephippidae), Lutjanus synagris Linnaeus, 1758 (Lutjanidae) and Rypticus randalli Courtenay, 1967 (Serranidae). The three species shared a karyotype composed of 2n=48 acrocentric chromosomes, single nucleolus organizer regions (NORs) and reduced amounts of centromeric heterochromatin. A single NOR-bearing pair was identified in all species by physical mapping of 18S rDNA while non-syntenic 5S rRNA genes were located at centromeric region of a single pair. The similar karyotypic macrostructure observed in unrelated groups of Percomorpharia reinforces the conservative karyoevolution of marine teleosteans. Nonetheless, the species could be differentiated based on the pair bearing ribosomal cistrons, revealing the importance of microstructural analyses in species with symmetric and stable karyotypes.
Biphasic Effect of Methadone on Hepatic Drug Metabolism

When methadone HC1 (30 mg/kg, po) was given acutely to mice, it was found to inhibit drug metabolism as evidenced by a prolongation of hexobarbital sleeping time and zoxazolamine paralysis time. Pharmacokinetic studies revealed that this acute dose of the narcotic analgesic could also prolong the plasma half-life of aminopyrine without any change in its volume of distribution. When added to the incubation mixture containing 10,000 g mouse liver supernatant fraction and a complete system for measuring aminopyrine . N-demethylase or aniline hydroxylase, metadone showed a dose-dependent inhibition of the enzymes; the former enzyme was inhibited to a greater extent than the latter one. However, subacute treatment of mice with methadone HC1 (30 mg/kg, po, twice daily for 3 days) resulted in increases in liver weight, microsomal protein, and cytochrome P-450 content in consonant with the increased activities of four hepatic drug-metabolizing enzymes: aminopyrine N-demethylase, aniline hydroxylase, p-nitroanisole, O-demethylase, and benzphetamine N-demethylase. Moreover, both hexobarbital sleeping time and zoxazolamine paralysis time were shortened. The plasma half-life of aminopyrine was decreased. These changes were prevented by simultaneous administration of puromycin diHCl (80 mg/kg, ip). Methadone thus seems to act in a manner very similar to that of propoxyphene or SKF-525A, acting as a potent inhibitor of hepatic drug metabolism when given acutely and as an inducer when given subacutely.
Direct Batch Evaluation of Desirable Eigenvectors of the DFT Matrix by Constrained Optimization

The process of the batch generation of orthonormal eigenvectors of a unitary matrix - like the DFT matrix - that are as close as possible to approximate eigenvectors having a desired feature - such as being samples of the Hermite Gaussian functions - is formulated as a constrained optimization problem. The adopted rationale is the collective evaluation of a complete set of eigenvectors in each eigenspace by the minimization of the squared Frobenius norm of the difference between the matrix whose columns are the sought vectors and the matrix whose columns are the corresponding approximate eigenvectors subject to the constraints that the sought vectors are orthonormal eigenvectors.
Adaptive GSA-Based Optimal Tuning of PI Controlled Servo Systems With Reduced Process Parametric Sensitivity, Robust Stability and Controller Robustness

This paper suggests a new generation of optimal PI controllers for a class of servo systems characterized by saturation and dead zone static nonlinearities and second-order models with an integral component. The objective functions are expressed as the integral of time multiplied by absolute error plus the weighted sum of the integrals of output sensitivity functions of the state sensitivity models with respect to two process parametric variations. The PI controller tuning conditions applied to a simplified linear process model involve a single design parameter specific to the extended symmetrical optimum (ESO) method which offers the desired tradeoff to several control system performance indices. An original back-calculation and tracking anti-windup scheme is proposed in order to prevent the integrator wind-up and to compensate for the dead zone nonlinearity of the process. The minimization of the objective functions is carried out in the framework of optimization problems with inequality constraints which guarantee the robust stability with respect to the process parametric variations and the controller robustness. An adaptive gravitational search algorithm (GSA) solves the optimization problems focused on the optimal tuning of the design parameter specific to the ESO method and of the anti-windup tracking gain. A tuning method for PI controllers is proposed as an efficient approach to the design of resilient control systems. The tuning method and the PI controllers are experimentally validated by the adaptive GSA-based tuning of PI controllers for the angular position control of a laboratory servo system.
Micro-to millimeter scale magnetic shielding

We present two key results in this work related to magnetic shielding. First, milliscale single layer magnetic shields were fabricated on 3D printed polymer molds and achieved shielding factors in excess of 4500. Second, microscale multilayer shields of alternating 10 μm layers of Permalloy and copper were microfabricated onto silicon using batch fabrication processes and characterized. While conventional electromagnetic interference (EMI) shielding simply requires a conductor for shielding by image charges, dC magnetic shielding requires high permeability material to provide a low reluctance path, redirecting magnetic fields around its volume. Leveraging our expertise in electroplating thick, high permeability (maximum μr > 8000) Permalloy over sharp topologies, we have demonstrated two processes of producing conformal electroplated shielding. The size, shape flexibility, and shielding factor of these structures enable compact integration of magnetic devices for magnetic microelectronics and atomic, molecular, and optical (AMO) microsystems.
Relative efficiencies of physician/assessor global estimates and patient questionnaire measures are similar to or greater than joint counts to distinguish adalimumab from control treatments in rheumatoid arthritis clinical trials.

OBJECTIVE To estimate relative efficiencies of the 7 rheumatoid arthritis (RA) Core Data Set measures to distinguish adalimumab from control treatments in 4 clinical trials. METHODS Four adalimumab clinical trials were analyzed for arithmetic and percentage changes for each Core Data Set measure from baseline to endpoint: 3 assessor/physician measures -- swollen joints, tender joints, and global estimate; 1 laboratory test -- C-reactive protein; and 3 patient measures -- physical function, pain, and global estimate. Relative efficiencies of each measure to distinguish adalimumab from control group responses were assessed, with tender joint count as the referent measure. RESULTS Relative efficiencies were in a similar range for physician/assessor, patient, and laboratory measures, with some variation between trials. Among physician/assessor measures, relative efficiencies for global estimates were greater than for swollen and tender joint counts in 8/8 comparisons. Among patient measures, relative efficiencies for global estimates were greater than for physical function and pain scores in at least 6/8 comparisons. Among all measures, relative efficiencies for patient global estimates were greater than for swollen joint counts in 5/8 comparisons, and for tender joint counts in 8/8 comparisons. CONCLUSION Patient and physician/assessor measures distinguished adalimumab from control treatment groups in similar ranges. Among all measures, physician/assessor global estimate was most efficient, and tender joint count least efficient, in all 4 trials. This information suggests that while joint counts are the most specific measure to assess RA, their sensitivity to detect treatment effects in patients with RA is generally no greater, and usually less, than other measures.
Specific targeting of a DNA‐binding protein to the SPP1 procapsid by interaction with the portal oligomer

The icosahedral procapsid of tailed bacteriophages is composed of a large number of identical subunits and of minor proteins found in a few copies. Proteins present in a very low copy number are targeted to the viral procapsid by an unknown mechanism. Bacteriophage SPP1 procapsids and mature virions contain two copies of gp7 on average. Gp7 forms stable complexes with the SPP1 portal protein gp6. Deletion of the gp6 carboxyl‐terminus and the mutation Y467→C localized in the same region prevent gp6–gp7 complex formation. Gp7 binds double‐stranded and single‐stranded DNA. Gp6 competes for this interaction, and purified gp6–gp7 complexes do not bind DNA. Procapsid structures assembled in the absence of gp6 or carrying the mutant gp6 Y467→C lack gp7. The gp6–gp7 interaction thus targets gp7 to the procapsid where the portal protein is localized asymmetrically at a single vertex of the icosahedral structure. The interaction between the two proteins is disrupted during viral assembly. Proteins homologous to gp6 and gp7 are coded by contiguous genes in a variety of phage genomes from Gram‐positive bacteria, suggesting that the gp6–gp7 complex is widespread in this group of phages. Transient association with the portal protein, an essential component of tailed bacteriophages and herpes viruses, provides a novel strategy to target minor proteins to the virion structure that might be operative in a large number of viruses.
Receptor recycling mediates plasma membrane recovery of dopamine D1 receptors in dendrites and axons after agonist‐induced endocytosis in primary cultures of striatal neurons

The pharmacological stimulation of G‐protein‐coupled receptor induces receptor internalization. Receptor's fate after the step of internalization remains poorly characterized despite its incidence on the neuronal responsiveness. In this context, we studied the dopamine (DA) D1 receptor (D1R) trafficking in a model of striatal neuronal culture that endogenously express the D1R. We first characterized by immunohistochemistry the spatial distribution of the compartments involved in the endocytic pathways and then the D1R trafficking in dendrites and axons. In dendrites, immunohistochemical analysis showed that acute stimulation by the D1R agonist SKF 82958 (1 μM) induces an internalization of D1R in early endosomes labeled with Alexa‐488‐conjugated transferrin. We show that, 20 min after removal of the agonist, the D1R immunolabeling pattern returns to the basal state in dendrites and in axons. Recovery was unaffected by cycloheximide (70 μM) but was prevented by monensin (100 μM) that inhibits endosomal acidification and receptor recycling. These data suggest that dendritic and axonal D1Rs are internalized after agonist stimulation and targeted to the recycling pathway demonstrating that the machinery involved in GPCR endocytosis and recycling is functional both in dendrites and in axons. Temporal characteristics observed for the recovery of D1R density to the basal state and those observed for the resensitization process strongly suggest that D1R recycling supports the receptor resensitization. Synapse 60:194–204, 2006. © 2006 Wiley‐Liss, Inc.
Analyzing scientific collaboration with “giants” based on the milestones of career

This paper explores how the patterns of collaboration change throughout a scientist's career, especially their collaboration with so‐called “giants”—well‐known elite scholars with very high scientific impact. We divide scientist's careers into five stages based on the number of years since obtaining their PhD, and for each stage, we calculate a number of indicators, such as publication count, normalized citation count, count of collaborations, count of collaborations with “giants,” and percentage of uninterrupted and continuous presence. Our analysis shows that although collaborating with “giants” may benefit a young scholar, they are more likely to achieve greater scientific success if they first work independently and only collaborate with “giants” later in their career. Meanwhile, high‐impact authors tend to work with “giants” early in their career, but not in the later stages, which forces us to reconsider the established notions of when is best to collaborate with elite scholars. Moreover, we find that high‐impact authors tend to have fewer co‐authors per article, regardless of the stage of their careers, indicating that collaboration is important, but the size of collaborations also matters.
A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver

Carbohydrates mediate their conversion to triglycerides in the liver by promoting both rapid posttranslational activation of rate-limiting glycolytic and lipogenic enzymes and transcriptional induction of the genes encoding many of these same enzymes. The mechanism by which elevated carbohydrate levels affect transcription of these genes remains unknown. Here we report the purification and identification of a transcription factor that recognizes the carbohydrate response element (ChRE) within the promoter of the L-type pyruvate kinase (LPK) gene. The DNA-binding activity of this ChRE-binding protein (ChREBP) in rat livers is specifically induced by a high carbohydrate diet. ChREBP's DNA-binding specificity in vitro precisely correlates with promoter activity in vivo. Furthermore, forced ChREBP overexpression in primary hepatocytes activates transcription from the L-type Pyruvate kinase promoter in response to high glucose levels. The DNA-binding activity of ChREBP can be modulated in vitro by means of changes in its phosphorylation state, suggesting a possible mode of glucose-responsive regulation. ChREBP is likely critical for the optimal long-term storage of excess carbohydrates as fats, and may contribute to the imbalance between nutrient utilization and storage characteristic of obesity.
Decreased Prevalence of Exercise Expiratory Flow Limitation from Pre- to Postpuberty.

PURPOSE We recently reported a high prevalence of expiratory flow limitation (EFL) independent of sex in prepubescent children that exceeds the prevalence reported in adults. It is unknown how transpubertal maturation and growth affect pulmonary function, specifically EFL, during exercise. The purpose of this longitudinal study was to investigate the changes in EFL, including sex differences, from pre- to postpuberty. METHODS Twenty-one children (age 12-16 yr, 11 boys and 10 girls) were recruited from 40 prepubescent children who completed testing in our laboratory ∼5 yr ago. Subjects completed pulmonary function tests before and after an incremental exercise test to exhaustion on a cycle ergometer. EFL was determined using the percent tidal volume overlap method. RESULTS Nineteen of 21 subjects (10 boys and 9 girls, ∼90%) exhibited EFL prepuberty, whereas only 7 of 21 subjects (5 boys and 2 girls, 33%) exhibited EFL postpuberty. Boys had a significantly greater forced vital capacity (FVC) than girls both pre- (∼15%) and postpuberty (boys: 4.73 ± 0.53 L; girls: 3.80 ± 0.29 L). Maximal aerobic capacity (V˙O2max) significantly increased (boys: ∼120%; girls: ∼110%) from pre- to postpuberty and was greater (P < 0.05) in boys postpuberty (boys: 2.76 ± 0.43 L·min; girls: 1.94 ± 0.35 L·min). V˙E/V˙CO2 significantly decreased (∼13%) in boys and girls during maximal exercise. Postpuberty, subjects regulated tidal breathing at significantly higher lung volumes (greater expiratory reserve volume/FVC and lower inspiratory reserve volume/FVC) during exercise compared with prepuberty. CONCLUSION Our findings suggest that the prevalence of EFL declines as children mature from pre- to postpuberty, likely because of increases in lung size, decreases in V˙E/V˙CO2, and/or changes in breathing mechanics that are greater than increases in maximal ventilation that occur with increased pulmonary gas exchange.
Sliding mode pulse width modulation for voltage control of a Voltage Source Inverter

In this paper, a Sliding Mode Control (SMC) based Pulse Width Modulation (PWM) method is proposed for the voltage control of a three-phase Voltage Source Inverter (VSI). This variable frequency PWM method is designed such that the average of the outputs, i.e, the three-phase voltage of VSI and the neutral point voltage of a star connected load, track the desired references. A suitable mathematical model of VSI is derived. Because of the control objective which is the tracking of a desired reference by the average of discontinuous output, some integral sliding surfaces are defined. Based on the mathematical model and the defined sliding surfaces, a controller is designed to generate suitable signals for the gates of the VSI switches. Simulation results verify the satisfactory performance of the proposed method.