Miracle-dz/UniFAR-FTUs huggingface dataset:
The Pharmacokinetic/Pharmacodynamic Pipeline: Translating Anticancer Drug Pharmacology to the Clinic

Progress in an understanding of the genetic basis of cancer coupled to molecular pharmacology of potential new anticancer drugs calls for new approaches that are able to address key issues in the drug development process, including pharmacokinetic (PK) and pharmacodynamic (PD) relationships. The incorporation of predictive preclinical PK/PD models into rationally designed early-stage clinical trials offers a promising way to relieve a significant bottleneck in the drug discovery pipeline. The aim of the current review is to discuss some considerations for how quantitative PK and PD analyses for anticancer drugs may be conducted and integrated into a global translational effort, and the importance of examining drug disposition and dynamics in target tissues to support the development of preclinical PK/PD models that can be subsequently extrapolated to predict pharmacologic characteristics in patients. In this article, we describe three different physiologically based (PB) PK modeling approaches, i.e., the whole-body PBPK model, the hybrid PBPK model, and the two-pore model for macromolecules, as well as their applications. General conclusions are that greater effort should be made to generate more clinical data that could validate scaled preclinical PB-PK/PD tumor-based models and, thus, stimulate a framework for preclinical to clinical translation. Finally, given the innovative techniques to measure tissue drug concentrations and associated biomarkers of drug responses, development of predictive PK/PD models will become a standard approach for drug discovery and development.
Therapeutic Vaccination for HPV Induced Cervical Cancers

Cervical Cancer is the second leading cause of cancer–related deaths in women worldwide and is associated with Human Papillomavirus (HPV) infection, creating a unique opportunity to treat cervical cancer through anti-viral vaccination. Although a prophylactic vaccine may be available within a year, millions of women, already infected, will continue to suffer from HPV-related disease, emphasizing the need to develop therapeutic vaccination strategies. A majority of clinical trials examining therapeutic vaccination have shown limited efficacy due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Current trends in clinical trials with therapeutic agents examine patients with pre-invasive lesions in order to prevent invasive cervical cancer. However, longer follow-up is necessary to correlate immune responses to lesion regression. Meanwhile, preclinical studies in this field include further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. As long as pre-clinical studies continue to advance, the prospect of therapeutic vaccination to treat existing lesions seem good in the near future. Positive consequences of therapeutic vaccination would include less disfiguring treatment options and fewer instances of recurrent or progressive lesions leading to a reduction in cervical cancer incidence.
Acute Erythemal Ultraviolet Radiation Causes Systemic Immunosuppression in the Absence of Increased 25-Hydroxyvitamin D3 Levels in Male Mice

Vitamin D is synthesised by ultraviolet (UV) irradiation of skin and is hypothesized to be a direct mediator of the immunosuppression that occurs following UV radiation (UVR) exposure. Both UVR and vitamin D drive immune responses towards tolerance by ultimately increasing the suppressive activities of regulatory T cells. To examine a role for UVR-induced vitamin D, vitamin D3-deficient mice were established by dietary vitamin D3 restriction. In comparison to vitamin D3-replete mice, vitamin D3-deficient mice had significantly reduced serum levels of 25-hydroxyvitamin D3 (25(OH)D3, <20 nmol.L−1) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3, <20 pmol.L−1). Following either acute erythemal UVR, or chronic sub-erythemal UVR (8 exposures over 4 weeks) treatment, serum 25(OH)D3 levels significantly increased in vitamin D3-deficient female but not male mice. To determine if UVR-induced vitamin D was a mediator of UVR-induced systemic immunosuppression, responses were measured in mice that were able (female) or unable (male) to increase systemic levels of 25(OH)D3 after UVR. Erythemal UVR (≥4 kJ/m2) suppressed contact hypersensitivity responses (T helper type-1 or -17), aspects of allergic airway disease (T helper type-2) and also the in vivo priming capacity of bone marrow-derived dendritic cells to a similar degree in female and male vitamin D3-deficient mice. Thus, in male mice, UVR-induced 25(OH)D3 is not essential for mediating the immunosuppressive effects of erythemal UVR.
Improved Direct Power Control of a Wind Turbine Driven Doubly Fed Induction Generator During Transient Grid Voltage Unbalance

This paper proposes an improved direct power control (DPC) strategy for a doubly fed induction generator (DFIG)-based wind power generation system under unbalanced grid voltage dips. The fundamental and double grid frequency power pulsations, which are produced by the transient unbalanced grid faults, are mathematically analyzed and accurately regulated. Five selectable control targets, with proper power references given, are designed for different applications during network unbalance. In order to provide enhanced control performance, two resonant controllers, which are tuned to have large gain at the power pulsation frequencies, are applied together with the proportional-integral controller to achieve full control of the DFIG output power. The effectiveness of the proposed DPC strategy is verified by the experimental results of a 5-kW DFIG system under different unbalanced voltage dips, which are generated by a specially designed voltage dip generator.
An Electroencephalographic Classification for Coma

ABSTRACT: Background: The assessment of thalamocortical function in comatose patients in the intensive care unit (ICU) can be difficult to determine. Since the electroencephalogram (EEG) affords such assessment, we have developed an EEG classification for comatose patients in our general ICU. Methods: One hundred EEGs were classified in a blinded fashion by two EEGers, using our method and that of Synek. Interobserver agreement was assessed using kappa score determination. Results: Kappa scores were 0.90 for our system and 0.75 for the Synek system. (The Kappa score represents the inter-rater agreement that is beyond chance; 0.90 is almost perfect agreement, while 0.75 is substantial agreement). Conclusion: Our system for classifying EEGs in comatose patients has a higher interobserver reliability than one that was previously published. This EEG classification scheme should be useful in clinical electrophysiological research involving ICU patients, allowing for internal consistency and comparisons among centres.
Feature Selection using Modified Particle Swarm Optimization

Feature selection is the process by which relevant features are selected from large datasets in order to improve the performance of the classification systems. There are various approaches that are used for feature selection such as Soft Computing, Hill Climbing etc. Particle Swarm Optimization is now a days popularly used soft computing technique for feature selection due to its searching ability, simplicity and low computation cost. But the main problem with Particle Swarm Optimization is premature convergence which in turn affects the classification performance. In this paper, a modified Particle Swarm Optimization is proposed for feature selection. To handle the problem of premature convergence, a flipping operator is introduced before the updation of velocity and position of the particle. Fitness of each particle is computed using Support Vector Machine based fitness function. To establish the effectiveness of proposed approach, testing is done on various benchmark datasets like wine, zoo, sonar etc. Results obtained on these datasets are compared with the standard approach and satisfactory improvements are observed.
The Power of Participation? Power Relations and Processes in Employee-owned Companies

Introducing employee participation in a company can be expected to change the power relations and the power processes within the organization. This is particularly true when the majority ownership of a company moves into the hand of its employees. Drawing on three case studies of East German companies this paper describes how the introduction of employee ownership interrelates with power relations and processes in the company. Moreover, some overarching patterns were derived from the analysis finally resulting in seven propositions about how employee ownership and power are linked to each other.
Neutrophilic Bronchial Inflammation Correlates with Clinical and Functional Findings in Patients with Noncystic Fibrosis Bronchiectasis

Background. Neutrophilic bronchial inflammation is a main feature of bronchiectasis, but not much is known about its relationship with other disease features. Aim. To compare airway inflammatory markers with clinical and functional findings in subjects with stable noncystic fibrosis bronchiectasis (NCFB). Methods. 152 NFCB patients (62.6 years; females: 57.2%) underwent clinical and functional cross-sectional evaluation, including microbiologic and inflammatory cell profile in sputum, and exhaled breath condensate malondialdehyde (EBC-MDA). NFCB severity was assessed using BSI and FACED criteria. Results. Sputum neutrophil percentages inversely correlated with FEV1 (P < 0.0001; rho = −0.428), weakly with Leicester Cough Questionnaire score (P = 0.068; rho = −0.58), and directly with duration of the disease (P = 0.004; rho = 0.3) and BSI severity score (P = 0.005; rho = 0.37), but not with FACED. Sputum neutrophilia was higher in colonized subjects, P. aeruginosa colonized subjects showing greater sputum neutrophilia and lower FEV1. Patients with ≥3 exacerbations in the last year showed a significantly greater EBC-MDA than the remaining patients. Conclusions. Sputum neutrophilic inflammation and biomarkers of oxidative stress in EBC can be considered good biomarkers of disease severity in NCFB patients, as confirmed by pulmonary function, disease duration, bacterial colonization, BSI score, and exacerbation rate.
Cascade Dual Buck Inverter With Phase-Shift Control

This paper presents a new type of cascade inverter based on dual buck topology and phase-shift control scheme. The proposed cascade dual buck inverter with phase-shift control inherits all the merits of dual buck type inverters and overcomes some of their drawbacks. Compared to traditional cascade inverters, it has much enhanced system reliability thanks to no shoot-through problems and lower switching loss with the help of using power MOSFETs. With phase-shift control, it theoretically eliminates the inherent current zero-crossing distortion of the single-unit dual buck type inverter. In addition, phase-shift control and cascade topology can greatly reduce the ripple current or cut down the size of passive components by increasing the equivalent switching frequency. A cascade dual buck inverter has been designed and tested to demonstrate the feasibility and advantages of the system by comparing single-unit dual buck inverter, 2-unit and 3-unit cascade dual buck inverters at the same 1 kW, 120 V ac output conditions.
Antibody-drug conjugates with high drug loading

The present invention provides transglutaminase-mediated antibody-drug conjugates with high antibody-drug ratio (DAR) comprising 1) glutamine-containing tags, endogenous glutamines, and/or endogenous glutamines made reactive by antibody engineering or an engineered transglutaminase (e.g., with altered substrate specifity); and 2) amine donor agents comprising amine donor units, linkers, and agent moieties, wherein the DAR is at least about 5. The invention also provides methods of making and methods of using such higher drug loaded antibody-drug conjugates.
Osteogenic differentiation of mouse adipose-derived adult stromal cells requires retinoic acid and bone morphogenetic protein receptor type IB signaling

Although the multilineage potential of human adipose-derived adult stromal cells (ADAS) has been well described, few published studies have investigated the biological and molecular mechanisms underlying osteogenic differentiation of mouse ADAS. We report here that significant osteogenesis, as determined by gene expression and histological analysis, is induced only when mouse ADAS are cultured in the presence of retinoic acid with or without recombinant human bone morphogenetic protein (BMP)-2 supplementation. Furthermore, a dynamic expression profile for the BMP receptor (BMPR) isoform IB was observed, with dramatic up-regulation during osteogenesis. Western blot analysis revealed that retinoic acid enhanced levels of BMPR-IB protein during the first 7 days of osteogenic differentiation and that RNAi-mediated suppression of BMPR-IB dramatically impaired the ability of ADAS to form bone in vitro. In contrast, absence of BMPR-IA did not significantly diminish ADAS osteogenesis. Our data therefore demonstrate that the osteogenic commitment of multipotent mouse ADAS requires retinoic acid, which enhances expression of the critical BMPR-IB isoform.
Deploying Virtual Machines as Sandboxes for the Grid

The ability to securely run arbitrary untrusted code on a wide variety of execution platforms is a challenging problem in the Grid community. One way to achieve this is to run the code inside a contained, isolated environment, namely a "sandbox". Virtual machines provide a natural solution to the security and resource management issues that arise in sandboxing. We explore different designs for the VM-enabled sandbox and evaluate them with respect to various factors like structure, security guarantees, user convenience, feasibility and overheads in one such grid environment. Our experiments indicate that the use of on-demand VMs imposes a constant startup overhead, with I/O-intensive applications incurring additional overheads depending on the design of the sandbox.
Unusual features of the leader sequence of Rous sarcoma virus packaging mutant TK15

TK15, a mutant derived from a temperature-sensitive mutant of Rous sarcoma virus (tsNY68), has extremely low infectivity although it has intact viral genes. Biological and biochemical analyses of the virus and virus-induced transformants showed that the mutant has a defect in the packaging of its own genomic RNA possibly owing to a deletion near the 5' end (S. Kawai and T. Koyama, J. Virol. 51:147-153, 1984; T. Koyama, F. Harada, and S. Kawai, J. Virol. 51:154-162, 1984). Nucleotide sequence analysis of the provirus DNA of the mutant revealed that the deletion extends from the 3' end of the primer binding site to 22 bases upstream of the gag initiation codon and also suggested that possible binding between an extra region of the primer molecule and the viral genome resulting from the deletion causes another defect in the replication of the TK15 genome. It was suggested that the deletion of 237 bases in TK15 was generated during reverse transcription of the genome by the skipping of a sequence between identical 13-base sequences present in the primer binding site and 35 to 22 bases upstream of the gag initiation codon of the parental virus.
Effects of noise and nonlinearity on the calibration of a non-binary capacitor array in a successive approximation analog-to-digital converter

A successive approximation analog-to-digital converter using a nonbinary capacitor array is presented. A perceptron learning rule is used as the capacitor calibration algorithm. The nonlinearity is analyzed using the Volterra series. The effects of noise and nonlinearity are modeled to verify the calibration robustness. With the presence of noise and nonlinearity, the capacitor weights are adaptively calibrated to match the physical capacitors with better than 22-bit accuracy. The accuracy is no longer limited by capacitor matching.
Trajectory tracking control for a nonholonomic mobile robot using an improved ILC

This paper develops a kinematic path-tracking algorithm for a nonholonomic mobile robot using an improved iterative learning control (I-ILC) technique. The proposed algorithm produces a velocity command to the wheeled robot, in addition, the state disturbances and measurement noises are taken into consideration. In the learning rule, an adjustable parameter is defined and by adjusting this parameter we can obtain the best learning rule. From the simulation results we find that the system outputs and control inputs are bounded to converge to the desired values. The MATLAB software is used for simulation to verify the feasibility and validity of the proposed learning algorithm.
The angular sizes of dwarf stars and subgiants Surface brightness relations calibrated by interferometry

The availability of a number of new interferometric measurements of Main Sequence and subgiant stars makes it possible to calibrate the surface brightness relations of these stars using exclusively direct angular diameter measurements. These empirical laws make it possible to predict the limb darkened angular diameters $\theta_{\rm LD}$ of dwarfs and subgiants using their dereddened Johnson magnitudes, or their effective temperature. The smallest intrinsic dispersions of $\sigma \le 1\%$ in $\theta_{\rm LD}$ are obtained for the relations based on the K and L magnitudes, for instance $\log \theta_{\rm LD} = 0.0502\,(B-L) + 0.5133 - 0.2\,L$ or $\log \theta_{\rm LD} = 0.0755\,(V-K) + 0.5170 - 0.2\rm \,K$. Our calibrations are valid between the spectral types A0 and M2 for dwarf stars (with a possible extension to later types when using the effective temperature), and between A0 and K0 for subgiants. Such relations are particularly useful for estimating the angular sizes of calibrators for long-baseline interferometry from readily available broadband photometry.
3D model for CAR‐mediated cytotoxicity using patient‐derived colorectal cancer organoids

Immunotherapy using chimeric antigen receptor (CAR)‐engineered lymphocytes has shown impressive results in leukemia. However, for solid tumors such as colorectal cancer (CRC), new preclinical models are needed that allow to test CAR‐mediated cytotoxicity in a tissue‐like environment. Here, we developed a platform to study CAR cell cytotoxicity against 3‐dimensional (3D) patient‐derived colon organoids. Luciferase‐based measurement served as a quantitative read‐out for target cell viability. Additionally, we set up a confocal live imaging protocol to monitor effector cell recruitment and cytolytic activity at a single organoid level. As proof of principle, we demonstrated efficient targeting in diverse organoid models using CAR‐engineered NK‐92 cells directed toward a ubiquitous epithelial antigen (EPCAM). Tumor antigen‐specific cytotoxicity was studied with CAR‐NK‐92 cells targeting organoids expressing EGFRvIII, a neoantigen found in several cancers. Finally, we tested a novel CAR strategy targeting FRIZZLED receptors that show increased expression in a subgroup of CRC tumors. Here, comparative killing assays with normal organoids failed to show tumor‐specific activity. Taken together, we report a sensitive in vitro platform to evaluate CAR efficacy and tumor specificity in a personalized manner.
AUT 1 , a Gene Essential for Autophagocytosis in the Yeast Saccharomyces cerevisiae

Autophagocytosis is a starvation-induced process responsible for transport of cytoplasmic proteins to the vacuole. In Saccharomyces cerevisiae, autophagy is characterized by the phenotypic appearance of autophagic vesicles inside the vacuole of strains deficient in proteinase yscB. The AUT1 gene, essential for autophagy, was isolated by complementation of the sporulation deficiency of a diploid aut1-1 mutant strain by a yeast genomic library and characterized. AUT1 is located on the right arm of chromosome XIV, 10 kb from the centromere, and encodes a protein of 310 amino acids, with an estimated molecular weight of 36 kDa. Cells carrying a chromosomal deletion of AUT1 are defective in the starvation-induced bulk flow transport of cytoplasmic proteins to the vacuole. aut1 null mutant strains are completely viable but show decreased survival rates during starvation. Homozygous Daut1 diploid cells fail to sporulate. The selective cytoplasm-to-vacuole transport of aminopeptidase I is blocked in logarithmically growing and in starved Daut1 cells. Deletion of the AUT1 gene had no obvious influence on secretion, fluid phase endocytosis, or vacuolar protein sorting. This supports the idea of autophagocytosis as being a novel route transporting proteins from the cytoplasm to the vacuole.
Expression patterns of Wnts, Frizzleds, sFRPs, and misexpression in transgenic mice suggesting a role for Wnts in pancreas and foregut pattern formation

It is well established that gut and pancreas development depend on epithelial‐mesenchymal interactions. We show here that several Wnt, Frizzled, and secreted frizzled‐related protein (sFRP) encoding mRNAs are present during mouse pancreatic morphogenesis. Wnt5a and 7b mRNA is broadly expressed in foregut mesenchyme starting around embryonic day 10 in mice. Other members expressed are Wnt2b, Wnt5b, and Wnt11. In addition, genes for the Wnt receptors, Frizzled2, 3, 4, 5, 6, 7, 8, and 9 are expressed. To understand potential Wnt functions in pancreas and foregut development in vivo, we analyzed transgenic F0 mouse fetuses expressing Wnt1 and 5a cDNAs under control of the PDX‐1 gene promoter. In PDX‐Wnt1 fetuses, the foregut region normally comprising the proximal duodenum instead resembles a posterior extension of the stomach, often associated with complete pancreatic and splenic agenesis. Furthermore, the boundary between expression domains of gastric and duodenal markers is shifted in a posterior direction. In PDX‐Wnt5a fetuses, several structures derived from the proximal foregut are reduced in size, including the pancreas, spleen, and stomach, without any apparent shift in the stomach to duodenum transition. In these fetuses, overall pancreatic morphology is changed and the pancreatic epithelium is dense and compact, consistent with Wnt5A effects on cell movements and/or attachment. Taken together, these results suggest that Wnt genes participate in epithelial‐mesenchymal signaling and may specify region identity in the anterior foregut. © 2002 Wiley‐Liss, Inc.