Miracle-dz/UniFAR-FTUs huggingface dataset:
Review of UCN‐01 Development: A Lesson in the Importance of Clinical Pharmacology

UCN‐01 is a protein kinase inhibitor under development as a novel anticancer drug. The initial pharmacologic features in patients were not predicted from preclinical experiments. The distribution volume and the systemic clearance were much lower than those in experimental animals (mice, rats, and dogs), and the elimination half‐life was unusually long (>200 hours). The unbound fraction in human plasma was also much smaller than that in dogs, rats and mice, as was the binding of UCN‐01 to human alpha‐1 acid glycoprotein much stronger than that to human serum albumin or human γ‐globulin. The association constants for alpha‐1 acid glycoprotein and human plasma were approximately 8 × 108 (mol/L)−1, indicating extremely high affinity. In this review article, the authors discuss the pharmacologic features of UCN‐01 across species and provide a perspective on how this information could be applied prospectively to the future development of this agent.
UvA-DARE ( Digital Academic Repository ) Assessing acceptance of assistive social agent technology by older adults : the Almere model

This paper proposes a model of technology acceptance that is specifically developed to test the acceptance of assistive social agents by elderly users. The research in this paper develops and tests an adaptation and theoretical extension of the Unified Theory of Acceptance and Use of Technology (UTAUT) by explaining intent to use not only in terms of variables related to functional evaluation like perceived usefulness and perceived ease of use, but also variables that relate to social interaction. The new model was tested using controlled experiment and longitudinal data collected regarding three different social agents at elderly care facilities and at the homes of older adults. The model was strongly supported accounting for 59–79% of the variance in usage intentions and 49–59% of the variance in actual use. These findings contribute to our understanding of how elderly users accept assistive social agents.
Optimal software rejuvenation policy with discounting

Software rejuvenation is a preventive maintenance technique that has been extensively studied in the recent literature. We consider a generalized problem to estimate the optimal software rejuvenation schedule. More precisely, the software rejuvenation model is formulated via the semi-Markov process, and the optimal software rejuvenation schedule which minimizes the expected total discounted cost over an infinite time horizon is derived analytically. Further, we develop a statistically nonparametric algorithm to estimate the optimal software rejuvenation schedule, provided that the complete sample data of failure time is given. In numerical examples, we investigate how the discount factor affects the optimal policy and examine an asymptotic property for the statistical estimation algorithm.
Commutation torque ripple reduction in a position sensorless brushless DC motor drive

This paper presents a novel method to reduce commutation torque ripple in a position sensorless brushless DC (BLDC) motor drive. To compensate the commutation torque ripple completely, conventional methods should know commutation interval, so that they need current sensors. However, the proposed method measures commutation interval from the terminal voltage of a brushless DC motor, calculates a PWM duty ratio using the measured commutation interval to suppress the commutation torque ripple, and applies to the calculated PWM duty ratio only during the next commutation. Experimental results verify that the proposed method implemented in an air-conditioner compressor controller considerably reduces not only the pulsating currents but also vibrations of a position-sensorless BLDC motor.
Structure of the gene for the transition state regulator, abrB: regulator synthesis is controlled by the spo0A sporulation gene in Bacillus subtilis

Sporulation begins coincidentally with the expression of several stationary‐phase‐associated gene products during the transition state of a culture from exponential to stationary phase. Mutations in the stage 0 sporulation genes prevent the expression of these gene products in addition to blocking sporulation. Suppressor mutations in the abrB gene, in a spo0 background, restore stationary‐phase‐associated gene expression but not sporulation. The nature of the abrB gene product was investigated by isolating and sequencing the abrB gene. The abrB gene coded for a 96‐amino‐acid protein (molecular weight 10773) and contained a helix‐turn‐helix structure common to DNA binding proteins. Analysis of expression of the abrB gene using lacZ transcription fusions and direct measurement of mRNA content by hybridization showed that the spo0A gene repressed transcription of the abrB gene. Primer extension analysis of abrB gene mRNA revealed two initiation sites. The downstream site was dramatically repressed in spo0A+ strains, while the upstream site appeared not to be regulated by spo0A. Five abrB mutant alleles were cloned and sequenced. One mutation, abrB 4, resided within the structural gene and continued to overexpress abrB messenger RNA from both promoters. A promoter mutation, abrB 15, reduced transcription from the downstream promoter but not the upstream promoter. Thus, the phenotype of abrB mutations results from inactivation of the abrB gene product or by prevention of its overexpression. The results suggest that the abrB gene codes for a regulator which controls several genes whose products are normally produced during the transition phase between active growth and sporulation. The level of this regulator is, in turn, controlled by the spo0A gene. The pleiotropic phenotypes of spo0A mutants result from uncontrolled overexpression of the abrB regulator.
Living donor liver transplantation versus deceased donor liver transplantation for hepatocellular carcinoma: Comparable survival and recurrence

Several studies have reported higher rates of recurrent hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT) versus deceased donor liver transplantation (DDLT). It is unclear whether this difference is due to a specific biological effect unique to the LDLT procedure or to other factors such as patient selection. We compared the overall survival (OS) rates and the rates of HCC recurrence after LDLT and DDLT at our center. Between January 1996 and September 2009, 345 patients with HCC were identified: 287 (83%) had DDLT and 58 (17%) had LDLT. The OS rates were calculated with the Kaplan‐Meier method, whereas competing risks methods were used to determine the HCC recurrence rates. The LDLT and DDLT groups were similar with respect to most clinical parameters, but they had different median waiting times (3.1 versus 5.3 months, P = 0.003) and median follow‐up times (30 versus 38.1 months, P = 0.02). The type of transplant did not affect any of the measured cancer outcomes. The OS rates at 1, 3, and 5 years were equivalent: 91.3%, 75.2%, and 75.2%, respectively, for the LDLT group and 90.5%, 79.7%, and 74.6%, respectively, for DDLT (P = 0.62). The 1‐, 3‐, and 5‐year HCC recurrence rates were also similar: 8.8%, 10.7%, and 15.4%, respectively, for the LDLT group and 7.5%, 14.8%, and 17.0%, respectively, for the DDLT group (P = 0.54). A regression analysis identified microvascular invasion (but not the graft type) as a predictor of HCC recurrence. In conclusion, in well‐matched cohorts of LDLT and DDLT recipients, LDLT and DDLT provide similarly low recurrence rates and high survival rates for the treatment of HCC. Liver Transpl 18:315–322, 2012. © 2012 AASLD.
Mapping Evidence of Patients’ Experiences in Integrated Care Settings: A Protocol for a Scoping Review

Introduction Integrated care (IC) models have emerged to address gaps in care for individuals with complex healthcare needs. Although the clinical and cost-effectiveness of IC models are well-established, our understanding of whether IC models facilitate a patient-centred care experience from the patients’ perspective is not well understood. This scoping review aims to comprehensively map the literature to provide a broad overview of patients’ experiences in IC settings with a focus on the experiences of complex patients with comorbid mental and physical illnesses. It also aims to describe current gaps identified in the literature in our understanding of aspects of care that are often unrecognised. Methods and analysis Using established scoping review frameworks and guidelines, we will perform a comprehensive search in the following databases: MEDLINE, EMBASE, PsycINFO, CINAHL, AMED and the Cochrane Library to identify relevant studies on patients’ experiences in IC models. Grey literature sources and studies bibliographies will also be searched to identify relevant studies and documents. Data will be extracted and summarised using descriptive statistical and qualitative analyses. We will also consult with stakeholders from various backgrounds to enhance the comprehensiveness of this review. Ethics and dissemination This review requires no ethical approval. Findings from this study will be disseminated through publication in a peer-reviewed journal, clinical conferences and in knowledge translation settings, aiming to improve clinical practice and care delivery.
Penetratin tandemly linked to a CTL peptide induces anti‐tumour T‐cell responses via a cross‐presentation pathway

Recently there has been increasing evidence to suggest that membrane translocating peptides enter cells by a receptor‐dependent pathway. There have been some studies on the mechanism of major histocompatibility complex (MHC) class I presentation of membrane translocating peptides incorporating cytotoxic T lymphocyte epitopes. However, these have been on different cell lines and only a limited number of inhibitors of the antigen presentation pathway were used. Herein, we demonstrate a comprehensive study utilizing a full spectrum of inhibitors to various pathways of MHC class I to elucidate the mechanism of the membrane translocating peptide, penetratin from Antennapedia (Int). It is clear that Int, RQIKIWFQNRRMKWKK when tandemly linked to a cytotoxic T lymphocyte peptide of ovalbumin, SIINFEKL (IntSIIN) is endocytosed via phagocytosis or macropinocytosis by dendritic cells in an ATP‐dependent manner and is processed by a proteasome‐ and tapasin‐independent pathway for presentation and loading to MHC class I molecules. In addition, the majority of antigen is taken up by negatively charged receptors. IntSIIN activates T cells in vitro and in vivo and protects mice against challenge with an ovalbumin‐expressing tumour.
Sequential Loop Closure Based Adaptive Output Feedback

This paper presents a new, systematic method of synthesizing an output feedback adaptive controller for a class of uncertain, non-square multi-input/multi-output systems. The control design process consists of first designing an inner-loop controller for a reduced order plant model to enforce command tracking of selected inner-loop variables, with an adaptive element used to accommodate parametric uncertainties in the plant. Once this inner-loop control design is complete, an outer-loop is then designed, which prescribes the inner-loop commands to enforce command tracking of selected outer-loop variables. The main challenge that needs to be addressed when designing the inner-loop controller is the determination of a corresponding square and strictly positive real transfer function. This is accomplished by appropriate selection of two gain matrices that allow the realization of such a transfer function, thereby allowing a globally stable adaptive output feedback law to be generated. The outer-loop controller is designed around the plant with existing adaptive inner-loop controller such that global stability of the closed-loop system is guaranteed. The design of the outer-loop uses components of a closed-loop reference model in a judicious manner which enables a modular approach, without requiring any re-design of the inner-loop controller. In addition, this architecture facilitates the use of an additional state-limiter to enforce desired limits on the state variables. A numerical example based on a scramjet powered, generic hypersonic vehicle model is presented, demonstrating the efficacy of the proposed control design.
What is the role of the aorta in directing coronary blood flow?

To the editor: The recent article by Davies and colleagues1 discussed the role of the aorta in directing coronary circulation. They mainly treated the subject from the viewpoint of blood pressure; however, a further point needs to be clarified—namely, the coronary blood flow. The aorta serves predominantly as a cushioning reservoir of blood during systole, and thereafter expels it to the peripheral circulation during diastole (reservoir function). One of the most important organs to …
Globin X is a six-coordinate globin that reduces nitrite to nitric oxide in fish red blood cells

Significance Hemoglobin is generally assumed to be the only globin in vertebrate RBCs. In addition to its foremost role as an oxygen carrier, mammalian hemoglobin can also operate as a nitrite reductase, producing the signaling molecule nitric oxide (NO) from nitrite. Over the last 15 yr, several novel globins have been identified with six-coordinate heme geometry and uncertain physiological functions. Here we report that a six-coordinate globin of ancient origin, named Globin X, is present in fish RBCs. We establish that Globin X is a fast nitrite reductase, and this activity can regulate NO production from fish RBCs and modulate platelet activation. Thus we provide evidence that the ancestral globins in blood were efficient nitrite reductases. The discovery of novel globins in diverse organisms has stimulated intense interest in their evolved function, beyond oxygen binding. Globin X (GbX) is a protein found in fish, amphibians, and reptiles that diverged from a common ancestor of mammalian hemoglobins and myoglobins. Like mammalian neuroglobin, GbX was first designated as a neuronal globin in fish and exhibits six-coordinate heme geometry, suggesting a role in intracellular electron transfer reactions rather than oxygen binding. Here, we report that GbX to our knowledge is the first six-coordinate globin and the first globin protein apart from hemoglobin, found in vertebrate RBCs. GbX is present in fish erythrocytes and exhibits a nitrite reduction rate up to 200-fold faster than human hemoglobin and up to 50-fold higher than neuroglobin or cytoglobin. Deoxygenated GbX reduces nitrite to form nitric oxide (NO) and potently inhibits platelet activation in vitro, to a greater extent than hemoglobin. Fish RBCs also reduce nitrite to NO and inhibit platelet activation to a greater extent than human RBCs, whereas GbX knockdown inhibits this nitrite-dependent NO signaling. The description of a novel, six-coordinate globin in RBCs with dominant electron transfer and nitrite reduction functionality provides new insights into the evolved signaling properties of ancestral heme-globins.
Non-invasive, quantitative monitoring of hyperthermia-induced EGFR activation in xenograft tumours

Purpose: To examine the molecular mechanism of cellular EGFR activation during hyperthermia treatment. Materials and methods: EGR activities in tumour cells were quantified through the use of a recently developed split-luciferase-based EGFR reporter system which allowed us to monitor EGFR activation in vitro as well as in vivo in a non-invasive manner. Results: We found that hyperthermia treatment of MDA-MB231 breast cancer cells resulted in a strong induction of EGFR activity in tissue culture as well as in xenograft tumours. Furthermore, we found that this induction is mediated by the heat shock protein Hsp90. Administration of the specific Hsp90 inhibitor geldanamycin as well as RNAi directed against HSP90 effectively inhibited EGFR activation, suggesting an essential role for Hsp90 in hyperthermia-induced EGFR activation. In addition, cells treated with geldanamycin were sensitised to heat treatment, suggesting that adding Hsp90 inhibitors to hyperthermia regimens might have a beneficial effect for cancer treatment. Conclusions: Our bioluminescent imaging reporter provided a powerful tool to examine hyperthermia-induced EGFR activation in vitro as well as in vivo. Hsp90 was found to be a key factor mediating heat-induced EGFR activation in tumour cells.
Inhibition of cerebral ischemia/reperfusion injury-induced apoptosis: nicotiflorin and JAK2/STAT3 pathway

Nicotiflorin is a flavonoid extracted from Carthamus tinctorius. Previous studies have shown its cerebral protective effect, but the mechanism is undefined. In this study, we aimed to determine whether nicotiflorin protects against cerebral ischemia/reperfusion injury-induced apoptosis through the JAK2/STAT3 pathway. The cerebral ischemia/reperfusion injury model was established by middle cerebral artery occlusion/reperfusion. Nicotiflorin (10 mg/kg) was administered by tail vein injection. Cell apoptosis in the ischemic cerebral cortex was examined by hematoxylin-eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Bcl-2 and Bax expression levels in ischemic cerebral cortex were examined by immunohistochemial staining. Additionally, p-JAK2, p-STAT3, Bcl-2, Bax, and caspase-3 levels in ischemic cerebral cortex were examined by western blot assay. Nicotiflorin altered the shape and structure of injured neurons, decreased the number of apoptotic cells, down-regulates expression of p-JAK2, p-STAT3, caspase-3, and Bax, decreased Bax immunoredactivity, and increased Bcl-2 protein expression and immunoreactivity. These results suggest that nicotiflorin protects against cerebral ischemia/reperfusion injury-induced apoptosis via the JAK2/STAT3 pathway.
Crystal structure of π initiator protein–iteron complex of plasmid R6K: Implications for initiation of plasmid DNA replication

We have determined the crystal structure of a monomeric biologically active form of the π initiator protein of plasmid R6K as a complex with a single copy of its cognate DNA-binding site (iteron) at 3.1-Å resolution. The initiator belongs to the family of winged helix type of proteins. The structure reveals that the protein contacts the iteron DNA at two primary recognition helices, namely the C-terminal α4′ and the N-terminal α4 helices, that recognize the 5′ half and the 3′ half of the 22-bp iteron, respectively. The base-amino acid contacts are all located in α4′, whereas the α4 helix and its vicinity mainly contact the phosphate groups of the iteron. Mutational analyses show that the contacts of both recognition helices with DNA are necessary for iteron binding and replication initiation. Considerations of a large number of site-directed mutations reveal that two distinct regions, namely α2 and α5 and its vicinity, are required for DNA looping and initiator dimerization, respectively. Further analysis of mutant forms of π revealed the possible domain that interacts with the DnaB helicase. Thus, the structure–function analysis presented illuminates aspects of initiation mechanism of R6K and its control.
A NOVEL DOCUMENT CLUSTERING FOR ORGANIZING THE WEB PAGES

The exponential growth of information on the World Wide Web has prompted for developing efficient and effective methods for organizing and retrieving the information. Clustering techniques play an important role in searching and organization of web pages. In this paper we proposed an approach for web search results clustering based on a new document clustering algorithm. It is an alternative to a single ordered result of search engines. This approach presents a list of clusters to the user. This believes that clusters of search results are easier to browse than a single ordered list. Experimental results show that the new approach has better performance than that of conventional web search result clustering.
Region-specific proteolysis differentially regulates type 1 inositol 1,4,5-trisphosphate receptor activity

The inositol 1,4,5 trisphosphate receptor (IP3R) is an intracellular Ca2+ release channel expressed predominately on the membranes of the endoplasmic reticulum. IP3R1 can be cleaved by caspase or calpain into at least two receptor fragments. However, the functional consequences of receptor fragmentation are poorly understood. Our previous work has demonstrated that IP3R1 channels, formed following either enzymatic fragmentation or expression of the corresponding complementary polypeptide chains, retain tetrameric architecture and are still activated by IP3 binding despite the loss of peptide continuity. In this study, we demonstrate that region-specific receptor fragmentation modifies channel regulation. Specifically, the agonist-evoked temporal Ca2+ release profile and protein kinase A modulation of Ca2+ release are markedly altered. Moreover, we also demonstrate that activation of fragmented IP3R1 can result in a distinct functional outcome. Our work suggests that proteolysis of IP3R1 may represent a novel form of modulation of IP3R1 channel function and increases the repertoire of Ca2+ signals achievable through this channel.
Calreticulin promotes tumor lymphocyte infiltration and enhances the antitumor effects of immunotherapy by up‐regulating the endothelial expression of adhesion molecules

Tumor‐induced angiogenesis has been shown to suppress immune responses. One mechanism is to suppress leukocyte–endothelial cell interaction by down‐regulating the expression of adhesion molecules, such as intercellular adhesion molecule (ICAM)‐1, vascular cell adhesion molecule (VCAM)‐1 and E‐selectin on the tumor endothelium, which enables tumor cells to escape immune surveillance. Calreticulin (CRT), a chaperone protein mainly located in the endoplasmic reticulum, has been shown to exert anti‐angiogenic activity and inhibit tumor growth. Here, we demonstrate that in addition to inhibiting angiogenesis, CRT also enhances the expression of both ICAM‐1 and VCAM‐1 on tumor endothelial cells. This expression results in enhanced leukocyte–endothelial cell interactions and increased lymphocyte infiltration into tumors. Therefore, combining intramuscular CRT gene transfer with intratumoral cytokine gene therapies significantly improves the antitumor effects of immunotherapy by markedly increasing the levels of tumor‐infiltrating lymphocytes. This combined treatment increased the levels of infiltrating lymphocytes to those achieved using four times the cytokine dosage. The combined therapy also resulted in lower levels of immunosuppressive molecules and higher levels of activated T‐cells in the tumor microenvironment than immunotherapy alone. In conclusion, this study describes a new antitumor mechanism of CRT that involves the up‐regulation of tumor endothelial adhesion molecules and the enhanced infiltration of tumor‐specific lymphocytes. Thus, CRT treatment can make tumor cells more vulnerable to immunotherapy and improve the therapeutic efficacy of immunotherapy.
Simulation and experimental studies on double-fed induction generator power control at subsynchronous operating speed

Two control schemes for active and reactive power of a double-fed induction generator with the stator connected direct to the constant frequency, three phase grid are described. First the direct and quadrature rotor current components are generated based on the mathematical model of the machine. The second scheme used a PI controller to generate the rotor current reference components. The principles of both schemes are described in detail in this paper with a strong experimental approach. A complete simulation model is developed and several studies are performed to test its under different conditions. A laboratory test setup consisting of a wound rotor induction machine and driven by a variable speed squirrel cage induction motor is used to validate the control schemes proposed and the simulation results.