Miracle-dz/UniFAR-FTUs huggingface dataset:
In vitro targeting of Polo-like kinase 1 in bladder carcinoma

Despite the improvements in neoadjuvant chemotherapy, the outcome of patients with advanced bladder cancer has changed very little over the past 30 years. In the present study we tested and compared the in vitro antitumor activities of four different inhibitors of Polo-like kinase 1 (PLK1) (BI 2536, BI 6727, GW843682X, and GSK461364), against 3 bladder carcinoma cell lines RT4, 5637 and T24. The impact on radiosensitivity and drug interactions in simultaneous treatments with cisplatin, methotrexate, and doxorubicin were also investigated. Our results showed that PLK1 inhibition prevented cell proliferation and clonogenicity, causing significant inhibition of invasion of tumor cells, though modest differences were observed between drugs. Moreover, all PLK1 inhibitors induced G2/M arrest, with the subsequent induction of death in all 3 cell lines. Drug interactions studies showed auspicious results for all PLK1 inhibitors when combined with the commonly used cisplatin and methotrexate, though combinations with doxorubicin showed mostly antagonistic effects. Comparably, the four PLK1 inhibitors efficiently sensitized cells to ionizing radiation. Our findings demonstrate that irrespective of the inhibitor used, the pharmacological inhibition of PLK1 constrains bladder cancer growth and dissemination, providing new opportunities for future therapeutic intervention. However, further laboratorial and pre-clinical tests are still needed to corroborate the usefulness of using them in combination with other commonly used chemotherapeutic drugs.
Ceritinib in ALK-rearranged non-small-cell lung cancer.

BACKGROUND Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. METHODS In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. RESULTS A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5). CONCLUSIONS Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.).
Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy

Approximately two‐thirds of Duchenne muscular dystrophy (DMD) patients show intragenic deletions ranging from one to several exons of the DMD gene and leading to a premature stop codon. Other deletions that maintain the translational reading frame of the gene result in the milder Becker muscular dystrophy (BMD) form of the disease. Thus the opportunity to transform a DMD phenotype into a BMD phenotype appeared as a new treatment strategy with the development of antisense oligonucleotides technology, which is able to induce an exon skipping at the pre‐mRNA level in order to restore an open reading frame. Because the DMD gene contains 79 exons, thousands of potential transcripts could be produced by exon skipping and should be investigated. The conventional approach considers skipping of a single exon. Here we report the comparison of single‐ and multiple‐exon skipping strategies based on bioinformatic analysis. By using the Universal Mutation Database (UMD)‐DMD, we predict that an optimal multiexon skipping leading to the del45‐55 artificial dystrophin (c.6439_8217del) could transform the DMD phenotype into the asymptomatic or mild BMD phenotype. This multiple‐exon skipping could theoretically rescue up to 63% of DMD patients with a deletion, while the optimal monoskipping of exon 51 would rescue only 16% of patients. Hum Mutat 28(2), 196–202, 2007. © 2006 Wiley‐Liss, Inc.
Influence of high altitude on cerebral blood flow and fuel utilization during exercise and recovery

This study assessed the dynamic response of global cerebral blood flow (CBF) and cerebral fuel utilization during and following incremental supine exercise to exhaustion. Global CBF increased more during exercise and recovery at high altitude (HA) compared with sea level (SL) such that cerebral oxygen delivery ( CDO2 ) was maintained. The increase in cerebral metabolic rate of oxygen during maximal exercise at HA was half the increase observed at SL. Arterial lactate production during exercise at the same absolute intensities was greater at HA compared with SL, but reduced at the same relative intensities. Cerebral carbohydrate uptake (lactate and glucose) is greater than oxygen uptake at HA compared with SL, indicating a shift towards an increased non‐oxidative metabolic utilization. These results suggest that CBF increases to maintain CDO2 during exercise at HA while changes in arterial lactate concentration and exercise intensity augment the oxidative and non‐oxidative pathways to cerebral metabolism at HA.
Direct experience and the strength of the personal norm–behavior relationship

This study investigates whether the behavioral influence of personal norms with regard to repeated pro-social behavior depends on direct experience of this behavior. Based on previous norm and attitude research, it is hypothesized that (a) direct experience strengthens the influence of personal norms on behavior, and (b) direct experience is a stronger moderator in this case than in the attitude–behavior case. The case in question is the purchase of organic red wine. It is found that the outcome of consumers' choice between organic and nonorganic wine depends on their personal (moral) norms, after controlling for attitudes and subjective social norms. However, the influence of personal norms, though not of attitude, depends on whether the consumer has direct experience of buying organic red wine. Hence, both hypotheses are confirmed. © 2002 Wiley Periodicals, Inc.
Analysis of Bottleneck Delay and Throughput in Wireless Mesh Networks

Wireless mesh networking has emerged as a promising technology in providing economical and scalable broadband Internet accesses. A wireless mesh network consists of mesh routers and mesh clients, connected in an ad hoc manner via wireless links. A subset of the mesh routers, referred to as gateway nodes, are capable of external Internet connections. Since other mesh routers and clients have to access the Internet through the gateway nodes, these nodes can easily become bottlenecks in the network. In this paper, we present a novel queuing model based analysis of the delay and throughput of the gateway nodes. Our simulation results suggest that the analytical results are quite accurate, which provides an effective guideline for gateway-related design and optimization in wireless mesh networks
Type V Protein Secretion Pathway: the Autotransporter Story

SUMMARY Gram-negative bacteria possess an outer membrane layer which constrains uptake and secretion of solutes and polypeptides. To overcome this barrier, bacteria have developed several systems for protein secretion. The type V secretion pathway encompasses the autotransporter proteins, the two-partner secretion system, and the recently described type Vc or AT-2 family of proteins. Since its discovery in the late 1980s, this family of secreted proteins has expanded continuously, due largely to the advent of the genomic age, to become the largest group of secreted proteins in gram-negative bacteria. Several of these proteins play essential roles in the pathogenesis of bacterial infections and have been characterized in detail, demonstrating a diverse array of function including the ability to condense host cell actin and to modulate apoptosis. However, most of the autotransporter proteins remain to be characterized. In light of new discoveries and controversies in this research field, this review considers the autotransporter secretion process in the context of the more general field of bacterial protein translocation and exoprotein function.
A Profit Optimization Framework of Energy Storage Devices in Data Centers: Hierarchical Structure and Hybrid Types

This paper investigates the hierarchical deployment and over-provisioning of energy storage devices (ESDs) in data ceners by (i) adopting a realistic power delivery architecture (from Intel) for centralized ESD structure as the starting point, (ii) presenting a novel and realistic power delivery architecture, borrowing the best features of the centralized ESD structure from Intel and distributed single-level ESD structures from Google and Microsoft, and supporting the case that different types of ESDs are employed for each of the data center, rack, and server levels, (iii) providing an optimal design (i.e., determining the ESD type, and ESD provisioning at each level) and control (i.e., scheduling the charging and discharging of various ESDs) framework to maximize the amortized profit of the hierarchical ESD structure. The amortized one-time capital cost (capex), operating cost (opex), and cost associated with battery aging and replacement are considered in the profit optimization. Constraints on ESD volume and realistic characteristics of ESDs and power conversion circuitries are accounted for in the framework. (iv) conducting experiments using real data center workload traces from Google based on realistic data center specifications, demonstrating the effectiveness of the proposed design and control framework.
Some Effects of Schematic Processing on Consumer Expectations and Disconfirmation Judgments

Recent research has shown that processing based on the product-category schemas of consumers can influence the manner in which consumers evaluate products. This article presents a series of studies that explore how processing based on such schemas interacts with consumer expectations prior to the trial of a new product and influences disconfirmation judgments and product evaluations following the trial. An initial study finds that, when attributes included in the description of a new product are very discrepant from a prior category schema, consumers may switch schemas in forming pretrial expectations. A second study finds that more negative product evaluations following the trial may result when consumers' experience with a product during the trial is very different from schema expectations, compared with the situation in which the product matches schema expectations. A third study demonstrates that disconfirmation judgments and post-trial evaluations may occur through processing at the product-category schema level, rather than through processing at the product attribute level. Copyright 1992 by the University of Chicago.
The Protective Effect of Granulocyte Colony-Stimulating Factor on Endometrium and Ovary in a Rat Model of Diabetes Mellitus

Aims: To evaluate the effect of granulocyte colony-stimulating factor (G-CSF) on the endometrium and ovaries in an experimental diabetes mellitus (DM) rat model. Methods: A total of 18 female Sprague-Dawley albino mature rats (8 weeks, 200-220 g) were used in this study. Diabetes was induced by intraperitoneal (i.p.) injection of streptozocin randomly in 12 rats. No drug was administered to the remainder of the rats (control group, group 1, n = 6). The other 12 rats were randomly divided into 2 groups; 1 ml/kg i.p. saline was given as vehicle to group 2 (diabetic nontreated control group, n = 6) and 100 µg/kg/day of i.p. G-CSF was given to group 3 (G-CSF-treated group, n = 6) for 4 weeks. After 4 weeks, blood samples were collected and hysterectomy with bilateral oophorectomy was performed for histopathological examination. Results: The mean endometrial gland degeneration and stromal fibrosis scores were significantly higher in group 2 compared with groups 1 and 3. Ovarian follicle degeneration, stromal degeneration and stromal fibrosis scores were significantly higher in group 2 compared with groups 1 and 3. Plasma TGF-β and malondialdehyde levels were significantly lower in groups 1 and 3 compared with group 2. Antimüllerian hormone levels were significantly lower in group 2 compared with groups 1 and 3. Conclusion: Glucose toxicity occurred severely in the ovaries and endometrium of the DM rats. After G-CSF treatment, ovarian and endometrial injury and fibrosis scores decreased significantly. The effects of G-CSF in rat models give hope to improved treatment of human DM complications such as premature ovarian failure and endometrial dysfunction.
Performance sensitivity of space-sharing processor scheduling in distributed-memory multicomputers

Processor scheduling in distributed-memory systems has received considerable attention in recent years. Several commercial distributed-memory systems use space-sharing processor scheduling. In space sharing, the set of processors in a system is partitioned and each partition is assigned for the exclusive use of a job. Space sharing policies can be divided into fixed, static, or dynamic categories. For distributed-memory systems, dynamic policies incur high overhead. Thus, static policies are considered as these policies provide better performance than the fixed policies. Several static policies have been proposed in the literature. In a previously proposed adaptive static policy, the partition size is a function of the number of queued jobs. This policy, however, tends to under-utilize the system resources. To improve the performance of this policy, we propose a new policy in which the partition size is a function of the total number of jobs in the system, as opposed to only the queued jobs. The results presented demonstrate that the new policy performs substantially better than the original policy for the various workload and system parameters. Another major contribution is the evaluation of the performance sensitivity to job structure, variances in inter-arrival times and job service times, and network topology.
Two Dogmas About Quantum Mechanics

We argue that the intractable part of the measurement problem -- the 'big' measurement problem -- is a pseudo-problem that depends for its legitimacy on the acceptance of two dogmas. The first dogma is John Bell's assertion that measurement should never be introduced as a primitive process in a fundamental mechanical theory like classical or quantum mechanics, but should always be open to a complete analysis, in principle, of how the individual outcomes come about dynamically. The second dogma is the view that the quantum state has an ontological significance analogous to the significance of the classical state as the 'truthmaker' for propositions about the occurrence and non-occurrence of events, i.e., that the quantum state is a representation of physical reality. We show how both dogmas can be rejected in a realist information-theoretic interpretation of quantum mechanics as an alternative to the Everett interpretation. The Everettian, too, regards the 'big' measurement problem as a pseudo-problem, because the Everettian rejects the assumption that measurements have definite outcomes, in the sense that one particular outcome, as opposed to other possible outcomes, actually occurs in a quantum measurement process. By contrast with the Everettians, we accept that measurements have definite outcomes. By contrast with the Bohmians and the GRW 'collapse' theorists who add structure to the theory and propose dynamical solutions to the 'big' measurement problem, we take the problem to arise from the failure to see the significance of Hilbert space as a new kinematic framework for the physics of an indeterministic universe, in the sense that Hilbert space imposes kinematic (i.e., pre-dynamic) objective probabilistic constraints on correlations between events.
Proteomic Analysis of Pathways Involved in Estrogen-Induced Growth and Apoptosis of Breast Cancer Cells

Background Estrogen is a known growth promoter for estrogen receptor (ER)-positive breast cancer cells. Paradoxically, in breast cancer cells that have been chronically deprived of estrogen stimulation, re-introduction of the hormone can induce apoptosis. Methodology/Principal Findings Here, we sought to identify signaling networks that are triggered by estradiol (E2) in isogenic MCF-7 breast cancer cells that undergo apoptosis (MCF-7:5C) versus cells that proliferate upon exposure to E2 (MCF-7). The nuclear receptor co-activator AIB1 (Amplified in Breast Cancer-1) is known to be rate-limiting for E2-induced cell survival responses in MCF-7 cells and was found here to also be required for the induction of apoptosis by E2 in the MCF-7:5C cells. Proteins that interact with AIB1 as well as complexes that contain tyrosine phosphorylated proteins were isolated by immunoprecipitation and identified by mass spectrometry (MS) at baseline and after a brief exposure to E2 for two hours. Bioinformatic network analyses of the identified protein interactions were then used to analyze E2 signaling pathways that trigger apoptosis versus survival. Comparison of MS data with a computationally-predicted AIB1 interaction network showed that 26 proteins identified in this study are within this network, and are involved in signal transduction, transcription, cell cycle regulation and protein degradation. Conclusions G-protein-coupled receptors, PI3 kinase, Wnt and Notch signaling pathways were most strongly associated with E2-induced proliferation or apoptosis and are integrated here into a global AIB1 signaling network that controls qualitatively distinct responses to estrogen.
Master Planned Estates: Pariah or Panacea?

Master planned estates in Australia emerge from two major directions: one aims to address the inadequacies of 1970s suburbanisation and the other comes from governments and developers seeking to realise alternatives. The very idea of master planning has a longer history, one that arguably dates back to 19th-century Utopian Socialism and Baron Haussmann's redesign of Paris, which involved a large-scale, comprehensive alternative vision realised by a sanctioned authority. Master planning thereby partakes of both utopianism and authoritarianism. These associations have infused the discussion and construction of Australian master planned estates rendering them both pariah and panacea. But research and my own experience suggests that they are far more panaceas than pariahs.
Students' Biases in Conditional Probability Reasoning

Summary In this paper, we present results from a study aimed to assess potential relationships between biases in conditional probability reasoning (fallacy of the transposed conditional, fallacy of the time axis, conjunction fallacy, base rate fallacy and confusing independence and mutually exclusiveness) and formal knowledge of the concepts. Factor analysis of the responses by 414 psychology students to a questionnaire suggest that the psychological biases investigated are unrelated to conditional probability problem solving performance in these students. Comparison of responses of two groups before and after instruction shows systematic improvement in problem solving capacity but little change in part of the items related to psychological biases.
Tryptophan-mediated charge-resonance stabilization in the bis-Fe(IV) redox state of MauG

The diheme enzyme MauG catalyzes posttranslational modifications of a methylamine dehydrogenase precursor protein to generate a tryptophan tryptophylquinone cofactor. The MauG-catalyzed reaction proceeds via a bis-Fe(IV) intermediate in which one heme is present as Fe(IV)=O and the other as Fe(IV) with axial histidine and tyrosine ligation. Herein, a unique near-infrared absorption feature exhibited specifically in bis-Fe(IV) MauG is described, and evidence is presented that it results from a charge-resonance-transition phenomenon. As the two hemes are physically separated by 14.5 Å, a hole-hopping mechanism is proposed in which a tryptophan residue located between the hemes is reversibly oxidized and reduced to increase the effective electronic coupling element and enhance the rate of reversible electron transfer between the hemes in bis-Fe(IV) MauG. Analysis of the MauG structure reveals that electron transfer via this mechanism is rapid enough to enable a charge-resonance stabilization of the bis-Fe(IV) state without direct contact between the hemes. The finding of the charge-resonance-transition phenomenon explains why the bis-Fe(IV) intermediate is stabilized in MauG and does not permanently oxidize its own aromatic residues.
Comparison of perinatal outcome between adolescent and adult pregnancies

Abstract Objective: The aim of this study was to compare perinatal outcomes between adolescent and adult pregnancies. Material and methods: In 527 adolescent and 1334 adult pregnant women who delivered at Ondokuz Mayis University Obstetrics and Gynecology Department between 2006 and 2013, perinatal outcomes were retrospectively compared in terms of including spontaneous abortion, induced abortion rate, dilatation and curettage (D&C), pregnancy-induced hypertension, premature prelabor and prelabor rupture of membranes, polihydramnios, oligohydramnios, maternal anemia, delivery modes and also neonatal outcomes including 5th minute Apgar score and fetal birth weight. Results: The ratio of pregnancy induced hypertension and postpartum hemorrhage was higher in adults, but, anemia was more common in adolescents. There was statistically significant difference in the mode of delivery; the ratio of cesarean section was higher in adults whereas the rate of induced abortions and D&C significantly increased in adolescents. Low birth weight (LBW) and extremely LBW rates were significantly higher in adolescents, however, 5th minute Apgar scores were found to be higher than adult group. Conclusion: These results show that the perinatal care is fairly improved in Turkey.