Miracle-dz/UniFAR-FTUs huggingface dataset:
Novel Protease Inhibitors (PIs) Containing Macrocyclic Components and 3(R),3a(S),6a(R)-bis-Tetrahydrofuranylurethane That Are Potent against Multi-PI-Resistant HIV-1 Variants In Vitro

ABSTRACT Natural products with macrocyclic structural features often display intriguing biological properties. Molecular design incorporating macrocycles may lead to molecules with unique protein-ligand interactions. We generated novel human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a macrocycle and bis-tetrahydrofuranylurethane. Four such compounds exerted potent activity against HIV-1LAI and had 50% effective concentrations (EC50s) of as low as 0.002 μM with minimal cytotoxicity. GRL-216 and GRL-286 blocked the replication of HIV-1NL4-3 variants selected by up to 5 μM saquinavir, ritonavir, nelfinavir, lopinavir, or atazanavir; they had EC50s of 0.020 to 0.046 μM and potent activities against six multi-PI-resistant clinical HIV-1 (HIVmPIr) variants with EC50s of 0.027 to 0.089 μM. GRL-216 and -286 also blocked HIV-1 protease dimerization as efficiently as darunavir. When HIV-1NL4-3 was selected by GRL-216, it replicated progressively more poorly and failed to replicate in the presence of >0.26 μM GRL-216, suggesting that the emergence of GRL-216-resistant HIV-1 variants is substantially delayed. At passage 50 with GRL-216 (the HIV isolate selected with GRL-216 at up to 0.16 μM [HIV216-0.16 μM]), HIV-1NL4-3 containing the L10I, L24I, M46L, V82I, and I84V mutations remained relatively sensitive to PIs, including darunavir, with the EC50s being 3- to 8-fold-greater than the EC50 of each drug for HIV-1NL4-3. Interestingly, HIV216-0.16 μM had 10-fold increased sensitivity to tipranavir. Analysis of the protein-ligand X-ray structures of GRL-216 revealed that the macrocycle occupied a greater volume of the binding cavity of protease and formed greater van der Waals interactions with V82 and I84 than darunavir. The present data warrant the further development of GRL-216 as a potential antiviral agent for treating individuals harboring wild-type and/or HIVmPIr.
Serum and Cerebrospinal Fluid Levels of Colistin in Pediatric Patients

ABSTRACT Using a liquid chromatography-tandem mass spectrometry method, the serum and cerebrospinal fluid (CSF) concentrations of colistin were determined in patients aged 1 months to 14 years receiving intravenous colistimethate sodium (60,000 to 225,000 IU/kg of body weight/day). Only in one of five courses studied (a 14-year-old receiving 225,000 IU/kg/day) did serum concentrations exceed the 2 μg/ml CLSI/EUCAST breakpoint defining susceptibility to colistin for Pseudomonas and Acinetobacter. CSF colistin concentrations were <0.2 μg/ml but increased in the presence of meningitis (∼0.5 μg/ml or 34 to 67% of serum levels).
Elevated Plasma Moxifloxacin Concentrations and SLCO1B1 g.−11187G>A Polymorphism in Adults with Pulmonary Tuberculosis

ABSTRACT Moxifloxacin exhibits concentration-dependent prolongation of human QTc intervals and bactericidal activity against Mycobacterium tuberculosis. However, moxifloxacin plasma concentrations are variable between patients. We evaluated whether human gene polymorphisms affect moxifloxacin plasma concentrations in tuberculosis patients from two geographic regions. We enrolled a convenience sample of 49 adults with drug-sensitive pulmonary tuberculosis from Africa and the United States enrolled in two treatment trials of moxifloxacin as part of multidrug therapy. Pharmacokinetic parameters were evaluated by noncompartmental techniques. Human single-nucleotide polymorphisms of transporter genes were evaluated by analysis of covariance (ANCOVA) on moxifloxacin exposure and the peak (maximum) concentration (Cmax). The moxifloxacin area under the concentration-time curve from 0 to 24 h (AUC0–24) and Cmax were significantly increased by the drug milligram-per-kilogram dosage and the genotype of variant g. −11187G>A in the SLCO1B1 gene (rs4149015) but not by geographic region. The median moxifloxacin AUC0–24 was 46% higher and the median Cmax was 30% higher in 4 (8%) participants who had the SLCO1B1 g. −11187 AG genotype than in 45 participants who had the wild-type GG genotype (median AUC0–24 from the model, 34.4 versus 23.6 μg · h/ml [P = 0.005, ANCOVA]; median Cmax from the model, 3.5 versus 2.7 μg/ml [P = 0.009, ANCOVA]). Because moxifloxacin exhibits concentration-dependent prolongation of human QTc intervals and prolonged QTc intervals are associated with cardiac arrhythmia, further study is needed to evaluate the risk associated with the SLCO1B1 g. −11187G>A variant. (This study has been registered at ClinicalTrials.gov under identifier NCT00164463.)
Morality and Accountability in a Commercial Weight Management Group

Talk about food and eating behaviours invariably contains some reference to morality or accountability. However, there are very few studies that focus upon `mundane dieting'. This research addresses this by examining 37.83 hours of naturally occurring interaction of how women construct and orient to food and their dieting practices within an everyday type setting. Group members produced accounts with reference to a moral evaluation, such as blame or culpability. It became apparent that both the group leaders and group members could not orient to their behaviour or food without reference to a moral or accountable framework. Implications for health promotion literature and programmes, along with weight management groups are considered.
The Pathogen-Derived Aminoglycoside Resistance 16S rRNA Methyltransferase NpmA Possesses Dual m1A1408/m1G1408 Specificity

ABSTRACT Chemical modification of 16S rRNA can confer exceptionally high-level resistance to a diverse set of aminoglycoside antibiotics. Here, we show that the pathogen-derived enzyme NpmA possesses dual m1A1408/m1G1408 activity, an unexpected property apparently unique among the known aminoglycoside resistance 16S rRNA (m1A1408) methyltransferases. Although the biological significance of this activity remains to be determined, such mechanistic variation in enzymes acquired by pathogens has significant implications for development of inhibitors of these emerging resistance determinants.
High-level data-access analysis for characterisation of (sub)task-level parallelism on Java

In the era of future embedded systems the designer is confronted with multi-processor systems both for performance and energy reasons. Exploiting (sub)task-level parallelism is becoming crucial because the instruction-level parallelism alone is insufficient. The challenge is to build compiler tools that support the exploration of the task-level parallelism in the programs. To achieve this goal, we have designed an analysis framework to evaluate the potential parallelism from sequential object-oriented programs. Parallel-performance and data-access analysis are the crucial techniques for estimation of the transformation effects. We have implemented support for platform-independent data-access analysis and profiling of Java programs, which is an extension to our earlier parallel-performance analysis framework. The toolkit comprises automated design-time analysis for performance and data-access characterisation, program instrumentation, program-profiling support and post-processing analysis. We demonstrate the usability of our approach on a number of realistic Java applications.
In Vitro Antifungal Susceptibility of Clinically Relevant Species Belonging to Aspergillus Section Flavi

ABSTRACT The in vitro antifungal susceptibility of 77 isolates belonging to different clinically relevant species of Aspergillus section Flavi, including those of different phylogenetic clades of A. flavus, was tested for nine antifungal agents using a microdilution reference method (CLSI, M38-A2). Terbinafine and the echinocandins demonstrated lower MICs/MECs for all species evaluated, followed by posaconazole. Amphotericin B showed MICs ≥ 2 μg/ml for 38 (49.4%) of the 77 isolates tested.
A prospective investigation of interpersonal influences on the pursuit of muscularity in late adolescent boys and girls

This project examined whether interpersonal pressure to be muscular predicted late adolescents’ pursuit of muscularity. Participants were 199 adolescents (16—19 years), mothers (n = 175), and friends (n = 159), assessed at two annual times. Pressure to be muscular was assessed with adolescents’, mothers’, and friends’ reports of their relationships. Adolescents reported pressure from fathers and romantic partners, appearance satisfaction, disordered eating, and pursuit of muscularity. Adolescents’, mothers’, and friends’ reports of pressure related to pursuit of muscularity at both times. Adolescents’ perceptions and mothers’ reports prospectively predicted pursuit of muscularity. Findings highlight the relevance of relationships to pursuit of muscularity in late adolescents.
Ceftazidime-Avibactam as Salvage Therapy for Infections Caused by Carbapenem-Resistant Organisms

ABSTRACT Ceftazidime-avibactam (CAZ-AVI) is a recently approved β-lactam–β-lactamase inhibitor combination with the potential to treat serious infections caused by carbapenem-resistant organisms. Few patients with such infections were included in the CAZ-AVI clinical trials, and clinical experience is lacking. We present a case series of patients with infections caused by carbapenem-resistant Enterobacteriaceae (CRE) or Pseudomonas aeruginosa (CRPa) who were treated with CAZ-AVI salvage therapy on a compassionate-use basis. Physicians who had prescribed CAZ-AVI completed a case report form. We used descriptive statistics to summarize patient characteristics and treatment outcomes. We used the Wilcoxon rank sum test and Fisher's exact test to compare patients by treatment outcome. The sample included 36 patients infected with CRE and two with CRPa. The most common infections were intra-abdominal. Physicians categorized 60.5% of patients as having life-threatening infections. All but two patients received other antibiotics before CAZ-AVI, for a median of 13 days. The median duration of CAZ-AVI treatment was 16 days. Twenty-five patients (65.8%) concurrently received other antibiotics to which their pathogen was nonresistant in vitro. Twenty-eight patients (73.7%, 95% confidence interval [CI], 56.9 to 86.6%) experienced clinical and/or microbiological cure. Five patients (20.8%) with documented microbiological cure died, whereas 10 patients (71.4%) with no documented microbiological cure died (P = 0.01). In three-quarters of cases, CAZ-AVI (alone or combined with other antibiotics) cured infections caused by carbapenem-resistant organisms, 95% of which had failed previous therapy. Microbiological cure was associated with improved survival. CAZ-AVI shows promising clinical results for infections for which treatment options are limited.
Quantitative Analysis of Gentamicin Exposure in Neonates and Infants Calls into Question Its Current Dosing Recommendations

ABSTRACT Optimal dosing of gentamicin in neonates is still a matter of debate despite its common use. We identified gentamicin dosing regimens from eight international guidelines and seven Swiss neonatal intensive care units. The dose per administration, the dosing interval, the total daily dose, and the demographic characteristics between guidelines were compared. There was considerable variability with respect to dose (4 to 6 mg/kg), dosing interval (24 h to 48 h), total daily dose (2.5 to 6 mg/kg/day), and patient demographic characteristics that were used to calculate individualized dosing regimens. A model-based simulation study in 1071 neonates was performed to determine the achievement of efficacious peak gentamicin concentrations according to predefined MICs (Cmax/MIC ≥ 10) and safe trough concentrations (Cmin ≤ 2 mg/liter) with recommended dosing regimens. MIC targets of 0.5 and 1 mg/liter were used. Dosing optimization was performed giving priority to the first day of treatment and with the goal of simplifying dosing. Current gentamicin neonatal guidelines allow to achieve effective peak concentrations for MICs ≤ 0.5 mg/liter but not higher. Model-based simulations indicate that to attain peak gentamicin concentrations of ≥10 mg/liter, a dose of 7.5 mg/kg should be administered using an extended dosing interval regimen. Trough concentrations of ≤2 mg/liter can be maintained with a dosing interval of 36 to 48 h in neonates according to gestational and postnatal age. For treatment beyond 3 days, therapeutic drug monitoring is advised to maintain adequate serum concentrations.
Rifampin Enhances the Activity of Amphotericin B against Fusarium solani Species Complex and Aspergillus flavus Species Complex Isolates from Keratitis Patients

ABSTRACT The in vitro activities of amphotericin B in combination with rifampin were assessed against 95 ocular fungal isolates. The interactions between amphotericin B and rifampin at 4, 8, 16, and 32 μg/ml were synergistic for 11.8%, 51.0%, 90.2%, and 94.1%, respectively, of Fusarium solani species complex isolates and for 13.6%, 45.5%, 93.2%, and 95.5%, respectively, of Aspergillus flavus species complex isolates. Antagonism was never observed for the amphotericin B-rifampin combinations.
A Pay-per-Use Licensing Scheme for Hardware IP Cores in Recent SRAM-Based FPGAs

Currently achievable intellectual property (IP) protection solutions for field-programmable gate arrays (FPGAs) are limited to single large "monolithic" configurations. However, the ever growing capabilities of FPGAs and the consequential increasing complexity of their designs ask for a modular development model, where individual IP cores from multiple parties are integrated into a larger system. To enable such a model, the availability of IP protection at the modular level is imperative. In this work, we propose an IP protection mechanism for FPGA designs at the level of individual IP cores, by making use of the self-reconfiguring capabilities of modern FPGAs and deploying a trusted third party to run a metering service, similar to the work of Giineysu et ah and Drimer et at The proposed scheme makes it possible to enforce a pay-per-use licensing scheme which holds considerable advantages, both for IP core providers as well as for system integrators. Moreover, the scheme has a minimal implementation overhead and is the first of its kind to be solely based on primitives that are already available in recent commercially available FPGA devices. This allows for an immediate and feasible deployment, in contrast to earlier proposed solutions.
Low social interactions in eating disorder patients in childhood and adulthood: A multi-centre European case control study

The objective of this article was to examine lifestyle behaviours in eating disorder (ED) patients and healthy controls. A total of 801 ED patients and 727 healthy controls from five European countries completed the questions related to lifestyle behaviours of the Cross-Cultural Questionnaire (CCQ). For children, the ED sample exhibited more solitary activities (rigorously doing homework [p<0.001] and watching TV [p<0.05] and less socializing with friends [p<0.05]) than the healthy control group and this continued in adulthood. There were minimal differences across ED sub-diagnoses and various cross-cultural differences emerged. Reduced social activities may be an important risk and maintaining factor for ED symptomatology.
Apparatus to measure high-temperature thermal conductivity and thermoelectric power of small specimens

A thermal conductivity apparatus based on the parallel heat-flow technique has been fabricated to measure the thermal conductivity of small specimens. The steady-state method is used to measure samples of 1×1×10mm3 dimension in the temperature range of room temperature–700 K. The details of instrument fabrication, the method of calibration, and typical measurements on test samples are described. The apparatus can also be used to measure the Seebeck coefficient in the same temperature range. As an example we report the thermal properties of CrSi2, which is a potential candidate for high-temperature thermoelectric applications.
In Vitro Activity of Nemonoxacin, a Novel Nonfluorinated Quinolone Antibiotic, against Chlamydia trachomatis and Chlamydia pneumoniae

ABSTRACT The in vitro activities of nemonoxacin, levofloxacin, azithromycin, and doxycycline were tested against 10 isolates each of Chlamydia trachomatis and Chlamydia pneumoniae. The MICs at which 90% of the isolates of both C. trachomatis and C. pneumoniae were inhibited (MIC90s) were 0.06 μg/ml (range, 0.03 to 0.13 μg/ml). The minimal bactericidal concentrations at which 90% of the isolates were killed by nemonoxacin (MBC90s) were 0.06 μg/ml for C. trachomatis (range, 0.03 to 0.125 μg/ml) and 0.25 for C. pneumoniae (range, 0.015 to 0.5 μg/ml).
On the Permanence of EEG Signals for Biometric Recognition

Brain signals have been investigated for more than a century in the medical field. However, despite the broad interest in clinical applications, their use as a biometric identifier has been only recently considered by the scientific community. In this paper, we focus on the permanence across time of brain signals, specifically of electroencephalographic (EEG) signals, issue of paramount importance for the deployment of brain-based biometric recognition systems in real life, not yet fully addressed. In particular, we speculate about the stability of EEG features by analyzing the recognition performance that can be achieved when comparing EEG signals acquired during different sessions. We carry out an extensive set of experimental tests, performed on several EEG-based biometric systems over a large database, comprising three recordings taken from 50 healthy subjects in resting state conditions, acquired in a time span of approximately one month and a half. The results confirm that a significant level of permanence can be guaranteed.
Comments on “Joint Global and Local Structure Discriminant Analysis”

Joint global and local structure discriminant analysis (JGLDA) is a recently-developed linear discriminant analysis approach, which considers the diversity of data across classes. In this communication, however, we will show that the discussion on the characterization of within-class locality and within-class diversity of previous efforts on local linear discriminant analysis (LLDA) and JGLDA is flawed.
Communication online with fellow cancer patients: Writing to be remembered, gain strength, and find survivors

This qualitative research explored how cancer patients’ writing and reading on the Internet play a role in their illness experience. Focus-group interviews were conducted, with 34 cancer patients participating. A grounded qualitative analysis method was applied to analyze the interview transcripts. The results show that by writing personal blogs, cancer patients reconstructed their life story, expressed their closure of life, and expected to be remembered after death. Reading fellow cancer patients’ stories online significantly influenced cancer patients’ perceptions and expectations of their own illness prognosis, and that influence was sometimes greater than that of the doctors’ influence.
Improving in-memory database index performance with Intel® Transactional Synchronization Extensions

The increasing number of cores every generation poses challenges for high-performance in-memory database systems. While these systems use sophisticated high-level algorithms to partition a query or run multiple queries in parallel, they also utilize low-level synchronization mechanisms to synchronize access to internal database data structures. Developers often spend significant development and verification effort to improve concurrency in the presence of such synchronization. The Intel® Transactional Synchronization Extensions (Intel® TSX) in the 4th Generation Core™ Processors enable hardware to dynamically determine whether threads actually need to synchronize even in the presence of conservatively used synchronization. This paper evaluates the effectiveness of such hardware support in a commercial database. We focus on two index implementations: a B+Tree Index and the Delta Storage Index used in the SAP HANA® database system. We demonstrate that such support can improve performance of database data structures such as index trees and presents a compelling opportunity for the development of simpler, scalable, and easy-to-verify algorithms.
Best-offset hardware prefetching

Hardware prefetching is an important feature of modern high-performance processors. When the application working set is too large to fit in on-chip caches, disabling hardware pre-fetchers may result in severe performance reduction. A new prefetcher was recently introduced, the Sandbox prefetcher, that tries to find dynamically the best prefetch offset using the sandbox method. The Sandbox prefetcher uses simple hardware and was shown to be quite effective. However, the sandbox method does not take into account prefetch timeliness. We propose an offset prefetcher with a new method for selecting the prefetch offset that takes into account prefetch timeliness. We show that our Best-Offset prefetcher outperforms the Sandbox prefetcher on the SPEC CPU2006 benchmarks, with equally simple hardware.
Potential of Ergosterol Synthesis Inhibitors To Cause Resistance or Cross-Resistance in Trichophyton rubrum

ABSTRACT Superficial mycoses caused by Trichophyton rubrum are among the most common infections worldwide. T. rubrum infections are difficult to treat and are often associated with recurrences after interruption of the antifungal therapy. Nevertheless, reports on T. rubrum resistance to commonly used antifungal drugs are rare. In this study, we compared the in vitro resistance frequencies and development of resistance to terbinafine, itraconazole, amorolfine, and ciclopirox in T. rubrum. Results demonstrated that naturally occurring mutants were isolated at a frequency of 10−7 for itraconazole and 10−9 for terbinafine and amorolfine. To mimic conditions of body sites in which low drug levels are reached during therapy, T. rubrum was propagated for 10 transfers in media containing subinhibitory drug concentrations. Resistance to itraconazole, terbinafine, and amorolfine emerged at a higher frequency than was seen with spontaneous mutation. Itraconazole-resistant mutants also showed decreased susceptibility to amorolfine as well as to terbinafine, and amorolfine-resistant mutants were also less susceptible to terbinafine. No mutant resistant to ciclopirox was isolated, suggesting no propensity of T. rubrum to develop resistance to this drug. How different drug mechanisms of action can influence the onset of resistance is discussed.