Miracle-dz/UniFAR-FTUs huggingface dataset:
Bactericidal efficacy of liposomal aminoglycosides against Burkholderia cenocepacia.

OBJECTIVES Burkholderia cenocepacia (formally a genotype of Burkholderia cepacia complex called genomovar III) has emerged as a serious opportunistic pathogen in individuals with cystic fibrosis. We developed a liposomal antibiotic formulation composed of 1,2-distearoyl-sn-glycero-3-phosphocholine and cholesterol (molar ratio 2:1) to overcome B. cenocepacia's resistance to commonly used aminoglycosidic antibiotics. METHODS The dehydration-rehydration vesicles technique was used to entrap antibiotics in liposomes. The size of liposome formulations was measured and encapsulation efficiencies were determined by microbiological assays. MICs of free and liposomal antibiotics against the clinical isolates of B. cenocepacia were determined by the standard broth dilution method and in vitro time--kill studies were performed using free and liposomal antibiotics at one, two or four times the MICs. We studied the mechanism of action of these formulations by using transmission electron microscopy (TEM), fluorescence-activated cell sorter (FACS) analysis, lipid-mixing assay and immunocytochemistry. RESULTS The encapsulation efficiencies of amikacin, gentamicin and tobramycin into liposomes were 52.08 +/- 5.4%, 27.72 +/- 1.14% and 28.08 +/- 1.54%, respectively. The liposome formulations were more stable in PBS at 4 degrees C than in PBS, bronchoalveolar lavage fluid or plasma at 37 degrees C. The TEM studies along with lipid-mixing assays and FACS analysis indicated the lipid contact of the liposomal bilayers and bacterial cell membranes. Most importantly, our liposomal formulations reduced MICs for highly antibiotic-resistant strains and enhanced the antibiotics' penetration into the bacterial cells. For instance, bacterial eradication by liposomal tobramycin was 4-fold higher than free tobramycin. CONCLUSIONS A liposomal drug delivery system might enhance the efficacy of commonly used aminoglycosides.
DIAMOND: a Computerized System for the Management and Evaluation of District‐wide Diabetes Care

A computerized diabetic clinic management system, DIAMOND, has been developed with the collaboration of local general practitioners (GPs) to assist communication about diabetic patients across the district. DIAMOND is written in a Windows format using Microsoft Access and its dataset is in line with BDA and Diabcare recommendations. DIAMOND is user‐friendly and includes displays and help messages throughout and does not require advanced computer knowledge. The main index contains two primary tables: a patient registration table with demographic data and an episode table with clinically important physical and biochemical measures. All entered data are coded to facilitate audit and an audit function, which automatically presents data, either numerically or graphically, is included in the report facility. DIAMOND also incorporates a system for patient education and training (PEATS) which may be operated by a health professional or the patient. Over 4500 patients in Newham are presently registered on DIAMOND with in excess of 15000 episodes. Evaluation of this information is providing important clinical information both within individual GP practices and district‐wide to assist future plans for health care provision.
Introduction: The pace of grammaticalization in a typological perspective

A grammaticalization process, by which an item shifts from lexicon to grammar, is by definition a cline or a continuum. Consequently, items undergoing grammaticalization processes can occupy different positions on the cline between its two extremes. The main claim we want to argue for in this thematic issue is that the same idea of gradation can be extended to language typology, by showing that, within a language family, comparable grammaticalization phenomena can be at the outset or on-going in one language and have reached a stage further down the cline in another language, or even that grammaticalization phenomena present in one language may be absent in the other one. Thus, with respect to Romance, several authors, such as Boysen (1966), Delattre (1966), Harris (1978), Posner (1996), Lamiroy (1999 and 2003), Marchello-Nizia (2006), Detges (2006), Carlier (2007) and Lindschouw (2010, 2011), have pointed out that for the majority of grammaticalization phenomena, French is further on the cline than the other Romance languages. Research on several independent domains, viz. word order (Marchello-Nizia 1995), prepositions (Lamiroy 2001), external possessor constructions (Lamiroy 2003), existential sentences (Meulleman, forthc.), tense, mood, demonstratives, auxiliaries (Lamiroy & De Mulder 2011 and De Mulder & Lamiroy, forthc.), the partitive (Carlier & Lamiroy forthc.), has furthermore shown that in most of these domains, Italian is ahead of Spanish, although the respective positions of Italian and Spanish on the cline seem to allow for more variability than the position of French. These studies suggest that with respect of the pace of grammaticalization, the three Romance languages can be situated on a scale in the following way. The pace of grammaticalization
Predicting online gambling self-exclusion: an analysis of the performance of supervised machine learning models

Abstract As gambling operators become increasingly sophisticated in their analysis of individual gambling behaviour, this study evaluates the potential for using machine learning techniques to identify individuals who used self-exclusion tools out of a sample of 845 online gamblers, based on analysing trends in their gambling behaviour. Being able to identify other gamblers whose behaviour is similar to those who decided to use self-exclusion tools could, for instance, be used to share responsible gaming messages or other information that aids self-aware gambling and reduces the risk of adverse outcomes. However, operators need to understand how accurate models can be and which techniques work well. The purpose of the article is to identify the most accurate technique out of four highly diverse techniques and to discuss how to deal analytically and practically with a rare event like self-exclusion, which was used by fewer than 1% of gamblers in our data-set. We conclude that balanced training data-sets are necessary for creating effective models and that, on our data-set, the most effective method is the random forest technique which achieves an accuracy improvement of 35 percentage points versus baseline estimates.
Guts and Brains : An Integrative Approach to the Hominin Record

The human brain and its one hundred billion neurons compose the most complex organ in the body and harness more than 20 per cent of all the energy we produce. Why do we have such large and energy-demanding brains, and how have we been able to afford such an expensive organ for thousands of years? Guts and Brains discusses the key variables at stake in such a question, including the relationship between brain size and diet, diet and social organization, and large brains and the human sexual division of labour. This interdisciplinary volume provides an entry for the reader into understanding the development of both early primates and our own species.
Mammalian Tumor Suppressor Int6 Specifically Targets Hypoxia Inducible Factor 2α for Degradation by Hypoxia- and pVHL-independent Regulation*

The hypoxia-inducible factors HIF-1α and HIF-2α are structurally similar as regards their DNA-binding and dimerization domains, but differ in their transactivation domains and, as is shown by experiments using hif-1α-/- and hif-2α-/- mice, in their functions. This implies that HIF-1α and HIF-2α may have unique target genes. To address this discrepancy and identify HIF-2α-specific target genes, we performed yeast two-hybrid analysis and identified the tumor suppressor Int6/eIF3e/p48 as a novel target gene product involved in HIF-2α regulation. The int6 gene was first identified from a screen in which the mouse mammary tumor virus was employed as an insertional mutagen to identify genes whose functions are critical for breast tumor formation. Here, by using two-hybrid analysis, immunoprecipitation in mammalian cells, and HRE-reporter assays, we report the specific interaction of HIF-2α (but not HIF-1α or HIF-3α) with Int6. The results indicate that the direct interaction of Int6 induces proteasome inhibitor-sensitive HIF-2α degradation. This degradation was clearly observed in renal cell carcinoma 786-O cells, and was found to be both hypoxia- and pVHL-independent. Furthermore, Int6 protein knockdown by int6-siRNA vectors or the dominant-negative mutant Int6-ΔC increased endogenous HIF-2α expression, even under normoxia, and induced sets of critical angiogenic factors comprising vascular endoplasmic growth factor, angiopoietin, and basic fibroblast growth factor mRNA. These results indicate that Int6 is a novel and critical determinant of HIF-2α-dependent angiogenesis as well as cancer formation, and that int6-siRNA transfer may be an effective therapeutic strategy in pathological conditions such as heart and brain ischemia, hepatic cirrhosis, and obstructive vessel diseases.
Disappearance of insectivorous birds from tropical forest fragments

Determining the impact of forest disturbance and fragmentation on tropical biotas is a central goal of conservation biology. Among tropical forest birds, understory insectivores are particularly sensitive to habitat disturbance and fragmentation, despite their relatively small sizes and freedom from hunting pressure. Why these birds are especially vulnerable to fragmentation is not known. Our data indicate that the best determinant of the persistence of understory insectivorous birds in small fragments is the ability to disperse through deforested countryside habitats. This finding contradicts our initial hypothesis that the decline of insectivorous birds in forest fragments is caused by impoverished invertebrate prey base in fragments. Although we observed significantly fewer insectivorous birds in smaller fragments, extensive sampling of invertebrate communities (106,082 individuals) and avian diets (of 735 birds) revealed no important differences between large and small fragments. Neither habitat specificity nor drier fragment microclimates seemed critical. Bird species that were less affected by forest fragmentation were, in general, those that used the deforested countryside more, and we suggest that the key to their conservation will be found there.
Combination antifungal therapy for cryptococcal meningitis.

BACKGROUND Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days. METHODS We conducted a randomized, three-group, open-label trial of induction therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection. All patients received amphotericin B at a dose of 1 mg per kilogram of body weight per day; patients in group 1 were treated for 4 weeks, and those in groups 2 and 3 for 2 weeks. Patients in group 2 concurrently received flucytosine at a dose of 100 mg per kilogram per day for 2 weeks, and those in group 3 concurrently received fluconazole at a dose of 400 mg twice daily for 2 weeks. RESULTS A total of 299 patients were enrolled. Fewer deaths occurred by days 14 and 70 among patients receiving amphotericin B and flucytosine than among those receiving amphotericin B alone (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% confidence interval [CI], 0.30 to 1.08; unadjusted P=0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39 to 0.97; unadjusted P=0.04). Combination therapy with fluconazole had no significant effect on survival, as compared with monotherapy (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44 to 1.41; P=0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45 to 1.11; P=0.13). Amphotericin B plus flucytosine was associated with significantly increased rates of yeast clearance from cerebrospinal fluid (-0.42 log10 colony-forming units [CFU] per milliliter per day vs. -0.31 and -0.32 log10 CFU per milliliter per day in groups 1 and 3, respectively; P<0.001 for both comparisons). Rates of adverse events were similar in all groups, although neutropenia was more frequent in patients receiving a combination therapy. CONCLUSIONS Amphotericin B plus flucytosine, as compared with amphotericin B alone, is associated with improved survival among patients with cryptococcal meningitis. A survival benefit of amphotericin B plus fluconazole was not found. (Funded by the Wellcome Trust and the British Infection Society; Controlled-Trials.com number, ISRCTN95123928.).
Intraindividual and Interindividual Variabilities in Endogenous Cortisol 6β-Hydroxylation Clearance as an Index for In Vivo CYP3A Phenotyping in Humans

This study was designed to evaluate the in vivo activity of cytochrome P450 3A (CYP3A) in 49 healthy Japanese subjects aged 22–58 years using endogenous cortisol 6β-hydroxylation clearance [CLm(6β)], a novel biomarker for CYP3A phenotyping. CLm(6β) in the 49 healthy subjects was 2.40 ± 0.79 ml/min with an approximately 4-fold interindividual variability of CYP3A activity. The mean clearance in the 24 women was 2.50 ± 0.89 ml/min; the value in the women was higher than in the 25 men (2.30 ± 0.69 ml/min) by approximately 9%. We also measured the change of CLm(6β) in 14 healthy subjects in the morning at 10:00–12:00 every 2 or 3 days over a period of 36–53 days and observed a 1.5-fold to 3.4-fold day-to-day intraindividual variability in the CYP3A activity. The mean value for CLm(6β) in each subject for 36–53 days was 2.54 ± 0.76 ml/min (n = 14). We also evaluated the CLm(6β) every 2 hours from 8:00–20:00 in 26 healthy subjects. The within-day intraindividual clearance variability was 1.1-fold to 2.5-fold (2.45 ± 0.91 ml/min, n = 26). No characteristic diurnal rhythms were observed in the in vivo activity of CYP3A.
Why are some species more commonly afflicted by arthritis than others? A comparative study of spondyloarthropathy in primates and carnivores

Spondyloarthropathy is a painful arthritic affliction of humans that also occurs in wild mammals. Important questions remain concerning the underlying causes of spondyloarthropathy in mammals, particularly regarding whether it is infectious in origin or driven by genetic predisposition and environmental stressors. Moreover, spondyloarthropathy has negative effects on host fitness, leading to potential conservation concerns if it impacts threatened species. Using a comparative data set on the prevalence of joint disease in 34 primate species and 100 carnivore species, we tested predictions involving the epidemiological correlates of spondyloarthropathy in wild mammals. Analyses revealed that 5.6% of primates and 3.6% of carnivores exhibited signs of spondyloarthropathy, with maximum incidence as high as 22% in great apes and 27% in bears. We tested whether prevalence of spondyloarthropathy increases with population density and group size, greater contact with soil, a slower host life history, increased ranging, dietary factors and body mass. We found general support for an effect of body mass, with larger bodied primates and carnivores exhibiting a higher prevalence of spondyloarthropathy. In addition, more threatened species experienced higher rates of spondyloarthropathy, with this association influenced by body mass and phylogeny. The effect of body mass could reflect that larger animals are exposed to more pathogens through greater consumption of resources, or that joints of larger bodied mammals experience greater biomechanical stresses, resulting in inflammation and activation of local joint infections.
HEMA but not TEGDMA induces autophagy in human gingival fibroblasts

Polymerized resin-based materials are successfully used in restorative dentistry. Despite their growing popularity, one drawback is the release of monomers from the polymerized matrix due to an incomplete polymerization or degradation processes. Released monomers are responsible for several adverse effects in the surrounding biological tissues, inducing high levels of oxidative stress. Reactive oxygen species are important signaling molecules that regulate many signal-trasduction pathways and play critical roles in cell survival, death, and immune defenses. Reactive oxygen species were recently shown to activate autophagy as a mechanism of cell survival and cell death. Although the toxicity induced by dental resin monomers is widely studied, the cellular mechanisms underlying these phenomena are still unknown. The aim of the study was to investigate the behavior of human gingival cells exposed to 2-hydroxy-ethyl methacrylate (HEMA) and triethylene glycol dimethacrylate (TEGDMA) to better elucidate the mechanisms of cell survival and cell death induced by resin monomers. Primary culture of human gingival cells were exposed to 3 mmol/L of HEMA or 3 mmol/L of TEGDMA for 24, 48, and 72 h. Morphological investigations were performed by transmission electron microscopy to analyze the ultrastructure of cells exposed to the monomers. The expression of protein markers for apoptosis (caspase – 3 and PARP) and autophagy (beclin – 1 and LC3B I/II) were analyzed by western blot to investigate the influence of dental resin monomers on mechanisms underlying cell death. Results showed that HEMA treatment clearly induced autophagy followed by apoptosis while the lack of any sign of autophagy activation is observed in HGFs exposed to TEGDMA. These data indicate that cells respond to monomer-induced stress by the differential induction of adaptive mechanisms to maintain cellular homeostasis.
Study on Modeling of Mckibben Pneumatic Artificial Muscle

Based on the analysis of performance of the Mckibben pneumatic artificial muscles, investigation was carried out on the functional mechanism of pneumatic artificial muscle of the braided type. A geometric model was derived for Mckibben Pneumatic artificial muscle, taking the radial constraints at both ends into consideration. Numerical calculation was also done with the geometric model. Comparison was made between the ideal cylinder model and the current model, and conclusion was drawn that the geometric model put forward may even more exactly express the behavior and properties of the Mckibben pneumatic artificial muscle actuator. It is of significance for such study with findings in the construction of more exact pneumatic artificial muscle models.
Visual performance after reduced blinking in eyes with soft contact lenses or after LASIK.

PURPOSE To evaluate visual performance during concentrated visual work in patients wearing soft contact lenses or after LASIK. METHODS Thirty-one eyes of 17 patients who had worn soft contact lenses before LASIK were examined by the following tests immediately and 10 seconds after eye opening: 1) functional visual acuity, which is defined as visual acuity measured after prolonged eye opening without blinking; 2) surface regularity index (SRI) and surface asymmetry index (SAI) in corneal topography; and 3) higher order aberration measured with NIDEK OPD-Scan. Results were compared in the same patients before (with soft contact lenses and no eye surgery) and 1 month after LASIK (without soft contact lenses). RESULTS Functional visual acuity was significantly decreased 10 seconds after eye opening compared with immediately after eye opening, both with soft contact lenses and after LASIK, and decreased to a greater extent with soft contact lenses. The SRI and SAI were significantly increased 10 seconds after eye opening compared with immediately after eye opening, both with soft contact lenses and after LASIK, and increased to a greater extent with soft contact lenses. Higher order aberration was increased 10 seconds after eye opening with soft contact lenses, but not after LASIK. CONCLUSIONS Our results suggest that prolonged eye opening induces a decreased quality of vision in eyes of soft contact lens wearers and after LASIK. Under conditions in which blinking is restricted due to concentrated visual work, such as visual display terminal work, reading, and driving, visual performance may be more compromised with soft contact lens wear than after LASIK.
Don't blame it (all) on the pause: further ERP evidence for a prosody-induced garden-path in running speech

This paper investigates the prosodic relevance of a pause which, along with other prosodic parameters, served to indicate an Intonational Phrase (IPh) boundary. Event-related brain potentials (ERPs) were recorded while subjects listened to both intact and altered German Early and Late Closure (EC/LC) sentences. The EC sentences were prosodically highly accepted and well comprehended even when the original pause at the boundary position was removed. Furthermore, a reversed garden-path (initial EC preference in LC sentences) was successfully induced by a false IPh boundary irrespective of whether the pause was present or not. The ERP patterns disclosed the on-line processing of simple and garden-path sentences in more detail. The data clearly demonstrate that in the presence of other prosodic parameters pause insertion is a completely dispensable cue for boundary marking. The ERP technique proved to be superior to behavioral on-line measures as data collection does not interrupt speech presentation.
Genetic Engineering Activates Biosynthesis of Aromatic Fumaric Acid Amides in the Human Pathogen Aspergillus fumigatus

ABSTRACT The Aspergillus fumigatus nonribosomal peptide synthetase FtpA is among the few of this species whose natural product has remained unknown. Both FtpA adenylation domains were characterized in vitro. Fumaric acid was identified as preferred substrate of the first and both l-tyrosine and l-phenylalanine as preferred substrates of the second adenylation domain. Genetically engineered A. fumigatus strains expressed either ftpA or the regulator gene ftpR, encoded in the same cluster of genes, under the control of the doxycycline-inducible tetracycline-induced transcriptional activation (tet-on) cassette. These strains produced fumaryl-l-tyrosine and fumaryl-l-phenylalanine which were identified by liquid chromatography and high-resolution mass spectrometry. Modeling of the first adenylation domain in silico provided insight into the structural requirements to bind fumaric acid as peptide synthetase substrate. This work adds aromatic fumaric acid amides to the secondary metabolome of the important human pathogen A. fumigatus which was previously not known as a producer of these compounds.
Temporal and Physiological Characteristics of Elite Women`s and Men`s Singles Badminton

Through a descriptive study of the temporal and physiological characteristics of elite singles badminton players, we were able to analyze a large sample of male and female Spanish players (n=79) who participated in national, international and world level competitions. We collected data on (a) temporal structure and actions in play, which were video-recorded and retrospectively analysed for all matches, (b) heart rates and (c) blood lactate concentration from capillary samples taken from the earlobe. These data were used to describe elite singles badminton competition in relation to sex and competition levels. Results showed that elite singles badminton is a highly demanding sport, with high maximum and mean heart rate (192 and 174 beats.min-1), a total match time over 30 minutes and an average rallies of 89 per match. Moreover, rallies had a rally length (work time) of 6.8 s and 13.9 s rest (rest time) between rallies. Significant differences existed between men`s and women`s modalities at all competition levels except for the World Championships, and between levels of elite competition. These findings have allowed recommendations to be made with regard to the preparation of players for competition at the highest level.