Miracle-dz/UniFAR-FTUs huggingface dataset:
Detecting balancing selection in genomes: limits and prospects

In spite of the long‐term interest in the process of balancing selection, its frequency in genomes and evolutionary significance remain unclear due to challenges related to its detection. Current statistical approaches based on patterns of variation observed in molecular data suffer from low power and a high incidence of false positives. This raises the question whether balancing selection is rare or is simply difficult to detect. We discuss genetic signatures produced by this mode of selection and review the current approaches used for their identification in genomes. Advantages and disadvantages of the available methods are presented, and areas where improvement is possible are identified. Increased specificity and reduced rate of false positives may be achieved by using a demographic model, applying combinations of tests, appropriate sampling scheme and taking into account intralocus variation in selection pressures. We emphasize novel solutions, recently developed model‐based approaches and good practices that should be implemented in future studies looking for signals of balancing selection. We also draw attention of the readers to the results of recent theoretical studies, which suggest that balancing selection may be ubiquitous but transient, leaving few signatures detectable by existing methods. Testing this new theory may require the development of novel high‐throughput methods extending beyond genomic scans.
GRP78(BiP) facilitates the cytosolic delivery of anthrax lethal factor (LF) in vivo and functions as an unfoldase in vitro

Anthrax toxin is an A/B bacterial protein toxin which is composed of the enzymatically active Lethal Factor (LF) and/or Oedema Factor (EF) bound to Protective Antigen 63 (PA63) which functions as both the receptor binding and transmembrane domains. Once the toxin binds to its cell surface receptors it is internalized into the cell and traffics through Rab5‐ and Rab7‐associated endosomal vesicles. Following acidification of the vesicle lumen, PA63 undergoes a dynamic change forming a beta‐barrel that inserts into and forms a pore through the endosomal membrane. It is widely recognized that LF, and the related fusion protein LFnDTA, must be completely denatured in order to transit through the PA63 formed pore and enter the eukaryotic cell cytosol. We demonstrate by protease protection assays that the molecular chaperone GRP78 mediates the unfolding of LFnDTA and LF at neutral pH and thereby converts these proteins from a trypsin resistant to sensitive conformation. We have used immunoelectron microscopy and gold‐labelled antibodies to demonstrate that both GRP78 and GRP94 chaperones are present in the lumen of endosomal vesicles. Finally, we have used siRNA to demonstrate that knock‐down of GRP78 results in the emergence of resistance to anthrax lethal toxin and oedema toxin action.
Involvement of sphingosine 1-phosphate (S1P) receptor type 1 and type 4 in migratory response of mouse T cells toward S1P.

Sphingosine 1-phosphate (S1P), a pleiotropic lysophospholipid, regulates signal transduction pathway via G-protein-coupled receptors termed S1P1-5 in several types of the cells including lymphocytes. Higher levels of S1P4 mRNA as well as S1P1 mRNA are expressed in lymphoid tissues such as the spleen, thymus, lymph nodes, and Payer's patches. In contrast to S1P1 that plays an essential role in lymphocyte egress, little is known about the role of S1P4 in immune system. In this study, we found that S1P at 10 to 100 nM significantly induced the cell migration and the significant levels of S1P1 and S1P4 mRNA were expressed in mouse CD4 T cells, D10.G4. 1 mouse Th2 cells, and EL-4.IL-2 mouse thymoma cells. In D10.G4. 1 and EL-4.IL-2 cells, S1P-induced migration was almost completely inhibited by pretreatment with pertussis toxin, Clostoridium difficile toxin B, and (S)-enantiomer of FTY720-phosphate, a potent agonist at S1P1 and S1P4. The members of the Rho family small GTPase, Cdc42 and Rac were activated by S1P stimulation in these cells. The transfection with dominant negative or constitutively active forms of Cdc42 and Rac revealed that the activation of both Cdc42 and Rac is essential for S1P-induced migration of these cells. The immunoprecipitation assays using CHO cells co-expressing both S1P4 and S1P1 receptors indicated that S1P4 and S1P1 are associated on the cell surface. These results suggest that the association of S1P4 and S1P1 plays an important role in migratory response of mouse T cells toward S1P.
Lung cancer risk among US radiologic technologists, 1983–1998

While exposure to moderate to high‐dose ionizing radiation is an established risk factor for lung cancer, the relationship between lung cancer and chronic low dose radiation remains uncertain. We examined lung cancer risk among 71,894 US radiologic technologists who were certified during 1926–1982, responded to a baseline questionnaire (1983–1989), and were free of cancer other than non‐melanoma skin cancer at baseline. Study participants were followed until completion of a second questionnaire (1994–1998), death, or August 31, 1998. We identified 287 lung cancer cases: 66 incident cases and 221 decedents. Exposure to radiation was inferred based on work history information provided in the baseline questionnaire. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazard models adjusted for age, race/ethnicity and smoking. Smoking‐adjusted lung cancer risk was not related to working as a radiologic technologist in early years when radiation exposures were likely highest (RR = 0.9; 95% CI, 0.5–1.8 for year first worked before 1940 compared to year first worked ≥1960), nor was risk related to the year first worked after 1940 or the number of years worked in any decade. While lung cancer risk was increased in radiologic technologists who held patients for X‐rays, or who allowed others to take numerous practice X‐rays on them, the trend was not statistically significant in either case. Although we adjusted for smoking, the possibility of residual confounding exists. Overall, we find very limited evidence that chronic low‐to‐moderate dose occupational exposure increased lung cancer risk in the US Radiologic Technologist cohort. © 2006 Wiley‐Liss, Inc.
Crystal Structures of Biapenem and Tebipenem Complexed with Penicillin-Binding Proteins 2X and 1A from Streptococcus pneumoniae

ABSTRACT Biapenem is a parenteral carbapenem antibiotic that exhibits wide-ranging antibacterial activity, remarkable chemical stability, and extensive stability against human renal dehydropeptidase-I. Tebipenem is the active form of tebipenem pivoxil, a novel oral carbapenem antibiotic that has a high level of bioavailability in humans, in addition to the above-mentioned features. β-lactam antibiotics, including carbapenems, target penicillin-binding proteins (PBPs), which are membrane-associated enzymes that play essential roles in peptidoglycan biosynthesis. To envisage the binding of carbapenems to PBPs, we determined the crystal structures of the trypsin-digested forms of both PBP 2X and PBP 1A from Streptococcus pneumoniae strain R6, each complexed with biapenem or tebipenem. The structures of the complexes revealed that the carbapenem C-2 side chains form hydrophobic interactions with Trp374 and Thr526 of PBP 2X and with Trp411 and Thr543 of PBP 1A. The Trp and Thr residues are conserved in PBP 2B. These results suggest that interactions between the C-2 side chains of carbapenems and the conserved Trp and Thr residues in PBPs play important roles in the binding of carbapenems to PBPs.
Beyond the Usual Suspects: New Research Themes in Comparative Public Policy

Abstract The principal paradox of comparative public policy has remained over the years: there is no clear and broadly shared definition of the field. This article engages with the debate about what comparative public policy is from a distinctive perspective. Drawing from a systematic analysis of published research articles that maps out the usual comparative suspects, it reflects on what comparative public policy does and does not do in terms of comparative scope and country range, and the extent to which the limitations in the comparative scope matter for cumulative knowledge, theory building and the consolidation of the field. The article discusses different strategies to address the challenge of extending the range of comparative analysis.
Working postures of dental students: ergonomic analysis using the Ovako Working Analysis System and rapid upper limb assessment.

BACKGROUND As dentistry is a profession that demands a manipulative precision of hand movements, musculoskeletal disorders are among the most common occupational diseases. OBJECTIVES This study estimated the risk of musculoskeletal disorders developing in dental students using the Ovako Working Analysis System (OWAS) and Rapid Upper Limb Assessment (RULA) methods, and estimated the diagnostic agreement between the 2 methods. METHODS Students (n = 75), enrolled in the final undergraduate year at the Araraquara School of Dentistry--UNESP--were studied. Photographs were taken of students while performing diverse clinical procedures (n = 283) using a digital camera, which were assessed using OWAS and RULA. A risk score was attributed following each procedure performed by the student. The prevalence of the risk of musculoskeletal disorders was estimated per point and for a 95% CI. To assess the agreement between the 2 methods, Kappa statistics with linear weighting were used. The level of significance adopted was 5%. RESULTS There was a high prevalence of the mean score for risk of musculoskeletal disorders in the dental students evaluated according to the OWAS method (p = 97.88%; 95% CI: 96.20-99.56%), and a high prevalence of the high score (p = 40.6; 95% CI: 34.9-46.4%) and extremely high risk (p = 59.4%; 95% CI: 53.6-65.1%) according to RULA method Null agreement was verified (k = 0) in the risk di agnosis of the tested methods. CONCLUSION The risk of musculoskeletal disorders in dental students estimated by the OWAS method was medium, whereas the same risk by the RULA method was extremely high. There was no diagnostic agreement between the OWAS and RULA methods.
Neural network-based approach for the classification of wireless-capsule endoscopic images

The importance of computer-assisted diagnosis in endoscopy is to assist the physician in detecting the status of tissues by characterising the features from the endoscopic image. In this paper schemes have been developed to extract new texture features from the texture spectra in the chromatic and achromatic domains for a selected region of interest from each colour component histogram of images acquired by the new M2A swallowable imaging capsule. The concept of fusion of multiple classifiers dedicated to specific feature parameters and the implementation of an advanced intelligent scheme have been also adopted in this study. The high detection accuracy of the proposed systems provides thus an indication that such intelligent schemes could be used as a supplementary diagnostic tool in capsule endoscopy.
The role of psychological and socio-demographical factors for electric bike use in Norway

Abstract The electric bike (e-bike) is emerging as a new sustainable transport mode in Norway and has the potential to lead to increased cycling among the population. However, little is known about psychosocial determinants of e-bike use. The aim of the study was to examine the role of normative and environmental beliefs, the perceived attributes of e-bikes, and innovativeness and demographical factors related to e-bike use in a Norwegian sample. An online survey was used to collect data from 910 respondents, including both e-bike users (252) and non-users (658). The respondents were recruited via a commercial panel (response rate 42.04%) and a Facebook post. A structural equation modeling analysis was used to analyze the data. The structural model had a good fit to the data. The results showed that attitudes towards e-bike use followed by innovativeness were the most important predictors of e-bike use. The normative processes measured within the Norm Activation Model activated positive attitudes towards e-bike use, which in turn predicted e-bike use. There was a negative relationship between e-bike and conventional bike use, while a positive relationship was found between car and e-bike use. The results are discussed with regard to their implications for interventions aiming to promote e-bike use.
Effects of catecholamine application to brain-dead donors on graft survival in solid organ transplantation1

Background. In a recent single-center study, donor use of catecholamines was identified to reduce kidney allograft rejection. This study investigates the effects of donor employment of adrenergic agents on graft survival in a large data base, including liver and heart transplants. Methods. The study was based on the registry of the Eurotransplant International Foundation including 2415 kidney, 755 liver, and 720 heart transplants performed between January 1 and December 31, 1993. A total of 1742 donor record forms referring to the cadaveric donor activities in 1993 were systematically reviewed with regard to employment of adrenergic agents. Catecholamine use was simply coded dichotomously and divided into three strata according to zero, single, and combined application. Multivariate Cox regression including age, gender, cause of brain death, cold ischemia, HLA-mismatching, number of previous transplants, and urgency in liver transplants was applied for statistical analysis. Results. Donor employment of catecholamines was associated with increased 4-year graft survival after kidney transplantation (hazard ratio [HR], 0.85; 95% confidence interval [95% CI], 0.74–0.98). The benefit is conferred in a dose-dependent manner and compares in quantitative terms with prospective HLA matching on class I and class II antigens (HR, 0.90; 95% CI, 0.84–0.97). Use of norepinephrine was predictive of initial nonfunction after heart transplantation (HR, 1.66; 95% CI, 1.14–2.43), but did not compromise liver grafts (HR, 0.94; 95% CI, 0.67–1.32). Conclusions. Optimizing the management of brain-dead organ donors, including the possibility of selective administration of adrenergic agents, may provide a major benefit on graft survival without adverse side effects for the recipients. Further investigation on best use of adrenergic drugs, optimum dosage, and duration is warranted.
Chinese Tourists’ Perceptions of Service Quality in West African Hotels: A Case Study of Senegal

ABSTRACT The quality of service from the clients’ perspective in the hotel business is a remarkable basis for growth. Previous researches revealed that visitor perception of service quality influences service delivery and ultimate satisfaction. In Senegal, and West Africa at large, hotels embarking on putting in place relevant service quality systems are aiming to meet the levels of satisfaction of their visitors. This supports gaining a competitive advantage and attracting international visitors, including those from new markets such as China. The current study reveals the five major dimensions that influence Chinese visitors’ perceptions of service quality of hotels in Senegal. The results may be significant to providers of hotel services and contribute to the improvement of business through modification of the product and service needs of Chinese visitors across West African hotels.
Internalization and Degradation of Recombinant Human Coagulation Factor VIIa by the Human Hepatoma Cell Line HuH7

Summary Previous studies demonstrated that several normal and transformed cultured human cell lines specifically bind human coagulation factors VII and VIIa via tissue factor. In the present study, we show that 125I- radiolabeled recombinant human factor VIIa (125I-rFVIIa) binds to a human hepatoma cell line (HuH7). In the presence of rabbit polyclonal anti-human tissue factor apoprotein IgG, binding of 125I-rFVIIa to the HuH7 cells was decreased ∼60%, suggesting the presence of tissue factor-independent binding sites for 125I-rFVIIa on these cells. The binding isotherm of 125I-rFVIIa for the HuH7 cells in the presence of anti-tissue factor IgG exhibited a hyperbolic profile and was time-, temperature- and calcium-dependent. Furthermore, binding at 4° C was specific, dose-dependent and saturable. Scatchard analysis of the binding data demonstrated a single class of binding sites with a dissociation constant (Kd) of 3.2 nM and 27,000 binding sites per cell. At 4° C, 125I-rFVIIa bound to, and eluted from, the cell was indistinguishable from offered 125I-rFVIIa as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by autoradiography. The molecular properties of the tissue factor-independent binding protein were studied by using the cleavable cross-linking agent 3, 3’- dithiobis(sulfosuccinimidylpropionate). A cross-linking product of 125I-rFVIIa and a cell surface protein with an apparent Mr ∼100,000 was observed. The cross-linking reaction was strongly inhibited by a 100-fold molar excess of unlabeled rFVIIa, but not by rabbit polyclonal anti-human tissue factor apoprotein IgG, indicating that cross-linking does not involve the extracellular domain of tissue factor. After binding, internalization of 125I-rFVIIa by the HuH7 cells was observed at 37° C in the presence of rabbit polyclonal anti-human tissue factor apoprotein IgG. Internalization of 125I-rFVIIa proceeds at a rate of 0.4 fmol 125I-rFVIIa/min/106 cells, reaching a steady state after 2 h. Following binding and internalization, 125I-rFVIIa reappeared in the culture medium within 30 min, at approximately the same rate as internalized 125I-rFVIIa. This 125I-rFVIIa probably represents degradation of 125I-rFVIIa into small peptides, since it could not be precipitated by rabbit polyclonal affinity-purified anti-FVII IgG or by trichloroacetic acid. Chloroquine treatment of the HuH7 cells inhibited the degradation of 125I-rFVIIa, suggesting that degradation presumably occurs via a lysosomal-dependent pathway. These studies demonstrate that the liver may play an important role in the clearance mechanism(s) of FVIIa.
Sequence Conversion by Single Strand Oligonucleotide Donors via Non-homologous End Joining in Mammalian Cells*

Double strand breaks (DSBs) can be repaired by homology independent nonhomologous end joining (NHEJ) pathways involving proteins such as Ku70/80, DNAPKcs, Xrcc4/Ligase 4, and the Mre11/Rad50/Nbs1 (MRN) complex. DSBs can also be repaired by homology-dependent pathways (HDR), in which the MRN and CtIP nucleases produce single strand ends that engage homologous sequences either by strand invasion or strand annealing. The entry of ends into HDR pathways underlies protocols for genomic manipulation that combine site-specific DSBs with appropriate informational donors. Most strategies utilize long duplex donors that participate by strand invasion. Work in yeast indicates that single strand oligonucleotide (SSO) donors are also active, over considerable distance, via a single strand annealing pathway. We examined the activity of SSO donors in mammalian cells at DSBs induced either by a restriction nuclease or by a targeted interstrand cross-link. SSO donors were effective immediately adjacent to the break, but activity declined sharply beyond ∼100 nucleotides. Overexpression of the resection nuclease CtIP increased the frequency of SSO-mediated sequence modulation distal to the break site, but had no effect on the activity of an SSO donor adjacent to the break. Genetic and in vivo competition experiments showed that sequence conversion by SSOs in the immediate vicinity of the break was not by strand invasion or strand annealing pathways. Instead these donors competed for ends that would have otherwise entered NHEJ pathways.
Assignment of cloned genes to the seven electrophoretically separated Candida albicans chromosomes

By using orthogonal-field alternating gel electrophoresis (OFAGE), field-inversion gel electrophoresis (FIGE), and contour-clamped homogeneous field gel electrophoresis (CHEF), we have clearly resolved 11 chromosomal bands from various Candida albicans strains. OFAGE resolves the smaller chromosomes better, while FIGE, which under our conditions causes the chromosomes to run in the reverse order of OFAGE, is more effective in separating the larger chromosomes. CHEF separates all chromosomes under some conditions, but these conditions do not often resolve homologs. The strains examined are highly polymorphic for chromosome size. Fourteen cloned Candida genes, isolated on the basis of conferral of new properties to or complementation of auxotrophic deficiencies in Saccharomyces cerevisiae, and three sequences of unknown function have been hybridized to Southern transfers of CHEF, FIGE, and OFAGE gels. Four sets of resolvable bands have been shown to be homologous chromosomes. On the basis of these data, we suggest that C. albicans has seven chromosomes. Genes have been assigned to the seven chromosomes. Two chromosomes identified genetically have been located on the electrophoretic karyotype.
Intracellular location of catabolite activator protein of Escherichia coli

The catabolite activator protein was assayed in extracts from the minicell-producing Escherichia coli strain P678-54. The level of catabolite activator protein was found to be the same in both parent cells and purified minicells, regardless of whether the bacteria were grown on glucose (which leads to low intracellular cyclic adenosine monophosphate levels) or on glycerol-yeast extract or LB broth (which lead to high cyclic adenosine monophosphate concentrations in the cell). Thus, at any given time most catabolite activator protein molecules are found in the cytoplasm. The implications of this for the mechanism of catabolite activator protein action at catabolite-sensitive operons are discussed.
Differential Regulation of GABAA Receptor Gene Expression by Ethanol in the Rat Hippocampus Versus Cerebral Cortex

Abstract: Previous research has shown that chronic ethanol consumption dramatically alters GABAA receptor α1 and α4 subunit gene expression in the cerebral cortex and GABAA receptor α1 and α6 subunit gene expression in the cerebellum. However, it is not yet known if chronic ethanol consumption produces similar alterations in GABAA receptor gene expression in other brain regions. One brain region of interest is the hippocampus because it has recently been shown that a subset of GABAA receptors in the hippocampus is responsive to pharmacologically relevant concentrations of ethanol. Therefore, we directly compared the effects of chronic ethanol consumption on GABAA receptor subunit gene expression in the hippocampus and cerebral cortex. Furthermore, we investigated whether the duration of ethanol consumption (14 or 40 days) would influence regulation of GABAA receptor gene expression in these two brain regions. Chronic ethanol consumption produced a significant increase in the level of GABAA receptor α4 subunit peptide in the hippocampus following 40 days but not 14 days. The relative expression of hippocampal GABAA receptor α1, α2, α3, α2/3, or γ2 was not altered by either period of chronic ethanol exposure. In marked contrast, chronic ethanol consumption for 40 days significantly increased the relative expression of cerebral cortical GABAA receptor α4 subunits and significantly decreased the relative expression of cerebral cortical GABAA receptor α1 subunits. This finding is consistent with previous results following 14 days of chronic ethanol consumption. Hence, chronic ethanol consumption alters GABAA receptor gene expression in the hippocampus but in a different manner from that in either the cerebral cortex or the cerebellum. Furthermore, these alterations are dependent on the duration of ethanol exposure.