Miracle-dz/UniFAR-FTUs huggingface dataset:
Antigen‐binding site anatomy and somatic mutations in antibodies that recognize different types of antigens

The number of antibody structures co‐crystallized with their respective antigens has increased rapidly in the last few years, thus offering a formidable source of information to gain insight into the structure–function relationships of this family of proteins. We have analyzed here 140 unique middle‐resolution to high‐resolution (<3 Å) antibody structures, including 55 in complex with proteins, 39 with peptides, and 46 with haptens. We determined (i) length variations of the hypervariable loops, (ii) number of contacts with antigen, (iii) solvent accessible area buried upon binding, (iv) location and frequency of antigen contacting residues, (v) type of residues interacting with antigens, and (vi) putative somatic mutations. Except for somatic mutations, distinctive profiles were identified for all the variables analyzed. Compared with contacts, somatic mutations occurred with less abundance at any given position and extended beyond the regions in contact, with no clear difference among antibodies that recognize different types of antigens. This observation is consistent with the fact that although antigen recognition accomplished by shape and physicochemical complementarity is selective in nature, the somatic mutation process is stochastic and selection for mutations leading to improved affinity is not directly related to contact residues. Thus, the knowledge emerging from this study enhances our understanding of the structure–function relationship in antibodies while providing valuable guidance to design libraries for antibody discovery and optimization. Copyright © 2012 John Wiley & Sons, Ltd.
Economic Reform during the First Four Years of Kim Jong-un’s Rule

The paper evaluates the effects of domestic and external actions on the probability of reform in North Korea. It applies the theory of Janos Kornai on socialist systems, in particular the main line of causation, as well as elements of rational choice theory. The CRE model provides a tool for systematically processing information on North Korea that is typically incomplete. The effects of 23 actions that have taken place since 2012 in the fields of ideology, property rights, coordination, military affairs and external influence are discussed. The combined outcome is mixed and corresponds with reality, where neither a retreat to pre-1990 socialism nor a full-fledged reform could be observed. However, new insights are found on single effects and their interplay. This provides a practical tool for scholars who aim for a systematic understanding of the past, and for politicians who need to conduct an advance impact analysis of future policies.
post‐synaptic excitation and inhibition from primary afferents in neurones of the spinocervical tract

1. Intra‐ and extracellular recordings were made from cells of the spinocervical tract in the lumbosacral spinal cord. A convergence of monosynaptic excitatory post‐synaptic potentials (EPSPs) and disynaptic inhibitory post‐synaptic potentials (IPSPs) was a general pattern of effects from the low threshold cutaneous fibres. Unitary IPSPs, probably mediated via the same disynaptic path, were evoked by light touch of hairs, which was also the adequate stimulus for exciting the cells. The receptive field for unitary IPSPs was closely related to the excitatory receptive field but was eccentric, not of a surround type.
Search for Novel Candidate Mutations for Metronidazole Resistance in Helicobacter pylori Using Next-Generation Sequencing

ABSTRACT Metronidazole resistance is a key factor associated with Helicobacter pylori treatment failure. Although this resistance is mainly associated with mutations in the rdxA and frxA genes, the question of whether metronidazole resistance is caused by the inactivation of frxA alone is still debated. Furthermore, it is unclear whether there are other mutations involved in addition to the two genes that are associated with resistance. A metronidazole-resistant strain was cultured from the metronidazole-susceptible H. pylori strain 26695-1 by exposure to low concentrations of metronidazole. The genome sequences of both susceptible and resistant H. pylori strains were determined by Illumina next-generation sequencing, from which putative candidate resistance mutations were identified. Natural transformation was used to introduce PCR products containing candidate mutations into the susceptible parent strain 26695-1, and the metronidazole MIC was determined for each strain. Mutations in frxA (hp0642), rdxA (hp0954), and rpsU (hp0562) were confirmed by the Sanger method. The mutated sequence in rdxA was successfully transformed into strain 26695-1, and the transformants showed resistance to metronidazole. The transformants containing a single mutation in rdxA showed a low MIC (16 mg/liter), while those containing mutations in both rdxA and frxA showed a higher MIC (48 mg/liter). No transformants containing a single mutation in frxA or rpsU were obtained. Next-generation sequencing was used to identify mutations related to drug resistance. We confirmed that the mutations in rdxA are mainly associated with metronidazole resistance, and mutations in frxA are able to enhance H. pylori resistance only in the presence of rdxA mutations. Moreover, mutations in rpsU may play a role in metronidazole resistance.
Role of phosphodiesterases III and IV in the modulation of vascular cyclic AMP content by the NO/cyclic GMP pathway

1 The effect on cyclic nucleotide contents of selective inhibitors of cyclic nucleotide phosphodiesterase (PDE) isoforms III and IV (respectively SK&F 94120 and rolipram) and their interactions with endothelium and NO have been studied in rat aorta in the presence of indomethacin (10 μm). The participation of NO was assessed by using either NG‐nitro‐L‐arginine methyl ester (L‐NAME) (NO synthase inhibitor: 30 μm) or 3‐morpholinosydnonimine (SIN‐1, NO donor: 10 μm with SOD 100 units ml−1). 2 The presence of endothelium significantly increased both adenosine 3′:5′‐cyclic monophosphate (cyclic AMP, 1.7 fold) and guanosine 3′:5′‐cyclic monophosphate (cyclic GMP, 2.2 fold) contents. Cyclic GMP was largely affected by L‐NAME or SIN‐1 treatment, this was riot the case for cyclic AMP suggesting that the presence of endothelium modified cyclic AMP content in aorta independently of the NO production. 3 In the presence or absence of endothelium, neither SK&F 94120 nor rolipram, alone or combined, significantly modified cyclic GMP content. 4 The PDE III inhibitor significantly affected cyclic AMP content only in non treated aorta without endothelium. In contrast, the PDE IV inhibitor increased cyclic AMP in all conditions. These increases were generally about 2 fold but markedly higher in aorta treated with SIN‐1 and superoxide dismutase (SOD, 6 fold). Association of a low concentration of the PDE III inhibitor (5 μm) with the PDE IV inhibitor (30 μm) potentiated the effect of the PDE IV inhibitor on cyclic AMP content, except for aorta without endothelium treated with SIN‐1 plus SOD. 5 These data indicate that the presence of the endothelium could increase cyclic AMP content independently of NO and prostacyclin (PGI2) production. Furthermore, an increase in cyclic GMP content (modulated by NO production) could enhance the cyclic AMP accumulation induced by the PDE IV inhibitor. This result supports the hypothesis that PDE III inhibition by endogenous cyclic GMP may potentiate the effect of PDE IV inhibition on cyclic AMP content. Taken together with our previous studies on relaxation, these results suggest that the NO/cyclic GMP pathway could induce PDE IV‐dependent regulation of cyclic AMP via PDE III inhibition.
Gallbladder bile composition in patients with Crohn 's disease.

AIM To further elucidate the pathogenesis and mechanisms of the high risk of gallstone formation in Crohn's disease. METHODS Gallbladder bile was obtained from patients with Crohn's disease who were admitted for elective surgery (17 with ileal/ileocolonic disease and 7 with Crohn's colitis). Fourteen gallstone patients served as controls. Duodenal bile was obtained from ten healthy subjects before and after the treatment with ursodeoxycholic acid. Bile was analyzed for biliary lipids, bile acids, bilirubin, crystals, and crystal detection time (CDT). Cholesterol saturation index was calculated. RESULTS The biliary concentration of bilirubin was about 50% higher in patients with Crohn's disease than in patients with cholesterol gallstones. Ten of the patients with Crohn's disease involving ileum and three of those with Crohn's colitis had cholesterol saturated bile. Four patients with ileal disease and one of those with colonic disease displayed cholesterol crystals in their bile. About 1/3 of the patients with Crohn's disease had a short CDT. Treatment of healthy subjects with ursodeoxycholic acid did not increase the concentration of bilirubin in duodenal bile. Several patients with Crohn's disease, with or without ileal resection/disease had gallbladder bile supersaturated with cholesterol and short CDT and contained cholesterol crystals. The biliary concentration of bilirubin was also increased in patients with Crohn's colitis probably not due to bile acid malabsorption. CONCLUSION Several factors may be of importance for the high risk of developing gallstones of both cholesterol and pigment types in patients with Crohn's disease.
The ‘anvil’ profile in femtosecond laser‐assisted penetrating keratoplasty

Editor, T he introduction of the femtosecond (FS) laser technology in the surgery room has allowed great advances in the field of corneal surgery and in particular in penetrating keratoplasty (PK). The FS laser enables to design vertical and lamellar intrastromal incisions with a variety of shapes and angulations at a precise depth, with minimal collateral tissue injury (Yoo & Hurmeric 2011). Various incision patterns for the creation of a particular flap shape in PK have been described, to have a watertight closuring effect of the surgical wound, to prepare a biomechanically stable flap and to improve the healing process (Bahar et al. 2008; Yoo & Hurmeric 2011; Maier et al. 2012). An optimised wound shape maximises the surface area of the wound incision and improve fit and stability of the graft–host junction. In this letter, we describe a new anvil-shaped laser incision used in PK. This design has the purpose to create a more structurally stable and predictable wound configuration with the aim of a faster recovery of vision and higher optical quality compared with the conventional blade trephination and the most common laser-cut patterns. The ‘anvil’ profile is designed as described in the following (Fig. 1). Donor and recipient corneal trephination are performed using a 150 kHz FS laser (iFS150 , Intralase FS Laser; Abbott Medical Optics – AMO, Santa Ana, CA, USA). As concerned iFS150 settings, we refer to the following technical parameters for the donor trephination:
Pareto Local Search for MOMDP Planning

Standard single-objective methods such as value iteration are not applicable to multi-objective Markov decision processes (MOMDPs) because they depend on a maximization, which is not defined if the rewards are multi-dimensional. As a result, special multi-objective algorithms are needed to find a set of policies that contains all optimal trade-offs between objectives, i.e. a set of Pareto optimal policies. In this paper, we propose Pareto local policy search (PLoPS), a new planning method for MOMDPs based on Pareto local search (PLS) [3]. This method produces a good set of policies by iteratively scanning the neighbourhood of locally non-dominated policies for improvements. It is fast because neighbouring policies can be quickly identified as improvements, and their values can be computed incrementally. We test the performance of PLoPS on several MOMDP benchmarks, and compare it to popular decision-theoretic and evolutionary alternatives. The results show that PLoPS outperforms the alternatives.
Curriculum knowledge organization and representation based on ontology

Currently most present web-based course still organized knowledge in accordance with sections. In view of the existing problems of the above knowledge organization form, this paper takes the curriculum of computer organization as an example to discuss ontology-based knowledge representation. In the extraction of concepts and their relationships, this paper not only borrows ideas from WorldNet, a quite common ontology that has considerable influence in the international computing linguistics, but also depends on the actual need of the course to expand and redefine them, in order to improve the sharability and reusability of the established curricular ontology. Moreover, methods of storage and exchange of ontology-based database are introduced in detail for providing better knowledge display and organization in actual applications.
Genetic variation and population differentiation in the lichen‐forming ascomycete Xanthoria parietina on the island Storfosna, central Norway

Genetic diversity and fine‐scale population structure in the lichen‐forming ascomycete Xanthoria parietina was investigated using sequence variation in part of the intergenic spacer (IGS) and the complete internal transcribed spacer (ITS) regions of the nuclear ribosomal DNA. Sampling included 213 and 225 individuals, respectively, from seven populations in two different habitats, bark and rock, on the island Storfosna off the central west coast of Norway. Both markers revealed significant variation and a total of 10 IGS and 16 ITS haplotypes were found. There were no signs of significant positive spatial autocorrelation at any spatial size class down to 10% of transect length, nor did we find significant deviations from neutrality or signs of historical population expansion. Analysis of molecular variance (amova) indicated that most of the genetic variance observed was within populations, but when populations were grouped according to habitat, more than a quarter of the variance was explained among groups. Pairwise comparisons of populations (FST, exact tests of population differentiation) revealed significant differentiation between populations in different habitats (on bark or rock), but not between populations in the same habitat. Haplotype networks show that internal and presumably old haplotypes are shared between habitats, whereas terminal haplotypes tend to be unique to a habitat, mostly bark. We interpret the observed pattern to mean that there is no evidence of restricted gene flow between populations in the same habitat at the present spatial scale (interpopulation distances one or a few kilometres). On the other hand, differentiation between habitats is considerable, which we attribute to restricted gene flow between habitats (habitat isolation). Evidence suggests that the observed differentiation did not evolve locally. Estimates of divergence time between populations in the respective habitats indicate that an ancestral population started to diverge at least 34 000 years ago but probably much further back in time.
Combined intrathecal and epidural magnesium sulfate supplementation of spinal anesthesia to reduce post‐operative analgesic requirements: a prospective, randomized, double‐blind, controlled trial in patients undergoing major orthopedic surgery

Background: New ways of decreasing post‐operative analgesic drug requirements are of special interest after major surgery. Magnesium sulfate (MgSO4) alters pain processing and reduces the induction and maintenance of central sensitization by blocking the N‐methyl‐d‐aspartate (NMDA) receptor in the spinal cord. We investigated whether supplementation of spinal anesthesia with combined intrathecally and epidurally infused MgSO4 reduced patients’ post‐operative analgesia requirements.
Clinical and Economic Outcomes of Nonadherence to Highly Active Antiretroviral Therapy in Patients With Human Immunodeficiency Virus

Background:Nonadherence with highly active antiretroviral therapy (HAART) is common in typical human immunodeficiency virus (HIV) patient care settings, but the consequences have not been well described. This study aimed to quantify the clinical and economic effects of nonadherence and estimate the cost-effectiveness of improving adherence in treatment-naive HIV patients. Methods:A Markov model was developed to project quality-adjusted life expectancy and direct medical costs for patients on an initial once-daily regimen of efavirenz, lamivudine, and stavudine XR. The model compared 2 adherence scenarios: “ideal” (based on clinical trials) and “typical” (based on observational studies in actual practice). Disease progression was a function of viral load, CD4 count, and adherence. Data on HIV natural history, treatment benefits, costs, and utilities were derived from the literature. Results:With typical adherence, patients lose 1.2 quality-adjusted life years (QALYs) that could be gained with ideal adherence. Improving adherence to ideal levels is cost-effective at $29,400/QALY gained. As much as $1600/y per patient could be spent on an intervention to improve adherence to ideal levels, and the incremental cost-effectiveness would remain less than $50,000/QALY gained. A cost-effectiveness ratio of $50,000/QALY is a commonly accepted minimum standard for cost-effective medical interventions in the United States, although many experts believe this standard has drifted upwards over time. Conclusions:Typical adherence with HAART reduces quality-adjusted life expectancy by 12% compared with ideal adherence. Interventions to improve adherence appear to be a highly cost-effective use of resources.
The Influence Of Corporate Social Responsibility On Human Resource Policy. Study On Transnational Corporations

Often, transnational companies are accused of selfish human resource policies that focus on profit maximization without taking into account the needs of different stakeholders. This way, transnational companies are harmful both to employees in the country of origin, who lose their jobs, and employees from emerging countries, who carry out activities similar to those in developed countries, but in exchange for lower wages. Transnational companies bring many counterarguments, including: practicing fair human resource policies, ensuring higher salaries than average salaries in the countries where they operate, ensuring safe working conditions, employing fair recruitment and selection rules. This paper is based on the premise that corporate social responsibility supports the rethinking of human resource policies, as it favours the respect of ethics in human resource matters. The analysis we carried out showed a positive correlation between corporate social responsibility and corporate human resource policies. Organizations with a high level of corporate social responsibility are inclined to establish relevant and correct human resource policies.
CXCL9 Regulates TGF-β1–Induced Epithelial to Mesenchymal Transition in Human Alveolar Epithelial Cells

Epithelial to mesenchymal cell transition (EMT), whereby fully differentiated epithelial cells transition to a mesenchymal phenotype, has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). CXCR3 and its ligands are recognized to play a protective role in pulmonary fibrosis. In this study, we investigated the presence and extent of EMT and CXCR3 expression in human IPF surgical lung biopsies and assessed whether CXCR3 and its ligand CXCL9 modulate EMT in alveolar epithelial cells. Coexpression of the epithelial marker thyroid transcription factor-1 and the mesenchymal marker α-smooth muscle actin and CXCR3 expression was examined by immunohistochemical staining of IPF surgical lung biopsies. Epithelial and mesenchymal marker expression was examined by quantitative real-time PCR, Western blotting, and immunofluorescence in human alveolar epithelial (A549) cells treated with TGF-β1 and CXCL9, with Smad2, Smad3, and Smad7 expression and cellular localization examined by Western blotting. We found that significantly more cells were undergoing EMT in fibrotic versus normal areas of lung in IPF surgical lung biopsy samples. CXCR3 was expressed by type II pneumocytes and fibroblasts in fibrotic areas in close proximity to cells undergoing EMT. In vitro, CXCL9 abrogated TGF-β1–induced EMT. A decrease in TGF-β1–induced phosphorylation of Smad2 and Smad3 occurred with CXCL9 treatment. This was associated with increased shuttling of Smad7 from the nucleus to the cytoplasm where it inhibits Smad phosphorylation. This suggests a role for EMT in the pathogenesis of IPF and provides a novel mechanism for the inhibitory effects of CXCL9 on TGF-β1–induced EMT.
Determination Suppressive Effect of Satellite 369 on Accumulation of Cucumber Mosaic Virus by Real-Time Reverse Transcript-Polymerase Chain Reaction

Sat369 is a 369-nt cucumber mosaic virus satellite RNA (CMV-sartRNA), it can attenuate the symptom induced by CMV. To study the mechanism by which the symptom was altered, real-time reverse transcript-polymerase chain reaction (RT-PCR) was applied to examine the accumulation kinetics of viral genes at the absence or presence of sat369. The results showed that sat369 depressed the accumulation of all viral genes but with different degrees, its effects on 2b, 1a and 2a genes were more remarkable than that of MP and CP genes, and the suppression effects were more considerable at early than later stage of infection. Besides this, the time points of maximum levels of CMV genes were delayed by 7 days in the presence of sat369. These results were confirmed by northern blotting, and indicated that the attenuated symptom in the presence of sat369 might be the results of low accumulation levels of CMV genes, especially at early time post-inoculation, 1a, 2a and 2b genes were all involved in this complex interaction.
Evolutionary Dynamics of an Ipomopsis Hybrid Zone: Confronting Models with Lifetime Fitness Data

Interspecific hybridization is a recurring aspect of the evolution of many plant and animal groups. The temporal dynamics of hybrid zones and the evolutionary consequences of hybridization should depend on fitness of parental and hybrid individuals expressed in different environments. We measured lifetime fitness, including survival and reproduction, of plants of Ipomopsis aggregata, Ipomopsis tenuituba, and their F1 hybrids, in experimental plantings in a natural hybrid zone. Fitness, measured as the finite rate of increase (λ), depended strongly on environment. Each parental species performed well in its home locale and poorly in the locale of the other species. Hybrids performed as well as parents overall but enjoyed their highest fitness in the hybrid site. Furthermore, F1 hybrids with I. tenuituba as maternal parent survived well only at the hybrid site, suggesting a \documentclass{aastex} \usepackage{amsbsy} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{bm} \usepackage{mathrsfs} \usepackage{pifont} \usepackage{stmaryrd} \usepackage{textcomp} \usepackage{portland,xspace} \usepackage{amsmath,amsxtra} \usepackage[OT2,OT1]{fontenc} \newcommand\cyr{ \renewcommand\rmdefault{wncyr} \renewcommand\sfdefault{wncyss} \renewcommand\encodingdefault{OT2} \normalfont \selectfont} \DeclareTextFontCommand{\textcyr}{\cyr} \pagestyle{empty} \DeclareMathSizes{10}{9}{7}{6} \begin{document} \landscape $$\mathrm{cytonuclear}\,\times \mathrm{environment}\,$$ \end{document} interaction. These results support an “environmental cline” model of hybrid zone dynamics, with complexities in the fitness of hybrids consistent also with an “evolutionary novelty” model. Combined with those of earlier studies of pollination, our results suggest that both vegetative adaptation to physical environment and floral adaptation to pollinators contribute to observed patterns of phenotypic expression in this hybrid zone and to persistence of the hybrid zone.