Miracle-dz/UniFAR-FTUs huggingface dataset:
The Borrelia hermsii Factor H Binding Protein FhbA Is Not Required for Infectivity in Mice or for Resistance to Human Complement In Vitro

ABSTRACT The primary causative agent of tick-borne relapsing fever in North America is Borrelia hermsii. It has been hypothesized that B. hermsii evades complement-mediated destruction by binding factor H (FH), a host-derived negative regulator of complement. In vitro, B. hermsii produces a single FH binding protein designated FhbA (FH binding protein A). The properties and ligand binding activity of FhbA suggest that it plays multiple roles in pathogenesis. It binds plasminogen and has been identified as a significant target of a B1b B cell-mediated IgM response in mice. FhbA has also been explored as a potential diagnostic antigen for B. hermsii infection in humans. The ability to test the hypothesis that FhbA is a critical virulence factor in vivo has been hampered by the lack of well-developed systems for the genetic manipulation of the relapsing fever spirochetes. In this report, we have successfully generated a B. hermsii fhbA deletion mutant (the B. hermsii YORΔfhbA strain) through allelic exchange mutagenesis. Deletion of fhbA abolished FH binding by the YORΔfhbA strain and eliminated cleavage of C3b on the cell surface. However, the YORΔfhbA strain remained infectious in mice and retained resistance to killing in vitro by human complement. Collectively, these results indicate that B. hermsii employs an FhbA/FH-independent mechanism of complement evasion that allows for resistance to killing by human complement and persistence in mice.
Structural basis for sulfation-dependent self-glycan recognition by the human immune-inhibitory receptor Siglec-8

Significance Siglec-8 downregulates eosinophil- and mast cell-mediated inflammatory responses upon engagement by specific self-glycans. We used solution NMR spectroscopy to determine the structure of the N-terminal lectin domain of human Siglec-8 in complex with its preferred glycan target 6′-sulfo sialyl Lewisx. Quantitative binding studies with differently sulfated glycans and structure-based mutants demonstrate that Siglec-8 simultaneously recognizes a terminal N-acetylneuraminic acid (sialic acid) and an underlying 6-O–sulfated galactose, yielding a tight and unique specificity. We offer direct structural and mechanistic insights into how the self-glycan code is deciphered by Siglec-8, emphasize the crucial role of glycan sulfation in immunological control of inflammation, and provide a rational framework for designing Siglec-8 agonists to harness its signaling pathway in allergic and inflammatory disorders. Siglec-8 is a human immune-inhibitory receptor that, when engaged by specific self-glycans, triggers eosinophil apoptosis and inhibits mast cell degranulation, providing an endogenous mechanism to down-regulate immune responses of these central inflammatory effector cells. Here we used solution NMR spectroscopy to dissect the fine specificity of Siglec-8 toward different sialylated and sulfated carbohydrate ligands and determined the structure of the Siglec-8 lectin domain in complex with its prime glycan target 6′-sulfo sialyl Lewisx. A canonical motif for sialic acid recognition, extended by a secondary motif formed by unique loop regions, recognizing 6-O–sulfated galactose dictates tight specificity distinct from other Siglec family members and any other endogenous glycan recognition receptors. Structure-guided mutagenesis revealed key contacts of both interfaces to be equally essential for binding. Our work provides critical structural and mechanistic insights into how Siglec-8 selectively recognizes its glycan target, rationalizes the functional impact of site-specific glycan sulfation in modulating this lectin–glycan interaction, and will enable the rational design of Siglec-8–targeted agonists to treat eosinophil- and mast cell-related allergic and inflammatory diseases, such as asthma.
The Mitochondrial Cytochrome Oxidase Subunit I Gene Occurs on a Minichromosome with Extensive Heteroplasmy in Two Species of Chewing Lice, Geomydoecus aurei and Thomomydoecus minor

In animals, mitochondrial DNA (mtDNA) typically occurs as a single circular chromosome with 13 protein-coding genes and 22 tRNA genes. The various species of lice examined previously, however, have shown mitochondrial genome rearrangements with a range of chromosome sizes and numbers. Our research demonstrates that the mitochondrial genomes of two species of chewing lice found on pocket gophers, Geomydoecus aurei and Thomomydoecus minor, are fragmented with the 1,536 base-pair (bp) cytochrome-oxidase subunit I (cox1) gene occurring as the only protein-coding gene on a 1,916–1,964 bp minicircular chromosome in the two species, respectively. The cox1 gene of T. minor begins with an atypical start codon, while that of G. aurei does not. Components of the non-protein coding sequence of G. aurei and T. minor include a tRNA (isoleucine) gene, inverted repeat sequences consistent with origins of replication, and an additional non-coding region that is smaller than the non-coding sequence of other lice with such fragmented mitochondrial genomes. Sequences of cox1 minichromosome clones for each species reveal extensive length and sequence heteroplasmy in both coding and noncoding regions. The highly variable non-gene regions of G. aurei and T. minor have little sequence similarity with one another except for a 19-bp region of phylogenetically conserved sequence with unknown function.
Optimal coordination of directional overcurrent relays using hybrid BBO/DE algorithm and considering double primary relays strategy

Finding optimal settings of directional overcurrent relays (DOCRs) has been extensively solved by many scenarios with adopting different traditional and modern optimization algorithms. For the sack of simplicity, all the conducted studies in the literature are restricted on a condition that all DOCRs are numerical, static, or electromechanical. There is a fact that when jumping from electromechanical or static relays to numerical relays the former devices could be used as a second wall of protection instead of just throwing them. With a very extreme condition, which may not happen in the real-world applications, all buses will have double primary DOCRs, which where act as backup DOCRs for other buses. That is, the dimension of any given problem is duplicated and becomes very hard to be feasibly and optimally solved. This paper covers this uncommon scenario, and a new hybrid algorithm with some additional sub-algorithms is developed to solve the IEEE 6-bus test system. Moreover, both numerical with electromechanical DOCRs and numerical with static DOCRs are considered in this study.
Serum lipid profile in psoriatic patients: correlation between vascular adhesion protein 1 and lipoprotein (a)

Psoriasis is a chronic inflammatory skin disease characterized by excessive cellular replication. Apolipoproteins are genetically determined molecule whose role has been implied in cardiovascular pathology. Vascular adhesion protein−1 (VAP−1) is an adhesion molecule with an enzymatic activity that partakes in the migration process of lymphocytes into sites of inflammation. Our purpose was to evaluate the plasma lipid profiles, apolipoproteins (A1, B) and Lp (a) and VAP−1 in order to compare the lipid profile in psoriatic patients with non‐affected persons and correlation between VAP−1 and Lp (a). We determined serum concentrations of lipids, lipoproteins , apolipoproteins and VAP−1 in 90 patients with psoriasis and 90 age matched controls. Serum Lp (a), apo A1 and apo B were measured by immunoprecipitation assays, and the lipids and lipoproteins were measured by enzymatic methods.The VAP−1 were masured by ELISA method. The mean levels of total cholesterol, LDL, apo B and VAP−1 in patients with psoriasis were found to be significantly higher than those of healthy subjects (P<0.05. In psoriatic patients, elevation of VAP‐1 correlated with elevation of Lp (a) (p = 0.025). This study shows that high serum lipid level and VAP−1, is significantly more common in psoriasis. This fact may be responsible for higher prevalence of cardiovascular accident in psoriatic patients. Copyright © 2012 John Wiley & Sons, Ltd.
Regulatory T-Cells: Diverse Phenotypes Integral to Immune Homeostasis and Suppression

Regulatory T-cells (TREG) are diverse populations of lymphocytes that regulate the adaptive immune response in higher vertebrates. TREG delete autoreactive T-cells, induce tolerance, and dampen inflammation. TREG cell deficiency in humans (i.e., IPEX [Immunodysregulation, Polyendocrinopathy and Enteropathy, X-linked syndrome]) and animal models (e.g., “Scurfy” mouse) is associated with multisystemic autoimmune disease. TREG in humans and laboratory animal species are similar in type and regulatory function. A molecular marker of and the cell lineage specification factor for TREG is FOXP3, a forkhead box transcription factor. CD4+ TREG are either natural (nTREG), which are thymus-derived CD4+CD25+FOXP3+ T-cells, or inducible (i.e., Tr1 cells that secrete IL-10, Th3 cells that secrete TGF-β and IL-10, and Foxp3+ Treg). The proinflammatory Th17 subset has been a major focus of research. TH17 CD4+ effector T-cells secrete IL-17, IL-21, and IL-22 in autoimmune and inflammatory disease, and are dynamically balanced with TREG cell development. Other lymphocyte subsets with regulatory function include: inducible CD8+ TREG, CD3+CD4−CD8− TREG (double-negative), CD4+Vα14+ (NKTREG), and γδ T-cells. TREG have four regulatory modes of action: secretion of inhibitory cytokines (e.g., IL-10 and TGF-β), granzyme-perforin-induced apoptosis of effector lymphocytes, depriving effector T-cells of cytokines leading to apoptosis, or inhibition of dendritic cell function. The role of TREG in mucosal sites, inflammation/infection, pregnancy, and cancer as well as a review of TREG as a modulatory target in drug development will be covered.
The Expression of S100A4 in Human Pancreatic Cancer Is Associated With Invasion

Objectives Pancreatic cancer is one of the most lethal malignancies; its poor prognosis is strongly associated with invasion and metastasis. Expression of S100A4 has been reported to correlate with poor prognosis in various cancers. We have investigated the role of S100A4 in pancreatic cancer tumorigenesis and its clinicopathologic significance. Methods Protein expression of S100A4 was examined by Western blot in pancreatic cancer cell lines and a human pancreatic ductal epithelium cell line, HPDE-6. Then the expressions of S100A4, TP53, and CD133 were examined immunohistochemically in resected specimens from 83 patients with pancreatic cancer to clarify their clinicopathologic significance. Survival analyses were performed using the Kaplan-Meier method and the Mantel-Cox method. Results Forty-eight (58%) of 83 patients with pancreatic cancer positively expressed S100A4, and 50 (60%) and 29 (36%) patients positively expressed TP53 and CD133, respectively. S100A4 expression was significantly correlated with perineural invasion (P = 0.029) and invasion pattern (P = 0.001). Neither TP53 nor CD133 expression showed significant correlations with any other parameters. Conclusions Our present results suggest that S100A4 plays an important role in the invasiveness, particularly with perineural invasion and invasion pattern, of pancreatic cancer. Development of new strategies targeting S100A4 or its downstream effectors is warranted.
Developmental changes in multispecific organic anion transporter 1 expression in the rat kidney.

BACKGROUND The cDNA of the multispecific organic anion transporter 1 (OAT1) responsible for the tubular secretion of organic anions was recently isolated. In the current study, we investigated the developmental changes in OAT1 expression in the rat kidney. METHODS Ontogenic expression of rat OAT1 was investigated by Northern blot, in situ hybridization, Western blot, and immunohistochemical analysis. In addition, para-aminohippurate (PAH) accumulation was measured using fetal, neonatal, and adult rat kidney slices. RESULTS In Northern blot analysis, OAT1 was detected as early as on embryonic day 18 in the fetal kidney. The expression level of OAT1 mRNA increased remarkably just after birth (postnatal day 0). In situ hybridization revealed OAT1 expression on embryonic day 19. In both the fetal and neonatal kidneys, OAT1 mRNA was localized in a relatively deep region in the cortex. Western blot analysis detected OAT1 protein on embryonic day 20, and the expression level increased after birth. Immunohistochemical analysis did not reveal OAT1 staining in the fetal kidneys. A faint signal of OAT1 protein was detected on postnatal day 0; thereafter, the expression level increased. In the functional study using kidney slices, low but definite probenecid-sensitive PAH accumulation was noted in fetal rat kidney on embryonic day 20. After birth, probenecid-sensitive PAH uptake was increased. CONCLUSIONS The present study consistently demonstrates the remarkable increase of OAT1 expression after birth, and the immature excretory capacity of the proximal tubules of the neonatal kidney can be attributed, at least in part, to the low expression level of OAT1.
The presence of accessory cusps in chimpanzee lower molars is consistent with a patterning cascade model of development

Tooth crown morphology is of primary importance in fossil primate systematics and understanding the developmental basis of its variation facilitates phenotypic analyses of fossil teeth. Lower molars of species in the chimp/human clade (including fossil hominins) possess between four and seven cusps and this variability has been implicated in alpha taxonomy and phylogenetic systematics. What is known about the developmental basis of variation in cusp number – based primarily on experimental studies of rodent molars – suggests that cusps form under a morphodynamic, patterning cascade model involving the iterative formation of enamel knots. In this study we test whether variation in cusp 6 (C6) presence in common chimpanzee and bonobo lower molars (n = 55) is consistent with predictions derived from the patterning cascade model. Using microcomputed tomography we imaged the enamel‐dentine junction of lower molars and used geometric morphometrics to examine shape variation in the molar crown correlated with variation in C6 presence (in particular the size and spacing of the dentine horns). Results indicate that C6 presence is consistent with predictions of a patterning cascade model, with larger molars exhibiting a higher frequency of C6 and with the location and size of later‐forming cusps correlated with C6 variation. These results demonstrate that a patterning cascade model is appropriate for interpreting cusp variation in Pan and have implications for cusp nomenclature and the use of accessory cusp morphology in primate systematics.
Selenium and vitamin E status of healthy and institutionalized elderly subjects: analysis of plasma, erythrocytes and platelets

Levels of selenium in whole blood, plasma, erythrocytes and platelets, glutathione peroxidase (EC 1.11.1.9; GSH-Px) activity in erythrocytes and platelets and vitamin E, low-density-lipoprotein (LDL)-cholesterol and vitamin E: LDL cholesterol in plasma were measured in seventy-five healthy subjects aged < 65 years and twenty-eight healthy and twenty-three institutionalized elderly people aged > 65 years. Healthy elderly subjects had significantly lower levels of Se in whole blood and plasma when compared with younger subjects. Other measurements of Se status were not significantly different. In the healthy subjects plasma levels of vitamin E and LDL-cholesterol increased with age to 60 years and decreased above 80 years. Vitamin E: LDL cholesterol values were not affected by age. Measurements of Se and vitamin E status in the institutionalized elderly compared with the healthy elderly were all reduced with the exception of platelet Se levels and erythrocyte GSH-Px activity. Ageing per se had minimal effect on Se and vitamin E status but intercurrent illness and decreased food intake can lead to reduced levels in the elderly.
Propacetamol as Adjunctive Treatment for Postoperative Pain After Cardiac Surgery

Postoperative pain management after cardiac surgery has been mainly based on parenteral opioids. However, because opioids have numerous side effects, coadministration of non-opioid analgesics has been introduced as a method of reducing opioid dose. In this prospective, randomized, double-blinded study, we evaluated the efficacy of propacetamol, an IV administered prodrug of acetaminophen (paracetamol), as an adjunctive analgesic after cardiac surgery. Seventy-nine patients scheduled for elective coronary artery bypass grafting were randomized to receive either propacetamol 2 g (n = 40) or placebo (n = 39) IV in 6-h intervals for 72 h. From the time of extubation, patients had access to an opioid (oxycodone) via a patient-controlled analgesia device. Pain was evaluated on a visual analog scale four times daily, whereas respiratory function tests (forced vital capacity, forced expiratory volume in 1 s, peak expiratory flow, and arterial blood gas measurements) were performed once a day. The prespecified primary efficacy variable (cumulative oxycodone consumption at the end of the 72-h postoperative period) was 123.5 mg (51.3 mg) (mean [sd]) in the propacetamol group and 141.8 mg (57.5 mg) in the placebo group (difference in mean, 18.3 mg = 13%; 95% confidence interval, 6.1–42.7 mg;P = 0.15). Pain scores did not differ between the groups at rest (P = 0.65) or during a deep breath (P = 0.72). The groups were also similar in terms of pulmonary function tests, postoperative bleeding, and hepatic function tests, and no significant differences were noted in the incidences of adverse effects. After completion of the study, a post hoc analysis was also performed analyzing the first 24 h as split into 6-h intervals. This analysis showed a significantly (P = 0.036) smaller consumption of oxycodone in the propacetamol group at 24 h (47.1 mg [20.7 mg] versus 57.9 mg [23.9 mg]; difference in mean, 10.8 mg; 95% confidence interval, 0.7–20.9 mg). In conclusion, propacetamol did not enhance opioid-based analgesia in coronary artery bypass grafting patients, nor did it decrease cumulative opioid consumption or reduce adverse effects within 3 days after surgery. However, post hoc analysis showed that oxycodone requirement was reduced within the first 24 h in the propacetamol group.
Understanding the influences on self-confidence among first-year undergraduate nursing students in Ireland.

AIM To report a mixed-methods study of the development of self-confidence in Irish nursing students undertaking the first year of an undergraduate nursing programme. BACKGROUND Self-confidence underpins nurses' competence to carry out care effectively, yet there is little empirical evidence of how this attribute is fostered in pre-registration preparation. There is an assumption, however, that self-confidence develops independently and spontaneously. DESIGN A sequential, mixed methods three-phase design was used. METHOD The design involved pretest and posttest measurements of self-confidence, focus group interviews, a student self-evaluation questionnaire and analysis of the relevant curriculum content. Data were collected between September 2007-April 2008 and sampling was from three cohorts of students at three different Institutes of Technology in Ireland. Data collection matched the nature of the data, including descriptive, non-inferential statistics and qualitative content analysis. RESULTS There was considerable variation in the amount and nature of theoretical preparation. Factors in clinical practice exerted the most influence. Self-confidence fluctuated during the first clinical placement and as students' self-confidence developed, simultaneously, motivation towards academic achievement increased. Conversely, self-confidence was quickly eroded by poor preceptor attitudes, lack of communication, and feeling undervalued. CONCLUSION The development of self-confidence is complex and multi-factorial. This study offers further understanding of facilitators and barriers that may be relevant elsewhere in promoting student nurses' developing self-confidence. The development of self-confidence must be recognized as a central tenet for the design and delivery of undergraduate programmes.
Pharmacological Disintegration of Lipid Rafts Decreases Specific Tetramer Binding and Disrupts the CD3 Complex and CD8 Heterodimer in Human Cytotoxic T Lymphocytes

Accumulating evidence strongly supports the role of lipid rafts in the regulation of T‐lymphocyte activation, but the organization and molecular composition of these cholesterol‐ and sphingolipid‐rich membrane microdomains in different subsets of T cells remain poorly investigated. Here, we show that pharmacological disruption of lipid rafts in human CD8+ cytotoxic T‐lymphocyte (CTL) clones disturbs the integrity of CD3 complex and CD8 heterodimer, without affecting the reactivity with T‐cell receptor (TCR)‐specific antibodies. This demonstrates that interaction with completely assembled CD3 complex is not required for the stable expression of TCR at the cell surface. The effect of raft disruption on CD3 and CD8 expression correlates with failure to bind specific tetrameric complexes by a proportion of surface TCR molecules. However, the interaction of specific tetramer with the rest of surface TCR pools appears to be unaffected, demonstrating that TCR‐signalling complexes may differ in their requirement for cholesterol to stably maintain their composition and to rearrange for efficient tetramer binding. Together with previously published data, our results support the existence of molecular and/or structural heterogeneity of lipid rafts that may play an important role in controlling distinct functional properties of T‐cell subsets.
Understanding the Risk of an Avian Flu Pandemic: Rational Waiting or Precautionary Failure?

The precautionary principle (PP) has been proposed as the proper guide for the decision‐making criteria to be adopted in the face of the new catastrophic risks that have arisen in the last decades. This article puts forward a workable definition of the PP based on the so‐called α‐maximin expected utility approach, applying it to the possible outbreak of the avian flu disease among humans. Moreover, it shows how the shortage and/or lack of effective drugs against the infection of the virus A(H5N1) among humans can be considered a precautionary failure.