Miracle-dz/UniFAR-FTUs huggingface dataset:
CXCL10/CXCR3‐mediated responses promote immunity to respiratory syncytial virus infection by augmenting dendritic cell and CD8+ T cell efficacy

The induction of inflammatory cytokines during respiratory viral infections contributes to both disease pathogenesis and resolution. The present studies investigated the role of the chemokine CXCL10 and its specific receptor, CXCR3, in the host response to pulmonary respiratory syncytial virus (RSV) infection. Antibody‐mediated neutralization of CXCL10 resulted in a significant increase in disease pathogenesis, including airway hyperresponsiveness (AHR), mucus gene expression, and impaired viral clearance. When the pulmonary cytokine levels were examined, only type I IFN and IL‐12p70 were significantly reduced. These latter observations were reflected in reduced dendritic cell (DC) numbers and DC maturation in the lungs of RSV‐infected mice treated with anti‐CXCL10. Neutralization of the only known receptor for CXCL10, CXCR3, resulted in similar increases in pathogenic responses. When bone marrow‐derived DC were incubated with CXCL10 and RSV, an up‐regulation of type I IFN was observed. In addition, T lymphocytes were also examined and a significant decrease in the number of RSV M2 peptide‐specific CD8+ T cells was identified. These findings highlight a previously unappreciated role for the CXCL10:CXCR3 signaling axis in RSV‐infected animals by recruiting virus‐specific T cells into the lung and promoting viral clearance.
Mass spectrometric quantification of amyloid-beta in cerebrospinal fluid and plasma

Alzheimer’s disease (AD) is the most common neurodegenerative disease among the elderly and accounts for 60-80% of all cases of dementia. Currently, the diagnosis of AD is based on cognitive tests and mental state exams, but the peptide amyloid-beta (Aβ) in cerebrospinal fluid (CSF) is increasingly used in clinical trials and settings. As for most protein and peptide biomarkers, quantification is performed using antibody-based techniques such as enzyme-linked immunosorbent assay (ELISA). However these immunoassays suffer from high variability in measurements of Aβ concentrations, hampering its use as a diagnostic marker. The aim of this thesis was to develop an antibody independent method for absolute quantification of Aβ in human CSF, free of the specificity and reproducibility issues associated with antibody-based quantification. The method was based on solid-phase extraction (SPE) and liquid chromatography (LC)-tandem mass spectrometry (MS/MS). Stable isotope labeled Aβ peptides were used as internal standards, enabling absolute quantification. The method was first tested in a pilot study with CSF samples from AD patients and controls. As expected, the level of the 42 amino acid variant of Aβ (Aβ1-42) was decreased in AD CSF as compared to controls (p<0.01). The results were similar to those obtained with conventional ELISA, and an even better separation between the groups was obtained when using the Aβ1-42/Aβ1-40 ratio. To investigate whether the antibody independent method would give similar results across different research centers, an inter-laboratory study was initiated which included three other laboratories using similar LC-MS/MS methods. Results showed good agreement and highlighted the importance of a certified reference material (CRM) to further increase the agreement between laboratories and MS methods. The method was further optimized, validated and published as a candidate reference measurement procedure (RMP). An RMP is required to set the value of a CRM used as a ‘gold standard’ to harmonize CSF Aβ measurements. To investigate if the large number of Aβ peptides in addition to Aβ1-38, Aβ1-40 and Aβ1-42 found in CSF could also be found in human plasma, an immunoprecipitation-based method for enrichment of Aβ peptides was developed. Sixteen Nor C-terminally truncated Aβ peptides were reproducibly detected using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS. While quantification of Aβ1-38, Aβ1-40 and Aβ1-42 using LC-MS/MS showed no AD association, the method may be useful in clinical trials of drugs affecting amyloid precursor protein (APP) processing or Aβ homeostasis. In summary, absolute quantification of Aβ1-42 using the developed LC-MS-MS method overcomes many of the issues associated with antibody-based methods. The method is currently being considered for formal certification as a RMP to determine the absolute concentration of Aβ1-42 in a CRM to harmonize CSF Aβ1-42 measurements across techniques and analytical platforms.
Mechanism of Inhibition of Xanthine Oxidoreductase by Allopurinol: Crystal Structure of Reduced Bovine Milk Xanthine Oxidoreductase Bound with Oxipurinol

Inhibitors of xanthine oxidoreductase block conversion of xanthine to uric acid and are therefore potentially useful for treatment of hyperuricemia or gout. We determined the crystal structure of reduced bovine milk xanthine oxidoreductase complexed with oxipurinol at 2.0 Å resolution. Clear electron density was observed between the N2 nitrogen of oxipurinol and the molybdenum atom of the molybdopterin cofactor, indicating that oxipurinol coordinated directly to molybdenum. Oxipurinol forms hydrogen bonds with glutamate802, arginine880, and glutamate1261, which have previously been shown to be essential for the enzyme reaction. We discuss possible differences in the hypouricemic effect of inhibitors, including allopurinol and newly developed inhibitors, based on their mode of binding in the crystal structures.
Heterogeneity in the Phosphorylation of Micro tubule‐Associated Protein MAP 1B During Rat Brair Development

Abstract: The patterns of isoforms and of immunoreactivity of the microtubule‐associated protein MAP1 B toward a panel of antibodies to phosphorylation‐sensitive epitopes are different in distinct rat brain regions and change during development. This suggests the occurrence of a considerable degree of heterogeneity in the phosphorylation state of rat brain MAP1 B. It appears that MAP1 B can be phosphorylated at multiple sites that may be conventionally classified into at least two modes of phosphorylation. Mode I of phosphorylation induces significant upward shifts in the electrophoretic mobility of the protein, giving rise to “high” MAP1B isoforms, whereas the mode II of MAP1B phosphorylation does not greatly affect the electrophoretic mobility of the protein. These MAP1B phosphorylation modes are differentially regulated throughout development and show some regional specificity. Cytosolic MAP1 B is highly phosphorylated both at mode I and mode II sites in the developing rat brain, as well as in the adult olfactory bulb, where axonal growth takes place. In most adult rat brain regions, cytosolic MAP1B is highly phosphorylated at mode II sites but largely dephosphorylated at certain mode I sites. However, MAP1 B present in the particulate fraction of most rat brain region homogenates may be partially dephosphorylated at certain mode II sites, although it contains some phosphorylated mode I sites. These data are compatible with the view that different protein kinases, possibly including casein kinase II and proline‐directed protein kinases, might regulate the state of phosphorylation of MAP1B in distinct localizations along the development of different neuronal populations in the brain.
Evaluating the Importance of Apoptotic Index, Mitotic Index and Turnover Index in Premalignant and Malignant Lesions of Cervix

Aim: To evaluate the premalignant and malignant lesions of the uterine cervix on light microscopy for apoptosis. To calculate and correlate the apoptotic index (AI), mitotic index (MI) and turnover index of the lesions. Materials and methods: A 2-year retrospective (November 2007 to October 2009) and 1-year prospective study (November 2009 to October 2010). A total of 95 cases of premalignant and malignant lesions of cervix were studied. The hematoxylin-eosin stained slides were screened for apoptosis under oil immersion lens. Apoptotic index (AI) was calculated as the number of Apoptotic cells and Apoptotic bodies, expressed as percentage of total no. of tumour cells counted in each case. Mitotic index (MI) was calculated by counting mitosis among 1000 tumour cells. Turnover index (TOI) was obtained by adding MI and AI, i.e., (TOI = MI + AI). After calculating, all these indices were correlated with different grades of the cervical lesions. Results: Premalignant lesions were divided into four subgroups. On statistical analysis, it was found that the difference in the apoptotic indices and turnover indices in all the four subgroups was not statistically significant. However for mitotic indices, significant statistical difference was found in Subgroup II (mild dysplasia vs. moderate dysplasia) with a p value of 0.03 and in subgroup IV (squamous metaplasia vs. moderate/severe dysplasia) with a p value of 0.0005. Within the malignant group, we compared well differentiated with less well differentiated subgroup. Statistical analysis revealed a significant difference in TOI between the two subgroups of malignant tumours (p = 0.04). Statistical comparison between premalignant and malignant group of lesions showed a highly significant difference between the AI, MI and TOI with p value of 0.0001. Conclusion: We conclude that proliferative and apoptotic indices are useful in distinguishing between benign and malignant lesions of the cervix. Proliferative activity of a lesion is a reliable indicator of its malignant potential and together with apoptotic count gives an idea about the net growth of a tumour.
Extracorporeal membrane oxygenation for treating severe cardiac and respiratory disease in adults: Part 1--overview of extracorporeal membrane oxygenation.

s v c ( b s XTRACORPOREAL MEMBRANE OXYGENATION (ECMO) is mechanical support of the lungs and/or heart or a period of days to weeks by a modified heart-lung machine. here are 2 basic types of ECMO: venovenous (VV), which rovides support for the lungs only, and venoarterial (VA), hich provides support for both the heart and the lungs. VV CMO is primarily used for treating severe but potentially eversible respiratory failure, and VA ECMO is primarily used or treating severe cardiac or cardiorespiratory failure. Because A ECMO may be used as a bridge to a longer form of echanical support or to a heart transplant, the underlying ause of the cardiac failure need not necessarily be reversible. The Extracorporeal Life Support Organization (ELSO, www. lso.med.umich.edu/), based in Ann Arbor, MI, provides an mportant source of information on the indications for, outomes from, and complications of ECMO. ELSO is an interational consortium of health care professionals from over 100 edical centers that maintains a database, develops guidelines, nd produces an annual report. Data from the 2008 annual eport1 are widely quoted in this article and summarized in able 1. ELSO also publishes a textbook called Extracorporeal ardiopulmonary Support in Critical Care,2 but it is widely nown as “the red book”; this is an excellent resource. ECMO is a well-established therapy in pediatric patients, articularly for treating neonatal respiratory failure; a survival dvantage in pediatric patients for ECMO over conventional reatment has been convincingly shown in 4 randomized trials.3
Autoinducer 2 Controls Biofilm Formation in Escherichia coli through a Novel Motility Quorum-Sensing Regulator (MqsR, B3022)

ABSTRACT The cross-species bacterial communication signal autoinducer 2 (AI-2), produced by the purified enzymes Pfs (nucleosidase) and LuxS (terminal synthase) from S-adenosylhomocysteine, directly increased Escherichia coli biofilm mass 30-fold. Continuous-flow cells coupled with confocal microscopy corroborated these results by showing the addition of AI-2 significantly increased both biofilm mass and thickness and reduced the interstitial space between microcolonies. As expected, the addition of AI-2 to cells which lack the ability to transport AI-2 (lsr null mutant) failed to stimulate biofilm formation. Since the addition of AI-2 increased cell motility through enhanced transcription of five motility genes, we propose that AI-2 stimulates biofilm formation and alters its architecture by stimulating flagellar motion and motility. It was also found that the uncharacterized protein B3022 regulates this AI-2-mediated motility and biofilm phenotype through the two-component motility regulatory system QseBC. Deletion of b3022 abolished motility, which was restored by expressing b3022 in trans. Deletion of b3022 also decreased biofilm formation significantly, relative to the wild-type strain in three media (46 to 74%) in 96-well plates, as well as decreased biomass (8-fold) and substratum coverage (19-fold) in continuous-flow cells with minimal medium (growth rate not altered and biofilm restored by expressing b3022 in trans). Deleting b3022 changed the wild-type biofilm architecture from a thick (54-μm) complex structure to one that contained only a few microcolonies. B3022 positively regulates expression of qseBC, flhD, fliA, and motA, since deleting b3022 decreased their transcription by 61-, 25-, 2.4-, and 18-fold, respectively. Transcriptome analysis also revealed that B3022 induces crl (26-fold) and flhCD (8- to 27-fold). Adding AI-2 (6.4 μM) increased biofilm formation of wild-type K-12 MG1655 but not that of the isogenic b3022, qseBC, fliA, and motA mutants. Adding AI-2 also increased motA transcription for the wild-type strain but did not stimulate motA transcription for the b3022 and qseB mutants. Together, these results indicate AI-2 induces biofilm formation in E. coli through B3022, which then regulates QseBC and motility; hence, b3022 has been renamed the motility quorum-sensing regulator gene (the mqsR gene).
In silico analysis of AHJD-like viruses, Staphylococcus aureus phages S24-1 and S13′, and study of phage S24-1 adsorption

Staphylococcus aureus is a clinically important bacterium that is commensal in both humans and animals. Bacteriophage (phage) attachment to the host bacterial surface is an important process during phage infection, which involves interactions between phage receptor‐binding proteins and host receptor molecules. However, little information is available on the receptor‐binding protein of S. aureus phages. S. aureus virulent phages S24‐1 and S13′ (family Podoviridae, genus AHJD‐like viruses) were isolated from sewage. In the present study, we investigated the receptor‐binding protein of AHJD‐like viruses using phage S24‐1. First, based on a comparative genomic analysis of phages S24‐1 and S13′, open reading frame 16 (ORF16) of phage S24‐1 was speculated to be the receptor‐binding protein, which possibly determines the host range. Second, we demonstrated that this was the receptor‐binding protein of phage S24‐1. Third, our study suggested that wall teichoic acids in the cell walls of S. aureus are the main receptor molecules for ORF16 and phage S24‐1. Finally, the C‐terminal region of ORF16 may be essential for binding to S. aureus. These results strongly suggest that ORF16 of phage S24‐1 and its homologs may be the receptor‐binding proteins of AHJD‐like viruses.
Induction of Glutathione Synthesis Explains Pharmacodynamics of High-Dose Busulfan in Mice and Highlights Putative Mechanisms of Drug Interaction

Busulfan is an example of a drug eliminated through glutathione S-transferase (GST)-catalyzed conjugation with reduced glutathione (GSH). We studied the pharmacokinetics and toxicity of busulfan in C57BL6 mice in correlation with liver GST activity and GSH synthesis by accurate determination of precursors, namely, γ-glutamyl-cysteine and cysteine. A significantly lower incidence of acute toxicity was observed in mice receiving busulfan 16.5 mg/kg twice a day compared with animals receiving 33 mg/kg once a day. In both cases, a total dose of 132 mg/kg was administered over 4 days. The difference in toxicity was explained by pharmacokinetics since a strong induction of clearance was observed only in animals treated twice daily. Induction of metabolism was correlated with an increase in liver cysteine content and enhanced glutathione synthesis rate, whereas GST activity was unchanged. To our knowledge, this is the first time that in vivo flux of GSH synthesis has been shown to be closely related to a drug plasma clearance and toxicity. These results allow hypothesizing that GSH liver synthesis may directly influence busulfan clearance in humans with possible implications in the occurrence of hepatic veno-occlusive disease.
Adaptation to Faces and Voices

Exposure, or adaptation, to faces or voices biases perceptions of subsequent stimuli, for example, causing faces to appear more normal than they would be otherwise if they are similar to the previously presented stimuli. Studies also suggest that there may be cross-modal adaptation between sound and vision, although the evidence is inconsistent. We examined adaptation effects within and across voices and faces and also tested whether adaptation crosses between male and female stimuli. We exposed participants to sex-typical or sex-atypical stimuli and measured the perceived normality of subsequent stimuli. Exposure to female faces or voices altered perceptions of subsequent female stimuli, and these adaptation effects crossed modality; exposure to voices influenced judgments of faces, and vice versa. We also found that exposure to female stimuli did not influence perception of subsequent male stimuli. Our data demonstrate that recent experience of faces and voices changes subsequent perception and that mental representations of faces and voices may not be modality dependent. Both unimodal and cross-modal adaptation effects appear to be relatively sex-specific.
Experimental investigation of dual wave optimized reflector stacks in solidly mounted resonators

Optimizing the reflector stacks for both longitudinal and shear waves is critical in the design of SMRs for high Quality factor (Q) filters. In this work, we experimentally investigate two design approaches for reflector stack optimization, i.e. the phase error approach and the diffraction grating method (DGM). Various SiO2/W reflector stacks were fabricated and analyzed: one stack using DGM and four others using the phase error approach. The extracted ID Q shows the expected trend except for the quarter-wave like stack. 2D FEM simulations reveal that the quarter-wave stack with an increased top-oxide layer shows improved shear reflection. The DGM stack showed the highest experimental Q of 1700. The results indicate that these approaches are applicable for any reflector stack combination.
Diagnostic triage and the role of natriuretic peptide testing and echocardiography for suspected heart failure: an appropriateness ratings evaluation by UK GPs.

BACKGROUND Some UK GPs are acquiring access to natriuretic peptide (NP) testing or echocardiography as diagnostic tests for heart failure. This study developed appropriateness ratings for the diagnostic application of these tests in routine general practice. AIM To develop appropriateness ratings for the diagnostic application of NP testing or echocardiography for heart failure in general practice. DESIGN AND SETTING An appropriateness ratings evaluation in UK general practice. METHOD Four presenting symptoms (cough, bilateral ankle swelling, dyspnoea, fatigue), three levels of risk of cardiovascular disease (low, intermediate, high), and dichotomous categorisations of cardiovascular/chest examination and electrocardiogram result, were used to create 540 appropriateness scenarios for patients in whom NP testing or echocardiography might be considered. These were rated by a 10-person expert panel, consisting of GPs and GPs with specialist interests in cardiology, in a two-round RAND Appropriateness Method. RESULTS Onward referral for NP testing or echocardiography was rated as an appropriate next step in 217 (40.2%) of the 540 scenarios; in 194 (35.9%) it was rated inappropriate. The ratings also show where NP testing or echocardiography were ranked as equivalent next steps and when one test was seen as the more appropriate than the other. CONCLUSION NP testing should be the routine test for suspected heart failure where referral for diagnostic testing is considered appropriate. An abnormal electrocardiogram status makes referral to echocardiography an accompanying, or more appropriate, next step alongside NP testing, especially in the presence of dyspnoea. Abnormal NP testing should subsequently be followed up with referral for echocardiography.
Simultaneous phase and amplitude extraction from a single defocused image of a homogeneous object

We demonstrate simultaneous phase and amplitude extraction from a single defocused image of a homogeneous object. Subject to the assumptions explicitly stated in the derivation, the algorithm solves the twin‐image problem of in‐line holography and is capable of analysing data obtained using X‐ray microscopy, electron microscopy, neutron microscopy or visible‐light microscopy, especially as they relate to defocus and point projection methods. Our simple, robust, non‐iterative and computationally efficient method is applied to data obtained using an X‐ray phase contrast ultramicroscope.
Oxidative enzyme activities of the vastus lateralis muscle and the functional status in patients with COPD

BACKGROUND Enzymatic and histochemical abnormalities of the peripheral muscle may play a role in exercise intolerance in patients with chronic obstructive pulmonary disease (COPD). A study was undertaken to measure the mitochondrial enzyme activity of the vastus lateralis muscle in patients with COPD and to evaluate the relationship between enzyme activities and functional status. METHODS Fifty seven patients with COPD of mean (SD) age 66 (7) years with forced expiratory volume in one second (FEV1) 39 (15)% predicted and peak oxygen uptake (V˙o 2) of 14 (4) ml/min/kg and 15 normal subjects of similar age were included in the study. Each subject performed a stepwise exercise test up to maximal capacity during which five-breath averages of V˙o 2were measured. Muscle specimens were obtained by percutaneous needle biopsy of the vastus lateralis muscle and the activity of two mitochondrial enzymes (citrate synthase (CS) and 3-hydroxyacyl CoA dehydrogenase (HADH)) was measured. The functional status of the patients was classified according to peakV˙o 2. RESULTS CS and HADH activities were markedly reduced in patients with COPD compared with normal subjects (22.3 (2.7) versus 29.5 (7.3) μmol/min/g muscle (p<0.0001) and 5.1 (2.0) versus 6.7 (1.9) μmol/min/g muscle (p<0.005), respectively). The activity of CS decreased progressively with the deterioration in the functional status while that of HADH was not related to functional status. Using a stepwise regression analysis, percentage predicted functional residual capacity (FRC), the activity of CS, oxygen desaturation during exercise, age, and inspiratory capacity (% pred) were found to be significant determinants of peakV˙o 2. The regression model explained 59% of the variance in peak V˙o 2 (p<0.0001). CONCLUSIONS The oxidative capacity of the vastus lateralis muscle is reduced in patients with moderate to severe COPD compared with normal subjects of similar age. In these individuals the activity of CS correlated significantly with peak exercise capacity and independently of lung function impairment.
The use of body surface area as a criterion of drug dosage in cancer chemotherapy.

Summary The rationale for the use of body surface area as the criterion of dosage in anticancer chemotherapy has been outlined. The similarity in the dosage per unit of surface area of methotrexate, mechlorethamine, actinomycin D, and TSPA for certain laboratory animals and man is described. This is in contrast to the dissimilarity in the dosages per unit of weight for these compounds among laboratory animals and man, and among humans of different ages. It is suggested that cancer chemotherapists consider the applicability of body surface area as a criterion of drug dosage in their laboratory and clinical studies.