Miracle-dz/UniFAR-FTUs huggingface dataset:
Dissection of Functional Sites in Herpesvirus Saimiri Complement Control Protein Homolog

ABSTRACT Herpesvirus saimiri is known to encode a homolog of human complement regulators named complement control protein homolog (CCPH). We have previously reported that this virally encoded inhibitor effectively inactivates complement by supporting factor I-mediated inactivation of complement proteins C3b and C4b (termed cofactor activity), as well as by accelerating the irreversible decay of the classical/lectin and alternative pathway C3 convertases (termed decay-accelerating activity). To fine map its functional sites, in the present study, we have generated a homology model of CCPH and performed substitution mutagenesis of its conserved residues. Functional analyses of 24 substitution mutants of CCPH indicated that (i) amino acids R118 and F144 play a critical role in imparting C3b and C4b cofactor activities, (ii) amino acids R35, K142, and K191 are required for efficient decay of the C3 convertases, (iii) positively charged amino acids of the linker regions, which are dubbed to be critical for functioning in other complement regulators, are not crucial for its function, and (iv) S100K and G110D mutations substantially enhance its decay-accelerating activities without affecting the cofactor activities. Overall, our data point out that ionic interactions form a major component of the binding interface between CCPH and its interacting partners.
Postnatal changes in responses of rat dorsal horn cells to afferent stimulation: a fibre‐induced sensitization

1 In vivo extracellular recordings were made of 171 dorsal horn cells in both superficial and deep laminae in urethane‐anaesthetized newborn rats aged 3, 6, 10 and 21 days, and their response to single and repeated stimuli to primary afferent fibres investigated. 2 No long‐latency spike responses were evoked in response to C fibre stimulation in pups at postnatal day 3 (P3) or P6, while by P10, 35 % of cells had a C fibre response. Latencies of response to A fibre skin stimulation were very long and varied widely in the youngest animals, particularly in superficial cells, but mean latencies decreased with postnatal age, from 33.1 ± 2.78 ms at P3 to 7.3 ± 0.3 ms at P21. The mean number of spikes evoked by a single A fibre skin stimulus was remarkably consistent between cells and not significantly different in superficial and deep laminae at each age. The mean value of 5.1 ± 0.6 at P3 increased to 7.0 ± 1.4 at P10. 3 Repeated stimulation of cutaneous A fibres at 0.5 Hz at twice the threshold level did not significantly alter the magnitude of the evoked response but led to shifts in latency, or ‘latency jitter’, which decreased with age. Deeper cells displayed more latency jitter than superficial cells. 4 Repeated stimulation of cutaneous A fibres at 0.5 Hz at twice the threshold level produced considerable sensitization in a population of dorsal horn cells in the neonate. This sensitization was unlike the classic C fibre‐evoked ‘wind‐up’ observed in adult dorsal horn. The direct A fibre‐evoked activity did not increase, but the background activity increased during repetitive stimulation leading to a prolonged after‐discharge beyond the stimulation period. At P6, 33 % of cells were sensitized, displaying a mean after‐discharge of 70.6 ± 18 s. At P10, only 6 % were sensitized, with a mean after‐discharge of 63 s, and by P21, sensitization was no longer observed. 5 The present study demonstrates that the postsynaptic activity evoked in neonatal dorsal horn cells by cutaneous afferents differs considerably from that in adults. The results may account for the known behavioural reflex sensitization to low‐intensity cutaneous stimulation observed in neonatal rats and man.
Relationship Between a Sepsis Intervention Bundle and In-Hospital Mortality Among Hospitalized Patients: A Retrospective Analysis of Real-World Data

BACKGROUND: Sepsis is a systemic response to infection that can lead to tissue damage, organ failure, and death. Efforts have been made to develop evidence-based intervention bundles to identify and manage sepsis early in the course of the disease to decrease sepsis-related morbidity and mortality. We evaluated the relationship between a minimally invasive sepsis intervention bundle and in-hospital mortality using robust methods for observational data. METHODS: We performed a retrospective cohort study at the University of California, San Francisco, Medical Center among adult patients discharged between January 1, 2012, and December 31, 2014, and who received a diagnosis of severe sepsis/septic shock (SS/SS). Sepsis intervention bundle elements included measurement of blood lactate; drawing of blood cultures before starting antibiotics; initiation of broad spectrum antibiotics within 3 hours of sepsis presentation in the emergency department or 1 hour of presentation on an inpatient unit; administration of intravenous fluid bolus if the patient was hypotensive or had a lactate level >4 mmol/L; and starting intravenous vasopressors if the patient remained hypotensive after fluid bolus administration. Poisson regression for a binary outcome variable was used to estimate an adjusted incidence-rate ratio (IRR) comparing mortality in groups defined by bundle compliance measured as a binary predictor, and to estimate an adjusted number needed to treat (NNT). RESULTS: Complete bundle compliance was associated with a 31% lower risk of mortality (adjusted IRR, 0.69, 95% confidence interval [CI], 0.53–0.91), adjusting for SS/SS presentation in the emergency department, SS/SS present on admission (POA), age, admission severity of illness and risk of mortality, Medicaid/Medicare payor status, immunocompromised host status, and congestive heart failure POA. The adjusted NNT to save one life was 15 (CI, 8–69). Other factors independently associated with mortality included SS/SS POA (adjusted IRR, 0.55; CI, 0.32–0.92) and increased age (adjusted IRR, 1.13 per 10-year increase in age; CI, 1.03–1.24). CONCLUSIONS: The University of California, San Francisco, sepsis bundle was associated with a decreased risk of in-hospital mortality across hospital units after robust control for confounders and risk adjustment. The adjusted NNT provides a reasonable and achievable goal to observe measureable improvements in outcomes for patients diagnosed with SS/SS.
Platelet adhesion signalling and the regulation of thrombus formation

Platelets perform a central role in haemostasis and thrombosis. They adhere to subendothelial collagens exposed at sites of blood vessel injury via the glycoprotein (GP) Ib-V-IX receptor complex, GPVI and integrin α2β1. These receptors perform distinct functions in the regulation of cell signalling involving non-receptor tyrosine kinases (e.g. Src, Fyn, Lyn, Syk and Btk), adaptor proteins, phospholipase C and lipid kinases such as phosphoinositide 3-kinase. They are also coupled to an increase in cytosolic calcium levels and protein kinase C activation, leading to the secretion of paracrine/autocrine platelet factors and an increase in integrin receptor affinities. Through the binding of plasma fibrinogen and von Willebrand Factor to integrin αIIbβ3, a platelet thrombus is formed. Although increasing evidence indicates that each of the adhesion receptors GPIb-V-IX and GPVI and integrins α2β1 and αIIbβ3 contribute to the signalling that regulates this process, the individual roles of each are only beginning to be dissected. By contrast, adhesion receptor signalling through platelet endothelial cell adhesion molecule 1 (PECAM-1) is implicated in the inhibition of platelet function and thrombus formation in the healthy circulation. Recent studies indicate that understanding of platelet adhesion signalling mechanisms might enable the development of new strategies to treat and prevent thrombosis.
Pathogenicity of biological control agents for livestock ectoparasites: a simulation analysis

The management of arthropod ectoparasites of livestock currently relies largely on the use of neurotoxic chemicals. However, concerns over the development of resistance, as well as operator and environmental contamination, have stimulated research into alternative approaches to their control, including the use of biological pathogens. The search for suitable pathogens often focuses on identifying the most highly virulent agents for application. However, practical issues such as the ability of a pathogen to penetrate to the skin through hair or wool, tolerance of high skin surface temperatures and high residual activity may mean that the most virulent pathogens are not necessarily the most appropriate for commercial application. Here, a simulation model is constructed and used to highlight a range of key features which characterize suitable pathogens for such application. Sensitivity analysis shows that even a relatively low probability of infection following contact between infectious and susceptible individuals may give acceptable control, providing it is counterbalanced by higher survival of both infected and infectious parasite hosts in order to allow the rate of transmission to exceed the threshold required to suppress parasite population growth. The model highlights the need for studies attempting to identify sustainable biocontrol agents to explore the use of pathogens which have a range of the characteristics that contribute to overall pathogenicity, but which are also most compatible with practical application systems.
情報の歴史 : 象形文字から人工知能まで = The longest chronicle : history informs

１ 情報の記録—われわれはどのように情報を記録し、伝達しはじめたのか。 ２ 情報の分岐—経典と写本と図書館が、古代世界のデータベースを準備する ３ 情報と物語—航海術と印刷術は、情報文化の表現を多様に変えていく ４ 技術と情報—産業革命が社会と技術を近づけ、人々の世界観を変質させる。 ５ 情報の拡大—資本と労働が対立し、世界は激しい情報の多様化をおこす。 ６ 戦争と情報—宗教は後退し、資本の矛盾が情報文化に辛い試練を迫る。 ７ 情報の文化—環境危機をかかえたグローバル・コミュニケーションの時代へ。
Inhalational induction of anaesthesia with 8% sevoflurane in children: conditions for endotracheal intubation and side-effects

Background and objective: This study was designed to assess the conditions for endotracheal intubation or insertion of a laryngeal mask airway following an inhalational induction using 8% sevoflurane and nitrous oxide without the use of muscle relaxants or opioids. Methods: There were two groups: 30 children had endotracheal intubation and 30 children had a laryngeal mask airway inserted. Induction of anaesthesia was accomplished using an inspiratory concentration of sevoflurane 8% in a nitrous oxide and oxygen mixture. After an end-expiratory concentration of sevoflurane of at least 4% had been reached, when the pupils were miotic and centred, the trachea was intubated or a laryngeal mask inserted. The time to loss of consciousness and successful airway management was recorded. Jaw relaxation, movements, visibility, and position of the vocal cords and vital parameters were monitored. Results: Jaw relaxation was complete in all children. The vocal cords were completely visible in all patients of the tracheal intubation group, whereas vocal cord relaxation was incomplete in five children. Nevertheless, all children had an atraumatic intubation or insertion of the laryngeal mask without the use of a muscle relaxant. Vital signs were stable in both groups. There were no cases of restlessness and/or postoperative shivering. Four patients in the endotracheal group (13.3%) were nauseous and three (10%) vomited, while two children (6.6%) in the laryngeal mask group experienced nausea and vomiting. Conclusions: Induction with sevoflurane in nitrous oxide and oxygen leads to fast loss of consciousness and provides ideal conditions for managing the airway without supplemental opioids or muscle relaxants. Furthermore, sevoflurane using this technique was very well tolerated, indicated by high haemodynamic stability and a reduced rate of postoperative restlessness, shivering, nausea and vomiting.
Outcome of admission to a medium secure psychiatric unit

Background This is the first long-term follow-up of patients discharged from a medium secure unit. Aims To describe the short– and long-term outcomes of admission for all patients discharged during a 14-year period. Method A longitudinal cohort study of all 234 patients discharged from the Denis Hill Unit, Bethlem Royal Hospital, between 1980 and 1994, followed for an average 6.6 years. Results Although 48% of admissions were from prison, only 8% returned there, with most being transferred to another psychiatric bed. One-fifth of patients spent none of the follow-up time in the community; 75% of patients had at least one readmission; only 24% were convicted of further offences. Conclusions Re-offending rates are comparable with those for patients discharged from high-security hospitals, and much lower than those for released prisoners. The high readmission rates indicate the need for a range of services to maintain former patients in the community.
Cardiac Fibroblasts Arrest at the G1/S Restriction Point in Response to Interleukin (IL)-1β

Although responsible for only approximately one-third of the overall myocardial mass, the interstitial fibroblasts of the heart serve a fundamental role in establishing the functional integrity of myocardium and are the major source of myocardial extracellular matrix production. Their importance in clinical medicine is underscored by the observation that fibroblast numbers increase in response to several pathologic circumstances that are associated with an increase in extracellular matrix production, such as long standing hypertension and myocardial injury/infarction. Up to the present time, however, there has been little information available on either the kinetics of the cardiac fibroblast cell cycle, or the fundamental mechanisms that regulate its entry into and exit from the cell cycle. Previous work from our laboratory examining the effects of interleukin (IL)-1β on myocardial growth and gene expression in culture indicated that cardiac fibroblasts have a diminished capacity to synthesize DNA in response to mitogen in the presence of this cytokine. The mechanism of IL-1β action was not clear, however, and could have resulted from action at several different points in the cell cycle. The investigations described in this report indicate that IL-1β exerts its effect on the fibroblast cell cycle at multiple levels through altering the expression of cardiac fibroblast cyclins, cyclin-dependent kinases, and their inhibitors, which ultimately affect the phosphorylation of the retinoblastoma gene product.
Etude de marqueurs moléculaires et des variants de l’EGFR dans les gliomes infiltrants de l’adulte

Les difficultes de classification et les traitements decevants des gliomes infiltrants conduisent a rechercher des marqueurs diagnostiques, pronostiques et theranostiques. Dans notre travail, nous avons i) recherche les deletions 1p, 19q, 10p, 10q et une amplification de l’EGFR, et etudie l’expression de l’INA, ii) analyse l'expression genique et proteique de l'EGFR. La deletion complete 1p19q est associee au phenotype oligodendroglial et a une survie plus longue alors que les pertes 10p et 10q sont liees au phenotype astrocytaire et a un pronostic defavorable. Une forte expression d’INA est un marqueur de bon pronostic, predictif de la deletion 1p19q mais l'etude immunohistochimique ne permet de remplacer l'analyse genomique. La presence d'une amplification du gene de l’EGFR est un marqueur de malignite lie au type histologique et au grade (glioblastomes et astrocytomes de grade III) ainsi qu'a la presence du mutant vIII. Par epissage alternatif, le gene de l’EGFR donne les transcrits variants v1, v2, v3, v4 qui codent pour les isoformes proteiques a, b, c et d. Nos resultats montrent que les profils d’expression des variants et des isoformes different selon le type histologique. Les glioblastomes ont des niveaux d'expression plus eleves des variants EGFRv3, -v4 et du mutant EGFRvIII que les autres types tumoraux. Nous avons comme projets de correler nos resultats a la presence ou l'absence des mutations IDH1/2, d'analyser l'expression genique et proteique de l'EGFR dans d'autres types tumoraux et de preciser le role des isoformes en utilisant des modeles experimentaux de cultures cellulaires.
Imported strongyloidosis: a longitudinal analysis of 31 cases.

BACKGROUND Attention regarding imported tropical diseases is typically focused on malaria, although other parasitic diseases such as strongyloidosis may also cause serious health problems. The importance of assessing clinical features and of proper diagnosis and treatment is presented on the basis of 31 patients with imported strongyloidosis. METHODS A retrospective analysis was performed regarding patients treated for strongyloidosis in two referral centers in Switzerland from 1998 to 2002. RESULTS Imported strongyloidosis was investigated in 12 travelers and 19 immigrants. The reasons for diagnostic work-up were clinical symptoms in 84% and eosinophilia and screening in each of 22.5%. All patients had a history of travel or residence in endemic areas. Initial therapy was effective in 20 patients, and there was a tendency for a better response to ivermectin compared with the response to other drugs. A significant reduction in blood eosinophil count and serologic antibody titer was observed in patients responding to therapy after an average of 96 and 270 days, respectively. CONCLUSIONS Strongyloidosis must be suspected in travelers and immigrants with skin or abdominal symptoms from regions where Strongyloides stercoralis is highly endemic. The results of this case series confirm that ivermectin is the drug of choice in treating imported strongyloidosis. Response to therapy can be assessed by serology and differential white blood count performed over 6 months after therapy.
Low Free-Thyroxine Levels are a Risk Factor for Subclinical Atherosclerosis in Euthyroid Hyperlipidemic Patients

Background Patients displaying overt and subclinical hypothyroidism have more cardiovascular risk factors. Consequently, they are more likely to develop atherosclerosis and cardiovascular diseases. Objective To analyze whether low free-thyroxine levels (FTL) would also be associated with atherosclerosis in euthyroid patients. Methods We selected a group of 1434 healthy euthyroid male patients without known histories of thyroid disease and with levels of thyroid-stimulating hormone values within the normal range (mean 1.70 ± 0.76 mUl/l, range 0.13–4.01 mUl/l). Mean age of these patients who had been referred for assessment of hyperlipidemia was 44.6 years and mean FTL was 14.25 ± 3.06 pmol/l. We divided the population according to the degree of atherosclerosis in the carotid arteries. Results Mean age, body mass index, systolic blood pressure, cigarettes/day, blood level of glucose, cholesterol levels, and fibrinogen levels were significantly higher for the patients with atherosclerotic lesions whereas mean FTL was lower for patients with carotid atherosclerosis (P = 0.0002). The relationship between FTL and carotid atherosclerosis was independent from the following cardiovascular risk factors: age, hypertension, amount of excess weight, cholesterol level, fibrinogen level, smoking status, and presence versus absence of diabetes mellitus. Conclusions Low FTL is a risk factor for atherosclerosis in male euthyroid hyperlipidemic patients.
Usefulness of EGFR mutation screening in pleural fluid to predict the clinical outcome of gefitinib treated patients with lung cancer

The importance of epidermal growth factor receptor (EGFR) gene mutation has been recognized in nonsmall cell lung cancer (NSCLC), requiring the standardization of mutation screening system including the kind of samples. Here, we examined the EGFR mutation status in 61 pleural fluid samples from NSCLC cases using direct sequencing, nonenriched PCR, mutant‐enriched PCR and peptide nucleic acid‐locked nucleic acid (PNA‐LNA) PCR clamp assay. The mutant‐enriched PCR assay detected 16 mutant cases. Among them, the nonenriched PCR assay failed to detect 3 mutant cases. Regarding the discrepancy between mutant‐enriched PCR and PNA‐LNA PCR clamp assays, 3 cases of exon19‐deletions were detected only by mutant‐enriched PCR assay and no difference at the L858R mutation. There was no difference in results between direct sequencing and nonenriched PCR assay. We also correlated the EGFR mutation with clinical outcome of gefitinib‐treated 29 cases. EGFR mutations were present in 10 cases, revealing 7 partial response and 3 no change (NC). In EGFR wild‐type cases, 10 revealed NC and 9 progressive disease. The responders were significantly more frequent among the EGFR mutant cases than among the wild‐type (p < 0.0001). Overall survival (p = 0.0092) and progression‐free survival (p = 0.018) were significantly longer among the EGFR mutant cases than among the wild‐type. In summary, we evaluated the utility of EGFR mutation screening in pleural fluid using 4 assays that showed some discrepancies arising from the designs of the assays. As clinical importance, the EGFR mutation status in pleural fluid can be a biomarker for the favorable outcome of gefitinib‐treated NSCLC cases. © 2006 Wiley‐Liss, Inc.
Corneal surface asphericity, roughness, and transverse contraction after uniform scanning excimer laser ablation.

PURPOSE To examine the interaction between the excimer laser and residual tissue. METHODS Ten cadaveric porcine eyes with exposed corneal stroma and plastic test spheres underwent uniform 6-mm ablation with a scanning excimer laser. Corneal profilometry of the central 3 mm was measured with submicrometer resolution optical interferometry, before and after uniform excimer ablation. Eleven surface-marked eyes were photomicrographed before and after excimer ablation. Images were superimposed, and mark positional changes were measured. RESULTS Uniform scanning excimer laser ablation of the corneal stroma produces a significant central steepening and peripheral flattening in the central 3-mm of the diameter. The central 1-mm corneal curvature radius (r) decreased from r = 10.07 ± 0.44 (95% CI) to 7.22 ± 0.30 mm, and the central 2-mm radius decreased from r = 10.16 ± 0.44 to 8.10 ± 0.43 mm. Q values, measuring asphericity in the 2-mm radius of the central cornea, were significantly lower before than after ablation (-5.03 ± 4.01 vs. -52.4 ± 18.7). Surface roughness increased significantly from 0.65 ± 0.06 to 1.75 ± 0.32 μm after ablation. The central 2 mm of the stromal surface contracted by 2.21% ± 0.80% at a sustained temperature of 5°C. Ablation of plastic spheres produced no significant change. CONCLUSIONS The excimer laser interacts with the nonablated residual stromal surface in a characteristic fashion not seen with isotropic, inorganic material. Increases in asphericity, surface roughness, surface contraction, and stromal morphologic changes are supportive of this interaction. The surface changes demonstrated may be indicative of temperature-induced transverse collagen fibril contraction and stress redistribution, or the ablation threshold of the stromal surface may be altered. This phenomenon may be of increased importance using lasers with increased thermal load.