Miracle-dz/UniFAR-FTUs huggingface dataset:
Chitinases of the Avian Malaria Parasite Plasmodium gallinaceum, a Class of Enzymes Necessary for Parasite Invasion of the Mosquito Midgut*

The Plasmodium ookinete produces chitinolytic activity that allows the parasite to penetrate the chitin-containing peritrophic matrix surrounding the blood meal in the mosquito midgut. Since the peritrophic matrix is a physical barrier that the parasite must cross to invade the mosquito, and the presence of allosamidin, a chitinase inhibitor, in a blood meal prevents the parasite from invading the midgut epithelium, chitinases (3.2.1.14) are potential targets of malaria parasite transmission-blocking interventions. We have purified a chitinase of the avian malaria parasite Plasmodium gallinaceum and cloned the gene,PgCHT1, encoding it. PgCHT1 encodes catalytic and substrate-binding sites characteristic of family 18 glycohydrolases. Expressed in Escherichia coli strain AD494 (DE3), recombinant PgCHT1 was found to hydrolyze polymeric chitin, native chitin oligosaccharides, and 4-methylumbelliferone derivatives of chitin oligosaccharides. Allosamidin inhibited recombinant PgCHT1 with an IC50 of 7 μm and differentially inhibited two chromatographically separable P. gallinaceumookinete-produced chitinase activities with IC50 values of 7 and 12 μm, respectively. These two chitinase activities also had different pH activity profiles. These data suggest that theP. gallinaceum ookinete uses products of more than one chitinase gene to initiate mosquito midgut invasion.
Hyperacute lung rejection in the pig-to-human model. III. platelet receptor inhibitors synergistically modulate complement activation and lung injury

Background. The influence of platelet von Willebrand factor (vWF)–glycoprotein (GP)Ib-V-IX and GPIIb–IIIa receptor interactions in the context of hyperacute rejection (HAR) of pulmonary xenografts has not previously been explored. Methods. Aurintricarboxylic acid (ATA, an inhibitor of platelet-GPIb interactions with vWF), SC52012A (SC, a synthetic GPIIb/IIIa inhibiting peptide), or both were added to heparinized whole human blood before perfusion of isolated piglet lungs. Results were compared with unmodified blood (“unmodified”). Results. Perfusion of porcine lungs with unmodified human blood resulted in an immediate rise in pulmonary vascular resistance (PVR), fluid and platelet sequestration in the lung, and, without exception, cessation of function within 15 minutes with a mean survival of 8 minutes. Addition of ATA or SC before lung perfusion significantly decreased the rise in PVR, diminished histamine release, and prolonged survival to 31±11 and 31±22 minutes, respectively. When the therapies were combined, mean survival was 156±77 minutes (P <0.05 vs. either monotherapy). Complement activation was synergistically attenuated only when the drugs were used together. Conclusions. Platelet protein receptor adhesive interactions play an important role in amplification of complement activation during hyperacute lung rejection. Inhibiting recruitment of platelets at the site of initial immunologic injury to endothelial cells may protect porcine organs against thrombosis and inflammation during the initial exposure to human blood.
The role of MicroRNAs miR-200b and miR-200c in TLR4 signaling and NF-κB activation

Recognition of microbial products by members of the Toll-like receptor (TLR) family initiates intracellular signaling cascades that result in NF-κB activation and subsequent production of inflammatory cytokines. We explored the potential roles of microRNAs (miRNAs) in regulating TLR pathways. A target analysis approach to the TLR4 pathway adaptor molecules identified several putative targets of miR-200a, miR-200b and miR-200c. miRNA mimics were co-transfected with a NF-κB activity reporter plasmid into HEK293 cells stably expressing TLR4 (HEK293-TLR4). Mimics of both miR-200b and miR-200c, but not miR-200a, decreased NF-κB reporter activity in either untreated cells or in cells treated with endotoxin:MD2 as a TLR4 agonist. Transfection of HEK293-TLR4 cells with miR-200b or miR-200c significantly decreased expression of MyD88, whereas TLR4, IRAK-1 and TRAF-6 mRNAs were unaffected. When miR-200b or miR-200c mimics were transfected into the differentiated monocytic THP-1 cell line, the abundance of MyD88 transcripts, as well as LPS-induced expression of the pro-inflammatory molecules IL-6, CXCL9 and TNF-α were diminished. These data define miRNAs miR-200b and miR-200c as factors that modify the efficiency of TLR4 signaling through the MyD88-dependent pathway and can thus affect host innate defenses against microbial pathogens.
Primary Melanoma of the Vagina: A Clinicopathologic Analysis

Primary melanoma of the vagina is a rare tumor associated with a poor prognosis.The clinical and pathologic features of 15 patients treated at the University of Michigan Medical Center and Bowman Gray School of Medicine are reviewed.The presenting symptom of bleeding was noted in 80% of the patients.The cumulative 5-year survival was 17.4%. Two patients survived more than 5 years.All melanoma tumors were of the nodular type, 66% were located in the lower one-third of the vagina, and all patients were found to have invasion greater than 3 mm at the time of diagnosis.The majority of recurrences were located in the pelvis, with the lung being the most common metastatic site.Data from the literature were incorporated with these patients' data in a meta-analysis.Tumor thickness (6 mm or less) significantly (P=.015) affected the disease-free interval.Tumor size (less than 3 cm) significantly (P=.024) influenced survival, whereas age, stage, tumor location, and tumor thickness did not.There was no significant difference in survival among patients treated by surgical resection, irradiation, or surgical resection plus irradiation.The type of surgery, whether radical or conservative, also did not influence survival.One patient had a complete response to high-dose irradiation fractions (greater than 400 cGy), and this form of irradiation in conjunction with surgical resection is presented as a treatment option
Radical cystectomy in the treatment of bladder cancer in Iceland: A population-based study

Abstract Objective: Radical cystectomy (RC) is the standard treatment for muscle-invasive bladder cancer. Postoperative complications are reported to be as high as 65%. The objective of this study was to investigate complications and survival in Icelandic patients with bladder cancer who underwent RC. Materials and methods: All patients who had bladder cancer and underwent RC in Iceland from 2003 to 2012 were included. Information was obtained retrospectively from patients’ medical records and from the Icelandic Cause of Death Registry. Complications were classified according to the Clavien–Dindo classification system. The Kaplan–Meier method was used in the survival analysis. Only patients with transitional cell carcinoma (TCC) were included in the survival analysis. Results: Overall, 108 patients (male 81%, median age 68 years) underwent the procedure during the study period and 100 of them had TCC. Ileal conduit was performed in 86% of procedures and orthotopic neobladder in 14%. The median operation time was 266 min and the median blood loss during the procedure was 1000 ml. No patient died within 30 days of surgery, but one patient (0.9%) died within 90 days of surgery from complications of the surgery. Complications were reported for 62 patients (57%) overall. Major complications (Clavien 3–5) were reported in 32 patients (29%), and 30 patients (28%) had only minor complications (Clavien 1–2). Twenty-four patients (22%) had to undergo reoperation. Overall 5 year survival was 54%. Conclusion: Morbidity after RC is high but similar to that seen in other studies. Long-term survival of Icelandic patients is comparable to that in neighboring countries.
Characterization of Macrolide Efflux Pump mef Subclasses Detected in Clinical Isolates of Streptococcus pyogenes Isolated between 1999 and 2005

ABSTRACT The macrolide efflux mechanism of resistance, mef, was characterized in community-acquired respiratory tract infections with Streptococcus pyogenes. Fifty-four (4.6%) M phenotype isolates were screen tested as negative for mef(A). Of these 54 isolates, 5 (0.4%), 27 (2.3%), and 1 (0.1%) were considered to be mef(I) positive, a novel mosaic variant of mef, or a novel subclass of mef, respectively. This study shows (i) the definitive presence of mef(E) in S. pyogenes and its global distribution, (ii) the presence of a mosaic variant of mef composed of mef(A) and mef(E), (iii) the previously undescribed presence of mef(I) in S. pyogenes, and (iv) the presence of a novel subclass of mef in S. pyogenes.
TIF2, a 160 kDa transcriptional mediator for the ligand‐dependent activation function AF‐2 of nuclear receptors.

Nuclear receptors (NRs) act as ligand‐inducible transcription factors which regulate the expression of target genes upon binding to cognate response elements. The ligand‐dependent activity of the NR activation function AF‐2 is believed to be mediated to the transcription machinery through transcriptional mediators/intermediary factors (TIFs). We report here the cloning of the 160 kDa human nuclear protein TIF2, which exhibits all properties expected for a mediator of AF‐2: (i) it interacts in vivo with NRs in an agonist‐dependent manner; (ii) it binds directly to the ligand‐binding domains (LBDs) of NRs in an agonist‐ and AF‐2‐integrity‐dependent manner in vitro; (iii) it harbours an autonomous transcriptional activation function; (iv) it relieves nuclear receptor autosquelching; and (v) it enhances the activity of some nuclear receptor AF‐2s when overexpressed in mammalian cells. TIF2 exhibits partial sequence homology with the recently isolated steroid receptor coactivator SRC‐1, indicating the existence of a novel gene family of nuclear receptor transcriptional mediators.
The cost-effectiveness of infliximab (Remicade) in the treatment of rheumatoid arthritis in Sweden and the United Kingdom based on the ATTRACT study.

OBJECTIVE The cost per quality-adjusted life-year (QALY) of infliximab (Remicade) treatment in rheumatoid arthritis (RA) was estimated on the basis of a clinical trial comparing infliximab plus methotrexate with methotrexate alone in 428 patients with advanced disease [Anti-Tumour Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT)]. METHODS The effect of infliximab on disease progression and related costs and utilities was estimated using two disease progression models based on epidemiological cohorts followed for up to 15 yr in Sweden and the UK. The clinical trial data were used directly in the model and extrapolated to 10 yr using a cohort from the epidemiological studies matched for gender, age, time since onset of RA and disease severity. RESULTS One to two years of treatment with infliximab treatment reduced direct and indirect resource consumption in both countries, thereby partly offsetting the treatment cost. In the base case, including both direct and indirect costs, the cost per QALY gained was SEK 32 000 (euro 3440) in Sweden and GBP 21 600 (euro 34 800) for 1 yr of treatment. The respective QALY gains were 0.248 and 0.298. With 2 yr of treatment, the costs per QALY gained were SEK 150 000 (euro 16 100) and GBP 29 900 (euro;48 200). CONCLUSIONS Although 1-2 yr of treatment with infliximab will lead to savings in both direct and indirect costs, these will not offset the drug cost. However, the cost-effectiveness ratios remain within the usual range for treatments to be recommended for use.
Novel Characteristics of the Biological Properties of the Yeast Saccharomyces cerevisiae Eukaryotic Initiation Factor 2A*

Eukaryotic initiation factor 2A (eIF2A) has been shown to direct binding of the initiator methionyl-tRNA (Met-tRNAi) to 40 S ribosomal subunits in a codon-dependent manner, in contrast to eIF2, which requires GTP but not the AUG codon to bind initiator tRNA to 40 S subunits. We show here that yeast eIF2A genetically interacts with initiation factor eIF4E, suggesting that both proteins function in the same pathway. The double eIF2A/eIF4E-ts mutant strain displays a severe slow growth phenotype, which correlated with the accumulation of 85% of the double mutant cells arrested at the G2/M border. These cells also exhibited a disorganized actin cytoskeleton and elevated actin levels, suggesting that eIF2A might be involved in controlling the expression of genes involved in morphogenic processes. Further insights into eIF2A function were gained from the studies of eIF2A distribution in ribosomal fractions obtained from either an eIF5BΔ (fun12Δ) strain or a eIF3b-ts (prt1-1) strain. It was found that the binding of eIF2A to 40 and 80 S ribosomes was not impaired in either strain. We also found that eIF2A functions as a suppressor of Ure2p internal ribosome entry site-mediated translation in yeast cells. The regulation of expression from the URE2 internal ribosome entry site appears to be through the levels of eIF2A protein, which has been found to be inherently unstable with a half-life of ∼17 min. It was hypothesized that this instability allows for translational control through the level of eIF2A protein in yeast cells.
The prevalence of probable neuropathic pain in the US: results from a multimodal general-population health survey

Background The prevalence of neuropathic pain (NeP) has been estimated within specific health conditions; however, there are no published data on its broad prevalence in the US. The current exploratory study addresses this gap using the validated PainDetect questionnaire as a screener for probable NeP in a general-population health survey conducted with a multimodal recruitment strategy to maximize demographic representativeness. Materials and methods Adult respondents were recruited from a combination of Internet panels, telephone lists, address lists, mall-based interviews, and store-receipt invitations using a random stratified-sampling framework, with strata defined by age, sex, and race/ethnicity. Older persons and minorities were oversampled to improve prevalence estimates. Results were weighted to match the total adult US population using US Census data. Demographic information was collected, and respondents who experienced physical pain in the past 12 months completed the PainDetect and provided additional pain history. A cutoff score of 19 or greater on the PainDetect was used to define probable NeP. Results A total of 24,925 respondents (average response rate 2.5%) provided demographic data (52.2% female, mean age 51.5 years); 15,751 respondents reported pain (63.7%), of which 2,548 (15.7%, 95% confidence interval 14.9%–16.5%) had probable NeP based on the PainDetect, which was 10% (95% confidence interval 9.5%–10.5%) of all respondents. Among those reporting pain, the prevalence of probable NeP among Blacks and Hispanics was consistently higher than Whites in each age- and sex group. The highest prevalence among those with pain was among male Hispanics 35–44 years (32.4%) and 45–54 years (24.2%) old. The most commonly used medications reported by those with probable NeP were nonsteroidal anti-inflammatory drugs (44.2%), followed by weak opioids (31.7%), antiepileptics (10.9%), and strong opioids (10.9%). Conclusion This is the first study to provide an estimate of the prevalence of probable NeP in the US, showing significant variation by age and ethnicity.
Comparative visual function in four piscivorous fishes inhabiting Chesapeake Bay

SUMMARY Maintaining optimal visual performance is a difficult task in photodynamic coastal and estuarine waters because of the unavoidable tradeoffs between luminous sensitivity and spatial and temporal resolution, yet the visual systems of coastal piscivores remain understudied despite differences in their ecomorphology and microhabitat use. We therefore used electroretinographic techniques to describe the light sensitivities, temporal properties and spectral sensitivities of the visual systems of four piscivorous fishes common to coastal and estuarine waters of the western North Atlantic: striped bass (Morone saxatilis), bluefish (Pomatomus saltatrix), summer flounder (Paralichthys dentatus) and cobia (Rachycentron canadum). Benthic summer flounder exhibited higher luminous sensitivity and broader dynamic range than the three pelagic foragers. The former were at the more sensitive end of an emerging continuum for coastal fishes. By contrast, pelagic species were comparatively less sensitive, but showed larger day–night differences, consistent with their use of diel light-variant photic habitats. Flicker fusion frequency experiments revealed significant interspecific differences at maximum intensities that correlated with lifestyle and habitat. Spectral responses of most species spanned 400–610 nm, with significant day–night differences in striped bass and bluefish. Anadromous striped bass additionally responded to longer wavelengths, similar to many freshwater fishes. Collectively, these results suggest that pelagic piscivores are well adapted to bright photoclimates, which may be at odds with the modern state of eutrified coastal and estuarine waters that they utilize. Recent anthropogenic degradation of water quality in coastal environments, at a pace faster than the evolution of visual systems, may impede visually foraging piscivores, change selected prey, and eventually restructure ecosystems.
Platelet glycoprotein VI facilitates experimental lung metastasis in syngenic mouse models

Summary. Background: Glycoprotein (GP)VI is a key receptor for collagen on the platelet surface. It is a member of the immunoglobulin superfamily and is uniquely expressed on the surface of platelets, where it is assembled with the immunoreceptor tyrosine activation motif subunit, FcR‐γ. We have previously reported the generation of a murine model of GPVI deficiency that revealed profound defects in collagen‐induced platelet aggregation and in platelet activation following adhesion to collagen. Beyond the hemostasis/thrombosis paradigm, platelet receptors are emerging as significant participants in tumorigenesis and inflammation. Objective: In the current study, we have evaluated a role for platelet GPVI in primary tumor growth and experimental metastasis. Methods: Primary tumor induction and experimental metastasis assays were performed using syngenic immunocompetent animals and tumor cells derived from the C57BL/6J mouse strain in wild‐type (C57BL/6J) and N10 C57BL/6J congenic GPVI‐deficient mice. Results: Using either a Lewis lung carcinoma (D121) or melanoma (B16F10.1) cell line, we observed an approximately 50% reduction in the number of visible tumor foci in GPVI‐deficient mice as compared with control C57BL/6J mice. Additional studies were performed to compare the size of subcutaneously implanted tumor cells, that is, primary tumor growth. Here, we observed no noticeable size difference when comparing the presence or absence of platelet GPVI. Conclusions: The results demonstrate that the presence of platelet GPVI facilitates experimental tumor metastasis but does not contribute to the growth of primary tumors.
[High-dose chemotherapy in the treatment of children with malignant lymphoma].

BACKGROUND Children with primary refractory or recurrent malignant lymphoma have usually poor prognosis. Less than 10% of those, who were treated with conventional-dose regimens had survived for 2 years. In an attempt to improve the outcome for these patients, we explored the role of consolidation high-dose chemotherapy with autografting. METHODS AND RESULTS Forty-five patients with poor-prognosis lymphoma, of whom 27 were males, underwent megatherapy between January 1992 and December 1999. High-dose chemotherapy was indicated in patients with poor initial response to first-line chemotherapy (14 cases) or in the relapse (31 cases). The group consisted of 27 patients with Hodgkin's disease and 18 patients with non-Hodgkin's lymphoma. The median age was 14.7 years. The conditioning for Hodgkin's disease patients contained cyclophosphamide, etoposide and busulfan or carmustine. Patients with non-Hodgkin's lymphomas received cyclophosphamide, etoposide and busulfan or total body irradiation. Bone marrow was used as the source of haemopoietic stem cells in ten patients, peripheral blood in twenty-eight, and both sources were used in seven patients. After the median follow-up of 47 months, the final survival was 61%. Eleven patients died of the disease progression, four of the infectious complications, one at a car accident. Median time to relapse after the transplantation was 7.5 months. CONCLUSIONS Further improvement of these results will require earlier transplantation, improved preparative regiments or early posttransplant immunotherapy.
Release of vasoactive agents during cordocentesis: differences between normally grown and growth-restricted fetuses.

OBJECTIVE The purpose of this study was to evaluate whether cordocentesis is associated with the release of vasoactive substances and whether there are differences between normally grown and growth-restricted fetuses. STUDY DESIGN 6-Keto-prostaglandin F1 alpha (the stable metabolite of prostacyclin), endothelin-1, and cyclic guanosine monophosphate were measured in fetal blood at the beginning and closing of cordocentesis in 30 normally grown fetuses and 25 growth-restricted fetuses. This latter group was characterized by abnormal Doppler index values in umbilical artery and middle cerebral artery, suggestive of chronic hypoxemia as the causative factor of the impaired growth. In six growth-restricted fetuses bradycardia occurred at the end of the procedure. Umbilical artery pulsatility index was measured by Doppler ultrasonography immediately before and after the procedure. RESULTS The median interval between the two blood samples obtained by cordocentesis was 90 seconds (range 60 to 320 seconds). During this interval a significant rise of 6-keto-prostaglandin F1 alpha (p < or = 0.0001) and endothelin-1 (p = 0.03) was evidenced in normally grown fetuses. The increase in 6-keto-prostaglandin F1 alpha was significantly related (r = 0.52, p = 0.002) to the fall of umbilical artery pulsatility index occurring after the procedure. In growth-restricted fetuses cordocentesis induced a marked increase of endothelin-1 (p = 0.0002), which was significantly related to the severity of acidosis (r = 0.52, p = 0.018), whereas no modifications were evidenced for the other agents tested. The increase of endothelin-1 was higher in those growth-restricted fetuses showing bradycardia at the end of the procedure than in growth-restricted fetuses that did not (p = 0.04). The variations of the vasoactive substances assayed were not significantly related to the type of procedure (transamniotic or transplacental), the amount of blood aspirated during the procedure, the interval elapsing between the first and second samples, the gestational age at which the procedure was performed, and the degree of fetal smallness. CONCLUSION Cordocentesis induces the rapid release of vasoactive substances and the effect differs between normally grown and growth-restricted fetuses. This may explain the different hemodynamic response and the higher rate of complications occurring in the latter group after cordocentesis.