Miracle-dz/UniFAR-FTUs huggingface dataset:
The Severity of Toxic Reactions to Ephedra: Comparisons to Other Botanical Products and National Trends from 1993–2002

Objective. Ephedra is a botanical product widely used to enhance alertness, as a weight loss aide, and as a decongestant. Its reported adverse effects led the Food and Drug Administration (FDA) to ban ephedra-containing products in the United States in 2004. This study's purpose was to compare toxicity from botanical products containing ephedra to nonephedra products. Methods. The Toxic Exposure Surveillance System (TESS), a national poison center database, was utilized to determine the number and outcomes of cases involving botanical products reported from 1993–2002. Cases listing both a botanical product and any other drugs or chemicals were excluded a priori. Ten-year hazard rates (moderate outcomes + major outcomes + deaths per 1000 exposures) were used to compare botanical product categories. Results. There were 21,533 toxic exposures with definitive medical outcomes reported over the 10 yrs where a botanical product was the only substance involved. Of these, 4,306 (19.9%) had moderate or major medical outcomes and there were two deaths, for an overall hazard score of 200 per 1000 exposures. The number of ephedra reports to poison centers increased 150-fold over the 10-yr period. The hazard rate for products that contained only ephedra was 250 per 1000 exposures and 267 per 1000 exposures for products that contained ephedra and additional ingredients; whereas the hazard score for only nonephedra botanical products was 96 per 1000 exposures. The rate ratios for multibotanical products with ephedra (RR 1.33; 95% C.I. 1.27–1.40) and for single-ingredient ephedra products (RR 1.25; 95% C.I. 1.11–1.40) were both two to six times higher than those of other common botanical products. Yohimbe-containing products had the highest hazard score (417) and rate ratio (2.08; 95% C.I. 1.59–2.80). Conclusion. Ephedra-containing botanical products accounted for a significant number of toxic exposures with severe medical outcomes reported to poison centers. Hazard rate analysis suggests poison center–reported events involving ephedra-containing botanical products were much more likely to result in severe medical outcomes than those involving nonephedra-containing botanical products. These data support recommendations by policymakers that the sale of ephedra should be prohibited to protect consumers. Our data suggest that the botanical product, yohimbe, may also be associated with unacceptably high risks of toxicity and should receive close scrutiny from health policymakers.
Effects of Caffeine on Intraocular Pressure: The Blue Mountains Eye Study

Purpose:To examine the relationship between coffee and caffeine intakes and intraocular pressure (IOP). Materials and Methods:The Blue Mountains Eye Study examined 3654 participants aged 49+ years in an area west of Sydney, Australia. A detailed medical history questionnaire included average daily intakes of coffee and tea. The eye examination included Goldmann applanation tonometry and automated perimetry. Participants using glaucoma medications or who had previous cataract or glaucoma surgery or signs of pigmentary glaucoma/pigment dispersion, were excluded. Mean and maximum IOP calculations were used. Results:Participants with open-angle glaucoma (OAG) who reported regular coffee drinking had significantly higher mean IOP (19.63 mm Hg) than participants who said that they did not drink coffee (16.84 mm Hg), after multivariate adjustment, P = 0.03. Participants consuming ≥200 mg caffeine per day had higher mean IOP (19.47 mm Hg) than those consuming <200 mg caffeine per day (17.11 mm Hg), after adjusting for age, sex, and systolic blood pressure (SBP), P = 0.06. This association did not reach statistical significance after multivariate adjustment. No association between coffee or caffeine consumption and higher IOP was found in participants with ocular hypertension (OH) and those without open-angle glaucoma. Conclusions:In participants with open-angle glaucoma, this study identified a positive cross-sectional association between coffee consumption/higher caffeine intakes and elevated intraocular pressure.
Analysis of MHC Class II Antigen Processing by Quantitation of Peptides that Constitute Nested Sets

Peptides associated with class II MHC molecules are of variable length because in contrast to peptides associated with class I MHC molecules, their amino and C termini are not constrained by the structure of the peptide interaction with the binding site. The proteolytic processing events that generate these peptides are still not well understood. To address this question, peptides extracted from HLA-DR*0401 were analyzed using two types of mass spectrometry instrumentation. This enabled identification of >700 candidate peptides in a single analysis and provided relative abundance information on 142 peptides contained in 11 nested sets of 3–36 members each. Peptides of 12 residues or less occurred only at low abundance, despite the fact that they were predicted to fully occupy the HLA-DR*0401 molecule in a single register. Conversely, the relative abundance of longer species suggested that proteolytic events occurring after MHC binding determine the final structure of most class II-associated peptides. Our data suggest that C-terminal residues of these peptides reflect the action of peptidases that cleave at preferred amino acids, while amino termini appear to be determined more by proximity to the class II MHC binding site. Thus, the analysis of abundance information for class II-associated peptides comprising nested sets has offered new insights into proteolytic processing of MHC class II-associated peptides.
In-hospital outcomes of percutaneous coronary intervention in patients with chronic total occlusion: insights from the ERCTO (European Registry of Chronic Total Occlusion) registry.

AIMS In comparison with non-occlusive lesions, percutaneous coronary intervention (PCI) of chronic total occlusions (CTO) represents a greater challenge for the interventionalist, due to lower procedural success rates, relatively higher incidence of procedural complications and the increased rate of restenosis. The European Registry of Chronic Total Occlusion (ERCTO) was created with the goal of evaluating the real impact of CTO PCI in the European context, trying to analyse the rates of procedural success, technical information from the CTO procedures and patient outcome. METHODS AND RESULTS Data collection was carried out in 16 centres across Europe, starting from the beginning of January 2008. In two years of activity, a total of 1,914 patients with 1,983 CTO lesions were consecutively enrolled in the registry. Overall procedural success was achieved in 1,607 lesions (82.9%); anterograde procedures obtained higher procedural success of retrograde ones (83.2% versus 64.5%, p<0.001). Coronary perforation occurred more frequently in patients who underwent retrograde approach (4.7% versus 2.1%, p=0.04). Although no differences were observed in terms of 30-day major adverse cardiac events between anterograde and retrograde treated patients, a trend toward higher periprocedural non-Q-wave myocardial infarction was found in patients in which the retrograde approach was attempted (2.1% versus 1% p=0.08). Moreover, retrograde approach was related with longer procedural and fluoroscopy times (156.9±62.5 min vs. 98.2±52.8 min and 73.3±59.9 min vs. 38.2±43.9 min respectively, p<0.001) and higher contrast load administration (402±161 cc vs. 302±184 cc, p<0.001). CONCLUSIONS The first report of the ERCTO registry by the EuroCTO club shows a high procedural success rate obtained by expert European operators in a "real-world" consecutive series of patients, comparable with those reported by Japanese registries. The rate of observed procedural adverse events was low and similar to the non-CTO PCI series. In this registry, retrograde procedures were associated with extended fluoroscopy exposure and procedural time, increased contrast load administration as well as a higher incidence of coronary perforations. Such outcomes should become the standard of care that all centres undertaking CTO PCI should aspire to.
Finding Hidden Cliques of Size \sqrt{N/e} in Nearly Linear Time

Consider an Erd\"os-Renyi random graph in which each edge is present independently with probability 1/2, except for a subset $\sC_N$ of the vertices that form a clique (a completely connected subgraph). We consider the problem of identifying the clique, given a realization of such a random graph. The best known algorithm provably finds the clique in linear time with high probability, provided $|\sC_N|\ge 1.261\sqrt{N}$ \cite{dekel2011finding}. Spectral methods can be shown to fail on cliques smaller than $\sqrt{N}$. In this paper we describe a nearly linear time algorithm that succeeds with high probability for $|\sC_N|\ge (1+\eps)\sqrt{N/e}$ for any $\eps>0$. This is the first algorithm that provably improves over spectral methods. We further generalize the hidden clique problem to other background graphs (the standard case corresponding to the complete graph on $N$ vertices). For large girth regular graphs of degree $(\Delta+1)$ we prove that `local' algorithms succeed if $|\sC_N|\ge (1+\eps)N/\sqrt{e\Delta}$ and fail if $|\sC_N|\le(1-\eps)N/\sqrt{e\Delta}$.
Triterpene saponins with gastroprotective effects from tea seed (the seeds of Camellia sinensis).

Six new triterpene saponins, theasaponins A(1) (1), A(2) (2), A(3) (3), F(1) (4), F(2) (5), and F(3) (6), were isolated from the saponin fraction of the seeds of Camellia sinensis. The stereostructures of 1-6 were elucidated on the basis of chemical and physicochemical evidence. Theasaponin A(2) (2) showed an inhibitory effect on ethanol-induced gastric mucosal lesions in rats at a dose of 5.0 mg/kg, p.o. , and its activity was more potent than that of omeplazole. Structure-activity relationships for theasaponins on ethanol-induced gastroprotective activities may be suggested as follows: (1) the 28-acetyl moiety enhances activity; (2) theasaponins having a 23-aldehyde group exhibit more potent activities than those with a 23-hydroxymethyl group or a 23-methoxycarbonyl group.
δ and κ Opioid Receptors Are Differentially Regulated by Dynamin-dependent Endocytosis When Activated by the Same Alkaloid Agonist*

Many alkaloid drugs used as analgesics activate multiple opioid receptors. Mechanisms that distinguish the actions of these drugs on the regulation of individual μ, δ, and κ receptors are not understood. We have observed that individual cloned opioid receptors differ significantly in their regulation by rapid endocytosis in the presence of alkaloid drug etorphine, a potent agonist of μ, δ, and κ opioid receptors. Internalization of epitope-tagged δ opioid receptors from the plasma membrane is detectable within 10 min in the presence of etorphine. In contrast, κ receptors expressed in the same cells remain in the plasma membrane and are not internalized for ≥60 min, even when cells are exposed to saturating concentrations of etorphine. The rapid internalization of δ receptors is specifically inhibited in cells expressing K44E mutant dynamin I, suggesting that type-specific internalization of opioid receptors is mediated by clathrin-coated pits. Examination of a series of chimeric mutant κ/δ receptors indicates that at least two receptor domains, including the highly divergent carboxyl-terminal cytoplasmic tail, determine the type specificity of this endocytic mechanism. We conclude that structurally homologous opioid receptors are differentially sorted by clathrin-mediated endocytosis following activation by the same agonist ligand. These studies identify a fundamental mechanism of receptor regulation mediating type-specific effects of analgesic drugs that activate more than one type of opioid receptor.
Acetazolamide for severe apnea in Pitt–Hopkins syndrome

Acetazolamide for Severe Apnea in Pitt–Hopkins Syndrome Stijn L. Verhulst,* J. De Dooy, J. Ramet, N. Bockaert, R. Van Coster, B. Ceulemans, and W. De Backer Department of Pediatrics, Antwerp University Hospital, Edegem, Belgium Department of Pediatric Neurology, Ghent University Hospital, Ghent, Belgium Department of Pediatric Neurology, Antwerp University Hospital, Edegem, Belgium Department of Respiratory Medicine, Antwerp University Hospital, Edegem, Belgium
Motexafin gadolinium: a possible new radiosensitiser

Motexafin gadolinium (MGd, PCI-0120, Xcytrin®), a metallotexaphyrin developed by Pharmacyclics, is a redox active drug that selectively targets tumour cells with a potential action as a radiosensitiser. In vitro and in vivo models showed radiation enhancement when radiation followed MGd administration. Phase I and II clinical studies showed that MGd was well-tolerated with a maximum-tolerated dose set at 6.3 mg/kg. Acute side effects of discolouration of the sclera, skin and urine are reversible. The clinical efficacy was determined in an international Phase III trial for brain metastases with a significant difference in time to neurological progression for lung cancer brain metastases in favour of MGd and whole brain radiation versus whole brain radiation only. For the treatment of glioblastoma multiforme, promising results are found in a Phase I trial with a median survival of 17.3 months. Further investigation of the combination of MGd and radiotherapy will be worthwile.
Human Motor Neuron Diseases. Volume 36 of Advances in Neurology

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Contrasting requirements for ubiquitylation during Fc receptor‐mediated endocytosis and phagocytosis

Fc receptors on leukocytes mediate internalization of antibody‐containing complexes. Soluble immune complexes are taken up by endocytosis, while large antibody‐opsonized particles are internalized by phagocytosis. We investigated the role of ubiquitylation in internalization of the human FcγRIIA receptor by endocytosis and phagocytosis. A fusion of FcγRIIA to green fluorescent protein (GFP) was expressed in ts20 cells, which bear a temperature‐sensitive mutation in the E1 ubiquitin‐activating enzyme. Uptake of soluble IgG complexes mediated by FcγRIIA–GFP was blocked by incubation at the restrictive temperature, indicating that endocytosis requires ubiquitylation. In contrast, phagocytosis and phagosomal maturation were largely unaffected when ubiquitylation was impaired. FcγRIIA–GFP was ubiquitylated in response to receptor cross‐linking. Elimination of the lysine residues present in the cytoplasmic domain of FcγRIIA impaired endocytosis, but not phagocytosis. The proteasomal inhibitor clasto‐lactacystin β‐lactone strongly inhibited endocytosis, but did not affect phagocytosis. These studies demonstrate a role for ubiquitylation in the endocytosis of immune receptors, and reveal fundamental differences in the mechanisms underlying internalization of a single receptor depending on the size or multiplicity of the ligand complex.
Snow Leopard Permutations and Their Even and Odd Threads

Caffrey, Egge, Michel, Rubin and Ver Steegh recently introduced snow leopard permutations, which are the anti-Baxter permutations that are compatible with the doubly alternating Baxter permutations. Among other things, they showed that these permutations preserve parity, and that the number of snow leopard permutations of length $2n-1$ is the Catalan number $C_n$. In this paper we investigate the permutations that the snow leopard permutations induce on their even and odd entries; we call these the even threads and the odd threads, respectively. We give recursive bijections between these permutations and certain families of Catalan paths. We characterize the odd (resp. even) threads which form the other half of a snow leopard permutation whose even (resp. odd) thread is layered in terms of pattern avoidance, and we give a constructive bijection between the set of permutations of length $n$ which are both even threads and odd threads and the set of peakless Motzkin paths of length $n+1$.
Identification of retained N-formylmethionine in bacterial recombinant mammalian cytochrome P450 proteins with the N-terminal sequence MALLLAVFL...: roles of residues 3-5 in retention and membrane topology.

An N-terminal block to Edman degradation was observed when any of five different mammalian cytochrome P450 (P450) proteins was expressed in Escherichia coli using the N-terminal sequence MALLLAVFL. This block was also seen in Salmonella typhimurium. With all proteins examined, the block could be removed by mild acid hydrolysis (0.6--6 N HCl, 23 degrees C) to expose Met as the N-terminus, suggesting N-formylMet retention. The N-terminal peptide of a modified P450 1A2 ("mutant 1", containing a thrombin-sensitive site inserted at residue 25) was released with thrombin and analyzed by electrospray mass spectrometry and found to yield the M(r) expected for the N-formyl derivative (+/- 0.8 amu). The region of positions 3--5 was altered by random mutagenesis, and three P450 1A2-expressing clones were analyzed for nucleotide and amino acid sequences. The changes from LLL were to RER (P450 1A2a), VDS (P450 1A2b), and WRH (P450 1A2c); these all show slightly dissimilar hydropathy plots compared to the MALLLAVFL. sequence. Mutant P450 1A2a had the N-terminal Met removed to yield N-terminal Ala; P450 1A2b contained an unmodified Met at the N-terminus; P450 1A2c had an approximately 80% block of the N-terminal Met. Experiments with bacterial membranes containing expressed P450 1A2 mutant 1 and P450 1A2 mutant 2 (thrombin-sensitive site inserted at residue 46) suggest that thrombin site 2, but not 1, is sequestered in the membrane. Spheroplasts of bacteria expressing P450 1A2 and the mutants at positions 3--5 were treated with proteinase K; amino acid analysis indicated that no cleavage occurred. These results are interpreted in a model in which most of the mammalian P450 expressed in the bacterium is located in the cytosol, the region near residue 46 is in the inner membrane, the region near residue 25 is in the cytosol, and the N-terminus is either imbedded in the membrane or free in the cytosolic space, depending upon the sequence. However, the possibility that the differences in N-terminal processing are the result of direct changes in interactions with the deformylase and Met aminopeptidase cannot be excluded.
Isovolumetric regulation mechanisms in cultured cerebellar granule neurons

Cultured cerebellar granule neurons exposed to gradual reductions in osmolarity (− 1.8 mOsm/min) maintained constant volume up to − 50% external osmolarity (πo), showing the occurrence of isovolumetric regulation (IVR). Amino acids, Cl−, and K+ contributed at different phases of IVR, with early efflux threshold for [3H]taurine, d‐[3H]aspartate (as marker for glutamate) of πo− 2% and − 19%, respectively, and more delayed thresholds of − 30% for [3H]glycine and − 25% and − 29%, respectively, for Cl− (125I) and K+ (86Rb). Taurine seems preferentially involved in IVR, showing the lowest threshold, the highest efflux rate (five‐fold over other amino acids) and the largest cell content decrease. Taurine and Cl− efflux were abolished by niflumic acid and 86Rb by 15 mm Ba2+. Niflumic acid essentially prevented IVR in all ranges of πo. Cl−‐free medium impaired IVR when πo decreased to − 24% and Ba2+ blocked it only at a late phase of − 30% πo. These results indicate that in cerebellar granule neurons: (i) IVR is an active process of volume regulation accomplished by efflux of intracellular osmolytes; (ii) the volume regulation operating at small changes of πo is fully accounted for by mechanisms sensitive to niflumic acid, with contributions of both Cl− and amino acids, particularly taurine; (iii) Cl− contribution to IVR is delayed with respect to other niflumic acid‐sensitive osmolyte fluxes (osmolarity threshold of − 25% πo); and (iv), K+ fluxes do not contribute to IVR until a late phase (< − 30% πo).
CD14-Mac-1 interactions in Bacillus anthracis spore internalization by macrophages

Anthrax, a potentially lethal disease of animals and humans, is caused by the Gram-positive spore-forming bacterium Bacillus anthracis. The outermost exosporium layer of B. anthracis spores contains an external hair-like nap formed by the glycoprotein BclA. Recognition of BclA by the integrin Mac-1 promotes spore uptake by professional phagocytes, resulting in the carriage of spores to sites of spore germination and bacterial growth in distant lymphoid organs. We show that CD14 binds to rhamnose residues of BclA and acts as a coreceptor for spore binding by Mac-1. In this process, CD14 induces signals involving TLR2 and PI3k that promote inside-out activation of Mac-1, thereby enhancing spore internalization by macrophages. As observed with mice lacking Mac-1, CD14−/− mice are also more resistant than wild-type mice to infection by B. anthracis spores. Additionally, after B. anthracis spore challenge of CD14−/− mice, interference with the CD14-mediated signaling pathways results in increased mortality. Our results show that the binding and uptake of B. anthracis spores by phagocytic cells is a dynamic process and involves multiple receptors and signaling pathways.
[Scaling effects on landscape pattern indices].

The methods of spatial data aggregation based on majority and random rules were used in this study to reveal the scaling effects on landscape pattern in a classified TM imagery with 8 land cover types. For the majority rule-based aggregations, the proportion of most common cover types increased slowly, while that of less common cover types decreased rapidly with increasing grain. For random rule-based aggregation, each cover remained its original area on the aggregated maps. The largest patch sizes of shrub decreased, and those of the others increased in the majority rule-based aggregations with increasing scales. For random rule, the largest patch size of water (smallest cover type) decreased, but that of the others increased. The smallest patch size of each cover type was equal to the square of grain sizes. The average patch size of each cover type increased with increasing scales. However, the average patch size of dominant cover types increased rapidly in majority rule-based aggregations, while that of less common cover types increased rapidly in random rule-based aggregation. The patch count of each cover types decreased substantially with increasing grain. Random rule-based aggregation made landscape more fragmented and remained more patches. The diversity decreased in majority rule-based aggregation, and maintained its original value in random rule-based aggregation with increasing scales. Aggregation indices decreased with increasing map and measurement resolution, and the landscape became more aggregated in majority rule-based aggregation. However, under fixed measurement resolution (e.g., 30 m), aggregation indices increased and cover types were more clustered with increasing resolution. Moran's I decreased rapidly with increasing measurement and map resolution, and each cover type tended to be arranged randomly and independently in space. However, under fixed measurement resolution (e.g., 30 m), Moran's I increased and cover types were more clustered on aggregated maps than on original map with increasing map resolution.