Miracle-dz/UniFAR-FTUs huggingface dataset:
Toxicity of substituted anilines to Pseudokirchneriella subcapitata and quantitative structure‐activity relationship analysis for polar narcotics

This study evaluated the toxic effects of substituted anilines on Pseudokirchneriella subcapitata with the use of a closed algal toxicity testing technique with no headspace. Two response endpoints (i.e., dissolved oxygen production [DO] and algal growth rate) were used to evaluate the toxicity of anilines. Both DO and growth rate endpoints revealed similar sensitivity to the effects of anilines. However, trichloroanilines showed stronger inhibitory effects on microalgal photosynthetic reactions than that on algal growth. For various aquatic organisms, the relative sensitivity relationship for anilines is Daphnia magna > luminescent bacteria (Microtox) ≥ Pocelia reticulata ≥ Pseudokirchneriella subcapitata ≥ fathead minnow > Tetrahymena pyriformis. The susceptibility of P. subcapitata to anilines is similar to fish, but P. subcapitata is apparently less sensitive than the water flea. The lack of correlation between the toxicity revealed by different aquatic organisms (microalgae, D. magna, luminescent bacteria, and P. reticulata) suggests that anilines might have different metabolic routes in these organisms. Both hydrogen bonding donor capacity (the lowest unoccupied molecular orbital energy, Elumo) and hydrophobicity (1‐octanol:water partition coefficient, KOW) were found to provide satisfactory descriptions for the toxicity of polar narcotics (substituted anilines and chlorophenols). Quantitative structure‐activity relationships (QSARs) based on Elumo, log KOW, or both values were established with r2 values varying from 0.75 to 0.92. The predictive power for the QSAR models were found to be satisfactory through leave‐one‐out cross‐validation. Such relationships could provide useful information for the estimation of toxicity for other polar narcotic compounds.
Quantitative prediction of twinning stress in fcc alloys: Application to Cu-Al

Twinning is one of most prevalent deformation mechanisms in materials. Having established a quantitative theory to predict onset twinning stress crit in fcc elemental metals from their generalized planar-fault-energy GPFE surface, we exemplify its use in alloys where the Suzuki effect i.e., solute energetically favors residing at and near planar faults is operative; specifically, we apply it in Cu-xAl x is 0, 5, and 8.3 at. % in comparison with experimental data. We compute the GPFE via density-functional theory, and we predict the solute dependence of the GPFE and crit, in agreement with measured values. We show that crit correlates monotonically with the unstable twin fault energies the barriers to twin nucleation rather than the stable intrinsic stacking-fault energies typically suggested. We correlate the twinning behavior and electronic structure with changes in solute content and proximity to the fault planes through charge-density redistribution at the fault and changes to the layer- and site-resolved density of states, where increased bonding charge correlates with decrease in fault energies and crit.
Empirically supported treatments in pediatric psychology: constipation and encopresis.

OBJECTIVE To review the empirical research examining behavioral and medical treatments for constipation and fecal incontinence. METHOD Sixty-five articles investigating intervention efficacy were identified and reviewed. Twenty-three of the studies were excluded because they were case studies or were less well-controlled single-case designs. The intervention protocol for each study was identified and coded, with studies employing the same interventions matched and evaluated according to the Chambless criteria. RESULTS From the literature base to date, no well-established interventions have emerged. However, four probably efficacious treatments and three promising interventions were identified. Two different medical interventions plus positive reinforcement fit the criteria for the probably efficacious category (one with fiber recommendation and one without). Three biofeedback plus medical interventions fit efficacy category criteria: one probably efficacious for constipation with abnormal defecation dynamics (full medical intervention plus biofeedback for paradoxical contraction), and two fit the promising intervention criteria for constipation and abnormal defecation dynamics (full medical intervention plus biofeedback for EAS strengthening, correction of paradoxical contraction and home practice; and biofeedback focused on correction of paradoxical contraction, medical intervention without fiber recommendation, and positive reinforcement). Two extensive behavioral interventions plus medical intervention also met efficacy criteria for constipation plus incontinence (medical intervention without laxative maintenance plus positive reinforcement, dietary education, goal setting, and skills building presented in a small-group format fits criteria for a promising intervention; and positive reinforcement and skills building focused on relaxation of the EAS during defecation, but without biofeedback, plus medical intervention meets the probably efficacious criteria). CONCLUSIONS A discussion of the current weaknesses in this research area follows. Specific recommendations for future research are made including greater clarity in treatment protocol and sample descriptions, reporting cure rates rather than success rates, utilization of adherence checks, and investigation of potential differential outcomes for subgroups of children with constipation and incontinence.
Secure local filtering algorithms for distributed optimization

We study a class of local filtering algorithms for consensus-based distributed optimization in the presence of faulty or adversarial nodes. These algorithms do not require the regular nodes to know anything about the global network (other than their own neighbors), and are thus highly scalable. For this class of algorithms, we provide graph-theoretic conditions that guarantee consensus among the regular nodes under various bounds on the number of adversarial nodes (either across the entire network, or in the local neighborhood of any regular node). We prove that a consequence of reaching consensus is that the states of the regular nodes converge to the convex hull of the minimizers of their individual functions, regardless of the actions taken by the adversarial nodes.
Rearrangement of side-chains in a Zif268 mutant highlights the complexities of zinc finger-DNA recognition.

Structural and biochemical studies of Cys(2)His(2) zinc finger proteins initially led several groups to propose a "recognition code" involving a simple set of rules relating key amino acid residues in the zinc finger protein to bases in its DNA site. One recent study from our group, involving geometric analysis of protein-DNA interactions, has discussed limitations of this idea and has shown how the spatial relationship between the polypeptide backbone and the DNA helps to determine what contacts are possible at any given position in a protein-DNA complex. Here we report a study of a zinc finger variant that highlights yet another source of complexity inherent in protein-DNA recognition. In particular, we find that mutations can cause key side-chains to rearrange at the protein-DNA interface without fundamental changes in the spatial relationship between the polypeptide backbone and the DNA. This is clear from a simple analysis of the binding site preferences and co-crystal structures for the Asp20-->Ala point mutant of Zif268. This point mutation in finger one changes the specificity of the protein from GCG TGG GCG to GCG TGG GC(G/T), and we have solved crystal structures of the D20A mutant bound to both types of sites. The structure of the D20A mutant bound to the GCG site reveals that contacts from key residues in the recognition helix are coupled in complex ways. The structure of the complex with the GCT site also shows an important new water molecule at the protein-DNA interface. These side-chain/side-chain interactions, and resultant changes in hydration at the interface, affect binding specificity in ways that cannot be predicted either from a simple recognition code or from analysis of spatial relationships at the protein-DNA interface. Accurate computer modeling of protein-DNA interfaces remains a challenging problem and will require systematic strategies for modeling side-chain rearrangements and change in hydration.
Neuroanatomy of the complex tibial organ of Stenopelmatus (Orthoptera: Ensifera: Stenopelmatidae)

Stenopelmatidae (or “Jerusalem crickets”) belong to the atympanate Ensifera, lacking hearing organs in the foreleg tibiae. Their phylogenetic position is controversial, either as a taxon in Tettigonioidea or within the clade of Gryllacridoidea. Similarly, the origin of tibial auditory systems in Ensifera is controversial. Therefore, we investigated the neuronal structures of the proximal tibiae of Stenopelmatus spec. with the hypothesis that internal sensory structures are similar to those in tympanate Ensifera. In Stenopelmatus the complex tibial organ consists of three neuronal parts: the subgenual organ, the intermediate organ, and a third part with linearly arranged neurons. This tripartite organization is also found in tympanate Ensifera, verifying our hypothesis. The third part of the sense organ found in Stenopelmatus can be regarded by the criterion of position as homologous to auditory receptors of hearing Tettigonioidea. This crista acustica homolog is found serially in all thoracic leg pairs and contains 20 ± 2 chordotonal neurons in the foreleg. The tibial organ was shown to be responsive to vibration, with a broad threshold of about 0.06 ms−2 in a frequency range from 100–600 Hz. The central projection of tibial sensory neurons terminates into two equally sized lobes in the primary sensory neuropil, the medial ventral association center. The data are discussed comparatively to those of other Ensifera and mapped phylogenetically onto recently proposed phylogenies for Ensifera. The crista acustica homolog could represent a neuronal rudiment of a secondarily reduced ear, but neuronal features are also consistent with an evolutionary preadaptation. J. Comp. Neurol. 511:81–91, 2008. © 2008 Wiley‐Liss, Inc.
Multidrug Resistance Protein 4 (ABCC4)-mediated ATP Hydrolysis

Multidrug resistance protein 4 (MRP4/ABCC4), transports cyclic nucleoside monophosphates, nucleoside analog drugs, chemotherapeutic agents, and prostaglandins. In this study we characterize ATP hydrolysis by human MRP4 expressed in insect cells. MRP4 hydrolyzes ATP (Km, 0.62 mm), which is inhibited by orthovanadate and beryllium fluoride. However, unlike ATPase activity of P-glycoprotein, which is equally sensitive to both inhibitors, MRP4-ATPase is more sensitive to beryllium fluoride than to orthovanadate. 8-Azido[α-32P]ATP binds to MRP4 (concentration for half-maximal binding ∼3 μm) and is displaced by ATP or by its non-hydrolyzable analog AMPPNP (concentrations for half-maximal inhibition of 13.3 and 308 μm). MRP4 substrates, the prostaglandins E1 and E2, stimulate ATP hydrolysis 2- to 3-fold but do not affect the Km for ATP. Several other substrates, azidothymidine, 9-(2-phosphonylmethoxyethyl)adenine, and methotrexate do not stimulate ATP hydrolysis but inhibit prostaglandin E2-stimulated ATP hydrolysis. Although both post-hydrolysis transition states MRP4·8-azido[α-32P]ADP·Vi and MRP4·8-azido[α-32P]ADP·beryllium fluoride can be generated, nucleotide trapping is ∼4-fold higher with beryllium fluoride. The divalent cations Mg2+ and Mn2+ support comparable levels of nucleotide binding, hydrolysis, and trapping. However, Co2+ increases 8-azido[α-32P]ATP binding and beryllium fluoride-induced 8-azido[α-32P]ADP trapping but does not support steady-state ATP hydrolysis. ADP inhibits basal and prostaglandin E2-stimulated ATP hydrolysis (concentrations for half-maximal inhibition 0.19 and 0.25 mm, respectively) and beryllium fluoride-induced 8-azido[α-32P]ADP trapping, whereas Pi has no effect up to 20 mm. In aggregate, our results demonstrate that MRP4 exhibits substrate-stimulated ATP hydrolysis, and we propose a kinetic scheme suggesting that ADP release from the post-hydrolysis transition state may be the rate-limiting step during the catalytic cycle.
Harre and Madden's Multifarious Account of Natural Necessity

In this paper, I critically examine Harre and Madden's attempt, largely as it occurs in their Causal Powers, to secure for causes and laws of nature a kind of necessity which although consistent with commonsensical empiricism and anti-idealistic philosophy of science nevertheless runs counter to the humean-positivistic tradition, which denies the existence of any distinctively "natural" or causal necessity. In the course of the paper, I reveal the multifarious nature of their account and show that each part of that account, commonsensical or ontological, is inadequate. I indicate as well how the multifarious nature of the account allows and even encourages an evasive shifting about in the face of adversity, which shifting no doubt contributes to whatever illusion of adequacy is present in their treatment.
Microsatellite instability and allelic imbalance in primary and secondary colorectal cancer.

BACKGROUND Several studies of colorectal cancer have shown an association between the number and type of genomic defects and the stage of disease. A subset of colorectal tumours are due to inactivation of DNA mismatch repair genes and these tumours exhibit microsatellite instability. The aim of the present study was to compare and contrast the genomic defects present in both the primary and metastatic stages of the disease using microsatellite probes. METHODS Modifications of the allelic profiles of 25 microsatellite regions were studied in a total of 85 colorectal tumours using fluorescent polymerase chain reaction (PCR) technology and subsequent direct analysis on an automatic sequencer. This approach was used because it allows the study of microsatellite instability and allelic imbalance. Stepwise logistic regression analysis was used to develop a model to predict whether the tumour was primary or secondary from the percentage of allelic imbalance. Subsequently, a group of 17 patients with primary colorectal tumours was analysed prospectively to test the proposed model. RESULTS Six of 39 primary tumours showed microsatellite instability compared to 0 of 29 liver metastases (P = 0.03). Primary tumours showed significantly less allelic imbalance than liver metastases (P < 0.001). Three probes (d18s53, d9s158 and d10s191) were selected for use in a model to classify a tumour as primary or secondary on the basis of the degree of allelic imbalance. When tested prospectively this model had a specificity of 82%. CONCLUSIONS The present study demonstrates the potential importance of using microsatellite probes both as a diagnostic tool and as a research technique to investigate the mechanisms of tumour progression. An important clinical finding is that none of the colorectal liver metastases showed microsatellite instability (0 of 29). This analysis also confirmed other work that has shown a direct relationship between the degree of allelic imbalance and the stage of disease.
[Predictors of the course of schizophrenic diseases under neuroleptic long-term medication (author's transl)].

70 schizophrenic outpatients have been treated continuously after index hospital discharge with neuroleptic drugs for an average of 14.3 years. In predicting their outcome in several dimensions (rehospitalization rate, symptoms, social and work adjustment, self ratings) differential predictor patterns could be confirmed, at most accounting for 65% of the outcome variance. In part work adjustment at follow-up cold be predicted by premorbid social and sexual adjustment as well as by working capability at index discharge. The most powerful predictor for the number of social relations was the former frequency of social contacts. Rehospitalization was related to higher neuroleptic equivalence dose at index discharge among other predictors, whereas presence of symptoms could be predicted e.g. by formerly longer hospital stays. Although at the beginning of the treatment our sample was classified as "process schizophrenic" on "classic" prognostic scales, 40-60% of our cases had a relative good outcome. This results and the considerable decrease of the rehospitalization rate from 0.57 before treatment to 0.11 during treatment stand for a clear treatment related improvement of the spontaneous prognosis. The partly mutually independence of the outcome criteria and predictor patterns underlines the importance of multiaxial diagnosis.
Cyclophosphamide and antithymocyte globulin as a conditioning regimen for allogeneic marrow transplantation in patients with aplastic anaemia: a long‐term follow‐up

A total of 81 severe aplastic anaemia patients, aged 2–63 years, received human leucocyte antigen‐matched related marrow grafts after cyclophosphamide + antithymocyte globulin followed by postgrafting methotrexate + ciclosporin. Median follow‐up was 9·2 years. Ninety‐six per cent of patients had sustained engraftment, 24% developed acute graft‐versus‐host disease (GVHD), grade II in all but two patients, and 26% developed chronic GVHD; all surviving patients eventually responded to immunosuppressive therapy. Six patients developed cancer: one fatal lymphoma and five carcinomas (all five patients are now free of cancer). Survival was 88%. The regimen appeared well tolerated and effective in heavily pretreated patients with aplastic anaemia.
The thrombin E192Q–BPTI complex reveals gross structural rearrangements: implications for the interaction with antithrombin and thrombomodulin

Previous crystal structures of thrombin indicate that the 60‐insertion loop is a rigid moiety that partially occludes the active site, suggesting that this structural feature plays a decisive role in restricting thrombin‘s specificity. This restricted specificity is typified by the experimental observation that thrombin is not inhibited by micromolar concentrations of basic pancreatic trypsin inhibitor (BPTI). Surprisingly, a single atom mutation in thrombin (E192Q) results in a 10−8 M affinity for BPTI. The crystal structure of human thrombin mutant E192Q has been solved in complex with BPTI at 2.3 Å resolution. Binding of the Kunitz inhibitor is accompanied by gross structural rearrangements in thrombin. In particular, thrombin's 60‐loop is found in a significantly different conformation. Concomitant reorganization of other surface loops that surround the active site, i.e. the 37‐loop, the 148‐loop and the 99‐loop, is observed. Thrombin can therefore undergo major structural reorganization upon strong ligand binding. Implications for the interaction of thrombin with antithrombin and thrombomodulin are discussed.
Protection against Anthrax Lethal Toxin Challenge by Genetic Immunization with a Plasmid Encoding the Lethal Factor Protein

ABSTRACT The ability of genetic vaccination to protect against a lethal challenge of anthrax toxin was evaluated. BALB/c mice were immunized via gene gun inoculation with eucaryotic expression vector plasmids encoding either a fragment of the protective antigen (PA) or a fragment of lethal factor (LF). Plasmid pCLF4 contains the N-terminal region (amino acids [aa] 10 to 254) of Bacillus anthracis LF cloned into the pCI expression plasmid. Plasmid pCPA contains a biologically active portion (aa 175 to 764) ofB. anthracis PA cloned into the pCI expression vector. One-micrometer-diameter gold particles were coated with plasmid pCLF4 or pCPA or a 1:1 mixture of both and injected into mice via gene gun (1 μg of plasmid DNA/injection) three times at 2-week intervals. Sera were collected and analyzed for antibody titer as well as antibody isotype. Significantly, titers of antibody to both PA and LF from mice immunized with the combination of pCPA and pCLF4 were four to five times greater than titers from mice immunized with either gene alone. Two weeks following the third and final plasmid DNA boost, all mice were challenged with 5 50% lethal doses of lethal toxin (PA plus LF) injected intravenously into the tail vein. All mice immunized with pCLF4, pCPA, or the combination of both survived the challenge, whereas all unimmunized mice did not survive. These results demonstrate that DNA-based immunization alone can provide protection against a lethal toxin challenge and that DNA immunization against the LF antigen alone provides complete protection.
Evaluation of the Architect Epstein-Barr Virus (EBV) Viral Capsid Antigen (VCA) IgG, VCA IgM, and EBV Nuclear Antigen 1 IgG Chemiluminescent Immunoassays for Detection of EBV Antibodies and Categorization of EBV Infection Status Using Immunofluorescence Assays as the Reference Method

ABSTRACT Commercial immunoassays for detecting IgG and IgM antibodies against Epstein-Barr virus (EBV), viral capsid antigens (VCA), and IgGs toward EBV nuclear antigen-1 (EBNA-1) are routinely used in combination to categorize EBV infection status. In this study, we evaluated the performances of the Architect EBV VCA IgG, VCA IgM, and EBNA-1 IgG chemiluminescent microparticle assays (CMIAs) in EBV serological analyses using indirect immunofluorescence assays and anticomplement immunofluorescence assays as the reference methods for VCA IgG, VCA IgM, and EBNA-1 IgG antibody detection, respectively. A total of 365 serum samples representing different EBV serological profiles were included in this study. The κ values (concordances between the results) obtained in the Architect CMIA and those in the reference assays were 0.905 (P < 0.0001) for VCA IgM, 0.889 (P < 0.0001) for VCA IgG, and 0.961 (P < 0.0001) for EBNA-1 IgG. The sensitivities and specificities were, respectively, 91.08% and 99.48% for VCA IgM, 99.23% and 86.27% for VCA IgG, and 96.77% and 99.16% for EBNA-1 IgG. The sensitivities and specificities of the Architect CMIA panel were, respectively, 99.15% and 98.6% for diagnosing a primary infection, 97.62% and 93.39% for diagnosing a past EBV infection, and 92.42% and 97.82% for diagnosing the absence of an EBV infection. In summary, we demonstrated that the Architect EBV antibody panel performs very well for EBV antibody detection and correctly categorizes clinically relevant EBV infection states.
Rapid assessment of ceftazidime, ciprofloxacin, and gentamicin susceptibility in exponentially-growing E. coli cells by means of flow cytometry.

Exponentially growing E. coli cells were cultivated in the presence of ceftazidime, ciprofloxacin, and gentamicin in concentrations ranging from 0.5-8 minimal inhibitory concentration (MIC), permeabilized by means of cold shock in EDTA/azide, and stained with the DNA-specific dye combination of ethidium bromide and mithramycin before the fluorescence, light scattering, and cell number were measured flow-cytometrically. In order to evaluate the applicability of the cold-shock procedure, cells were also permeabillized by 70% ethanol. Permeabilization by cold shock, which eliminates washing of the cells, reduced the preparation time to <5 min. A statistically significant increase in light scattering and fluorescence, i.e., cell size and DNA content, could be detected already after 30 min of ceftazidime and ciprofloxacin exposure, even at sub-MIC concentrations. The results obtained with these drugs with cold-shock permeabilization were similar to those seen with ethanol fixation. For gentamicin-treated cells, however, a majority of the cells lost their fluorescence after cold shock. In gentamicin-treated cells fixed in ethanol, there was no consistent effect on either light scattering or fluorescence; however, we observed a substantial fragmentation and leakage of DNA in such cells. The cell proliferation was completely inhibited within 30 min of gentamicin incubation. For all three drugs, loss of light scattering and DNA were associated with cellular disintegration, i.e., reduced viability. The present results demonstrate that effects of ceftazidime, ciprofloxacin, and gentamicin on E. coli can be detected by flow cytometry within 1 h from the beginning of drug exposure to the completed measurement.