gebhart/patrepeval huggingface dataset:
Secondary structural predictions for the clostridial neurotoxins (1994)

The primary structures of a family of ten clostridial neurotoxins have recently been deduced yet little information is presently available concerning their secondary or tertiary structures. Because the overall similarity percentage of multiply aligned sequences is high, the secondary structures of these metalloendopeptidases are also expected to be conserved. The neural net program, PHD (Rost and Sander, Proc. Natl. Acad. Sci. USA 90:7558-7562, 1993), predicted that the secondary structures of the neurotoxins were indeed conserved in both single and multiple sequence modes of analysis. Predictions for the amounts of helical, extended, and loop states from the single sequence analyses were consistent with previously published data from circular dichroism studies on some of these neurotoxins. In the single analysis mode, only the aligned regions were predicted to show conservation of the three-state structure. In contrast, the multiple sequence analysis predicted that a conserved state (variable loops) also exists in non-aligned regions. Alignments with the primary structure of the prototypic metalloendopeptidase thermolysin showed that about 25% of the residues within this enzyme are similar to those in the neurotoxins. A comparison of thermolysin's known secondary structure with the predictions from this study showed that about 80% of thermolysin's residues could be structurally aligned with those in the neurotoxins. These predictions provide the necessary framework to build a homologous low-resolution tertiary structure of the neurotoxin active site that will be essential in the development of synthetic inhibitors.
Cell intrinsic alterations underlie hematopoietic stem cell aging (2005)

Loss of immune function and an increased incidence of myeloid leukemia are two of the most clinically significant consequences of aging of the hematopoietic system. To better understand the mechanisms underlying hematopoietic aging, we evaluated the cell intrinsic functional and molecular properties of highly purified long-term hematopoietic stem cells (LT-HSCs) from young and old mice. We found that LT-HSC aging was accompanied by cell autonomous changes, including increased stem cell self-renewal, differential capacity to generate committed myeloid and lymphoid progenitors, and diminished lymphoid potential. Expression profiling revealed that LT-HSC aging was accompanied by the systemic down-regulation of genes mediating lymphoid specification and function and up-regulation of genes involved in specifying myeloid fate and function. Moreover, LT-HSCs from old mice expressed elevated levels of many genes involved in leukemic transformation. These data support a model in which age-dependent alterations in gene expression at the stem cell level presage downstream developmental potential and thereby contribute to age-dependent immune decline, and perhaps also to the increased incidence of leukemia in the elderly.
Results of a phase I/II open‐label, safety and efficacy trial of coagulation factor IX (recombinant), albumin fusion protein in haemophilia B patients (2015)

This study demonstrated the efficacy for weekly routine prophylaxis of rIX-FP to prevent spontaneous bleeding episodes and for the treatment of bleeding episodes. In addition no safety issues were detected during the study and an improved PK profile was demonstrated.
Antiinflammatory polysaccharide produced by serratia piscatorum (1974)

Crude preparations of protease and culture filtrate of Serratia piscatorum IFO 12527 contained a heat-resistant, large molecular and non-proteinous anti-inflammatory ingredient(s) (PLS). The active ingredient was precipitated with Rivanol or Cetavlon, and purified by extraction with n-butanol or by adsorption with Lloyd’s reagent. From these and other chemical data, PLS is considered to be an acid polysaccharide. PLS injected i.m. inhibited the edema induced by carrageenin and anti-serum in rat feet. The effect on carrageenin edema was 37 times as potent as that of indomethacin and 200 times that of hydrocortisone acetate. These anti-edema effects were not observed by oral administration. PLS, i.m., inhibited cotton pellet granuloma more markedly than hydrocortisone acetate, without decreasing the weight of the adrenals and thymus. It had weak activating effect on kinin-forming systems in the rat plasma in vitro. Additional pharmacological properties of PLS are also described.
Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype (2016)

Reducing expression of the fetal hemoglobin (HbF) repressor BCL11A leads to a simultaneous increase in γ-globin expression and reduction in β-globin expression. Thus, there is interest in targeting BCL11A as a treatment for β-hemoglobinopathies, including sickle cell disease (SCD) and β-thalassemia. Here, we found that using optimized shRNAs embedded within an miRNA (shRNAmiR) architecture to achieve ubiquitous knockdown of BCL11A profoundly impaired long-term engraftment of both human and mouse hematopoietic stem cells (HSCs) despite a reduction in nonspecific cellular toxicities. BCL11A knockdown was associated with a substantial increase in S/G2-phase human HSCs after engraftment into immunodeficient (NSG) mice, a phenotype that is associated with HSC exhaustion. Lineage-specific, shRNAmiR-mediated suppression of BCL11A in erythroid cells led to stable long-term engraftment of gene-modified cells. Transduced primary normal or SCD human HSCs expressing the lineage-specific BCL11A shRNAmiR gave rise to erythroid cells with up to 90% reduction of BCL11A protein. These erythrocytes demonstrated 60%-70% γ-chain expression (vs. < 10% for negative control) and a corresponding increase in HbF. Transplantation of gene-modified murine HSCs from Berkeley sickle cell mice led to a substantial improvement of sickle-associated hemolytic anemia and reticulocytosis, key pathophysiological biomarkers of SCD. These data form the basis for a clinical trial application for treating sickle cell disease.
Flame made nanoparticles permit processing of dense, flexible, Li+ conducting ceramic electrolyte thin films of cubic-Li7La3Zr2O12 (c-LLZO) (2016)

Conventional casting–sintering of flame made nanoparticles result in high density and ionic conductivity c-LLZO flexible thin film membranes.
Experiences with the Illumina high density bovine BeadChip (2011)

The effect of increasing SNP density on the accuracy and inflation of genomic predictions of protein yield was investigated. Three SNP densities were studied. One was based on the 50K chip (38,296 SNPs). The two others were based on the high-density (HD) chips; HD1 (692,598 SNPs) and a subset, HD2 (329,329 SNPs), obtained by reducing the multicollinearity of the HD1 SNPs. The data set consisted of 4211 Holstein Friesian (HF), Jersey (J) and HFxJ sires genotyped with the 50K chip. The HD1 data was obtained through either genotyping or imputation. The test animals (N=605) were the two youngest cohorts of the progeny-tested sires. The genomic breeding values (GBVs) of the test animals were predicted using Bayesian and nonparametric methods. All models included the polygenic effect. A higher SNP density was found to slightly improve the accuracy of prediction when Bayesian ridge regression was used to train on one breed and predict on a different breed. When using an across-breed analysis, the increase in SNP density did not increase the accuracy of predicting the GBVs. Furthermore, the genomic predictions were inflated compared to the model that included only the polygenic effect, with predictions obtained using the HD genotypes having greater inflation than those obtained from the 50K genotypes. The training data set may not have been large enough to take full advantage of the HD genotypes.
Role of the Colorless Polypeptides in Phycobilisome Assembly in Nostoc sp. (1983)

We have identified the function of the ;extra' polypeptides involved in phycobilisome assembly in Nostoc sp. These phycobilisomes, as those of other cyanobacteria, are composed of an allophycocyanin core, phycoerythrin- and phycocyanin-containing rods, and five additional polypeptides of 95, 34.5, 34, 32, and 29 kilodaltons. The 95 kilodalton polypeptide anchors the phycobilisome to the thylakoid membrane (Rusckowski, Zilinskas 1982 Plant Physiol 70: 1055-1059); the 29 kilodalton polypeptide attaches the phycoerythrin- and phycocyanin-containing rods to the allophycocyanin core (Glick, Zilinskas 1982 Plant Physiol 69: 991-997). Two populations of rods can exist simultaneously or separately in phycobilisomes, depending upon illumination conditions. In white light, only one type of rod with phycoerythrin and phycocyanin in a 2:1 molar ratio is synthesized. Associated with this rod are the 29, 32, and 34 kilodalton colorless polypeptides; the 32 kilodalton polypeptide links the two phycoerythrin hexamers, and the 34 kilodalton polypeptide attaches a phycoerythrin hexamer to a phycocyanin hexamer. The second rod, containing predominantly phycocyanin, and the 34.5 and 29 kilodalton polypeptides, is synthesized by redlight-adapted cells; the 34.5 kilodalton polypeptide links two phycocyanin hexamers. These assignments are based on isolation of rods, dissociation of these rods into their component biliproteins, and analysis of colorless polypeptide composition, followed by investigation of complexes formed or not formed upon their recombination.
Stereospecific Synthesis of P-Chiral Analogs of Oligonucleotides (2003)

As has been emphasized in corresponding chapters of this book, isotopic or elemental replacement of any of two nonbridging oxygens attached to internucleotide phosphorus atom(s) by substituent X (Fig. 1) creates, by virtue of asymmetry, new center(s) of chirality and results in the formation of m diastereoisomers of the oligonucleotide’s congener. The number m is determined by the number n of modified phosphates, according to formula m = 2n. With the exception of diastereoisotopomers (X= 17O or 18O), which are nonseparable by any so-far-developed separation technique, separation of diastereoisomeric oligonucleotides containing modified phosphates (Fig. 1, X = S; Se; C2H5O-; CH3-; ArNH-; R2N-) has been achieved by means of chromatographic techniques. Effectiveness of the separation depends, however, on the number of modifications within the oligonucleotide chain and is practically limited to n=l,2. Achievements in this field have been exhaustively summarized by Zon (1).
Peptide Methyl Ketones as Reversible Inhibitors of Cysteine Proteinases (1989)

Peptide methyl ketones represent a new class of reversible, competitive cysteine proteinase inhibitor with little or no effect on serine proteinases. The affinity of the inhibitors to papain (EC 3.4.22.3), cathepsin B (EC 3.4.22.1) and cathepsin L (EC 3.4.22.15) depends on the peptide chain length and on side-chain effects. Variations in the P1 and P4 positions (terminology of Schechter and Berger) and their influence on the efficiency of the inhibitors have been investigated. The most effective inhibitors display inhibition constants in the micromolar range. In contrast to the endopeptidases papain and the cathepsins B and L, the aminoendopeptidase cathepsin H (EC 3.4.22.16) is not inhibited by N-acylated peptide methyl ketones but only by amino methyl ketones containing a free alpha-amino group. The endopeptidases are not affected by amino methyl ketones.
Ligand Binding Induces an Ammonia Channel in 2-Amino-2-desoxyisochorismate (ADIC) Synthase PhzE (2011)

PhzE utilizes chorismate and glutamine to synthesize 2-amino-2-desoxyisochorismate (ADIC) in the first step of phenazine biosynthesis. The PhzE monomer contains both a chorismate-converting menaquinone, siderophore, tryptophan biosynthesis (MST) and a type 1 glutamine amidotransferase (GATase1) domain connected by a 45-residue linker. We present here the crystal structure of PhzE from Burkholderia lata 383 in a ligand-free open and ligand-bound closed conformation at 2.9 and 2.1 Å resolution, respectively. PhzE arranges in an intertwined dimer such that the GATase1 domain of one chain provides NH(3) to the MST domain of the other. This quaternary structure was confirmed by small angle x-ray scattering. Binding of chorismic acid, which was found converted to benzoate and pyruvate in the MST active centers of the closed form, leads to structural rearrangements that establish an ammonia transport channel approximately 25 Å in length within each of the two MST/GATase1 functional units of the dimer. The assignment of PhzE as an ADIC synthase was confirmed by mass spectrometric analysis of the product, which was also visualized at 1.9 Å resolution by trapping in crystals of an inactive mutant of PhzD, an isochorismatase that catalyzes the subsequent step in phenazine biosynthesis. Unlike in some of the related anthranilate synthases, no allosteric inhibition was observed in PhzE. This can be attributed to a tryptophan residue of the protein blocking the potential regulatory site. Additional electron density in the GATase1 active center was identified as zinc, and it was demonstrated that Zn(2+), Mn(2+), and Ni(2+) reduce the activity of PhzE.
Cryptococcal infection of the central nervous system. (1985)

Two patients with cryptococcal infection of the central nervous system are described. These cases illustrate the variability in mode of presentation of this disease. Upon diagnosis, both patients were initially treated with a combination of amphotericin B and 5-fluorocytosine. Despite an early clinical and serological response, limiting side effects occurred in both cases and 5-fluorocytosine treatment was terminated. In Case 2, 5-fluorocytosine therapy was reinstituted at lower dosages later in the course of the illness, with good results. Combination therapy is superior to amphotericin B alone. However, to circumvent significant toxicity problems close monitoring of renal function, peripheral blood counts and serum 5-fluorocytosine levels are essential. Treatment is usually administered for a minimum of six weeks and remission is assessed on clinical, mycological and serological grounds. Thereafter, adequate follow-up is mandatory.
Cartilage Repair With Chitosan-Glycerol Phosphate-Stabilized Blood Clots (2007)

A new biomaterial for cartilage repair has been developed and investigated in animal studies and in a clinical cohort. The biomaterial is a physiological solution of chitosan (a natural polysaccharide containing glucosamine residues) in a buffer containing glycerol phosphate (GP). The soluble and physiological characteristics of this polymer solution permit its combination with freshly drawn autologous whole blood to form a hybrid polymer-blood mixture that can be applied to cartilage and bone surfaces, to which it adheres and solidifies as a polymer-stabilized clot. Histology and electron microscopy analysis of in vitro-generated chitosan-GP/blood clots revealed the chitosan component to be dispersed among the blood components, to interact closely with platelets, and to impede platelet-mediated clot contraction, thereby maintaining a voluminous bioactive and adhesive clot at the site of application. Experiments in microdrilled cartilage lesions in adult rabbits comparing chitosan-GP/blood clots to controls (microdrilled only) highlighted the ability of chitosan-GP/blood clots to recruit more host cells and to increase subchondral vascularization and bone-remodeling activity during acute and intermediate stages of repair. This led to the establishment of more hyaline repair cartilage that was integrated with a porous subchondral bone plate. Microfractured cartilage defects in adult sheep treated with chitosan-GP/blood clots resulted in a statistically significant increase in tissue fill with a greater proportion of hyaline cartilage compared to controls (microfracture only). Patients with femoral condyle cartilage lesions have received chitosan-GP/blood implants to resurface articular cartilage as part of a compassionate use program for medical devices. Results to date suggest safety and clinical benefit of this approach that is free from both donor site morbidity and suture damage to healthy adjacent cartilage. This single-intervention approach is now the subject of a multicenter, randomized comparative clinical trial designed and initiated to investigate cartilage repair resulting from treatment with chitosan-GP and microfracture vs microfracture alone.
Small-Molecule MDM2-p53 Inhibitors: Recent Advances (2015)

Potent and selective small-molecule inhibitors of the p53-MDM2 interaction intended for the treatment of p53 wild-type tumors have been designed and optimized in a number of chemical series. This review details recent disclosures of compounds in advanced optimization and features key series that have given rise to clinical trial candidates. The structure-activity relationships for inhibitor classes are discussed with reference to x-ray structures, and common structural features are identified.
Improved Characteristics of a Human β-Glucuronidase−Antibody Conjugate after Deglycosylation for Use in Antibody-Directed Enzyme Prodrug Therapy (1996)

Antibody-directed enzyme prodrug therapy (ADEPT) aims at the specific activation of relatively nontoxic prodrugs into active drugs at the tumor site. One of the enzymes described to be useful in ADEPT is human beta-glucuronidase (GUS), which is expected to have low immunogenicity in patients. A major obstacle for the use of GUS, however, is its rapid glycan-specific hepatic clearance. The carbohydrates of GUS have been modified by subsequent treatment with NaIO4 and NaBH4 to improve its retention in the circulation. The modification of GUS did not decrease the enzyme activity. In vitro it was demonstrated that a conjugate prepared with a pancarcinoma specific monoclonal antibody (mAb) 323/A3 and the modified enzyme (mGUS), when bound to tumor cells, was capable of complete prodrug activation. In vivo, the 323/A3-mGUS conjugate was cleared faster from the circulation of BALB/c mice (t1/2 = 9 h) than mAb 323/A3 (t1/2 = 32 h), but it was retained in the circulation much longer than an immunoconjugate prepared with native GUS (t1/2 = 24 min). In nude mice bearing subcutaneous OVCAR-3 tumors the distribution of 323/A3-mGUS was qualitatively comparable to that of mAb 323/A3. The 323/A3-mGUS conjugate showed specific localization in the tumor but to a lesser extent than mAb 323/A3 (2.7% vs 6.4% injected dose per gram at 1 day after iv injection). A favorable tumor-to-blood ratio of > 2 was observed for the conjugate at 7 days after administration, which is necessary for tumor-specific prodrug activation.
Critical appraisal of animal models of multiple sclerosis (2011)

Experimental autoimmune encephalomyelitis (EAE) is a spectrum of neurological disorders in laboratory animals that is used to model multiple sclerosis (MS). However, few agents have translated from efficacy in EAE to the treatment of human disease. Although this may reflect species differences in pathological disease mechanisms, importantly it may also relate to the practice of how drugs and models are currently used. This often bears very little resemblance to the clinical scenarios where treatments are investigated, such that lack of appreciation of the biology of disease may doom drugs to failure. The use of EAE is critically appraised with the aim of provoking thought, improving laboratory practise and aiding researchers and reviewers to address quality issues when undertaking, reporting and interpreting animal studies related to MS research. This is important as many researchers using EAE could and should do more to improve the quality of the studies.
Aggregation-induced and crystallization-enhanced emissions of 1,2-diphenyl-3,4-bis(diphenylmethylene)-1-cyclobutene (2007)

1,2-Diphenyl-3,4-bis(diphenylmethylene)-1-cyclobutene can be induced to emit efficiently by aggregate formation, with the crystalline aggregates emitting brighter, bluer lights than their amorphous counterparts.
Comparison between Munich and Gammachirp models in audio compression (2009)

In this paper we present a new design of a psychoacoustic model for audio coding following the model used in the standard MPEG-1 audio layer 3. This architecture is based on appropriate wavelet packet decomposition instead of a short term Fourier transformation. Its important characteristic is to propose an analysis of the frequency bands that come closer to the critical bands of the ear. This study shows the best performance of the Gammachirp coder.
Tissue-specific expression of murineNkx3.1 in the male urogenital system (1997)

The molecular mechanisms involved in growth and morphogenesis of the mammalian urogenital system are largely undefined. In this study, we describe the cloning and characterization of a novel murine homeobox gene, Nkx3.1, which is expressed in the male urogenital system during late embryogenesis and adulthood. We show that Nkx3.1 encodes a 38 kDa homeoprotein that has DNA binding properties similar to those of other Nkx family members. By RNAse protection analysis, we demonstrate that Nkx3.1 is expressed in late-gestation embryos and adults by tissues of the male urogenital system, including the testis, seminal vesicle, and the prostate. In adult males, expression of Nkx3.1 in the prostate increases during sexual maturation, and is significantly reduced following castration, suggesting that androgens are required for maintenance of Nkx3.1 expression. In situ hybridization analysis of mid- and late-gestation male embryos shows that Nkx3.1 is expressed in the developing urogenital sinus, testis, and prostatic buds. In addition to its expression in the urogenital system, we also find that Nkx3.1 is expressed in the dorsal aorta and kidney. These results implicate Nkx3.1 in the growth and development of the prostate and/or other tissues of the male urogenital system, and suggest that Nkx3.1 may play a role in sexually dimorphic as well as non-sexually dimorphic organogenesis.
Pore-scale computation of material and transport properties of North-Sea reservoir rocks (2006)

The acquisition of digitized representations of rock microstructures has been established in the workflow for investigation of petrophysical, material, and transport properties. The availability of these data open the way for the development of methods that directly predict effective properties based on digitized topological information. The increasing number of effective properties that may be numerically calculated includes elastic moduli, electrical resistivities, fluid permeabilities, or constitutive relationships for multiphase flow. This work investigates different sandstone lithofacies in a North Sea field with these analyses. We compare samples acquired by X-ray Microtomography with digitized samples of reconstructed lithofacies. The latter are based on back-scattered electron images of standard 2D petrographic thin sections. The study largely shows an excellent agreement of the effective properties for the microCT and reconstructed samples for these heterogeneous rock types. Limitation in resolution of microCT data are revealed, where effective properties are sensitive to details of the microstructure. Our results allow interpretation of effective medium properties with respect to the investigated lithofacies and presentation of cross- property relations. Such cross-property relationships become especially useful, when one property is more readily obtained than another.