gebhart/patrepeval huggingface dataset:
Augmented Binary Substitution: Single-pass CDR germ-lining and stabilization of therapeutic antibodies (2015)

Although humanized antibodies have been highly successful in the clinic, all current humanization techniques have potential limitations, such as: reliance on rodent hosts, immunogenicity due to high non-germ-line amino acid content, v-domain destabilization, expression and formulation issues. This study presents a technology that generates stable, soluble, ultrahumanized antibodies via single-step complementarity-determining region (CDR) germ-lining. For three antibodies from three separate key immune host species, binary substitution CDR cassettes were inserted into preferred human frameworks to form libraries in which only the parental or human germ-line destination residue was encoded at each position. The CDR-H3 in each case was also augmented with 1 ± 1 random substitution per clone. Each library was then screened for clones with restored antigen binding capacity. Lead ultrahumanized clones demonstrated high stability, with affinity and specificity equivalent to, or better than, the parental IgG. Critically, this was mainly achieved on germ-line frameworks by simultaneously subtracting up to 19 redundant non-germ-line residues in the CDRs. This process significantly lowered non-germ-line sequence content, minimized immunogenicity risk in the final molecules and provided a heat map for the essential non-germ-line CDR residue content of each antibody. The ABS technology therefore fully optimizes the clinical potential of antibodies from rodents and alternative immune hosts, rendering them indistinguishable from fully human in a simple, single-pass process.
Alzheimer's Disease Is a Synaptic Failure (2002)

In its earliest clinical phase, Alzheimer's disease characteristically produces a remarkably pure impairment of memory. Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid beta protein.
Chemical reactions inside single-walled carbon nano test-tubes (2004)

We report the application of SWNTs as templates for forming covalent polymeric chains from C(60)O reacting inside SWNTs; the resulting peapod polymer topology is different from the bulk polymer in that it is linear and unbranched.
Crystal Structure of the Stress-Inducible Human Heat Shock Protein 70 Substrate-Binding Domain in Complex with Peptide Substrate (2014)

The HSP70 family of molecular chaperones function to maintain protein quality control and homeostasis. The major stress-induced form, HSP70 (also called HSP72 or HSPA1A) is considered an important anti-cancer drug target because it is constitutively overexpressed in a number of human cancers and promotes cancer cell survival. All HSP70 family members contain two functional domains: an N-terminal nucleotide binding domain (NBD) and a C-terminal protein substrate-binding domain (SBD); the latter is subdivided into SBDα and SBDβ subdomains. The NBD and SBD structures of the bacterial ortholog, DnaK, have been characterized, but only the isolated NBD and SBDα segments of eukaryotic HSP70 proteins have been determined. Here we report the crystal structure of the substrate-bound human HSP70-SBD to 2 angstrom resolution. The overall fold of this SBD is similar to the corresponding domain in the substrate-bound DnaK structures, confirming a similar overall architecture of the orthologous bacterial and human HSP70 proteins. However, conformational differences are observed in the peptide-HSP70-SBD complex, particularly in the loop L(α, β) that bridges SBDα to SBDβ, and the loop L(L,1) that connects the SBD and NBD. The interaction between the SBDα and SBDβ subdomains and the mode of substrate recognition is also different between DnaK and HSP70. This suggests that differences may exist in how different HSP70 proteins recognize their respective substrates. The high-resolution structure of the substrate-bound-HSP70-SBD complex provides a molecular platform for the rational design of small molecule compounds that preferentially target this C-terminal domain, in order to modulate human HSP70 function.
Three‐dimensional quantitative T1 and T2 mapping of the carotid artery: Sequence design and in vivo feasibility (2015)

The 3D T1 and T2 mapping of the carotid artery is feasible using variable flip angle and variable TE preparation acquisitions. We foresee application of this technique for plaque characterization and monitoring plaque progression in atherosclerotic patients.
Brain targeting of nerve growth factor using poly(butyl cyanoacrylate) nanoparticles (2009)

The nerve growth factor (NGF) is essential for the survival of both peripheral ganglion cells and central cholinergic neurons in the basal forebrain. The accelerated loss of central cholinergic neurons during Alzheimer's disease may be a determinant cause of dementia, and this observation may suggest a possible therapeutic benefit from treatment with NGF. In recent years, convincing data have been published involving neurotrophic factors for the modulation of dopaminergic transmission within the brain and concerning the ability of NGF to prevent the degeneration of dopaminergic neurons. In this connection, the administration of NGF may slow down the progression of Parkinson's disease. However, NGF, as well as other peptidic neurotrophic factors, does not significantly penetrate the blood-brain barrier (BBB) from the circulation. Therefore, any clinical usefulness of NGF as a potential CNS therapy will depend on the use of a suitable carrier system that enhances its transport through the BBB. The present study investigates brain delivery of NGF adsorbed on poly(butyl cyanoacrylate) (PBCA) nanoparticles coated with polysorbate 80 and the pharmacological efficacy of this delivery system in the model of acute scopolamine-induced amnesia in rats as well as in the model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonian syndrome. As shown by the passive avoidance reflex (PAR) test, the intravenous administration of the nanoparticle-bound NGF successfully reversed scopolamine-induced amnesia and improved recognition and memory. This formulation also demonstrated a significant reduction of the basic symptoms of Parkinsonism (oligokinesia, rigidity, tremor). In addition, the efficient transport of NGF across the BBB was confirmed by direct measurement of NGF concentrations in the murine brain. These results demonstrate that the PBCA nanoparticles coated with polysorbate 80 are an effective carrier system for the transport of NGF to the central nervous system across the BBB following intravenous injection. This approach may improve the NGF-based therapy of age-related neurodegenerative diseases.
Synthesis and Characterization of Highly Luminescent CdSe−Core CdS/Zn0.5Cd0.5S/ZnS Multishell Nanocrystals (2005)

We report on the preparation and structural characterization of CdSe nanocrystals, which are covered by a multishell structure from CdS and ZnS. By using the newly developed successive ion layer adhesion and reaction (SILAR) technique, we could gradually change the shell composition from CdS to ZnS in the radial direction. Because of the stepwise adjustment of the lattice parameters in the radial direction, the resulting nanocrystals show a high crystallinity and are almost perfectly spherical, as was investigated by X-ray diffraction and electron microscopy. Also, due to the radial increase of the respective valence- and conduction-band offsets, the nanocrystals are well electronically passivated. This leads to a high fluorescence quantum yield of 70-85% for the amine terminated multishell particles in organic solvents and a quantum yield of up to 50% for mercapto propionic acid-covered particles in water. Finally, we present experimental results that substantiate the superior photochemical and colloidal stability of the multishell particles.
Analysis of the relative level of gene expression from different retroviral vectors used for gene therapy. (1996)

We have analyzed the relative level of gene expression and viral titer from different types of retroviral vectors used for gene therapy, the LTR-based MFG vector and the internal promoter-containing vectors, LNCX, LNSX and LXSN. The CAT gene was used for comparison of retroviral vector gene expression in both transfected and transduced cells, while the neo gene was used to evaluate viral liter. In transfected cells, MFG-CAT expressed higher levels of CAT then the other vectors, LNC-CAT was next, while L-CAT-SN and LNS-CAT produced much lower levels. CAT expression from MFG-CAT was particularly high in the human T lymphoid cell lines CEM-SS and H9. In nonselected transduced cells. CAT expression from MFG was 10- to 50-fold higher than with the other vectors. Similar observations were made with retroviral constructs expressing human EPO and murine GM-CSF. In transient transfection assays, the titer of MFG was at least five-fold higher than the other vectors as determined by Southern analysis and G418 resistance. Analysis of the steady-state RNAs produced after transfection of the packaging cell lines showed that MFG expressed a significantly higher level of genomic RNA, which contains the packaging signal, than the other vectors while still expressing a high level of the subgenomic RNA encoding CAT. The high level of genomic RNA most likely contributes directly to the higher titer of MFG. We also compared viral titers from subcloned PA317 producer lines containing LNC-CAT and MFG-CAT-Neo, and confirmed that the titer of the MFG virus was higher than that of the LNCX. In selected subcloned transduced NIH3T3 cells, average levels of CAT activity were nine-fold higher from MFG-based vector. Our results suggest that there are significant differences in both the titer and the level of gene expression between retroviral vectors which are currently being used in gene therapy clinical trials.
99mTc radioimmunoscintigraphy of colorectal cancer. (1990)

The monoclonal antibody PR1A3 against a normal colonic columnar cell surface antigen has been labelled with 99mTc and used for imaging colorectal cancer. High uptake in undifferentiated cancer is seen. The tumour to mucosa ratio was up to 63:1 and the percentage of the injected activity in the tumour up to 1.7 X 10(-2%)g-1. As 99mTc is continuously available in a Nuclear Medicine Department, on receipt of a request the study may be completed within 24 h enabling radioimmunoscintigraphy to be used routinely in the management of patients with colorectal cancer.
Electromagnetic brain mapping (2001)

There has been tremendous advances in our ability to produce images of human brain function. Applications of functional brain imaging extend from improving our understanding of the basic mechanisms of cognitive processes to better characterization of pathologies that impair normal function. Magnetoencephalography (MEG) and electroencephalography (EEG) (MEG/EEG) localize neural electrical activity using noninvasive measurements of external electromagnetic signals. Among the available functional imaging techniques, MEG and EEG uniquely have temporal resolutions below 100 ms. This temporal precision allows us to explore the timing of basic neural processes at the level of cell assemblies. MEG/EEG source localization draws on a wide range of signal processing techniques including digital filtering, three-dimensional image analysis, array signal processing, image modeling and reconstruction, and, blind source separation and phase synchrony estimation. We describe the underlying models currently used in MEG/EEG source estimation and describe the various signal processing steps required to compute these sources. In particular we describe methods for computing the forward fields for known source distributions and parametric and imaging-based approaches to the inverse problem.
High Resolution Radon - a Review (2001)

m = W ⋅ G m = (G H H ⋅ (G ⋅ W ⋅ G 2 ⋅ G + λ W −1 −1 ) H 2 + λ I) ⋅ d (E 2) ⋅ G ⋅ d (E 3) The weighting matrix W is the key point. If it is the identity-matrix we end up with the standard least-squares decomposition. To obtain a high resolution decomposition some weights are put on the diagonal to enforce the focusing of the decomposition on its most significant spectral components. For example: H −1 ( ) ( ) ( ) ⎟ ⎠ ⎜
Artificial neural network for prediction of water quality in pipeline systems (2003)

The THM compounds develop in chlorinated water containing organic precursors, such as humic and fulvic acids. It has been reported that the relative contribution to the formation of THMs by the humic acids react more readily with the chlorine. Even though it is well known that TTHM increases with time, information about the reaction of the mechanism of the formation of THM and its species is still limited. This paper presented modelling techniques for the prediction of, multiple linear and nonlinear regression and artificial neural networks (ANN) and application resultsobserved water quality data in water distribution system. The model parameters are selected as used in formula proposed by American Water Works Association (1993), Urano (1983) and EngerholmAmy (1987). A steady state hydraulic analysis program (KYPIPE model) was applied to get hydraulic characteristics of the water distribution system under investigation.
Hypertrophic Cardiomyopathy in Cardiac Myosin Binding Protein-C Knockout Mice (2002)

Familial hypertrophic cardiomyopathy (FHC) is an inherited autosomal dominant disease caused by mutations in sarcomeric proteins. Among these, mutations that affect myosin binding protein-C (MyBP-C), an abundant component of the thick filaments, account for 20% to 30% of all mutations linked to FHC. However, the mechanisms by which MyBP-C mutations cause disease and the function of MyBP-C are not well understood. Therefore, to assess deficits due to elimination of MyBP-C, we used gene targeting to produce a knockout mouse that lacks MyBP-C in the heart. Knockout mice were produced by deletion of exons 3 to 10 from the endogenous cardiac (c) MyBP-C gene in murine embryonic stem (ES) cells and subsequent breeding of chimeric founder mice to obtain mice heterozygous (+/-) and homozygous (-/-) for the knockout allele. Wild-type (+/+), cMyBP-C(+/-), and cMyBP-C(-/-) mice were born in accordance with Mendelian inheritance ratios, survived into adulthood, and were fertile. Western blot analyses confirmed that cMyBP-C was absent in hearts of homozygous knockout mice. Whereas cMyBP-C(+/-) mice were indistinguishable from wild-type littermates, cMyBP-C(-/-) mice exhibited significant cardiac hypertrophy. Cardiac function, assessed using 2-dimensionally guided M-mode echocardiography, showed significantly depressed indices of diastolic and systolic function only in cMyBP-C(-/-) mice. Ca2+ sensitivity of tension, measured in single skinned myocytes, was reduced in cMyBP-C(-/-) but not cMyBP-C(+/-) mice. These results establish that cMyBP-C is not essential for cardiac development but that the absence of cMyBP-C results in profound cardiac hypertrophy and impaired contractile function.
Transdermal Nicotine for Active Ulcerative Colitis (1994)

The addition of transdermal nicotine to conventional maintenance therapy improves symptoms in patients with ulcerative colitis.
Molecular basis of genetic variation in debrisoquin hydroxylation in Chinese subjects: Polymorphism in RFLP and DNA sequence of CYP2D6 (1993)

Debrisoquin hydroxylation phenotype was determined in 124 Chinese persons living in Taiwan, and two poor metabolizers were identified with a urinary metabolic ratio (MR) greater than 12.6. The other subjects, extensive metabolizers, showed a normal frequency distribution of log(MR). Most subjects (50%) showed a 44/29 kb pattern in restriction fragment length polymorphism (RFLP) analysis with use of Xba I, and 30% and 15% of the subjects exhibited a homozygous 29/29 kb and 44/44 kb pattern, respectively. Among extensive metabolizers, subjects with the 44/44 kb pattern had a significant higher log(MR) than those with the 44/29 pattern, and the log(MR) of the subjects with the 44/29 kb pattern was significantly higher than that of the subjects with 29/29 kb pattern. All nine exons and intron 3 of C gamma P2D6 were amplified with polymerase chain reaction (PCR) and sequenced for four extensive metabolizers. Two major polymorphisms were found: one at position 188 of exon 1 and the other at position 4268 in exon 9. With PCR and endonuclease digestion, polymorphisms at exon 1, intron 3, and exon 9 were investigated. Only two of 254 alleles showed a heterozygous guanine at 1934 base pairs (G1934) to adenine (A) mutation, commonly found in white poor metabolizers. Approximately 70% of alleles showed thymine at 188 base pairs (T188), and 76% showed cytosine at 4268 base pairs (C4268) instead of C188 and G4268, as is found in most white subjects. Subjects with T188 or C4268 showed a significant higher log(MR) than subjects with homozygous C188 and G4268. The C/T188, G/A1934, G/C4268, and RFLP polymorphisms may explain the interracial variations between Chinese and white subjects, as well as the genetic variations among Chinese subjects.
A nonclausal connection-graph resolution theorem-proving program (1982)

A new theorem-proving program, combining the use of non-clausal resolution and connection graphs, is described. The use of nonclausal resolution as the inference system eliminates some of the redundancy and unreadability of clause-based systems. The use of a connection graph restricts the search space and facilitates graph searching for efficient deduction. I
Cryptosporidium and Giardia Recoveries in Natural Waters by Using Environmental Protection Agency Method 1623 (2002)

Relatively few studies have examined recoveries from source waters by using Environmental Protection Agency method 1623 with organism spike doses that are environmentally realistic and at turbidity levels commonly found in surface waters. In this study, we evaluated the filtration capacities and recovery efficiencies of the Gelman Envirochek (standard filter) and the Gelman Envirochek high-volume (HV) sampling capsules under environmental conditions. We also examined the performance of method 1623 under ambient conditions with matrix spike experiments using 10 organisms/liter. Under turbid conditions, the HV capsule filtered approximately twice the volume filtered by the standard filter, but neither could filter 10 liters without clogging. In low-turbidity waters, oocyst, but not cyst, recoveries were significantly higher when the HV capsule was used. In turbid waters, organism recoveries were lower than those in nonturbid waters and were not significantly different for the different filters. When the HV capsule was used, Cryptosporidium recoveries ranged from 36 to 75%, and Giardia recoveries ranged from 0.5 to 53%. For both organisms, recoveries varied significantly by site. Turbidity could explain variation in Giardia recoveries (r(2) = 0.80) but not variation in Cryptosporidium recoveries (r(2) = 0.16). The inconsistent recoveries across sites suggested that the background matrix of the ambient water affected recovery by method 1623. A control sample collected at the height of the winter rainy season detected one organism, highlighting the difficulty of using this method to accurately measure pathogen abundance under natural conditions. Our findings support the use of the HV filter under field conditions but suggest that designing a cost-effective and statistically valid monitoring program to evaluate sources and loads of protozoan pathogens may be difficult.
An Aromatic Microdomain at the Cannabinoid CB1 Receptor Constitutes an Agonist/Inverse Agonist Binding Region (2003)

The cannabinoid CB(1) receptor transmembrane helix (TMH) 3-4-5-6 region includes an aromatic microdomain comprised of residues F3.25, F3.36, W4.64, Y5.39, W5.43, and W6.48. In previous work, we have demonstrated that aromaticity at position 5.39 in CB(1) is crucial for proper function of CB(1). Modeling studies reported here suggest that in the inactive state of CB(1), the binding site of the CB(1) inverse agonist/antagonist SR141716A is within the TMH3-4-5-6 aromatic microdomain and involves direct aromatic stacking interactions with F3.36, Y5.39, and W5.43, as well as hydrogen bonding with K3.28. Further, modeling studies suggest that in the active state of CB(1), the CB agonist WIN55,212-2 binds in this same aromatic microdomain, with direct aromatic stacking interactions with F3.36, W5.43, and W6.48. In contrast, in the binding pocket model, the CB agonist anandamide binds in the TMH2-3-6-7 region in which hydrogen bonding and C-H.pi interactions appear to be important. Only one TMH3 aromatic residue, F3.25, was found to be part of the anandamide binding pocket. To probe the importance of the TMH3-4-5-6 aromatic microdomain to ligand binding, stable transfected cell lines were created for single-point mutations of each aromatic microdomain residue to alanine. Improper cellular expression of the W4.64A was observed and precluded further characterization of this mutation. The affinity of the cannabinoid agonist CP55,940 was unaffected by the F3.25A, F3.36A, W5.43A, or W6.48A mutations, making CP55,940 an appropriate choice as the radioligand for binding studies. The binding of SR141716A and WIN55,212-2 were found to be affected by the F3.36A, W5.43A, and W6.48A mutations, suggesting that these residues are part of the binding site for these two ligands. Only the F3.25A mutation was found to affect the binding of anandamide, suggesting a divergence in binding site regions for anandamide from WIN55,212-2, as well as SR141716A. Taken together, these results support modeling studies that identify the TMH3-4-5-6 aromatic microdomain as the binding region of SR141716A and WIN55,212-2, but not of anandamide.
Error-prone polymerization by HIV-1 reverse transcriptase. Contribution of template-primer misalignment, miscoding, and termination probability to mutational hot spots (1993)

We have observed previously that DNA template-directed polymerization by the type 1 human immunodeficiency virus reverse transcriptase is error-prone for single-nucleotide substitution, addition and deletion errors at homopolymeric sequences. We have also noted strong termination of processive synthesis at these positions (Bebenek, K., Abbotts, J., Roberts, J. D., Wilson, S. H., and Kunkel, T. A. (1989) J. Biol. Chem. 264, 16948-16956). Here we have tested three models to explain errors at these hot spots: template-primer misalignment for deletion errors, and dislocation and direct miscoding for substitution errors. The approach involves introducing single-nucleotide changes within or flanking the homopolymeric hot spots and examining the effects that these changes have on human immunodeficiency virus type 1 (HIV-1) reverse transcriptase error rate, error specificity, and termination probability. The results obtained suggest that single-nucleotide deletion errors in homopolymeric runs result from template-primer misalignment and that both direct miscoding and template-primer dislocation contribute to the base substitution hot spots. The data also suggest that base substitution errors at one position can be templated by the preceding nucleotide or either of the next two nucleotides. Frameshift error rates at homopolymeric sites were affected by changes in the sequences flanking the runs, including single-nucleotide differences in the single-stranded template strand and in the double-stranded primer region as many as six nucleotides distant from the hot spot. Both increases and decreases in frameshift fidelity were observed, and most of these correlated with concomitant increases or decreases in the probability that HIV-1 reverse transcriptase terminated processive synthesis within the run. These data provide further support for a relationship between the frameshift fidelity and the processivity of DNA-dependent DNA synthesis by HIV-1 reverse transcriptase.