gebhart/patrepeval huggingface dataset:
Molecular studies of anti‐HLA‐A2 using light‐chain shuffling: a structural model for HLA antibody binding (2004)

Human leukocyte antigen (HLA) A2 is one of the most immunodominant HLA antigens. Through a process of light-chain variable domain (VL) shuffling, we analyzed the VL domains' role in anti-HLA-A2/A28-binding site diversity. This was achieved by combining a VH3-30-encoded HLA-A2/A28-specific heavy-chain variable domain with 10(4) non-immune VL domains. Twelve HLA-A2/A28-specific antibodies were subsequently identified. VL gene analysis demonstrated an absence of Vlambda domains and that all have VkappaI-encoded light chains. The affinities correlated with the VkappaI gene present, with the seven highest affinity antibodies using Vkappa domains encoded by the O18 gene segment. A 300-fold difference in affinity was observed between the 12 antibodies, and homology modeling demonstrated a correlation between electrostatic surface potential of the antigen-binding site and affinity for HLA. Overlap between the T-cell receptor-binding site and that of the antibodies was indicated by inhibition of cytotoxic T-lymphocyte killing of peptide-pulsed target cells. A model of antibody binding to HLA-A2 suggested contact with both alpha helices of the HLA molecule, such that the antigen-binding site spans the peptide-binding groove. These data increase the understanding of antibody recognition of HLA and may facilitate the production of clonotypic antibodies with peptide-specific binding.
Heterogeneous populations of class II MHC+ cells in human dermal cell suspensions. Identification of a small subset responsible for potent dermal antigen-presenting cell activity with features analogous to Langerhans cells. (1993)

Little is known regarding the identification, classification, and function of class II MHC+ dendritic cells in the perivasculature of human connective tissues, such as the dermis. We developed a method for preparing papillary dermal cell suspensions from human keratome strips. Among the class II MHC+ populations of the dermis identified using triple color flow cytometry, cells of monocyte/macrophage lineage (CD45+ CD1- CD11b+ CD11clo-mid CD32+ CD36+ or - CD11a-) and mesenchymal cells of non-bone marrow origin (CD45-) were identified and characterized. Another distinct class II MHC+ subset was identified, which expressed a number of features analogous to epidermal Langerhans cells (LC) and other dendritic APC. These were a numerically minor population comprising only 2.7% +/- 1% (n = 7) of dermal cells. Like LC, they express HLA-DR, CD45, CD1a (albeit at a lower level of expression), CD1c, and CD32 and lack constitutive CD11a or ICAM-1. In contrast to LC, this dermal CD1a+CD1c+ subset expresses CD1b, CD11b, a higher level of CD11c, and intracytoplasmic factor XIIIa. Alloantigen presentation by unfractionated dermal cells was reduced by prior removal of this CD1b+ subset to the same degree achieved by removal of the entire DR+ population (20% of dermal cells), indicating that this was the critical DR+ subset. Cocultures of CD4+ T lymphocytes with cells sorted by flow cytometry into CD1c+DR+, CD1c-DR+ and DR- dermal cell subsets positively identified the CD1c+DR+ population as the most potent of potential APC subsets in human dermis. Thus, in distinction to other dermal macrophage and mesenchymal subsets with elongate morphology, the CD1aloCD1b,c+CD11c(hi)CD11b+CD32+DR+ population in human dermis is highly analogous to cells of LC/dendritic APC lineage in its phenotype and in its exclusive ability to potently present Ag to T lymphocytes. These studies identify and characterize the APC subset most potent in inducing activation of T cells initially entering the perivasculature of human dermis to be of LC/dendritic APC, and not tissue macrophage, lineage.
Hydrogen Peroxide Inducible DNA Cross-Linking Agents: Targeted Anticancer Prodrugs (2011)

The major concern for anticancer chemotherapeutic agents is the host toxicity. The development of anticancer prodrugs targeting the unique biochemical alterations in cancer cells is an attractive approach to achieve therapeutic activity and selectivity. We designed and synthesized a new type of nitrogen mustard prodrug that can be activated by high level of reactive oxygen species (ROS) found in cancer cells to release the active chemotherapy agent. The activation mechanism was determined by NMR analysis. The activity and selectivity of these prodrugs toward ROS was determined by measuring DNA interstrand cross-links and/or DNA alkylations. These compounds showed 60-90% inhibition toward various cancer cells, while normal lymphocytes were not affected. To the best of our knowledge, this is the first example of H(2)O(2)-activated anticancer prodrugs.
Epidemiology and genetics of alopecia areata (2002)

The frequency of alopecia areata and observed patterns of heritability are in keeping with a polygenic inheritance model but the genetics of alopecia areata is still poorly understood. The role of environmental factors in triggering disease initiation or exacerbation remains almost entirely speculative. Using the candidate gene approach, three susceptibility/severity factors have been identified. HLA alleles were the first to show a strong association with alopecia areata and some DQB and DR alleles have been demonstrated to confer a high risk for disease by both case-control and family-based studies. Interleukin (IL)-1 cluster genes, mainly the IL-1 receptor antagonist, show a strong association with disease severity in alopecia areata and a number of other autoimmune and inflammatory diseases. Finally, the association of alopecia areata with Down's syndrome, the high frequency of alopecia areata in autoimmune polyglandular syndrome type I due to mutations of the autoimmune regulator (AIRE) gene on chromosome 21q22.3 and the finding of association with MX1, another gene in the Down's syndrome region of chromosome 21 indicate this area of the genome as a promising target for future-family based investigations. The role of individual genes of the MHC, IL-1 cluster or chromosome 21q22.3 is difficult to establish and further genetic and functional investigations are needed to confirm their involvement in the pathogenesis of alopecia areata.
Highly efficient and stable red phosphorescent organic light-emitting device using bis[2-(2-benzothiazoyl)phenolato]zinc(II) as host material (2007)

The red-emitting phosphorescent organic light-emitting device employing Bis[2-(2-benzothiazoyl)phenolato]zinc(II) (Zn(BTP)2) as a host material has been demonstrated. The device generates saturated red emission with Commission Internationale de l’Eclairage coordinates of (0.67, 0.33), characterized by a low driving voltage of 3.2V and high external quantum efficiency of 10.3% at 10mA∕cm2. Moreover, the efficiency and lifetime are improved by using 30% NPB-doped Zn(BTP)2 host in the emitting layer, where NPB is 4,4′-bis(N-phenyl-1-naphthyl-amino)biphenyl. The maximum external quantum efficiency of the device reaches 12.6% at 1.7mA∕cm2. The device has exhibited excellent stability. The half-luminance lifetime is 240h at 80mA∕cm2 (initial luminance of 6070cd∕m2). The relationship between the employed host material and device performance is discussed.
Nonstructural Protein NP1 of Human Bocavirus 1 Plays a Critical Role in the Expression of Viral Capsid Proteins (2016)

A novel chimeric parvoviral vector, rAAV2/HBoV1, expressing a full-length cystic fibrosis transmembrane conductance regulator (CFTR) gene, is capable of correcting CFTR-dependent chloride transport in cystic fibrosis human airway epithelium. Previously, an HBoV1 nonstructural and capsid protein-expressing plasmid, pHBoV1NSCap, was used to package the rAAV2/HBoV1 vector, but yields remained low. In this study, we demonstrated that the nonstructural protein NP1 is required for the expression of capsid proteins. However, we found that the other four nonstructural proteins (NS1 to -4) are not required for expression of capsid proteins. By mutating theciselements that function as internal polyadenylation signals in the capsid protein-expressing mRNA, we constructed a simple HBoV1 capsid protein-expressing gene that expresses capsid proteins as efficiently as pHBoV1NSCap does, and at similar ratios, but independently of NP1. Our study provides a foundation to develop a better packaging system for rAAV2/HBoV1 vector production.
Differential effects of CD30 activation in anaplastic large cell lymphoma and Hodgkin disease cells (2000)

CD30 is a member of the tumor necrosis factor (TNF) receptor superfamily that is expressed on activated lymphocytes, as well as on neoplastic cells of Hodgkin disease (HD) and anaplastic large cell lymphoma (ALCL). A number of reports have shown that, depending on cellular context, CD30 signaling can exert a variety of effects, ranging from cell death to cellular proliferation. In the present study this disparity was examined, using a number of ALCL- and HD-derived cell lines. Activation of CD30 led to the induction of apoptotic death of ALCL cells, along with the selective reduction of TNF receptor-associated factor 2 and impairment in the ability of these cells to activate the pro-survival transcription factor nuclear factor kappa B (NF-kappa B). In contrast, HD cells, which constitutively express NF-kappa B, were not susceptible to CD30-induced apoptosis but could be sensitized following ectopic overexpression of a superdominant I kappa B. These studies suggest that NF-kappa B plays a determining role in the sensitivity or resistance of lymphoma cells to CD30-induced apoptosis, which may have important consequences in the clinical treatment of CD30-positive neoplasia. (Blood. 2000;96:4307-4312)
Constitutive endocytosis of HLA class I antigens requires a specific portion of the intracytoplasmic tail that shares structural features with other endocytosed molecules. (1989)

HLA class I antigens present in the human leukemia T-cell line HPB-ALL are shown to be endocytosed in the absence of specific antibodies. In 1 hr, approximately 10% of class I molecules initially present at the cell surface are found intracellularly. Genetically engineered mutants of the HLA-A2 gene lacking exon 6 or 7 or both were used to analyze whether the cytoplasmic region contributes to the internalization. The results indicate that amino acids encoded by exon 7 (spanning amino acid residues 323-340) are required for internalization, while deletion of exon 6 had no effect. In addition, a comparison of the cytoplasmic sequences of receptors that are known to be internalized via coated pits and the present data revealed that they share a structural feature that could constitute a specific signal required for endocytosis.
Near‐IR BODIPY Dyes à la Carte—Programmed Orthogonal Functionalization of Rationally Designed Building Blocks (2015)

Herein, we report the synthesis of polyfunctional BODIPY building blocks suitable to be subjected to several reaction sequences with complete chemoselectivity, thereby allowing the preparation of complex BODIPY derivatives in a versatile and programmable manner. The reactions included the Liebeskind-Srogl cross-coupling reaction (LSCC), nucleophilic aromatic substitution (SN Ar), Suzuki, Sonogashira, and Stille couplings, and a desulfitative reduction of the MeS group. This novel synthetic protocol is a powerful route to design a library of compounds with tailored photophysical properties for advanced applications. In this context, it is noteworthy that it offers a straightforward and cost-effective strategy to shift the BODIPY emission deep into the near-infrared spectral region while retaining high fluorescence quantum yields as well as highly efficient and stable laser action. These new dyes outperform the lasing behaviour of dyes considered as benchmarks over the red spectral region, overcoming the important drawbacks associated with these commercial laser dyes, namely low absorption at the standard pump wavelengths (355 and 532 nm) and/or poor photostability.
Beam Behavior within the Nearfield of a Vibrating Piston (1971)

A numerical investigation of the nearfield region of a vibrating piston was conducted. While existing literature is not exactly clear about how close to a transducer a regular beam pattern is formed, the results of this investigation show the limits of operation one can expect. From one interpretation of literature, a −3-dB beam with a minimum spot size equal to the transducer diameter would be expected to form beyond an axial distance z = 3.89 a2/λ. This investigation shows that such a beam forms at z = 0.75 a2/λ and has a minimum spot size equal to one-quarter the transducer radius. These results are verified for transducers with a/λ's ranging from 1 to 20 and can be extended with confidence to higher a/λ's. Similar results are also obtained for −1.5-, −4.5-, −6.0-, −7.5-, −9.0-, −10.5-, and −12-dB beams.
Initial viral load and the outcomes of SARS (2004)

We found preliminary evidence that higher initial viral load is independently associated with worse prognosis in SARS. Mortality data for patients with SARS should be interpreted in light of age, comorbidity and viral load. These considerations will be important in future studies of SARS.
Overexpression of the Hspa13 ( Stch ) gene reduces prion disease incubation time in mice (2012)

Prion diseases are fatal neurodegenerative disorders that include bovine spongiform encephalopathy (BSE) and scrapie in animals and Creutzfeldt-Jakob disease (CJD) in humans. They are characterized by long incubation periods, variation in which is determined by many factors including genetic background. In some cases it is possible that incubation time may be directly correlated to the level of gene expression. To test this hypothesis, we combined incubation time data from five different inbred lines of mice with quantitative gene expression profiling in normal brains and identified five genes with expression levels that correlate with incubation time. One of these genes, Hspa13 (Stch), is a member of the Hsp70 family of ATPase heat shock proteins, which have been previously implicated in prion propagation. To test whether Hspa13 plays a causal role in determining the incubation period, we tested two overexpressing mouse models. The Tc1 human chromosome 21 (Hsa21) transchromosomic mouse model of Down syndrome is trisomic for many Hsa21 genes including Hspa13 and following Chandler/Rocky Mountain Laboratory (RML) prion inoculation, shows a 4% reduction in incubation time. Furthermore, a transgenic model with eightfold overexpression of mouse Hspa13 exhibited highly significant reductions in incubation time of 16, 15, and 7% following infection with Chandler/RML, ME7, and MRC2 prion strains, respectively. These data further implicate Hsp70-like molecular chaperones in protein misfolding disorders such as prion disease.
Discovery of a Novel Series of Potent and Orally Bioavailable Phosphoinositide 3-Kinase γ Inhibitors (2012)

The phosphoinositide 3-kinases (PI3Ks) have been linked to an extraordinarily diversified group of cellular functions making these enzymes compelling targets for the treatment of disease. A large body of evidence has linked PI3Kγ to the modulation of autoimmune and inflammatory processes making it an intriguing target for drug discovery. Our high-throughput screening (HTS) campaign revealed two hits that were nominated for further optimization studies. The in vitro activity of the first HTS hit, designated as the sulfonylpiperazine scaffold, was optimized utilizing structure-based design. However, nonoptimal pharmacokinetic properties precluded this series from further studies. An overlay of the X-ray structures of the sulfonylpiperazine scaffold and the second HTS hit within their complexes with PI3Kγ revealed a high degree of overlap. This feature was utilized to design a series of hybrid analogues including advanced leads such as 31 with desirable potency, selectivity, and oral bioavailability.
Ascorbate Oxidation: UV Absorbance of Ascorbate and ESR Spectroscopy of the Ascorbyl Radical as Assays for Iron (1990)

Catalytic transition metals are an absolute requirement for the aerobic oxidation of ascorbate monoanion. Thus, for example, the concentration of iron can be determined by the metal-dependent rate of ascorbate oxidation in near-neutral solutions. The lower limit of detection of iron, as Fe(III)EDTA, by monitoring the decrease in absorbance at 265 nm of ascorbate is about 200 nM. However, by measuring the concentration of the ascorbyl radical by ESR spectroscopy the lower limit is about 10 nM. Using these assays, I have shown that the typical microliter laboratory syringe can introduce significant iron into solutions. Thus, for studies involving iron, these two tests can be used to determine the amount of contaminating iron in reagents as well as iron from other sources such as laboratory equipment.
Position-Based Quantum Cryptography: Impossibility and Constructions (2010)

In this work, we study position-based cryptography in the quantum setting. The aim is to use the geographical position of a party as its only credential. On the negative side, we show that if adversaries are allowed to share an arbitrarily large entangled quantum state, no secure position-verification is possible at all. We show a distributed protocol for computing any unitary operation on a state shared between the different users, using local operations and one round of classical communication. Using this surprising result, we break any position-verification scheme of a very general form. On the positive side, we show that if adversaries do not share any entangled quantum state but can compute arbitrary quantum operations, secure position-verification is achievable. Jointly, these results suggest the interesting question whether secure position-verification is possible in case of a bounded amount of entanglement. Our positive result can be interpreted as resolving this question in the simplest case, where the bound is set to zero. In models where secure positioning is achievable, it has a number of interesting applications. For example, it enables secure communication over an insecure channel without having any pre-shared key, with the guarantee that only a party at a specific location can learn the content of the conversation. More generally, we show that in settings where secure position-verification is achievable, other position-based cryptographic schemes are possible as well, such as secure position-based authentication and position-based key agreement.
Structural Basis of Selective Inhibition of Human Tankyrases (2012)

Tankyrases are poly(ADP-ribose) polymerases that have many cellular functions. They play pharmaceutically important roles, at least in telomere homeostasis and Wnt signaling, by covalently ADP-ribosylating target proteins and consequently regulating their functions. These features make tankyrases potential targets for treatment of cancer. We report here crystal structures of human tankyrase 2 catalytic fragment in complex with a byproduct, nicotinamide, and with selective inhibitors of tankyrases (IWR-1) and PARPs 1 and 2 (olaparib). Binding of these inhibitors to tankyrase 2 induces specific conformational changes. The crystal structures explain the selectivity of the inhibitors, reveal the flexibility of a substrate binding loop, and explain existing structure-activity relationship data. The first crystal structure of a PARP enzyme in complex with a potent inhibitor, IWR-1, that does not bind to the widely utilized nicotinamide-binding site makes the structure valuable for development of PARP inhibitors in general.
Direct Quantification of the Enteric Bacterium Oxalobacter formigenes in Human Fecal Samples by Quantitative Competitive-Template PCR (1999)

Homeostasis of oxalic acid appears to be regulated, in part, by the gut-associated bacterium Oxalobacter formigenes. The loss of this bacterium from the gut flora is associated with an increased susceptibility to hyperoxaluria, a condition which can lead to the formation of calcium oxalate crystalluria and kidney stones. In order to identify and quantify the presence of O. formigenes in clinical specimens, a quantitative-PCR-based assay system utilizing a competitive DNA template as an internal standard was developed. This quantitative competitive-template PCR test allows for the rapid, highly specific, and reproducible quantification of O. formigenes in fecal samples and provides a prototype for development of DNA-based quantitative assays for enteric bacteria.
Transtympanic Endoscopy for Drug Delivery to the Inner Ear Using a New Microendoscope (2002)

Anatomic variations of the round window (RW) niche found in approximately 33% of human temporal bones may account for some ofthe problems associated with local drug delivery to the inner car. A microendoscope with a total outer diameter of 1.2 mm was developed in particular for easy visualization and of drug delivery to the RW niche. It incorporated a thin fiber optic, a working/laser channel (0.3 mm) and an irrigation/suction channel (0.27 mm). When compared to a common 30 degree lens optic, with the microendoscope a greater area of the round window niche could be overseen. In addition, the endoscope could be advanced directly upon the surface of the RW membrane (RWM). The microendoscope may be used for evaluation of the anatomy of the RW niche prior to the placement of local drug delivery systems, for application of drugs directly onto the surface of the RWM or to verify the correct placement of inner ear drug delivery systems.
Free space optical components and systems based on LIGA technology (2002)

Due to its characteristics, LIGA technology is well suited to build up free space optical components with hybrid integration of optical elements by passive alignment. This is demonstrated by passive optical components and electro-opto-mechanical devices for telecommunication and sensor application.
Small Molecule Regulators of Protein Arginine Methyltransferases (2004)

Here we report the identification of small molecules that specifically inhibit protein arginine N-methyltransferase (PRMT) activity. PRMTs are a family of proteins that either monomethylate or dimethylate the guanidino nitrogen atoms of arginine side chains. This common post-translational modification is implicated in protein trafficking, signal transduction, and transcriptional regulation. Most methyltransferases use the methyl donor, S-adenosyl-L-methionine (AdoMet), as a cofactor. Current methyltransferase inhibitors display limited specificity, indiscriminately targeting all enzymes that use AdoMet. In this screen we have identified a primary compound, AMI-1, that specifically inhibits arginine, but not lysine, methyltransferase activity in vitro and does not compete for the AdoMet binding site. Furthermore, AMI-1 prevents in vivo arginine methylation of cellular proteins and can modulate nuclear receptor-regulated transcription from estrogen and androgen response elements, thus operating as a brake on certain hormone actions.
Quest for the AIDS vaccine (2007)

Researchers broadly agree that the best way to halt the AIDS epidemic is to develop a vaccine against HIV. But despite huge investment a vaccine is proving elusive, as <b>Alison Tonks</b> explains