gebhart/patrepeval huggingface dataset:
Dynamic antibody-binding properties in the pathogenesis of HIT (2012)

Rapid laboratory assessment of heparin-induced thrombocytopenia (HIT) is important for disease recognition and management. The utility of contemporary immunoassays to detect antiplatelet factor 4 (PF4)/heparin antibodies is hindered by detection of antibodies unassociated with disease. To begin to distinguish properties of pathogenic anti-PF4/heparin antibodies, we compared isotype-matched monoclonal antibodies that bind to different epitopes: KKO causes thrombocytopenia in an in vivo model of HIT, whereas RTO does not. KKO binding to PF4 and heparin is specifically inhibited by human HIT antibodies that activate platelets, whereas inhibition of RTO binding is not differentially affected. Heparin increased the avidity of KKO binding to PF4 without affecting RTO, but it did not increase total binding or binding to nontetrameric PF4(K50E). Single-molecule forced unbinding demonstrated KKO was 8-fold more reactive toward PF4 tetramers and formed stronger complexes than RTO, but not to PF4(K50E) dimers. KKO, but not RTO, promoted oligomerization of PF4 but not PF4(K50E). This study reveals differences in the properties of anti-PF4 antibodies that cause thrombocytopenia not revealed by ELISA that correlate with oligomerization of PF4 and sustained high-avidity interactions that may simulate transient antibody-antigen interactions in vivo. These differences suggest the potential importance of epitope specificity in the pathogenesis of HIT.
Quantum fluctuation theorems and power measurements (2020)

Work in the paradigm of the quantum fluctuation theorems of Crooks and Jarzynski is determined by projective measurements of energy at the beginning and end of the force protocol. In analogy to classical systems, we consider an alternative definition of work given by the integral of the supplied power determined by integrating up the results of repeated measurements of the instantaneous power during the force protocol. We observe that such a definition of work, in spite of taking account of the process dependence, has different possible values and statistics from the work determined by the conventional two energy measurement approach (TEMA). In the limit of many projective measurements of power, the system's dynamics is frozen in the power measurement basis due to the quantum Zeno effect leading to statistics only trivially dependent on the force protocol. In general the Jarzynski relation is not satisfied except for the case when the instantaneous power operator commutes with the total Hamiltonian at all times. We also consider properties of the joint statistics of power-based definition of work and TEMA work in protocols where both values are determined. This allows us to quantify their correlations. Relaxing the projective measurement condition, weak continuous measurements of power are considered within the stochastic master equation formalism. Even in this scenario the power-based work statistics is in general not able to reproduce qualitative features of the TEMA work statistics.
A helper-dependent adenovirus vector system: Removal of helper virus by Cre-mediated excision of the viral packaging signal (1996)

Adenoviruses are attractive vectors for the delivery of foreign genes into mammalian cells for gene therapy. However, current vectors retain many viral genes that, when expressed at low levels, contribute to the induction of a host immune response against transduced cells. We have developed a helper-dependent packaging system for production of vectors that have large regions of the genome deleted. Helper viruses were constructed with packaging signals flanked by loxP sites so that in 293 cells that stably express the Cre recombinase (293Cre), the packaging signal was efficiently excised, rendering the helper virus genome unpackageable. However, the helper virus DNA was replicated at normal levels and could thus express all of the functions necessary in trans for replication and packaging of a vector genome containing the appropriate cis-acting elements. Serial passage of the vector in helper virus-infected 293Cre cells resulted in an approximately 10-fold increase in vector titer per passage. The vector could be partially separated from residual helper virus by cesium chloride buoyant density centrifugation. Large scale preparations of vector yielded semi-purified stocks of approximately 10(10) transducing virions/ml, with < 0.01% contamination by the E1-deleted helper virus. This system should have great utility for the generation of adenovirus-based vectors with increased cloning capacity, increased safety and reduced immunogenicity.
Pseudotyping human immunodeficiency virus type 1 (HIV-1) by the glycoprotein of vesicular stomatitis virus targets HIV-1 entry to an endocytic pathway and suppresses both the requirement for Nef and the sensitivity to cyclosporin A (1997)

Human immunodeficiency virus type 1 (HIV-1) normally enters cells by direct fusion with the plasma membrane. In this report, HIV-1 particles capable of infecting cells through an endocytic pathway are described. Chimeric viruses composed of the HIV-1 core and the envelope glycoprotein of vesicular stomatitis virus (VSV-G) were constructed and are herein termed HIV-1(VSV) pseudotypes. HIV-1(VSV) pseudotypes were 20- to 130-fold more infectious than nonpseudotyped HIV-1. Infection by HIV-1(VSV) pseudotypes was markedly diminished by ammonium chloride and concanamycin A, a selective inhibitor of vacuolar H+ ATPases, demonstrating that these viruses require endosomal acidification to achieve productive infection. HIV-1 is thus capable of performing all of the viral functions necessary for infection when entry is targeted to an endocytic route. Maximal HIV-1 infectivity requires the presence of the viral Nef protein and the cellular protein cyclophilin A (CyPA) during virus assembly. Pseudotyping by VSV-G markedly suppressed the requirement for Nef. HIV-1(VSV) particles were also resistant to inhibition by cyclosporin A; however, the deleterious effect of a gag mutation inhibiting CyPA incorporation was not relieved by VSV-G. These results suggest that Nef acts at a step of the HIV-1 life cycle that is either circumvented or facilitated by targeting virus entry to an endocytic pathway. The findings also support the hypothesis that Nef and CyPA enhance HIV-1 infectivity through independent processes and demonstrate a mechanistic difference between reduction of HIV-1 infectivity by cyclosporin A and gag mutations that decrease HIV-1 incorporation of CyPA.
Nature of Col E 1 Plasmid Replication in Escherichia coli in the Presence of Chloramphenicol (1972)

The colicinogenic factor E(1) (Col E(1)) in Escherichia coli continues to replicate by a semiconservative mechanism in the presence of chloramphenicol (CAP) for 10 to 15 hr, long after chromosomal deoxyribonucleic acid (DNA) synthesis has terminated. Following CAP addition, the rate of synthesis of plasmid DNA gradually increases to an extent dependent on the medium employed. Within 2 to 4 hr after the addition of CAP, replication in a glucose-Casamino Acids medium approaches a maximum rate representing approximately eight times an average rate which would be required for a net doubling of DNA per cell in one generation. The number of copies of Col E(1) DNA molecules that accumulate under these conditions approaches about 3,000 copies per cell, representing a 125-fold increase over the normal level of 24 copies per cell. The system is particularly convenient for studying the mechanism of DNA replication.
Molecular genetics of biological rhythms (1993)

Reviews cellular model systems in an effort to determine the mechanism by which mutation can alter rhythmicity. The text explains how new research fits into the emerging picture of the genetic and molecular basis of biological rhythmicity.
Age classification from facial images (1994)

The ability to classify age from a facial image has not been pursued in computer vision. This research addresses the limited task of age classification of a facial image into a baby, young adult, and senior adult. This is the first reported work to classify age, and to successfully extract and use natural wrinkles. We present a theory and practical computations for visual age classification from facial images, based on cranio-facial changes in feature-position ratios, and on skin wrinkle analysis. Three age groups are classified.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Anti‐pig antibody levels in naïve baboons and cynomolgus monkeys (2002)

Anti-pig antibodies (APA) were analysed in serum from 28 naïve wild-caught baboons (originating from Kenya) and 31 naïve captive-bred cynomolgus monkeys (13 from the Philippines and 18 from Mauritius), using a haemolytic assay with pig erythrocytes (APA), flow cytometry on the porcine lymphoma T-cell cell line L35, and enzyme linked immunosorbent assay (ELISA) using alpha-Gal type II and type VI antigen. This was extended in baboon samples by the evaluation in two laboratories (Imutran, Cambridge, UK and Immerge, Boston, USA), and by antibody absorption using either immobilized alpha-Gal type II or alpha-Gal type VI. Anti-porcine antibodies were demonstrated in all assays with substantial variability within and between the three non-human primate groups. Immunoglobulin (Ig)M antibody levels tended to be similar to or higher than those in a pooled normal human standard serum while IgG levels tended to be lower. Highest antibody levels were recorded in Mauritius cynomolgus monkeys. There were statistically significant correlations between assays for IgM or IgG class anti-Gal antibodies using either alpha-Gal type II or alpha-Gal type VI as antigen, both for different assays and two laboratories involved. Also, significant correlations were observed between the anti-Gal and L35 binding assays. Baboon sera before and after absorption to immobilized alpha-Gal type II or type VI were analysed for anti-Gal type VI or type II antibody: levels were almost undetectable indicating that most anti-Gal antibodies react to epitopes shared between alpha-Gal type II and type VI oligosaccharides. Finally, the relation between APA and outcome of porcine heart xenotransplantation in cynomolgus monkeys and baboons showed no apparent relation between pre-transplant APA levels and the occurrence of hyperacute rejection (HAR) when compared with non-immunological cause of organ/recipient dysfunction or acute humoral xenograft rejection during the first 4 days post-transplantation or survival exceeding 4 days post-transplantation.
Levodopa-Induced Dyskinesias in Parkinson’s Disease: Etiology, Impact on Quality of Life, and Treatments (2008)

Levodopa is the most effective agent to alleviate motor dysfunction in Parkinson's disease but its long-term use is associated with the development of dyskinesias. Although the pathogenic processes behind the development of levodopa-induced dyskinesias are still being elucidated, it appears that chronic administration of this short-lived agent results in nonphysiologic pulsatile stimulation of striatal neurons and abnormal firing patterns in the basal ganglia. Dyskinesias have been associated with decreased quality of life, and a number of methodologies to evaluate severity of dyskinesias are now available. Strategies to avoid, reduce, or eliminate dyskinesias include providing more continuous dopaminergic stimulation, administering an antidyskinetic agent, and surgery. Several new compounds that may provide an antidyskinetic effect are also under investigation.
Depressed Dopamine Activity in Caudate and Preliminary Evidence of Limbic Involvement in Adults With Attention-Deficit/Hyperactivity Disorder (2007)

This study reveals depressed dopamine activity in caudate and preliminary evidence in limbic regions in adults with ADHD that was associated with inattention and with enhanced reinforcing responses to intravenous methylphenidate. This suggests that dopamine dysfunction is involved with symptoms of inattention but may also contribute to substance abuse comorbidity in ADHD.
Klotho protein supplementation reduces blood pressure and renal hypertrophy in db/db mice, a model of type 2 diabetes (2018)

These data indicate that klotho supplementation reduces blood pressure and albuminuria along with ameliorating renal RAS activation in db/db mice. Furthermore, these results suggest that klotho inhibits IGF signalling, induces SOD expression to reduce oxidative stress, and suppresses Akt-mTOR signalling to inhibit abnormal kidney growth. Collectively, the results suggest that klotho inhibits TGF-β and TNF signalling, resulting in a decline in renal fibrosis.
Cloning of the GATA-binding protein that regulates endothelin-1 gene expression in endothelial cells (1991)

Previously, we have identified two regions (A and B) of the endothelin-1 promoter that are important for the expression of this gene in cultured vascular endothelial cells. The cis-acting sequence in one of these regions (Region A) includes the core binding motif GATA, raising the possibility that this region of DNA mediates binding of a member of the GATA-binding protein family. In this report, we describe the use of polymerase chain reaction in conjunction with cDNA cloning to characterize the GATA-binding protein expressed in endothelial cells. The nucleotide sequence of endothelial cell cDNA clones is highly homologous to that of the chicken GATA-2 (NF-E1b) gene, indicating that our clones encode the human GATA-2 gene transcript. By RNA blot analysis, this gene is expressed in cultured cell lines derived from a number of different tissues. Transactivation experiments utilizing human GATA-2 eukaryotic expression vectors indicate that the GATA-2 protein interacts with the endothelin-1 GATA sequence to increase transcription of reporter genes in both BAEC and HeLa cells. These data provide the first evidence for a non-erythroid target gene regulated by GATA-2 and indicate that GATA-2 may have a more broad role in transcriptional regulation than the erythroid-specific GATA-1 protein.
On the Mechanism of Erythropoietin-induced Differentiation (1974)

Abstract Erythropoietin, a glycoprotein that induces normal erythrocyte development, has 16 to 18 sialic acid residues per mole. Desialation results in complete loss of biological activity when it is assayed in vivo. When the assay is done in vitro asialoerythropoietin has full activity, or when assayed at low levels of hormones is about three times more active than the native hormone. The loss of activity can be explained by the hepatic removal of asialoglycoproteins from the circulation (Morell, A. G., Irvine, R. A., Sternlieb, I., Scheinberg, I. H., and Ashwell, G. (1968) J. Biol. Chem. 243, 155). Asialoorosomucoid or stachyose injected into assay animals act as competitors and permit 25 to 35% of the original activity of erythropoietin to be seen in vivo after desialation. Treatment of asialoerythropoietin with galactose oxidase results in recovery of 45% of the original activity, confirming an earlier finding (Lukowsky, W. A., and Painter, R. H. (1972) Can. J. Biochem. 50, 909). Asialoerythropoietin is more sensitive to heat denaturation and trypsin action than the native hormone. Our data indicate that terminal sialic acid is required for chemical and biological stability but not for action on target cells of the bone marrow. The asialohormone has enhanced activity towards the target cells.
Early findings from a community-based, cluster-randomized, controlled oral cancer screening trial in Kerala, India (2000)

Though compliance with referral for confirmatory examination in the first round was lower than the 70% anticipated, intermediate end points, such as stage at diagnosis and case fatality, indicate that the trial is making fairly satisfactory progress.
Differential Role of NADP+ and NADPH in the Activity and Structure of GDP-D-mannose 4,6-Dehydratase from Two Chlorella Viruses (2007)

GDP-D-mannose 4,6-dehydratase (GMD) is a key enzyme involved in the synthesis of 6-deoxyhexoses in prokaryotes and eukaryotes. Paramecium bursaria chlorella virus-1 (PBCV-1) encodes a functional GMD, which is unique among characterized GMDs because it also has a strong stereospecific NADPH-dependent reductase activity leading to GDP-D-rhamnose formation (Tonetti, M., Zanardi, D., Gurnon, J., Fruscione, F., Armirotti, A., Damonte, G., Sturla, L., De Flora, A., and Van Etten, J.L. (2003) J. Biol. Chem. 278, 21559-21565). In the present study we characterized a recombinant GMD encoded by another chlorella virus, Acanthocystis turfacea chlorella virus 1 (ATCV-1), demonstrating that it has the expected dehydratase activity. However, it also displayed significant differences when compared with PBCV-1 GMD. In particular, ATCV-1 GMD lacks the reductase activity present in the PBCV-1 enzyme. Using recombinant PBCV-1 and ATCV-1 GMDs, we determined that the enzymatically active proteins contain tightly bound NADPH and that NADPH is essential for maintaining the oligomerization status as well as for the stabilization and function of both enzymes. Phylogenetic analysis indicates that PBCV-1 GMD is the most evolutionary diverged of the GMDs. We conclude that this high degree of divergence was the result of the selection pressures that led to the acquisition of new reductase activity to synthesize GDP-D-rhamnose while maintaining the dehydratase activity in order to continue to synthesize GDP-L-fucose.
Efficient Targeting of Conserved Cryptic Epitopes of Infectious Agents by Single Domain Antibodies (2004)

Antigen variation is a successful defense system adopted by several infectious agents to evade the host immune response. The principle of this defense strategy in the African trypanosome paradigm involves a dense packing of variant surface glycoproteins (VSG) exposing only highly variable and immuno-dominant epitopes to the immune system, whereas conserved epitopes become inaccessible for large molecules. Reducing the size of binders that target the conserved, less-immunogenic, cryptic VSG epitopes forms an obvious solution to combat these parasites. This goal was achieved by introducing dromedary Heavy-chain antibodies. We found that only these unique antibodies recognize epitopes common to multiple VSG classes. After phage display of their antigen-binding repertoire, we isolated a single domain antibody fragment with high specificity for the conserved Asn-linked carbohydrate of VSG. In sharp contrast to labeled concanavalin-A that stains only the flagellar pocket where carbohydrates are accessible because of less dense VSG packing, the single domain binder stains the entire surface of viable parasites, irrespective of the VSG type expressed. This corroborates the idea that small antibody fragments, but not larger lectins or conventional antibody fragments, are able to penetrate the dense VSG coat to target their epitope. The diagnostic potential of this fluorescently labeled binder was proven by the direct, selective, and sensitive detection of parasites in blood smears. The employment of this binder as a molecular recognition unit in immuno-toxins designed for trypanosomosis therapy becomes feasible as well. This was illustrated by the specific trypanolysis induced by an antibody::beta-lactamase fusion activating a prodrug.
Molecular and Cellular Biology of Blood Coagulation (1992)

BLOOD clotting is a host defense mechanism that, in parallel with the inflammatory and repair responses, helps protect the integrity of the vascular system after tissue injury. This system is normally quiescent but becomes active within seconds after injury. Cells (platelets, leukocytes, and endothelial cells) and the plasma blood-clotting proteins are critical in this reaction. The response to vascular injury culminates in the formation of a platelet plug, the generation of a fibrin clot, the deposition of white cells in the area of tissue injury, and the initiation of inflammation and repair.Molecular Basis of Blood CoagulationAll the protein . . .
Akt1 Activation Can Augment Hypoxia-Inducible Factor-1α Expression by Increasing Protein Translation through a Mammalian Target of Rapamycin–Independent Pathway (2006)

The phosphoinositide 3-kinase (PI3K)/Akt pathway is commonly activated in cancer; therefore, we investigated its role in hypoxia-inducible factor-1alpha (HIF-1alpha) regulation. Inhibition of PI3K in U87MG glioblastoma cells, which have activated PI3K/Akt activity secondary to phosphatase and tensin homologue deleted on chromosome 10 (PTEN) mutation, with LY294002 blunted the induction of HIF-1alpha protein and its targets vascular endothelial growth factor and glut1 mRNA in response to hypoxia. Introduction of wild-type PTEN into these cells also blunted HIF-1alpha induction in response to hypoxia and decreased HIF-1alpha accumulation in the presence of the proteasomal inhibitor MG132. Akt small interfering RNA (siRNA) also decreased HIF-1alpha induction under hypoxia and its accumulation in normoxia in the presence of dimethyloxallyl glycine, a prolyl hydroxylase inhibitor that prevents HIF-1alpha degradation. Metabolic labeling studies showed that Akt siRNA decreased HIF-1alpha translation in normoxia in the presence of dimethyloxallyl glycine and in hypoxia. Inhibition of mammalian target of rapamycin (mTOR) with rapamycin (10-100 nmol/L) had no significant effect on HIF-1alpha induction in a variety of cell lines, a finding that was confirmed using mTOR siRNA. Furthermore, neither mTOR siRNA nor rapamycin decreased HIF-1alpha translation as determined by metabolic labeling studies. Therefore, our results indicate that Akt can augment HIF-1alpha expression by increasing its translation under both normoxic and hypoxic conditions; however, the pathway we are investigating seems to be rapamycin insensitive and mTOR independent. These observations, which were made on cells grown in standard tissue culture medium (10% serum), were confirmed in PC3 prostate carcinoma cells. We did find that rapamycin could decrease HIF-1alpha expression when cells were cultured in low serum, but this seems to represent a different pathway.
Computer Assisted Knee Replacement (1998)

Accurate alignment of knee implants is essential for the success of total knee replacement. Although mechanical alignment guides have been designed to improve alignment accuracy, there are several fundamental limitations of this technology that will inhibit additional improvements. Various computer assisted techniques have been developed to examine the potential to install knee implants more accurately and consistently than can be done with mechanical guides. For example, computer integrated instrumentation incorporates highly accurate measurement devices to locate joint centers, track surgical tools, and align prosthetic components. Image guided knee replacement provides a three-dimensional preoperative plan that guides the placement of the cutting blocks and prosthetic components. Robot assisted knee replacement allows one to machine bones accurately without the use of standard cutting blocks. The rationale for the development of computer assisted knee replacement systems is presented, the operation of several different systems is described, the advantages and disadvantages of different approaches are discussed, and areas for future research are suggested.
Use of an agent to reduce scattering in skin (1999)

The application of the agent reduces the amount of refractive mismatch found in the tissue and markedly reduces random scattering, thereby making the skin less turbid for visible wavelengths for a controlled period of time.