gebhart/patrepeval huggingface dataset:
High-performance liquid chromatographic assay for taxol in human plasma and urine and pharmacokinetics in a phase I trial. (1987)

Taxol is a unique antineoplastic agent which appears to exert its cytotoxic action as a result of interference with microtubular structure and function. Clinical development of this drug will be facilitated by the availability of sensitive and specific methods for its quantitation in biological fluids. We have developed a reverse-phase high-performance liquid chromatographic assay for taxol capable of detecting concentrations as low as 50 nM, which can be automated using readily available equipment. With this assay we have performed pharmacologic studies of taxol during the conduct of a phase I trial of this compound at The Johns Hopkins Oncology Center. Following a 60- to 360-minute infusion, the plasma disappearance is biexponential, with harmonic mean alpha half-life and beta half-life values of 16.2 minutes and 6.4 hours, respectively. Volumes of distribution for the theoretical central compartment (VDc) and at steady state (VDss) were 8.6 and 67.1 L/m2. Mean plasma clearance was 253 ml/minute/m2. Urinary clearance was 29.3 ml/minute/m2 and 5.9% +/- 8.8% of the drug was identified in 48-hour urine collections. No metabolites have been identified. Over the 18-fold dose range studied, there was no evidence of nonlinearity or dose-dependent behavior. A rough correlation between area under the plasma disappearance curve and hematologic toxicity was observed.
Analysis of six candidate genes as potential modifiers of disease expression in canine XLPRA1, a model for human X-linked retinitis pigmentosa 3. (2007)

The haplotype distribution of RPGRIP1, NPM1, PDE6D, NPHP5, RANBP2, and ABCA4 suggests these genes are not modifiers of the disease phenotype observed in the XLPRA1 pedigree. The RPGRORF15 stop mutation does not affect the retinal expression of these genes at the mRNA level in the pre-degenerate stage of disease, but no conclusions can be made at this time about changes that may occur at the protein level.
Patho-genetic characterization of the muscular dystrophy gene myotilin (2007)

Myotilin is a muscle-specific Z-disc protein with putative roles in myofibril assembly and structural upkeep of the sarcomere. Several myotilin point mutations have been described in patients with Limb-Girdle Muscular Dystrophy Type 1A (LGMD1A), myofibrillar myopathy (MFM), spheroid body myopathy (SBM), and distal myopathy, four similar adult-onset, progressive, and autosomal dominant muscular dystrophies--collectively called the myotilinopathies. It is not yet known how myotilin mutations cause muscle disease.\n\nTo investigate myotilin's role in the pathogenesis of muscle disease, I have created and characterized transgenic mice expressing mutant (Thr57Ile) myotilin under the control of the human skeletal alpha-actin promoter. Like LGMD1A and MFM patients, these mice develop progressive myofibrillar pathology that includes Z-disc streaming, excess myofibrillar vacuolization, and plaque-like myofibrillar aggregation. These aggregates become progressively larger and more numerous with age. I show that the mutant myotilin protein properly localizes to the Z-disc, and also heavily populates the aggregates, along with several other Z-disc associated proteins. Whole muscle physiological analysis reveals that the extensor digitorum longus (EDL) muscle of transgenic mice exhibits significantly reduced maximum specific isometric force compared to littermate controls. Intriguingly, the soleus and diaphragm muscles are spared of any abnormal myopathology and show no reductions in maximum specific force. These data provide evidence that myotilin mutations promote aggregate-dependent contractile dysfunction.\n\nTo better understand myotilin function, I also created two separate lines of myotilin domain deletion transgenic mice: one expresses a deletion of the N-terminal domain and the second expresses a deletion of the minimal alpha-actinin binding site. Studies in these mice show that 1) the N-terminal domain of myotilin may be required for normal localization to the Z-disc; 2) interaction with alpha-actinin is not required for localization of myotilin to the Z-disc; and 3) deletion of the alpha-actinin binding site causes an aggregation phenotype similar to that of the TgT57I mouse and myotilinopathy patients.\n\nIn sum, I have established a promising patho-physiological mouse model that unifies the diverse clinical phenotypes of the myotilinopathies. This mouse model promises to be a key resource for understanding myotilin function, unraveling LGMD1A pathogenesis, and investigating therapeutics.
Nanoparticle-based vaginal drug delivery systems for HIV prevention (2009)

To date, few studies have been published that exploit nanoparticle-based microbicidal delivery to the vagina. The use of nanoparticles for vaginal drug delivery provides an approach to overcome the existing barriers to success.
Activation of TGF-β by Leishmania chagasi : Importance for Parasite Survival in Macrophages (2003)

TGF-beta is a potent regulatory cytokine that suppresses expression of inducible NO synthase and IFN-gamma, and suppresses Th1 and Th2 cell development. We examined whether functionally active TGF-beta is present in the local environment surrounding the invading protozoan Leishmania chagasi. Our prior data showed that TGF-beta levels are significantly increased in L. chagasi-infected mice. In the current study, we found TGF-beta was also abundant in bone marrows of humans with acute visceral leishmaniasis but not in those of uninfected controls. Furthermore, L. chagasi infection caused an increase in biologically active TGF-beta in human macrophage cultures without changing the total TGF-beta. Therefore, we investigated the means through which leishmania could augment activated but not total TGF-beta. Incubation of latent TGF-beta with Leishmania sp. promastigotes caused active TGF-beta to be released from the latent complex. In contrast, the nonpathogenic protozoan Crithidia fasciculata could not activate TGF-beta. TGF-beta activation by leishmania was prevented by inhibitors of cysteine proteases and by the specific cathepsin B inhibitor CA074. Physiologic concentrations of TGF-beta inhibited killing of intracellular L. chagasi in macrophages, although the phagocytosis-induced respiratory burst remained intact. In contrast, supraphysiologic concentrations of TGF-beta had no effect on parasite survival. We hypothesize that the combined effect of abundant TGF-beta stores at extracellular sites during infection, and the ability of the parasite to activate TGF-beta in its local environment, leads to high levels of active TGF-beta in the vicinity of the infected macrophage. Locally activated TGF-beta could, in turn, enhance parasite survival through its effects on innate and adaptive immune responses.
Use of colloidal gold surface plasmon resonance peak shift to infer affinity constants from the interactions between protein antigens and antibodies specific for single or multiple epitopes (1998)

The surface plasmon resonance (SPR) wavelength of colloidal gold particles coated with a monoclonal antibody is red-shifted when the antibody interacts with its specific ligand. This shift results from the change in the refractive index of the particles as induced by ligand binding. This property is used to monitor in real-time the association and dissociation kinetics of the interaction in solution. The monitoring is performed in a clinical chemistry automated analyzer during a few minutes of incubation at 37 degrees C. Data treatment allows calculation of the affinity constant of the interaction. The SPR wavelength shift does not necessarily require agglutination or aggregation of the particles to occur since particles coated with one monoclonal antibody specific for a single epitope on the ligand can be used in the procedure. The affinity constants measured by this procedure correlate with those calculated from Scatchard plots or BIAcore data.
Intra-abdominal desmoplastic small round cell tumor: immunohistochemical evidence for up-regulation of autocrine and paracrine growth factors. (1999)

Desmoplastic small round cell tumors (DSRCT) are highly aggressive tumors typically involving the serosal surfaces of the peritoneum. Patients often present with abdominal pain, an abdominal mass, ascites or signs of intestinal obstruction. Cytogenetic and molecular studies have identified a characteristic t(11;22)(p13;q12) translocation within the tumor cells. The fused gene product apparently aligns the NH2-terminal domain (NTD) of the EWS gene to the zinc finger DNA-binding domain of the WT1 gene. This product could lead to loss of the tumor suppressor effect of the WT1 gene as well as to an increase in EWS driven expression of growth factors normally repressed by WT1. We investigated this latter possibility by performing immunohistochemical studies on formalin fixed tissue from 10 cases of DSRCT and five Wilms' tumors using-antibodies to insulin-like growth factor (IGF)-II, the latency associated peptide of transforming growth factor (TGF)-beta 1, platelet-derived growth factor (PDGF)-AB chain and PDGF-alpha receptor, respectively. In general, tumor cells were strongly positive for these growth factors in DSRCT, while stromal cells were negative for IGF-II and positive for the other growth factors in parallel with the tumor cells. Wilms' tumor cells were essentially negative for PDGF-AB chains, but positive for IGF-II, and the latency associated peptide of TGF-beta 1 and variably positive for PDGF-alpha receptor. These findings support the proposed molecular mechanism of tumorigenesis for DSRCT and may help explain this tumor's poor prognosis.
Intermedia (1986)

A hypermedia system provides a tool for cooperative work by allowing writers and designers to share a network of linked documents where they can create documents, link their own and others' documents together, and leave notes for one another. This paper discusses issues that designers need to address in the development of hypermedia systems. Major issues involve what kind of linking, contexts, and visual modeling the system provides. The composite of the answers to these issues determines the nature of the hypermedia system and how useful it is to those using it as a tool for cooperative work. The following presents a variety of solutions including those that developers at the Institute for Research in Information and Scholarship implemented in the creation of Intermedia.
Human T-cell lymphotropic virus type III: immunologic characterization and primary structure analysis of the major internal protein, p24 (1985)

The major internal structural protein of human T-cell lymphotropic virus type III (HTLV-III), a virus etiologically implicated in acquired immunodeficiency syndrome (AIDS), was purified to homogeneity. This 24,000-molecular-weight protein (p24) was shown to lack immunologic cross-reacting antigenic determinants shared by other known retroviruses, including HTLV-I and HTLV-II, with the exception of equine infectious anemia virus (EIAV). A broadly reactive competition immunoassay was developed in which antiserum to EIAV was used to precipitate 125I-labeled HTLV-III p24. Although the major structural proteins of HTLV-III and EIAV competed in this assay, other type B, C, and D retroviral proteins lacked detectable reactivity. Thus, HTLV-III is more related to EIAV than to any other retroviruses. That the HTLV-III isolate is very distinct from HTLV-I and HTLV-II was further confirmed by the amino acid compositions of the major internal antigens of all three isolates. Moreover, comparison of the amino-terminal amino acid sequence of HTLV-III p24 with analogous sequences for HTLV-I and HTLV-II p24 showed that these proteins do not share significant sequence homology. In an attempt to evaluate immune response in individuals exposed to HTLV-III, sera from AIDS and lymphadenopathy syndrome patients as well as from clinically normal blood donor controls were tested for antibodies to HTLV-III p24. The results showed that sera from 93% of lymphadenopathy syndrome patients and 73% of AIDS patients exhibited high-titered antibodies to HTLV-III p24. In contrast, none of the normal control sera showed detectable reactivity to HTLV-III p24.
151. Synthetic antimalarials. Part XIV. Some 2-arylamino-4-aminoalkylaminoquinazolines (1947)

F. H. S. Curd, J. K. Landquist and F. L. Rose, J. Chem. Soc., 1947, 775 DOI: 10.1039/JR9470000775
A Standard Session Stopped-Flow NMR Tube (1987)

An NMR tube has been designed to allow stopped-flow NMR experiments to be done with no modification of the instrument. Thus this technique is made routine for organic and inorganic chemists. The tube can be used with any iron magnet or super-conducting system, but the technique requires a Fourier transform data collection capability. The tube is easily attached to standard stopped-flow supply and stopping syringes, making routine data collection possible at a 0.6 s/spectra sampling rate. A calibration procedure and a sample chemical kinetic study are included to demonstrate the use of the tube.
Assembly, Transport, and Function of MHC Class II Molecules (1994)

MHC class II molecules assemble in the endoplasmic reticulum in a chaperone-mediated fashion to form a nine-chain structure consisting of three alpha beta dimers associated with an invariant chain trimer. This complex is transported through the Golgi apparatus and into the endosomal system. The signal for endosomal targeting resides in the cytoplasmic tail of the invariant chain. Current evidence argues that the segregation of the class II-invariant chain complex from the constitutive pathway of membrane protein transport occurs in the trans-Golgi network. However, class II-invariant chain complexes that reach the cell surface are also rapidly internalized into endosomes. Within the endosomal system, probably in a late endosome/pre-lysosome, the invariant chain is degraded, releasing alpha beta dimers that bind peptides predominantly derived from endocytosed proteins. Evidence suggests that many of these peptides are actually generated in lysosomes. The precise mechanisms involved in forming class II-peptide complexes are unclear, although the existence of antigen-processing mutants argues that additional gene products, at least one of which is encoded in the MHC, are involved. After binding peptides, class II molecules are transported by an unknown route to the cell surface, where their primary function of presenting antigenic peptides to CD4+ T cells is carried out.
Studies of Zidovudine in Combination with Didanosine and Zalcitabine (1995)

A number of antiviral agents have been developed to treat individuals with HIV infection. Monotherapy treatment with the licensed reverse transcriptase (RT) inhibitors zidovudine (AZT), zalcitabine (ddC), and didanosine (ddI) has been shown to delay disease progression in the short term. However, after prolonged treatment viral resistance to these agents emerges. To overcome this development of resistance and subsequent destruction of the immune system leading to disease progression, combination therapies of two or more RT inhibitors have been investigated. In the past, studies have demonstrated that the antiviral drugs ddI and ddC have overlapping toxicities and show cross-resistance. Together, therefore, they are unlikely to prove successful as combination therapy. Conversely, AZT and ddI, and AZT and ddC, have additive or synergistic activities. Recent clinical trials have shown that these two combination therapies are well tolerated and are more effective than monotherapy in delaying the progression of HIV disease. Data from these studies suggest that the maximal benefit from combination therapies can be derived only if they are initiated early in the course of infection, e.g., when CD4 counts are greater than 150 cells/mm3. In clinical studies, AZT/ddI in combination, tended to have a more positive effect on CD4 cell count than the AZT/ddC combination, although the difference was statistically significant only when baseline CD4 count was greater than 100 cells/mm3. No serious side effects have been observed with either combination therapy (AZT/ddC or AZT/ddI) although not surprisingly, patients receiving ddI were more likely to suffer gastrointestinal side effects and those receiving ddC were more likely to suffer from peripheral neuropathy.
Visual odometry for ground vehicle applications (2006)

Abstract We present a system that estimates the motion of a stereo head, or a single moving camera, based on video input. The system operates in real time with low delay, and the motion estimates are used for navigational purposes. The front end of the system is a feature tracker. Point features are matched between pairs of frames and linked into image trajectories at video rate. Robust estimates of the camera motion are then produced from the feature tracks using a geometric hypothesize‐and‐test architecture. This generates motion estimates from visual input alone. No prior knowledge of the scene or the motion is necessary. The visual estimates can also be used in conjunction with information from other sources, such as a global positioning system, inertia sensors, wheel encoders, etc. The pose estimation method has been applied successfully to video from aerial, automotive, and handheld platforms. We focus on results obtained with a stereo head mounted on an autonomous ground vehicle. We give examples of camera trajectories estimated in real time purely from images over previously unseen distances (600 m) and periods of time. © 2006 Wiley Periodicals, Inc.
Protocols for gene transfer in neuroscience : towards gene therapy of neurological disorders (1996)

PROTOCOLS FOR GENE DELIVERY TO CULTURED CELLS USING PHYSICAL METHODS: Gene Therapy into Post-Mitotic Neurons in Culture by Microinjection PROTOCOLS FOR GENE DELIVERY USING RNA VIRUSES: Semliki Forest Virus Vectors for Gene Transfer PROTOCOLS FOR GENE DELIVERY USING ADENOVIRUSES AND ADENO-ASSOCIATED VIRUSES: Adeno-Associated Virus Vectors for Gene Transfer PROTOCOLS FOR GENE DELIVERY USING HERPES SIMPLEX VIRUS 1 VECTORS: Transcriptional Regulation of Herpes Simplex Virus Gene Expression: Implications for our Understanding of Latency PROTOCOLS FOR GENE DELIVERY USING CELLS: Murine Mucopolysaccharides Type VII: A Model System for Somatic Gene Therapy of the Central Nervous System PROTOCOLS FOR IN VIVO APPLICATION OF GENE TRANSFER METHODS: Replication-Competent Viral Therapy of Tumours in the Central Nervous System PROSPECTS AND SHORTCOMINGS OF NEUROLOGICAL GENE THERAPY.
Optimization of the Antenna Pattern of a Phased Array with Failed Elements (1986)

Using a phased array antenna on a system can add dimensions of flexibility and control. By varying the phase and amplitude of the current exciting each element, the far field antenna pattern can be modified in such a way as to obtain a desired, optimal pattern. The purpose of this thesis is to develop a rapid compensation method for any element failures by varying the currents exciting the remaining elements. Although many methods for optimizing the pattern of a full array are available, this work is unique because it develops methods of finding the optimum pattern of an array which contains failed or missing elements. Optimization methods in the literature which were investigated include thinned array analysis, adaptive array analysis, eigenvalue methods, null displacement techniques, and assorted iterative techniques. Another method discussed in this thesis, the direct technique, originated from the need for a quick optimization method, especially when very large arrays are used. (Thesis).
Mechanisms of tumor escape in the context of the T-cell-inflamed and the non-T-cell-inflamed tumor microenvironment (2016)

Checkpoint blockade therapy has been proven to be highly active across many cancer types but emerging evidence indicates that the therapeutic benefit is limited to a subset of patients in each cancer entity. The presence of CD8(+) T cells within the tumor microenvironment or the invasive margin of the tumor, as well as the up-regulation of PD-L1, have emerged to be the most predictive biomarkers for clinical benefit in response to checkpoint inhibition. Although the up-regulation of immune inhibitory mechanisms is one mechanism of immune escape, commonly used by T-cell-inflamed tumors, exclusion of an anti-tumor specific T-cell infiltrate displays another even more potent mechanism of immune escape. This review will contrast the mechanisms of immunogenic, T-cell-inflamed, and the novel concept of non-immunogenic, non-T-cell-inflamed, adaptive immune escape.
Elevated CXCL1 expression in breast cancer stroma predicts poor prognosis and is inversely associated with expression of TGF-β signaling proteins (2014)

Increased CXCL1 expression in breast cancer stroma correlates with poor patient prognosis. Furthermore, CXCL1 expression is localized to α-SMA and FSP1 positive fibroblasts, and is negatively regulated by TGF-β signaling. These studies indicate that decreased TGF-β signaling in carcinoma associated fibroblasts enhances CXCL1 expression in fibroblasts, which could contribute to breast cancer progression.
Transcriptional regulation of secondary growth in Arabidopsis thaliana (2003)

Despite its economic and environmental significance, understanding the molecular biology of secondary growth (i.e. wood formation) in tree species has been lagging behind that of primary growth, primarily due to the inherent difficulties of tree biology. In recent years, Arabidopsis has been shown to express all of the major components of secondary growth. Arabidopsis was induced to undergo secondary growth and the transcriptome profile changes were surveyed during secondary growth using 8.3 K Arabidopsis Genome Arrays. Twenty per cent of the approximately 8300 genes surveyed in this study were differentially regulated in the stems treated for wood formation. Genes of unknown function made up the largest category of the differentially expressed genes, followed by transcription regulation-related genes. Examination of the expression patterns of the genes involved in the sequential events of secondary growth (i.e. cell division, cell expansion, cell wall biosynthesis, lignification, and programmed cell death) identified several key candidate genes for the genetic regulation of secondary growth. In order to gain further insight into the transcriptional regulation of secondary growth, the expression patterns of the genes encoding transcription factors were documented in relation to secondary growth. A computational biology approach was used to identify regulatory cis-elements from the promoter regions of the genes that were up-regulated in wood-forming stems. The expression patterns of many previously unknown genes were established and various existing insights confirmed. The findings described in this report should add new information that can lead to a greater understanding of the secondary xylem formation process.
Configuration research and commercial solutions (1998)

In this paper we intend to motivate various research areas in configuration, based on our experience in developing commercial configuration solutions. Informal definitions are given for the configuration task and for configuration specification and description languages. We also offer an abstract characterization of the issue addressed in configuration models, most often represented as constraints or rules. With these definitions and examples of configuration problems from various domains, we motivate research in (1) a common ontology for configuration, (2) function representation and functional reasoning in configuration, and (3) scaling configuration to large problems.